Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Phase: PHASE3
Conditions: Acute Lymphoblastic Leukemia
Sponsor: St. Jude Children's Research Hospital

T O T X VI 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
IR B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D oc u me nt d ate d:  0 7- 1 7 -2 0 1 5  
SJ C R H 
T O T X VI C T G # - N C T 0 0 5 4 9 8 4 8
I nitial versi o n, date d: 0 6- 0 8 - 2 0 0 7, Res u b mitte d t o C P S R M C 0 7- 2 7 - 2 0 0 7 a n d 0 8-2 7 - 2 0 0 7 S u b mitte d t o I R B 9-1 7 -
2 0 0 7, Res u b mitte d t o I R B 9- 2 8 - 2 0 0 7 a n d 1 0-1 1 -2 0 0 7 .  (I R B a p pr o ve d: 1 0-2 3 -0 7) .  Acti vati o n Date: Oct o ber 2 6, 2 0 0 7 
Re visi o n 0. 1: Dece m ber 0 6, 2 0 0 7 (I R B A p pr o ve d: Dece m ber 1 4, 2 0 0 7) 
A me n d me nt 1. 0:  A pril 2 8, 2 0 0 8, Res u b mitte d t o C P S R M C Ma y 1 3, 2 0 0 8, Res u b mitte d t o I R B J u n e 2, 2 0 0 8 (I R B 
A p pr o ve d: J u n e 1 0, 2 0 0 8) 
Letter of A me n d me nt # 1 date d Marc h 1 1, 2 0 0 9 (I R B A p pr o ve d : A pril 1 4, 2 0 0 9) 
Re visi o n 1. 1 : A pril 2 0, 2 0 0 9 (I R B A p pr o ve d: A pril 2 3, 2 0 0 9). Acti vate d Ma y 8, 2 0 0 9 
A me n d me nt 2. 0:  A u g ust 2 0, 2 0 0 9, Res u b mitte d t o I R B o n 1 0/ 1 6/ 0 9 a n d 1 1/ 4/ 0 9 (I R B A p pr o ve d: N o ve m ber 5, 2 0 0 9) 
Res u b mitte d t o C P S R M C Oct o ber 5, 2 0 0 9. 
A me n d me nt 3. 0: J a n uar y 2 8, 2 0 1 0, R es u b mitte d t o C P S R M C Marc h 2 2, 2 0 1 0, Res u b mitt e d t o I R B A pril 2 1, 2 0 1 0 
I R B A p pr o ve d: A pril 2 2, 2 0 1 0) Acti vate d: Ma y 1 9, 2 0 1 0 
A me n d me nt 4. 0: J u n e 1 5, 2 0 1 0 (I R B A p pr o ve d: A u g ust 1 0, 2 0 1 0) 
A me n d me nt 5. 0: Se pte m ber 1 4, 2 0 1, Res u b mitte d t o I R B N o ve m ber 4, 2 0 1 1 
(I R B A p pr o ve d: Dece m ber 6, 2 0 1 1) Acti vate d: J a n uar y 1 8, 2 0 1 2 
Re visi o n 5. 1: Fe br uar y 2 7, 2 0 1 2 (I R B a p pr o ve d: A pril 3, 2 0 1 2) 
Acti vate d : A pril 1 8, 2 0 1 2 
Re visi o n 5. 2: J u n e 1 9, 2 0 1 2 (I R B a p pr o ve d: J u n e 2 5, 2 0 1 2) 
Acti vate d : A u g ust 2 1, 2 0 1 2 
Re visi o n 5. 3: J ul y 2 2, 2 0 1 3 (I R B a p pr o ve d: A u g ust 1 3, 2 0 1 3) 
Acti vate d: Se pte m ber 4, 2 0 1 3 
Re visi o n 5. 4: Oct o ber 2 1, 2 0 1 4. Res u b mitte d t o I R B Dece m ber 1 0, 2 0 1 4 a n d J a n uar y 1 4, 2 0 1 5.  
(I R B a p pr o ve d: J a n uar y 1 5, 2 0 1 5) Acti vate d: J a n uar y 2 9, 2 0 1 5 
Re visi o n 5. 5:  Marc h 2, 2 0 1 5 (I R B a p pr o ve d: A pril 1 4, 2 0 1 5) .  A cti vate d: J u ne 1 5 , 2 0 1 5. 
Re vi si o n 5. 6:  J ul y 1 7, 2 0 1 5 (I R B a p pr o ve d: J ul y 1 7, 2 0 1 5).  Acti vate d: J ul y 1 7, 2 0 1 5 
L O A, date d A pril 1 5, 2 0 1 6 (I R B a p pr o ve d: A pril 1 9, 2 0 1 6 Acti vate d : A u g ust 2 9, 2 0 1 6 
T O T A L T H E R A P Y S T U D Y X V I F O R N E W L Y DI A G N O S E D P A TI E N T S WI T H A C U T E 
L Y M P H O B L A S TI C L E U K E MI A 
Pri nci p al I n vesti g at or 
Si ma Je ha, M D 1 
C o - Pri nci p al I n vesti g at or 
C hi n g- H o n P ui, M D 1 
Secti o n C o or di n at ors 
P har mac o ki netics/ P har mac o ge n o mics  
Mar y V . Relli n g, P har m D2 
Willia m E. E va ns, P har m D
2 
Statistics  
C he n g C he n g, P h D 3 
Ja mes M. B o yett, P h D 3 
De p art me nts of 1O nc ol o gy, 2P h ar m ace utic al Scie nce s, 3Bi ost atistics 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S u b-I n vesti g at ors 
 
J o h n K. C h oi, M D, P h D4 
Heat her C o n kli n, P h D 7 
Patricia Fl y n n, M D 5 
A dit ya Ga ur, M D 5 
Ta nja Gr u ber, M D, P h D 1 
Ha na Ha ki m, M D 5 
Ra n dall Ha y de n, M D 4 
Hir ot o I na ba, M D, P h D 1 
S ue C. Kaste, D O 6 
Ke vi n R. Kr ull, P h D 7 
Wi n g Le u n g, M D, P h D 8 
M o ni ka Metz ger, M D
1 
R o bert J. O g g, P h D 6 
De qi n g Pei, M S 3 
S usa na Rai m o n di, P h D 4 
Wil b ur n E. Re d dic k, P h D
6 
Ra ul Ri beir o, M D 1 
Jeffre y R u b nitz, M D, P h D 1 
J o h n T orre y Sa n dl u n d, M D 1 
Yi n mei Z h o u, M S 3 
 
 
 
 
De p art me nts of 1O nc ol o gy, 2P h ar m ace utic al Scie nces, 3Bi ost atistics 4P at h ol o gy, 5I nfecti o us 
Dise ases, 6R a di ol o gic al Scie nces, 7E pi de mi ol o gy a n d C a ncer C o ntr ol, 8B o ne M arr o w 
Tr a ns pl a nt ati o n & C ell ul ar T her a py 
 
 
St. J u de C hil dre n’s Researc h H os pital  2 6 2  Da n n y T h o mas Place 
Me m p his, T N  3 8 1 0 5 
Tele p h o ne ( 9 0 1) 5 9 5- 3 3 0 0 
 
 
C o nte nts of  t his d oc u me nt m ay n ot be  extr acte d wit h o ut per missi o n fr o m t he Pri nci p al I nvesti g at or. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

 
1  
 
 
 
 
 
 
 
 
 
T O:   
I R B a n d C T- S R C  
  
  
  
 
F R O M: 
Si m a Je h a, M D 
 
D A T E:   
A pril 1 5, 2 0 1 6 
 
R E:  
T O T X VI, T ot al T her a p y St u d y X VI f or Ne wl y Di a g n ose d P atie nts wit h Ac ute 
L y m p h o bl astic Le u ke mi a  
 
Re: Letter of A me n d me nt ( L O A) t o c o nti n ue e nr oll me nt 
 
 
 
A me n d me nt 6. 0 was s u b mitte d o n 4- 8- 2 0 1 6, a n d is sc he d ule d f or re vie w b y t he C T- S R C o n 4- 1 9- 2 0 1 6. 
T his a me n d me nt is t o c o nti n ue e nr oll me nt be y o n d t he c urre nt 5 3 1 tar gete d accr ual t o all o w sec o n dar y 
o bj ecti ves t o be c o m plete d.  Partici pa nts e nr olle d o n A me n d me nt 6. 0 will c o ntri b ute t o se veral sec o n dar y 
a n d e x pl orat or y o bj ecti ves; h o we ver t he y will n ot be ra n d o mize d f or t he pri mar y P E G-as para gi nase 
o bj ecti ve, a n d will n ot be offere d partici pati o n i n t he f oll o wi n g researc h st u dies : N K cell rece pt or, 
ne ur oi ma gi n g, a n d i ntesti nal micr o bi o me o bj ecti ves. 
 
T O T X VI e nr oll me nt is n o w at 5 3 1 partici pa nts.  Wit h t his letter of a me n d me nt, we are re q uesti n g t hat 
e nr oll me nt c o nti n ue wit h t he c urre ntl y a p pr o ve d pr ot oc ol u ntil t he ne w A me n d me nt 6 is a p pr o ve d a n d 
acti vate d n oti n g t he f oll o wi n g s pecificati o ns: 
 
1.  Ne w patie nts will n ot be ra n d o mize d t o sta n dar d- vers us hi g h- d ose P E G as para gi nase; t he y will 
recei ve sta n dar d d ose. 
 
2.  Ne w patie nts will n ot be offere d partici pati o n i n N K cell rece pt or, ne ur oi ma gi n g or i ntesti nal 
micr o bi o me researc h. 
 
3.  Patie nts e nr olle d via t he L O A will be re-c o nse nte d wit h A me n d me nt 6. 0 at t he ne xt cli nic visit 
after A me n d me nt 6. 0 is acti vate d. 
 
4.  T he a b o ve i nf or mati o n will be e x plai ne d t o t he patie nt/ L A R a n d d oc u me nte d i n t he me dical 
rec or d. 
 
T he tra nsiti o n bet wee n A me n d me nt 5 a n d A me n d me nt 6 will all o w partici pa nts t o c o nti n ue be nefiti n g 
fr o m pr ot oc olize d c o m ple x t hera p y a n d c o ntri b ute t o a ns weri n g i m p orta nt sec o n dar y o bj ecti ves. T ha n k 
y o u f or c o nsi deri n g t his re q uest. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S Y N O P SI S 
 
A L L re gi me ns c o nsist of a c o m bi nati o n of m ulti ple a ge nts deli vere d o ver a peri o d of 2. 5 t o 3 
years i n 3 mai n p hases (re missi o n i n d ucti o n, c o ns oli dati o n, a n d c o nti n uati o n). See mi n gl y mi n or 
m o dificati o ns i n t he a d mi nistrati o n of dr u gs de v el o pe d o ver 3 0 years a g o (s uc h as 
merca pt o p uri n e, met h otr e x ate, vi ncristi ne, c ortic oster oi ds, a nt hrac ycli nes, a n d as para gi nase) ha ve 
ha d si g nifica nt i m pact o n o utc o me. F or e x a m ple, c ha n ges i n vi ncristi ne a n d as para gi n ase d osa ge 
f oll o wi n g i nte nsificati o n, a n d se q ue ntial es calati n g- d os e met h otre x ate f oll o we d b y as para gi nas e, 
si gnifica ntl y i m pr o ve d o utc o me of hi g h-ris k patie nts i n C C G trials 1. L o n ger e x p os ure t o 
as para gi n ase d uri n g earl y c o ns oli dati o n ha d a si g nifica nt i m pact o n o utc o me i n Da na Far ber 
st u dies2. Rece nt lar ge ra n d o mize d trials were de di cate d t o c o m pare merca pt o p uri ne t o 
t hi o g ua ni ne3, pre d nis o ne t o de x a met has o ne4; 5, si n gle t o tri ple i ntrat hecal t hera p y6 et c.  T he 
cu m ulati ve k n o wle d ge gat here d fr o m t hese a n d ot her trials f or m t he b asis of t he i m pressi ve c ure 
rates ac hie ve d i n c hil dr e n wit h A L L t o da y. 
 
T he pri mar y o bje cti ve of T O T X VI is t o c o m pare t he cli nical be nefit, t he p h ar mac o ki netics, a n d 
t he p har mac o d y n a mics of p ol yet h yle ne gl yc ol-c o nj u gate d ( P E G) as p ara gi nase gi ve n i n hi g h er 
d ose vers us t h ose of P E G-as para gi nase gi ve n i n c o n ve nti o nal d ose d uri n g t he c o nti n uati o n p hase. 
As para gi nas e is o ne of t h e ke y c o m p o ne nts of A L L t hera p y b ut its a d mi nistrati o n is c o m plicate d 
b y t he a vaila bilit y of differe nt pr e parati o ns, eac h wit h a differe nt p har mac o ki netic pr ofile 7. T he 
nati ve E. c oli as para gi nas e has bee n t h e m ost c o m m o nl y use d pre parati o n. P E G- as para gi nase, a 
l o n g-acti n g a n d less aller ge ni c f or m, is pr o gressi vel y re placi n g t he nati ve pr o d uct a n d is bei n g 
i ncreasi n gl y a d mi nistere d i ntra ve n o usl y i nstea d of i ntra m usc ularl y8.  M ost st u dies are e m piricall y 
ad o pti n g a P E G-as para gi nase d ose of 2, 5 0 0 u nits/ m 2, base d o n p u blis he d re p orts c o m pari n g t his 
d ose t o 6 d oses of 6, 0 0 0 u nits/ m 2 of nati ve E. c oli as para gi n ase.  H o we ver, t his d ose has faile d t o 
de plete C S F as para gi nas e i n s o me st u dies, s u g gesti n g it mi g ht be i na de q u ate f or C N S c o ntr ol.  
T his is of ut m ost i m p orta nce i n T O T X VI w here we rel y o n s yste mic c h e m ot hera p y i n a d diti o n t o 
i ntrat hecal t hera p y t o a v oi d cra nial irra diati o n.  I n a ra n d o mize d st u d y of 2, 5 0 0 u nits/ m2 P E G-
as para gi n ase i ntra m usc ul arl y e ver y ot her wee k f or 1 5 d oses vs. nati ve 2 5, 0 0 0 u nits/ m 2 E. c oli 
as para gi n ase i ntra m usc ul arl y e ver y wee k f or 3 0 d oses ( D F CI 9 1- 0 1), alt h o u g h t here was n o 
si gnifica nt differe nce i n E F S ( 8 4 % f or nati ve vs. 7 8 % f or P E G- as para gi nase, p = 0. 2 9), t h e tre n d 
is i n t he directi o n s u g gesti n g t hat 2, 5 0 0 u nits/ m2 of P E G-as para gi nase is sli g htl y less effecti ve 
t ha n t he 2 5, 0 0 0 u nits/ m2 of nati ve as para gi nas e.  As it is t he latter d ose of nati ve dr u g t hat has 
bee n use d o n T O T X V, we are c o mf orta bl e re pla ci n g t he m ore fre q ue ntl y a d mi nistere d 
i ntra m usc ular nati ve E. c oli as para gi nase wit h t he l o n ger acti n g, less i m m u n o ge ni c i ntra ve n o us 
P E G-as para gi nase, b ut w e pr o p ose t o test t he p ote ntial be nefits of a d mi nisteri n g P E G-
as para gi n ase at d oses hi g her t ha n t he 2, 5 0 0 u nits/ m 2 d uri n g c o nti n uati o n. 
 
Patie nts will be ra n d o mize d at t he c o m pleti o n of re missi o n i n d ucti o n i n T O T X VI t o c o m pare t he 
safet y, efficac y, a n d P K/ P D bet wee n t he “c o n ve nti o nal” a n d a hi g her d ose of P E G-as para gi nase. 
D uri n g t h e re missi o n i n d ucti o n p hase, T O T X V use d hi g h er d oses of nati ve E. c oli as para gi n ase 
( 1 0, 00 0 u nits/ m 2 per d ose) t ha n ot her p e diatric A L L pr ot o c ols ( 6, 0 0 0 u nits/ m2 per d ose) i nt o 
w hic h P E G-as para gi nas e has bee n s u bstit ute d at 2, 5 0 0 u nits/ m 2.  We ha ve c h ose n t o gi ve all 
chil dre n o n T O T X VI 3, 0 0 0 u nits/ m 2 i nstea d of t he “c o n ve nti o nal” d os e of 2 5 0 0 u nits/ m2 of P E G-
as para gi n ase, beca use we d o n ot wa nt t he i nte nsit y of as para gi nase i n t his St. J u de trial t o p ossi bl y 
be less t ha n t hat o n pri or St. J u de trials, all of w hic h use d 1 0, 0 0 0 u nits/ m 2 of nati ve E. c oli 
as para gi n ase. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
We ha ve bee n l ea ders i n re d uci n g pre ve nti ve cra ni al irra diati o n, a n d t he n eli mi nati n g it 
c o m pletel y i n T O T X V. T his is t he si n gle m ost i m p orta nt m o dificati o n t o decreas e l o n g-ter m 
a d verse effects a n d i m pr o ve q ualit y of life of s ur vi v ors. T his was ac hie ve d wit h t he i nte nsificati o n 
of C N S- directe d i ntrat h ecal a n d s yste mic c h e m ot hera p y. T h e ris k of C N S rela pse (a b o ut 3. 5 %) o n 
T O T X V c o m pares f a v ora bl y wit h t hat of re gi me ns still e m pl o yi n g pre v e nti ve cra ni al irra diati o n. 
M o re o ver, all patie nts wit h C N S rela pse are ali ve i n sec o n d re missi o n wit h retrie val t hera p y 
i ncl u di n g t hera pe utic C N S irra diati o n (as t he first c o urse of irra diati o n).  H o we ver a s u b gr o u p of 
pa tie nts wit h T-cell li nea ge, t( 1; 1 9)/E 2 A- P B X 1 , a n d t h ose wit h blasts i n t he C S F re mai n at hi g hest 
ris k of C N S rela pse; t hes e patie nts will recei ve 2 a d diti o nal i ntrat hecal treat me nts o n da y 4 a n d 1 1 
of i n d ucti o n o n T O T X VI t o re d uce t heir ris k of C N S rela pse. 
 
I n T O T X V w e c o nfir me d t hat t he prese n ce of mi ni mal resi d ual disease ( M R D) o n da y 1 9 is a 
si g nifica nt pr o g n ostic fact or. O ver 9 5 % p atie nts wit h ne gati ve M R D o n da y 1 9 re mai n i n 
re missi o n. I n T O T X VI, t hese patie nts will recei ve less i nte nsi ve Rei n d ucti o n II, a n d a re d uce d 
c u m ulati ve d ose of a nt hr ac ycli nes ( 8 0 m g/ m 2 i nstead of 1 1 0 m g/ m 2).  I n T O T X V, we o bs er ve d 
t hat patie nts wit h da y 1 9 M R D > 5 % ha d a dis mal o utc o me: 3 4. 5 % ha ve rel a pse d.  I n T O T X VI 
we will i nte nsif y i n d ucti o n t hera p y wit h fracti o nate d c ycl o p h os p ha mi de i n t hese patie nts t o 
ac hie ve m a xi mal c yt ore d ucti o n b y t he e n d of re missi o n i n d ucti o n (a critical e n d p oi nt t o ma xi mize 
t he c ha nces of d ura ble re missi o ns). 
 
T he maj orit y of patie nts will n o l o n ger ha v e s ur veilla nce marr o ws p ost re missi o n i n d ucti o n, as 
m o nit ori n g of M R D i n marr o w after re missi o n i n d ucti o n will o nl y b e perf or me d i n patie nts wit h 
p osi ti ve M R D o n da y 4 2 ( or w he n cli nicall y i n dicate d). I n T O T X V, we use d fl o w c yt o metr y a n d 
P C R i n ta n de m t o m o nit or M R D. Beca use of t he v er y hi g h c o nc or da nce bet wee n t he 2 met h o ds, 
i n T O T X VI w e will use pri maril y fl o w c yt o metr y, reser vi n g P C R f or cases w here le u ke mic cells 
d o n ot e x press s uita ble i m m u n o p he n ot y pes. 
 
I nfa nts wit h M L L rearra n ge m e nts ha ve a dis mal o utc o me des pite use of i nte nsi ve re gi me ns 
i ncl u di n g ste m cell tra ns pla ntati o n. T O T X VI will e x pl ore t he be nefit of a d di n g a pr o misi n g ne w 
t hera p y bl oc k de v el o pe d b y St J u de i n vesti gat ors9.  T he c urre nt dis mal o utc o me i n t his a ge gr o u p 
ma ke s t he dete cti o n of p ote ntial be nefit p ossi ble des pite t he e x pecte d s mall n u m ber of patie nts.   
 
Ot he r p har m ac ol o gic a dj ust me nts ha ve bee n ma de t o i m pr o ve q ualit y of life of o ur patie nts, 
decrease t he ris k of a d verse e ve nts, a n d mi ni mize i nc o n ve nie nce t o patie nts a n d staff.   
E x a m ples i ncl u de: 
 
a)  as para gi n ase will be a d mi nistere d i ntra ve n o usl y i nstea d of i ntra m usc ularl y; 
b)  t here is n o met h otre x ate wi n d o w i n T O T X VI as t he st u d y q u esti o n has bee n a ns were d o n 
T O T X V;  
c)  hi g h d ose met h otr e x ate will n ot be tar gete d i n l o w ris k patie nts (a b o ut half e nr olle d 
patie nts), e x ce pt w he n cli nicall y i n dicat e d;  
d)  c u m ulati ve a nt hrac ycli ne d ose will be re d uce d b y 3 0 m g/ m 2 i n half t he patie nts; 
e)  d urati o n of t hera p y h a d b ee n re d u ce d b y 2 6 wee ks i n b o ys; 
f) de x a met has o ne d ose has bee n re d u ce d after wee k 6 9 (f or a c u m ulati ve re d u cti o n of 8 0 
m g/ m 2 f or l o w-ris k patie nts a n d 2 4 0 m g/ m2 f or sta n dar d-ris k patie nts) 
 
All dia g n ostic sa m ples will be e x a mi ne d f or gl o bal ge n e e x pressi o n usi n g ge ne arra y c hi ps. T his 
will  c o nti n ue t o e nric h o ur u ni q ue data bas e o n t he ge n e e x pressi o n of A L L cells w hic h has 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
bec o me a n i n v al ua ble res o urce ( htt p:// w w w.stj u deresearc h. or g/ d ata/ A L L 1/i n de x. ht ml ) f or A L L 
i n vesti gat ors w orl d wi de. I n a d diti o n, t his will pr o vi de us wit h a n o p p ort u nit y t o vali date 
pr os pecti vel y t he ma n y retr os pecti ve o bser vati o ns ma de i n past c orrelati ve st u dies i ncl u di n g 
gl o bal ge n e e x pressi o n.  F or e x a m ple, t he e x pressi o n of se veral ge nes i n le u ke mic cells at 
dia g n osis was str o n gl y ass ociate d wit h da y 1 9 or d a y 4 6 (e n d of i n d u cti o n) M R D i n T O T X V, a n d 
was f o u n d t o be a n i n d e p e n de nt pre dict or of o verall treat m e nt o utc o me i n c orrelati ve st u dies of 
patie nts e nr olle d i n T otal XIII 1 0; 1 1.  T hese ge n es i ncl u de C A S P 8 A P 2 ( w hic h e nc o de a pr otei n t hat 
pr o m otes a p o pt osis a n d gl uc oc ortic oi d si g n ali n g) 1 0, a set of ge n es ass ociate d wit h i n vitro dr u g 
resista nce i n c hil d h o o d A L L1 1 -1 3 a n d ge nes e n c o di n g pr otei ns wit h k n o w n re g ul at or y f u ncti o ns i n 
cell c ycle pr o gressi o n 1 1.  I n T O T X VI, we will st u d y t he ass ociati o n of t hese ge n es’ e x pressi o n 
wit h M R D o n da ys 1 5 a n d 4 2, a n d wit h i nci de nce of rela pse. 
 
We will st u d y t he i n vitr o se nsiti vit y t o merca pt o p uri ne a n d t hi o g u a ni ne i n patie nts e nr olle d o n 
T O T X VI, a n d si m ulta ne o usl y deter mi ne t he se nsiti vit y of t h ese ne w cas es t o ot her a nti-le u ke mic 
a ge nts t hat we ha v e pre vi o usl y st u die d ( pre d nis o ne, vi ncristi ne, da u n or u bici n a n d as para gi nase). 
T his will per mit us t o el uci date ge n o mic det er mi n a nts of m ulti- dr u g cr oss resista nce t o all 6 a nti-
le u ke mic a ge nts. W e will als o use ot her ge n o me- wi de a p pr oac hes, i ncl u di n g S N P a n d ha pl ot y pe 
a nal ys es, t o i de ntif y ge nes a n d ge netic p ol y m or p his ms si g nifica ntl y li n ke d t o resista nce t o eac h of 
t hese me dicati o ns, a n d t o t he m ulti- dr u g cr oss resista nce p he n ot y pe. O ur pri or w or k f oc us e d 
pre d o mi na ntl y o n B-li nea ge A L L, a n d we ai m t o e xte n d t his w or k t o T- li nea ge A L L a n d 
i n vestigate cases st u die d i n T O T X V a n d T O X VI t o get h er. T his s u bset has a w orse pr o g n osis i n 
ma n y tr eat me nt pr ot oc ols, a n d t heref ore it is i m p orta nt t hat we u n dersta n d t he ge n o mic basis of 
dr u g resista nce i n t his s u bt y pe of c hil d h o o d A L L. 
 
We will st u d y t he ger mli ne ge n o mic deter mi na nts of ris k fact ors f or rela ps e, p o or res p o ns e ( M R D 
p ositi vit y), ac ute t o xicities, p har ma c ol o gi c p he n ot y pes a n d bi o mar kers a n d l o n g-ter m 
c o m plicati o ns of t hera p y as o utli ne d i n secti o n 2. 2. 1. T hese a n al ys es i n T O T X VI will be 
c o m pare d a n d i nter prete d i n t he c o nte xt of o n g oi n g a n d f ut ure ge n o mic a nal yses i n ot her A L L 
trials at St. J u de a n d else w here, wit h t h ose fi n di n gs re plicate d i n cli nical a n d la b orat or y setti n gs 
bec o mi n g ca n di dat es f or f ut ure use i n i n di vi d ualizi n g t hera p y. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Pr ot oc ol S u m m ar y 
T O T A L  T H E R A P Y  S T U D Y  X VI  F O R  N E W L Y  DI A G N O S E D  P A TI E N T S  WI T H  A C U T E  
L Y M P H O B L A S TI C  L E U K E MI A  
Pri nci p al I n ve sti g at or: Si ma J e ha, M. D.  
I N D h ol der: N ot a p plica ble, n o n -I N D/I D E st u d y 
B rief o ver vie w: Treat me nt will c o nsist of t hree mai n p hases: Re missi o n I n d ucti o n, C o ns oli dati o n, a n d 
C o nti n uati o n. T otal  d urati o n of t hera p y is 2 ½ t o 3 years.  
I nter v e nti o n: 
Re missi o n i n d ucti o n  
Dr u g: Pre d nis o ne  
Dr u g: Pre d nis ol o ne   
Dr u g: De xa met has o ne   
Dr u g: Vi ncristi ne   
Dr u g: Da u n or u bici n  
Dr u g: P E G -as para gi nase   
Dr u g: C ycl o p h os p ha mi de   
Dr u g: C ytara bi ne  
Dr u g: T hi o g ua ni ne   
Dr u g: Merca pt o p uri ne  
Dr u g: Dasati ni b ( P h + o nl y)  
Dr u g: Cl ofara bi n e ( M L L + i nfa nts o nl y)   
Dr u g: Et o p osi de ( M L L + i nfa nts o nl y)  
Dr u g: C ycl o p h os p ha mi de ( M L L + i nfa nts o nl y)   
Pr oce d ure: I ntrat hecal c he m ot hera p y  
 
C o ns oli dati o n treat me nt   
Dr u g: Met h otre xate   
Dr u g: Merca pt o p uri ne  
Pr oce d ure: I ntrat hecal c he m ot hera p y  
 
C o nti n uati o n treat me nt 
Ris k assi g n me nt Assi g ne d i nt er ve nti o n  
L o w risk   
Dr u g: Merca pt o p uri ne   
 
 
 
Dr u g: De xa met has o ne   
 
 
 
Dr u g: Vi ncristi ne   
 
 
 
Dr u g: Met h otre xate  
 
 
 
Dr u g: P e g -as para gi nase   
 
 
 
Dr u g: Met h otre xate   
 
 
 
Dr u g: D o x or u bici n  
 
 
 
Pr oce d ure: I ntrat hecal c he m ot hera p y  
 
St a n d ar d/ hi g h risk : 
Dr u g: Merca pt o p uri ne  
 
Dr u g: De xa met has o ne  
 
Dr u g: D o x or u bici n   
 
Dr u g: Vi ncristi ne   
 
Dr u g: Met h otre xate   
 
Dr u g: C ytara bi ne   
 
Dr u g: Et o p osi de  
 
 
 
Dr u g: P E G -as para gi nase   
 
 
 
Dr u g: C ycl o p h os p ha mi de  
 
 
 
Pr oce d ures i ntrat hecal c he m ot hera p y,  
 
 
 
Pr oce d ures ( hi g h ris k o nl y): e xter nal bea m R T ( C N S rela ps e) a n d H S C T  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
S a m ple size :  4 2 0 e val ua ble p artici pa nts i n 8. 6 years  
D at a m a n a ge me nt :  Data ma na ge me nt a n d statistical a nal ysis will be pr o vi de d l ocall y b y t he He mat ol o gical 
Mali g na ncies Pr o gra m c li nical researc h staff, Le u ke mia/ L y m p h o ma Di visi o n a n d Bi ostatistics De part me nt at St. 
J u de C hil dre n’s Researc h H os pital. 
 
H u m a n s u bjects : T he pri mar y ris k t o partici pa nts i n t his researc h st u d y is t o xicit y fr o m t he i nte nsi ve, m ulti- a ge nt 
c he m ot hera p y.  P artici pa nts ar e i nf or me d of t his a n d ot her p ote ntial si de effects d uri n g i nf or me d c o nse nt. A d verse 
e ve nts will be m o nit ore d, re p orte d a n d treate d a p pr o priatel y.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T a ble of c o nte nts 
 
1. 0  
O B J E C TI V E S .................................................................................................................. 1 
1. 1  
P ri mar y O bj ecti ve ........................................................................................................... 1 
1. 2  
S ec o n dar y T hera p e utic O bjecti ves .................................................................................. 1  
1. 3  
E x pl orat or y P har mac ol o gic O bj ecti ves .......................................................................... 1  
1. 4  
E x pl orat or y Bi ol o gic O bj ecti ves ..................................................................................... 1  
1. 5  
E x pl orat or y Ne ur oi ma gi n g O bjecti ves ........................................................................... 2  
1. 6  
E x pl orat or y I ntesti nal Micr o bi o me O bjecti ves ............................................................... 2  
2. 0  
B A C K G R O U N D A N D R A TI O N A L E ............................................................................ 2  
2. 1  
T he ra p y ........................................................................................................................... 2 
2. 2  
P har mac ol o gic St u dies .................................................................................................. 1 0  
2. 3  
B i ol o gi c St u dies ............................................................................................................ 1 4 
2. 4  
Ne ur oi ma gi n g St u dies ................................................................................................... 1 7  
2. 5  
P hila del p hia C hr o m os o me ( P h)- P ositi ve A L L ............................................................. 2 0  
2. 6  
Infa nt A L L .................................................................................................................... 2 2  
2. 7  
B ac k gr o u n d a n d R ati o nale f or I ntesti nal Micr o bi o me O bjecti ves ............................... 2 2  
2. 8  
In cl usi o n of W o me n a n d Mi n orities ............................................................................. 2 3  
3. 0  
E L I GI BI LI T Y C RI T E RI A A N D S T U D Y E N R O L L M E N T ......................................... 2 3 
3. 1  
In cl usi o n Criteria .......................................................................................................... 2 3  
3. 2  
E x cl usi o n Criteria ......................................................................................................... 2 4  
3. 3  
R esearc h Partici pa nt Recr uit me nt a n d Scree ni n g ......................................................... 2 4  
3. 4  
E nr oll me nt O n St u d y .................................................................................................... 2 4  
4. 0  
R I S K C L A S SI FI C A TI O N .............................................................................................. 2 4 
4. 1  
C riteria f or L o w- Ris k A L L (a p pr o xi matel y 4 8 % of patie nts) ...................................... 2 5 
4. 2  
C riteria f or Sta n dar d- Ris k A L L (a p pr o xi matel y 4 4 % of patie nts) ............................... 2 5 
4. 3  
C riteria f or Hi g h- Ris k A L L (a p pr o xi matel y 8 % of patie nts) ........................................ 2 5 
5. 0  
T R E A T M E N T P L A N .................................................................................................... 2 6  
5. 1  
Intrat hecal C he m ot hera p y ............................................................................................. 2 6  
5. 2  
R e missi o n I n d ucti o n C he m ot hera p y ( 6 t o 7 wee ks) ..................................................... 2 7  
5. 3  
C o ns oli dati o n Treat me nt ( 8 wee ks) .............................................................................. 2 9  
5. 4  
R ei nte nsificati o n Treat me nt (f or Hi g h- Ris k A L L) ....................................................... 3 2  
5. 5  
C o nti n uati o n Treat me nt ( 1 2 0 wee ks)............................................................................ 3 4  
5. 6  
He mat o p oietic Ste m Cell Tra ns pla ntati o n .................................................................... 4 1  
6. 0  
D R U G  I N F O R M A TI O N ................................................................................................ 4 1 
6. 1  
Dr u g S h orta ges a n d U n a vaila bilit y ............................................................................... 4 1  
7. 0  
T R E A T M E N T M O DI FI C A TI O N S ............................................................................... 4 2  
7. 1  
D o w n S y n dr o m e Partici p a nts ....................................................................................... 4 2  
7. 2  
R e nal D ysf u ncti o n ........................................................................................................ 4 3  
7. 3  
He patic D ysf u n cti o n ..................................................................................................... 4 3  
7. 4  
O be sit y .......................................................................................................................... 4 3 
7. 5  
Te stic ular Le u k e mia at Dia g n osis ................................................................................. 4 3 
7. 6  
Vi nc risti ne Ne ur ot o xicit y.............................................................................................. 4 4 
7. 7  
Ve n o us T hr o m b oe m b olis m ........................................................................................... 4 4  
7. 8  
A va sc ular Necr osis of B o ne .......................................................................................... 4 4 
7. 9  
P E G- As para gi n ase ........................................................................................................ 4 4  
7. 1 0  
T P M T Stat us a n d T hi o p uri ne D osa ge........................................................................... 4 5  
7. 1 1  
Pa ncreatitis .................................................................................................................... 4 6  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
7. 1 2  
P hila del p hia C hr o m os o me P ositi ve ( P h +) A L L ........................................................... 4 6  
8. 0  
D O S E M O DI FI C A TI O N S D U RI N G C O N TI N U A TI O N T H E R A P Y .......................... 4 7  
8. 1  
D ose  M o dificati o ns f or I na de q uate M yel os u p pressi o n ................................................ 4 7 
8. 2  
D ose  Decreases Base d o n Merca pt o p uri ne P har m ac ol o g y ........................................... 4 8 
8. 3  
Da sati ni b D osa ge A dj ust me nts ( P h + A L L Patie nts O nl y) ........................................... 4 8 
9. 0  
C O N TI N G E N C Y P L A N S F O R R E F R A C T O R Y DI S E A S E O R R E L A P S E ............... 4 9  
9. 1  
In d u cti o n Fail ures ......................................................................................................... 4 9  
9. 2  
He mat ol o gi c Rela pse .................................................................................................... 4 9  
9. 3  
E x tra me d ullar y Rela ps e ................................................................................................ 4 9 
9. 4  
E me r ge nce of C S F L y m p h o blasts d uri n g Re missi o n Re q uiri n g C N S Ra diati o n ......... 4 9 
1 0. 0  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C S T U DI E S ..................................... 5 0  
1 0. 1  
Hi g h- D ose Met h otre x ate ( H D M T X) ............................................................................ 5 0  
1 0. 2  
T hi o p uri nes ................................................................................................................... 5 0  
1 0. 3  
As para gi nas e, De x a met h as o ne a n d Bi o mar kers ........................................................... 5 0  
1 0. 4  
Plas ma H o m oc ystei n e ................................................................................................... 5 1  
1 1. 0  
E V A L U A TI O N S, T E S T S, A N D O B S E R V A TI O N S .................................................... 5 1  
1 1. 1  
Pretreat me nt E v al uati o n ................................................................................................ 5 1  
1 1. 2  
Data t o be O btai n e d Seri all y W hile O nst u d y ................................................................ 5 2  
1 1. 3  
Off- T h era p y E v al uati o ns .............................................................................................. 5 4  
1 2. 0  
E V A L U A TI O N C RI T E RI A ........................................................................................... 5 5  
1 2. 1  
Res p o nse Criteria .......................................................................................................... 5 5  
1 2. 2  
T o xicit y E val u ati o n Criteria ......................................................................................... 5 5  
1 2. 3  
F u ncti o nal M RI E val uati o n Criteria ............................................................................. 5 5  
1 3. 0  
S U P P O R TI V E C A R E .................................................................................................... 5 6  
1 3. 1  
Fe ver at Dia g n osis......................................................................................................... 5 6  
1 3. 2  
Meta b olic Dera n ge me nts .............................................................................................. 5 6  
1 3. 3  
H y p erle u k o c yt osis......................................................................................................... 5 6  
1 3. 4  
A vasc ular Necr osis of B o ne .......................................................................................... 5 6  
1 3. 5  
Pa nc yt o p e nias ............................................................................................................... 5 7  
1 3. 6  
N utriti o nal S u p ple me ntati o n ......................................................................................... 5 7  
1 3. 7  
Dr u g I nteracti o ns .......................................................................................................... 5 7  
1 3. 8  
D o w n S y n dr o m e ........................................................................................................... 5 7  
1 3. 9  
R S V Pr o p h yl a xis ........................................................................................................... 5 8  
1 3. 1 0  Pr o p h yla ctic A nti bi otics D uri n g Peri o ds of Pr ol o n ge d Ne utr o p e nia ............................ 5 8  
1 4. 0  
O F F- T R E A T M E N T A N D O F F- S T U D Y C RI T E RI A ................................................... 5 8  
1 4. 1  
Off Treat me nt Criteria .................................................................................................. 5 8  
1 4. 2  
Off St u d y Criteria ................................ ......................................................................... 5 8 
1 5. 0  
D A T A S A F E T Y M O NI T O RI N G B O A R D ................................................................... 5 9  
1 6. 0  
B I O L O GI C S T U DI E S ................................................................................................... 5 9 
1 6. 1  
Mi ni mal Resi d ual Disease ............................................................................................ 5 9  
1 6. 2  
Ge r mli ne D N A/ R N A .................................................................................................... 6 0 
1 6. 3  
De x a met has o ne/ As para gi nase Ser u m P har mac o d y na mic Bi o mar kers ........................ 6 0  
1 6. 4  
Deter mi nati o n of A L L Blast Se nsiti vit y t o A nti- Le u ke mic A ge nts, i n vitr o ............... 6 1 
1 6. 5  
N K Cell Rece pt or St u d y ............................................................................................... 6 1  
1 6. 6  
I nt esti nal Micr o bi o me Researc h ................................................................................... 6 1 
1 7. 0  
N E U R OI M A GI N G S T U DI E S ....................................................................................... 6 4  
1 7. 1  
M R I ma gi n g .................................................................................................................. 6 4  
1 7. 2  
Ge netic P ol y m or p his ms ................................................................................................ 6 5  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 7. 3  
Ps yc h ol o gical T esti n g ................................................................................................... 6 5  
1 7. 4  
F u ncti o nal M R I ma gi n g ................................................................................................ 6 6  
1 8. 0  
S T A T I S TI C A L C O N SI D E R A TI O N S ........................................................................... 6 7 
1 8. 1  
Safet y M o nit ori n g ......................................................................................................... 7 0  
1 8. 2  
Pri mar y O bj ecti ve ......................................................................................................... 8 0  
1 8. 3  
T hera p e utic O bjecti ves ................................................................................................. 8 9  
1 8. 4  
E x pl orat or y  P har mac ol o gic O bj ecti ves ........................................................................ 9 3  
1 8. 5  
E x pl orat or y Bi ol o gic al O bjecti ves ................................................................................ 9 3  
1 8. 6  
E x pl orat or y ne ur oi ma gi n g o bjecti ves ........................................................................... 9 6  
1 8. 7  
E x pl orat or y I ntesti nal Mi cr o bi o me O bjecti ve .............................................................. 9 8  
1 9. 0  
S A F E T Y A N D A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S ....................... 9 8  
1 9. 1  
Re p orti n g A d vers e E x perie nces ( A Es) a n d Deat hs ...................................................... 9 8  
2 0. 0  
IN F O R M E D C O N S E N T P R O C E S S ............................................................................ 1 0 0  
2 0. 1  
C o nse nt/asse nt at Re missi o n I n d ucti o n a n d P ost Re missi o n T hera pies ..................... 1 0 0 
2 0. 2  
C o nse nt at A ge of Maj orit y ......................................................................................... 1 0 1  
2 0. 3  
C o nse nt W he n E n glis h is N ot t he Pri mar y La n g ua ge ................................................. 1 0 2  
2 1. 0  
D A T A C O L L E C TI O N, M O NI T O RI N G A N D  C O N FI D E N TI A LI T Y ....................... 1 0 2 
2 1. 1  
Data C ollecti o n ........................................................................................................... 1 0 2  
2 1. 2  
St u d y M o nit ori n g ........................................................................................................ 1 0 2  
2 1. 3  
C o nfi de ntialit y ............................................................................................................ 1 0 3  
2 2. 0  
R E F E R E N C E S ............................................................................................................. 1 0 4  
 
A P P E N DI X I: 
Treat me nt Sc he mas a n d S pecial La b orat or y T ests  
A P P E N DI X II: Dr u g I nf or mati o n 
A P P E N DI X III:   Defi niti o ns Relate d t o I nfecti o us Diseases 
A P P E N DI X I V:  C o m m o n S u bstrates, I n hi bit ors a n d I n d ucers of  C Y P 3 A 4 
A P P E N DI X V:  Ra n d o mizati o n F or m 
A P P E N DI X VI:  Ps yc h ol o gical Test Batter y f or C hil dre n o ver T hree Years of A ge 
A P P E N DI X VII:  O verall Treat me nt Sc he ma 
A P P E N DI X VIII:  Tests Perf or me d f or G o o d Cli nical Care a n d f or Researc h 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1. 0  
O B J E C TI V E S  
 
T he  o verall ai m of t his st u d y is t o i m pr o ve t he c ure rate of c hil dre n wit h prec urs or B-cell 
an d prec urs or T-cell ac ute l y m p h o blastic le u ke mia ( A L L). 
 
1. 1  
Pri mar y O bj ecti ve 
 
T he  pri mar y o bje cti ve of t his st u d y is t o c o m pare t he distri b uti o ns of c o nti n u o us c o m plete 
remissi o n of patie nts ra n d o mize d o n t he first da y of t he c o nti n uati o n p hase t o recei ve a 
hi g her d ose of P E G-as para gi nase or t o recei ve t he c o n ve nti o nal d ose ( 2, 5 0 0 u nits/ m 2). 
 
1. 2  
Sec o n dar y T hera p e utic O bjecti ves 
 
1. 2 . 1 T o esti mate t he e ve nt-free s ur vi val a n d o verall s ur vi val of c hil dre n wit h 
A L L w h o are treate d wit h ris k- directe d t hera p y. 
1. 2. 2  T o st u d y w het her i nte nsif yi n g i n d ucti o n, i ncl u di n g fracti o nate d 
c ycl o p h os p ha mi de a n d t hi o g ua ni ne, i n patie nts wit h da y 1 5 M R D > 5 %, 
will res ult i n i m pr o ve d le u ke mia c yt ore d ucti o n i n t his s u b gr o u p c o m pare d 
t o T O T X V. 
1. 2. 3  T o assess w het her i nte nsificati o n of C N S- directe d i ntrat hecal a n d s yste mic 
che m ot hera p y will i m pr o ve o utc o me i n patie nts at hi g h ris k of C N S rela pse. 
 
1. 3  
E x pl orat or y P har mac ol o gic O bj ecti ves 
 
1. 3. 1  T o i de ntif y p har mac o ge netic, p har mac o ki netic a n d p har mac o d y na mic 
pre dict ors f or treat me nt-relate d o utc o mes i n t he c o nte xt of t he s yste mic 
t hera p y use d i n t he pr ot oc ol. 
1. 3. 2  T o c o m pare t he p har mac o ki netics a n d p har mac o d y na mics of P E G- 
as para gi nase gi ve n i n hi g her d ose ( 3, 5 0 0 or  3, 0 0 0 u nits/ m2) vers us t h ose of 
P E G-as para gi nase gi ve n i n c o n ve nti o nal d ose ( 2, 5 0 0 u nits/ m 2) i n t he 
c o nti n uati o n p hase. 
 
1. 4   
E x pl orat or y Bi ol o gic O bj ecti ves 
 
1. 4. 1 
T o deter mi ne t he pr o g n ostic val ue of le vels of mi ni mal resi d ual 
di sease i n peri p heral bl o o d at da y 8 of re missi o n i n d ucti o n. 
1. 4. 2  
T o vali date ne w mar kers a n d met h o ds f or M R D detecti o n. 
1. 4. 3 
T o ge n ot y pe nat ural killer ( N K) cell rece pt ors a n d meas ure t heir 
ex pressi o ns at dia g n osis a n d bef ore rei n d ucti o n, a n d t o ass ociate t hese 
feat ures wit h treat me nt o utc o me. 
1. 4. 4 
T o i de ntif y ne w pr o g n ostic fact ors b y  a p pl yi n g n e w tec h n ol o gies t o 
st u d y patie nt material (e. g., st ore d plas ma, ser u m, cere br os pi nal fl ui d, 
an d n or mal a n d le u ke mic cells). 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1. 5  
E x pl orat or y Ne ur oi ma gi n g O bjecti ves 
 
1. 5. 1  T o use  q ua ntitati ve M R meas ures ( Diff usi o n Te ns or I ma gi n g a n d hi g h 
res ol uti o n v ol u metric i ma gi n g) t o assess differe nces i n m yeli n a n d c ortical 
t hic k ness de vel o p me nt i n patie nts treate d f or A L L relati ve t o healt h y 
co ntr ols matc he d f or a ge a n d ge n der. 
1. 5. 2  T o assess t he i m pact of f olate pat h wa y ge netic p ol y m or p his ms o n m yeli n 
an d c ortical t hic k ness de vel o p me nt a n d ne ur oc o g niti ve perf or ma nce. 
1. 5. 3  T o assess t he i m pact of fr o ntal- parietal l o be m yeli n a n d c ortical t hic k ness 
de vel o p me nt o n ne ur oc o g niti ve perf or ma nce i n atte nti o n, w or ki n g 
me m or y, fl ue nc y, vis ual-s patial reas o ni n g a n d pr ocessi n g s pee d wit h b ot h 
ne ur oc o g niti ve testi n g a n d f u ncti o nal ma g netic res o na nce i ma gi n g. 
 
1. 6  
E x pl orat or y I ntesti nal Micr o bi o me O bjecti ves 
 
1. 6. 1  T o perf or m a c o m pre he nsi ve a nal ysis of t he i ntesti nal micr ofl ora i n 
patie nts wit h A L L pri or t o a n d s u bse q ue nt t o c he m ot hera p y usi n g ne xt 
g e nerati o n se q ue nci n g tec h n ol o gies as a n e x pl orat or y a p pr oac h. 
1. 6. 2  T o st u d y a n y alterati o n i n t he c o m p ositi o n a n d p o p ulati o n d y na mics of 
t he resi de nt i ntesti nal micr ofl ora i n patie nts wit h A L L after e x p os ure 
t o c he m ot hera p y c o m pare d t o pri or t o e x p os ure t o c he m ot hera p y. 
1. 6. 3  T o descri be t he fre q ue nc y a n d se verit y of gastr oi ntesti nal ill nesses 
d ur i n g i n d ucti o n c he m ot hera p y a n d o ver t he 6 m o nt h peri o d after 
co m pleti o n of i n d ucti o n i n patie nts w h o di d a n d t h ose w h o di d n ot 
ha ve c ha n ges i n i ntesti nal micr o bi ota. 
1. 6. 4  T o detect t he prese nce of pat h o ge ns f o u n d t o be a b u n da nt b y  t he 
micr o bi o me a nal ysis i n s u bse q ue nt st o ol sa m ples c ollecte d o ver t he 6 
m o nt h peri o d after c o m pleti o n of i n d ucti o n c he m ot hera p y. 
 
2. 0  
B A C K G R O U N D A N D  R A TI O N A L E 
 
2. 1  
T hera p y 
 
2. 1. 1  R is k assi g n me nt 
 
C hil d h o o d A L L c ure rat es e x cee d 8 0 % 1 4.  F urt her pr o gress r e q uires t he earl y i de ntificati o n 
of le u ke mia s u bt y pes t hat are resista nt or res p o nsi ve t o c urre nt c he m ot hera p y, s o t hat 
patie nts are n ot u n der- or o ver-treate d. T h e T O T X VI pr ot oc ol a p plies t he m ost 
c o m pre he nsi ve ris k classificati o n t o date, c o m bi ni n g blast cell i m m u n o p he n ot y pe a n d 
ge n ot y p e, wit h prese nti n g cli nical feat ur es a n d earl y tr eat me nt res p o ns e.  Acc or di n gl y, 
patie nts 1- 1 8 year- ol d are di vi de d i nt o t hree ris k gr o u ps: l o w -, sta n d ar d-, a n d hi g h-ris k 
(corres p o n di n g t o sta n d ar d-, hi g h -, a n d ver y hi g h-ris k cate g ories i n ot her pr ot oc ols)1 5.  
Infa nts c o nstit ute a se p arate ris k gr o u p 1 6; 1 7. 
 
B-cell prec urs or A L L cas es wit h a ge bet w ee n 1 a n d 1 0 years a n d prese nti n g le u k oc yt e 
c o u nt < 5 0 x 1 0 9/ L, le u ke mic cell D N A i n de x ≥1. 1 6 or T E L- A M L 1 f usi o n have a n o v erall 
e x celle nt pr o g n osis a n d are ge nerall y c o nsi dere d t o ha ve l o w-ris k le u ke mia.  H o we ver, as 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
ma n y as 1 5 % of t hes e cases still rela pse o n a nti meta b olite- base d t h era p y, f or u n k n o w n 
reas o ns1 8; 1 9.  Rece nt st u dies s h o we d t hat res p o ns e t o earl y treat me nt ca n i de ntif y patie nts 
w h o ha ve g o o d prese nti n g feat ur es b ut n o net heless ha ve a hi g h ris k of rela pse. I nteri m 
a nal ysis i n dicates t hat patie nts wit h n o detecta ble blasts o n da y 1 9 of re missi o n i n d ucti o n 
ha ve a n e x celle nt pr o g n osis i n T O T X V, i n a gree me nt wit h pre vi o us fi n di n gs wit h 
T O T XIII patie nts 2 0 T he ris k of rela pse i ncreas es i n patie nts wit h detecta ble blasts o n da y 
1 9 of i n d ucti o n: t h ose wit h 5 % or m ore blasts a m o n g b o ne m arr o w m o n o n uclear cells as 
meas ure d b y fl o w c yt o metr y h a ve a 5- year c u m ul ati ve ris k of rel a pse of 3 4 % + 2 2 %. P o or 
c yt or e d ucti o n o n da y 2 6 a n d detect a ble M R D ( ≥0. 0 1 %) at t he e n d of re missi o n i n d ucti o n 
( ~ da y 4 6) are a d diti o nal i n dicat ors of hi g h ris k of rela pse. He nce, patie nts wit h fa v ora ble 
prese nti n g feat ures b ut p o or earl y tr eat me nt res p o nse will be treate d as ha vi n g sta n dar d-
ris k AL L. T he re mai ni n g patie nts wit h fa v ora ble prese nti n g feat ures a n d g o o d res p o nse t o 
re missio n  i n d ucti o n t hera p y will be treate d o n t he l o w-ris k ar m. 
 
Beca use of t h eir ge n erall y p o or o ut c o me, cas es wit h C N S- 3 stat us ( ≥5 W B C/ μ L of 
cere br os pi nal fl ui d wit h i de ntifia ble blasts or cra ni al ner ve p als y), testic ular le u ke mia, or 
h y p o di pl oi d y ( < 4 4 c hr o m os o mes), will be treate d o n t he sta n dar d-ris k ar m 1 5; 2 1.  Patie nts 
wit h T -cell A L L, pre- B-cell A L L wit h t he t ( 1; 1 9) a n d E 2 A- P B X 1 f usi o n or M L L 
rearra n ge m e nt fare well pr o vi de d t hat t he y recei v e i nte nsi ve t hera p y2 2; 2 3.  He nce, t h e y are 
als o assi g n e d t o t he sta n d ar d-ris k gr o u p i n T O T X VI. 
 
Patie nts wit h P hila del p hia-c hr o m os o me ( B C R- A B L) - p ositi ve A L L h a ve a hi g h rel a pse 
hazar d. Se veral st u dies s h o we d t hat t heir pr o g n osis ca n be i m pr o ve d wit h all o ge n eic 
he mat o p oietic ste m cell tra ns pla ntati o n ( H S C T) 2 4.  T yr osi n e ki nase i n hi bit ors ha ve latel y 
be e n i nc or p orate d i nt o fr o ntli ne re gi me ns f or P h + A L L.  T O T X V was a me n de d i n J u ne 
2 0 0 4 t o i nc or p orate i mati ni b. T he ne w t yr osi ne ki nase i n hi bit or dasati ni b has acti vit y i n 
B C R -A B L - p ositi ve le u ke mias t hat are resista nt t o i mati ni b2 5 -2 7.  T heref ore, dasati ni b will 
replace i mati ni b i n T O T X VI (secti o n 2. 5 ). 
 
Patie nts wit h > 1 % blasts at t he e n d of re missi o n i n d ucti o n a n d t h ose wit h > 0. 1 % at 1 6 
wee ks p ost re missi o n i n d ucti o n als o ha ve ver y p o or pr o g n osis.  T heref ore, t hese patie nts 
are c o nsi d ere d t o ha v e hi g h-ris k le u ke mia a n d are ca n di dates f or all o ge nei c H S C T d uri n g 
t heir first re missi o n. 
 
We rece ntl y i de ntifie d a s u bset ( 1 2 %- 1 5 %) of T- A L L c haracterize d b y a n at y pical 
i m m u n o p he n ot y pe c o nsisti n g of l o w e x pressi o n of T-cell mar kers ( C D 5, C D 1, C D 8) a n d 
e x pressi o n of m yel oi d- a n d ste m cell- ass ociat e d mar kers ( C D 1 3, C D 3 3, C D 1 1 b, C D 3 4, 
C D 1 1 7 a n d/ or C D 1 3 3). T his earl y T-cell prec urs or ( E T P) s u bt y p e has a disti nct ge ne 
e x pressi o n pr ofile, a hi g h pre vale nce of u n us u al kar y ot y pes, a n d a n i ncreas e i n ge n e c o p y 
n u m ber c ha n ges a n d lesi o ns 2 8.  T hese patie nts ha d a mar ke dl y i nf eri or cl eara nce of 
le u kemic blasts d uri n g re missi o n i n d ucti o n t hera p y a n d a dis mal o utc o me: 1 0- year o verall 
s ur vi val f or t he 1 7 patie nts wit h at y pical T- A L L was 1 6. 5 % + 1 0. 6 % v ers us 8 4. 7 % + 6. 8 % 
f or t he 1 22 patie nts wit h t y pical T- A L L ( P < 0. 0 0 0 1). T hese patie nts will als o be c o nsi dere d 
t o ha ve hi g h-ris k le u ke mia i n T O T X VI. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 1. 2  R e missi o n i n d ucti o n 
 
Re missi o n i n d ucti o n c o nsists of 3 wee ks of pre d nis o ne, vi ncristi ne, da u n or u bici n, a n d 
P E G-as para gi nase, f oll o we d b y 2 wee ks of c ycl o p h os p ha mi de, c yt ara bi ne, a n d 
t hi o g ua ni ne c o m bi nati o ns. T his re missi o n i n d ucti o n is si milar t o t hat use d i n T O T X V 
e x ce pt f or f oll o wi n g m o dificati o ns: 
 
(a) T he o pti o nal 4- da y met h otre x ate wi n d o w t hera p y will n ot be offere d a n d st a n dar d 
i n d ucti o n will start o n da y 1. 
( b) I ntr a m usc ular L- as para gi nase will be s u bstit ute d wit h i ntra ve n o us P E G- 
as para gi n ase w hic h h as b ee n safel y a n d s uccessf ull y use d i n t he Da na- Far ber 
Ca ncer I nstit ute ( D F CI) pr ot oc ols. Earl y res p o n d ers will recei ve a si n gle d ose of 
P E G-as para gi nase (s u bstit uti n g f or t he 6 i ntra m us c ular d oses of L-as p ara gi nase o n 
T O T X V), w h ereas patie nts wit h 1 % or m ore blasts o n da y 1 5 will recei v e a n 
a d diti o nal d ose of P E G-as para gi nase (s u bstit uti n g f or t he a d diti o nal 3 d oses of L-
as para gi n ase gi ve n o n T O T X V f or t his s u b gr o u p).  T he rati o nale f or t his d ose is 
i n dicate d i n t he S y n o psis f or T O T X VI. 
(c) T hi o g ua ni ne will be gi v e n o n da ys 2 2 t o 3 5 i nstea d of merca pt o p uri ne. T he 2 wee k 
bl oc k of c ycl o p h os p ha mi de, c ytara bi ne a n d t hi o g u a ni ne has bee n wi del y us e d i n 
t he C hil dre n’s Ca ncer Gr o u p ( C C G) re gi me ns. Ra n d o mize d st u dies ha ve s u g geste d 
t hat t hi o g ua ni ne is ass oci ate d wit h i m pr o ve d o utc o me. W hile i nter mitte nt p ulses of 
t hi o g ua ni ne h a ve bee n safel y us e d i n se veral re gi me ns, pr ol o n ge d use of 
t hi o g ua ni ne h as bee n ass ociate d wit h i ncrease d i n ci de nce of ve n o occl usi ve disease 
of t he li ver a n d p ort al h y perte nsi o n. He n ce we will n ot use t hi o g ua ni ne be y o n d t his 
1 4 da y  c o urse, a n d will c o nti n ue t o use merca pt o p uri ne f or pr ol o n ge d 
a d mi nistrati o n d uri n g c o ns oli dati o n a n d c o nti n uati o n. 
( d) C ycl o p h os p ha mi de t hera p y will be i nte nsifie d i n patie nts wit h 5 % or m ore blasts 
o n da y 1 5 of i n d ucti o n beca use of t he hi g h ris k of rela pse ( 3 4 %) i n t his gr o u p of 
patie nts. Fracti o nate d c ycl o p h os p ha mi de is wi del y use d i n a d ult A L L pr ot oc ols, 
a n d has pr o ve n s afe a n d effecti ve i n c hil dre n wit h B ur kitt le u ke mia/l y m p h o ma a n d 
rela pse d A L L. 
(e) T O T X V has pr o v e n t hat pre ve nti ve cra nial irra diati o n ca n be eli mi nate d, 
irres pecti ve of ris k gr o u p, wit h i nte nsificati o n of C N S- directe d a n d s yste mic 
che m ot hera p y. C u m ulati ve ris k of C N S rela pse ( ~ 3. 5 %) o n T O T X V c o m p ares 
fa v ora bl y wit h t hat of re gi me ns still e m pl o yi n g pre ve nti ve cra ni al irra diati o n. 
M ore o ver, all patie nts wit h C N S rela pse are ali ve i n sec o n d re missi o n wit h 
retrie val t hera p y i ncl u di n g t hera pe utic C N S irra diati o n (as t he first c o urse of 
irra diati o n). Patie nts wit h T-cell li nea ge, t( 1; 1 9)/E 2 A- P B X 1, a n d t h ose wit h blasts 
i n the C S F are at hi g hest ris k of C N S rela pse, a n d t hese patie nts will recei ve 2 
a d diti o nal i ntrat hecal treat me nts o n da y 4 a n d 1 1 of i n d ucti o n o n T O T X VI t o 
re d uce t h eir ris k of C N S rela pse. 
(f) Patie nts wit h E T P i m m u n o p he n ot y p e will recei ve de x a met has o ne ( 1 0 m g/ m 2 per 
da y) i nstea d of pre d nis o n e d uri n g re missi o n i n d ucti o n. T he use of de x a met h as o ne 
d uri n g i n d ucti o n t hera p y is ass ociate d wit h s u peri or o utc o me, b ut i ncrease d 
t o xicit y, i n patie nts wit h T- A L L treate d i n t he AI E O P- B F M A L L 2 0 0 0 tri al2 9.  We 
feel t hat t he p ote ntiall y i ncreas e d ris k of tr eat me nt-relate d t o xicit y is j ustifia ble i n 
patie nts wit h t he E T P i m m u n o p he n ot y pe, i n vie w of t heir p o or o utc o me w he n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
treate d wit h c o n v e nti o nal c he m ot hera p y. 
( g) Patie nts w h o are T P M T heter oz y g ote (a b o ut 1 0 % of all patie nts) will recei ve 
merca pt o p uri n e d uri n g i n d ucti o n i nstea d of t hi o p uri ne.  T otal 1 6 i n d ucti o n t hera p y 
was c o m plicate d wit h re versi ble he patic v e n o occl usi ve disease ( V O D) i n a patie nt 
w h o is T P M T heter oz y g ote. Ge netic p ol y m or p his ms t hat decrease T P M T acti vit y 
are c orrel ate d wit h i ncrease d se nsiti vit y a n d t o xicit y t o t hi o p uri ne. I n vie w of t he 
lac k of V O D o n t he B F M st u dies usi n g t hi o g ua ni ne a n d i n W T patie nts e nr olle d 
t o- date o n T otal 1 6, al o n g wit h t he c orrel ati o n bet wee n i nci de n ce of V O D a n d 
T P M T acti vit y, T otal 1 6 will be a me n de d t o ha ve T P M T H E T/ deficie nt patie nts 
(a b o ut 1 0 % of t otal) recei ve merca pt o p uri ne as per T otal 1 5 d uri n g i n d u cti o n 
i nstea d of t hi o g u a ni ne. N o c ha n ges will be ma de f or W T patie nts; h o we ver, 
vi gila nt m o nit ori n g is rec o m me n de d.   
 
2. 1. 3 
C o ns oli dati o n t hera p y 
 
C o ns oli dati o n t hera p y c o nsists of H D M T X (a vera ge of 5 g m/ m 2 o ver 2 4 h o urs i n 
sta n dar d-/ hi g h-ris k or a v era ge of 2. 5 g m/ m 2 o ver 2 4 h o urs i n l o w-ris k cases) gi ve n e ver y 
ot her wee k f or 4 d oses wit h le uc o v ori n resc u e, t o get her wit h i ntrat hecal treat me nt pl us 
c o nc o mita nt dail y merca pt o p uri ne ( 5 0 m g/ m 2).  T he feasi bilit y a n d effecti v e ness of 
H D M T X gi ve n at 5 g m/ m 2 ha ve bee n d oc u me nte d i n lar ge n u m bers of patie nts treate d i n 
T O T X V, t he Berli n- Fra n kf urt- M ü nster ( B F M) 3 0 a n d t he Ass ociazi o ne It alia na E mat ol o gia 
O nc ol o gi a Pe diatrica ( AI E O P) st u dies 3 1.  I n fact, t he i m pr o ve d treat me nt o utc o me of T-
cell A L L cases i n t he B F M st u dies a n d of i nter me diate-ris k B-li nea ge A L L cases i n t he 
AI E O P st u d y w as attri b ute d i n part t o t he use of H D M T X at 5 g m/ m 2. Res ults of T otal 
p har mac ol o gic st u dies s u g gest t hat w hile H D M T X at 2. 5 g m/ m 2 is s ufficie nt f or m ost B-
li nea ge A L L cases3 2; 3 3, n o n- h y p er di pl oi d B-li nea ge blasts acc u m ulat e m ore met h otre x ate 
p ol y gl uta mates wit h hi g h- d ose t ha n wit h l o w- d ose met h otre x ate.  I n a D F CI st u d y wit h 
va st maj orit y of cases of B-li nea ge p he n ot y pe, c hil dre n recei ve d a si n gle u p-fr o nt d ose of 
4 g m/ m 2 ha d better o verall le u ke mia-free s ur vi val t ha n t h ose recei vi n g 4 0 m g/ m 2.3 4  I n 
a d diti o n, i n o ur st u d y X, hi g her e x p os ure t o met h otre x ate was m ost i m p orta nt a m o n g t he 
hi g her-ris k B- li nea ge cases ( p = 0. 0 0 7) 3 5; 3 6.  He nce, i n T O T X VI, H D M T X will be gi ve n 
si milar t o d osi n g o n T O T X V. T he g oal is t o pr o vi de a vera ge s yste mic e x p os ure t hat is 
ac hie ve d at 5 g m/ m 2 f or T-cell a n d sta n d ar d-/ hi g h-ris k B-li nea ge A L L, a n d a vera ge 
ex p os ure ac hie ve d at 2. 5 g m/ m 2 f or l o w-ris k B-li nea ge A L L, f or a t otal n u m ber of 4 d oses 
H D M T X. 
 
Tar geti n g s yste mic e x p os ure i n T O T X V a p peare d t o be s o me w hat less i m p orta nt i n t he 
l o w-ris k ar m t ha n i n t he sta n dar d-/ hi g h-ris k ar m. I nter-c o urse tar geti n g i n t he l o w-ris k ar m 
res ulte d i n 1 2 %, 7 0 %, a n d 1 8 % of c o urses bei n g b el o w, i n, a n d a b o ve t h e 2 4 hr plas ma 
c once ntr ati o n tar get r a n ge of 3 3 μ M +/- 2 0 %. A d diti o nall y, t here was a n acce pta bl y l o w 
pr o p o rti o n of c o urs es ( 6 %) wit h “ dela ye d e x creti o n” ( 4 2 hr plas ma M T X c o nce ntr ati o n > 
1. 0 μ M). Tar geti n g t he l o w-ris k ar m di d n ot ha ve a s u bsta ntial i m pact o n a v oi di n g e xtre me 
e x p os ures relati ve t o si m ulate d c o n ve nti o nal d osi n g: 2 % vs. 3 % ste a d y-state-
co nce ntr ati o ns < 4 0 % of tar get a n d 5 % vs. 3 % wit h stea d y-state-c o nce ntrati o ns > 4 0 % of 
target wit h tar gete d vs. si m ulate d c o n ve nti o nal d osi n g res p ecti vel y. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
I nter-c o urse tar geti n g i n t he sta n dar d-/ hi g h-ris k ar m res ulte d i n 2 3 %, 6 2 %, a n d 1 5 % of 
c o urses bei n g b el o w, i n, a n d a b o ve t he t ar get r a n ge of 6 5 u M +/- 2 0 %. A d diti o nall y, t here 
wa s a n acce pt a bl y l o w pr o p orti o n of c o urses ( 1 5 %) wit h “ dela ye d e x creti o n ” ( 4 2 hr 
plas ma M T X c o nce ntrati o n > 1. 0 u M). Tar geti n g t he sta n dar d-/ hi g h-ris k ar m a v oi de d 
e xtre me e x p os ures relati ve t o si m ulate d c o n ve nti o nal d osi n g: 3 % vs 0 % wit h stea d y-stat e 
c o nce ntr ati o ns < 4 0 % of tar get a n d 3 % vs. 1 0 % wit h stea d y-stat e-c o n ce ntr ati o ns > 4 0 % of 
target wit h tar gete d vs. si m ulate d c o n ve nti o nal d osi n g, res p ecti vel y. T he m e dia n 4 2 h o ur 
co nce ntr ati o n i n t he sta n dar d-/ hi g h-ris k ar m was 0. 5 4 u M, w hic h is q uite si milar t o t hat 
re p orte d ( 0. 4 3 u M) b y t h e B F M. M ore o v er, t he le uc o v ori n resc ue a d mi nistere d b y o ur 
gr o u ps was si milar, b ut t o xicit y was s u bsta ntiall y l o wer i n T O T X V t h a n t hat re p orte d b y 
B F M: ~ 4 % vs. 4 4 % gra d e 3 or 4 m uc ositis. T h us, it a p pears t hat t here ma y be m ore 
be nefit i n a v oi di n g t h e e xtre mes of e x p os ure i n t he sta n dar d/ hi g h t h a n i n t he l o w-ris k 
ar ms, alt h o u g h t ar get c o n ce ntrati o ns were better ac hie ve d i n t he l o w-ris k ar m. 
 
F or T O T X VI, o ur d ecisi o n is t o c o nti n ue tar geti n g H D M T X i n t he sta n dar d-/ hi g h- ris k 
ar m b ut n ot i n t he l o w-ris k ar m, u nless it is s pecificall y re q uest e d d ue t o cli nicia n c o ncer ns 
re gar di n g p atie nt i nsta bilit y.  T he reas o n f or t his is t hat t he d ose of 2. 5 g/ m2 g i ve n 
c o n ve nti o nall y t o t he T O T X V l o w-ris k gr o u p is ge nerall y a d e q uate: it res ults i n stea d y-
state c o nce ntrati o ns > 2 1 μ M i n 9 5 % of c o urses; t o xicit y was l o w, wit h i nfre q ue nt gra d e 3 
or 4 m uc ositis ( 1. 2 %); a n d usi n g a fi x e d 2. 5 g/ m 2 d ose, 9 5 % of t he ste a d y-state 
co nce ntr ati o ns w o ul d ha ve bee n < 4 6 μ M w hile t he hi g h est ste a d y-state c o nce ntrati o n 
w o ul d ha ve bee n 9 1 μ M. H o we ver, o n T O T X VI, if re nal d ysf u ncti o n, patie nt i nsta bilit y, or 
use of c o nc urre nt dr u gs lea ds t o c o ncer ns re gar di n g M T X cleara nce f or a n y partic ular 
co urse, t he cli nicia n ca n re q uest tar geti n g t o be perf or me d. 
 
We will c o nti n ue o ur tar geti n g a p pr oac h f or sta n d ar d-/ hi g h-ris k patie nts o n T O T X VI as 
we di d o n T O T X V. O ur g oals are t o c o nti n ue t o a v oi d u nacce pt a bl y l o w c o nce ntrati o ns 
(al beit i n a s mall % of c o urses), mi ni mize u nacce pta bl y hi g h c o n ce ntrati o ns, a v oi d GI 
t o xicit y, a n d mai ntai n t he maj orit y of c o urses i n t h e desire d tar get r a n ge.  Usi n g t his 
ap pr oac h, we ha d o nl y 5. 1 % of c o urses wit h gra de 3- 4 m uc ositis (c o m pare d t o as hi g h as 
4 4 % of c o urs es wit h B F M’s a d mi nistrati o n of 5 g/ m 2 wit h o ut tar geti n g). 
 
O ne of t he less o ns of t ar geti n g i nter-c o urse H D M T X was t hat we were n ot as s uccessf ul at 
ke e pi n g all c o urs es wit hi n + 2 0 % of t he tar get as w he n we p erf or me d i ntra-c o urse 
H D M T X tar geti n g 3 7.  We m o difie d T O T X V t o all o w i ntra-c o urse tar geti n g w he n p ossi ble 
b ut ha ve tar get e d o nl y a fe w cas es d ue t o t he m ore c o m plicate d l o gistics of nee di n g t o 
start H D M T X earl y e n o u g h i n t he da y t o all o w feasi ble i ntra-c o urse t ar geti n g. H o we ver, 
base d o n si m ulati o ns w hic h use d t he pre vi o us M T X cleara nce al o n g wit h a 2 h o ur M T X 
plas ma  c o nce ntrati o n t o tar get t he ste a d y-state c o n ce ntrati o n, 1 %, 9 1 %, a n d 8 % of c o urses 
w o ul d be bel o w, i n, a n d a b o ve t he tar get ra n ge. T h us, i n patie nts w h o ha ve e x perie nce d 
re nal d ysf u ncti o n, re q uir e c o nc urre nt dr u gs t hat mi g ht affect M T X cleara nce, or w h o are 
ot her wise u nsta ble, we will e m pl o y i ntra-c o urse tar geti n g of H D M T X. 
 
It s h o ul d be n ote d t h at a p pr o xi matel y 1 0 % of pr o visi o nal l o w-ris k A L L will be c ha n ge d t o 
sta n dar d-/ hi g h-ris k A L L beca use of p ositi ve mi ni mal resi d ual le u ke mia at t he e n d of 
i n d ucti o n.  I n t hes e cas es, H D M T X d osa ge after t he first d ose will be c h a n ge d t o t he 
hi g her a vera ge d os e of 5 g m/ m 2 ( 6 5 u M). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 1. 4  
C o nti n uati o n treat me nt 
 
Af ter c o ns oli dati o n t hera p y, patie nts will recei ve ris k- directe d c o nti n uati o n treat me nt.  
L o w-ris k patie nts will recei ve dail y merca pt o p uri ne a n d wee kl y met h otre x ate wit h 
p ulses of de x a met has o ne a n d vi ncristi ne e ver y 3 t o 5 wee ks (f or t he first t w o years).  I n 
ra n d o mize d trials, de x a met has o ne treat me nt was s u peri or t o pre d nis o ne i n r e d uci n g 
C N S rela pse a n d i m pr o vi n g e v e nt-free s ur vi v al 3 8  partl y d u e t o its s u peri or C N S 
pe netrati o n. Merca pt o p uri ne will be c o nti n ue d d uri n g t he wee k of de x a met has o ne a n d 
vi ncristi ne treat me nt i n t his st u d y t o i nte nsif y s yst e mic t hera p y, as t he d ose i nte nsit y of 
mer ca pt o p uri n e was t he m ost i m p orta nt p har mac ol o gic varia ble i n deter mi ni n g 
treat me nt o utc o me i n T O T XII st u d y3 9.  Met h otre x ate will n ot be gi v e n d uri n g t he wee k 
of de x a met has o ne pl us vi ncristi ne t o re d uce t he ris k of t y p hlitis. 
 
C o nti n uati o n treat me nt f or sta n dar d- a n d hi g h-ris k cases i nc or p orates effecti ve 
treat me nt c o m p o ne nts of t he m ost s uccessf ul cli nical trials t o date. I nte nsif yi n g 
as para gi n ase t hera p y d uri n g t he earl y p has e of treat me nt i m pr o ve d o utc o me f or all ris k 
gr o u ps i n t he D F CI st u di es 2, f or p o or earl y res p o n ders ( 9 0 % of w h o m ha d B- li nea ge 
A L L) i n t he C C G a u g me nte d t hera p y 1, a n d f or T-cell cases i n t he Pe di atric O nc ol o g y 
Gr o u p P O G- 8 7 0 4 st u d y 4 0.  I nte nsi v e L-as p ara gi n ase treat me nt f aile d t o i m pr o ve 
o utc o me s i n a st u d y of l o w-ris k B-li nea ge A L L. He nce, i nte nsi ve as para gi nase t hera p y 
will c o nti n ue t o be gi ve n t o patie nts wit h T-cell A L L as well as t h ose wit h hi g h-ris k B-
li nea ge A L L i n T O T X VI as i n T O T X V. 
 
I ntr a ve n o us P E G- as para gi nase is i ncreasi n gl y use d i n fr o ntli ne A L L re gi m e n. I n 
T O T X VI, p atie nts wit h sta n dar d- or hi g h-ris k A L L will recei ve P E G-as para gi n ase 
ever y 2 w ee ks f or a t otal of 1 5 d oses d uri n g t he first 3 0 wee ks of c o nti n uati o n t hera p y. 
L o w-ris k patie nts will o nl y recei ve 4 d os es ( 2 i n eac h re-i n d ucti o n). 
 
Alt h o u g h t he o pti mal d ose of t he differe nt pr e parati o ns of as para gi n ase is n ot fir ml y 
esta blis he d, e q ui vale nt E F S has bee n re p ort e d wit h P E G-as para gi nase 2, 5 0 0 u nits/ m 2 
a n d nati ve L- as para gi nas e at 6, 0 0 0 u nits/ m 2 x 6 d oses4 1.  He nce t he d ose of 2, 5 0 0 
u nit s/ m2 f or P E G- as para gi nase h as bee n wi del y a d o pte d.  H o we ver, P E G-as para gi n ase 
at 2, 5 0 0 u nits/ m2 faile d t o de plete C S F as para gi ne i n s o me st u dies, s u g gesti n g t his d ose 
is ina de q uate f or C N S c o ntr ol. M ore o ver, L- as para gi n ase was gi v e n at 1 0, 0 0 0 u nits/ 
m 2/ d ose o n T OT X V. Beca use as para gi nas e has bee n s h o w n t o be s uc h a n i m p orta nt 
c o m p o ne nt t o m o der n A L L trials, a n d si nce T O T X V use d hi g her t ha n c o n ve nti o nal L-
as para gi n ase d oses, o n T O T X VI, patie nts will be ra n d o mize d t o recei ve t h e 
c o n ve nti o nal P E G- as para gi n ase d ose ( 2, 5 0 0 u nits/ m 2), or t he hi g her P E G-as para gi n ase 
d ose ( 3, 5 0 0 or 3, 0 0 0 u nits/ m 2). T he differe nce i n p har mac o ki netics a n d 
p har mac o d y n a mic meas ures, a n d o utc o me, will be st u die d i n t he 2 ar ms a n d se parat el y 
f or 3, 5 0 0 a n d 3, 0 0 0 u nits/ m2 if b ot h d oses are use d i n t he hi g her P E G-as para gi nase ar m. 
 
As i n T O T X V, use of e pi p o d o p h yll ot o xi ns will be li mite d t o hi g h-ris k A L L i n T O T X VI 
t o decrease t he ris k of t h era p y-relate d A M L4 1.  We will use c ycl o p h os p ha mi de a n d 
ant hrac ycli n es t o i nte nsif y treat me nt i n sta n dar d-/ hi g h-ris k cases. H o we ver, t otal 
c u m ulati ve d ose of c ycl o p h os p ha mi de is li mite d t o 4. 6 g m/ m 2 f or t he vast maj orit y of 
t he patie nts a n d t o 5. 4 g m/ m2 i n a b o ut 7 % patie nts w h o ha ve 5 % or m ore blasts o n da y 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 5 of i n d ucti o n t o re d uce t he pr o ble m of sterilit y (es peciall y i n b o ys). A nt hrac ycli ne 
cu m ulati ve d osa ge is li mite d t o 2 3 0 m g/ m 2 i n sta n dar d/ hi g h-ris k patie nts, a n d t o 8 0 
m g / m2 i n l o w-ris k cases.  T hese d osa ges of a nt hr ac ycli nes are ass oci ate d wit h a ver y 
l o w ris k of car di o m y o pat h y4 2. 
 
Rei n d ucti o n treat me nt is a n i nte gral c o m p o ne nt of m ost c o nte m p orar y trials, wit h 
be nefits e xte n di n g t o l o w-ris k cases.  A C C G st u d y s h o w e d t hat a n a u g me nte d B F M 
re gi me n (e q ui v ale nt t o t he use of d o u ble rei n d ucti o n) ca n e v e n a b olis h t he a d verse 
pr o g n ostic i m pa ct of p o or earl y res p o nse 1.  He nce, i n T O T X VI, all patie nts (re gar dless 
of r is k stat us) will recei v e t w o c o urses of rei n d u cti o n, al beit at differe nt i nte nsit y as 
deter mi ne d b y ris k gr o u p assi g n me nt.  I n l o w-ris k patie nts, d o x or u bici n will be o mitte d 
fr o m re-i n d u cti o n II, re d uci n g t he t otal c u m ulati ve a nt hrac ycli ne d ose t o 8 0 m g/ m 2 
(c o m pare d t o 1 1 0 m g/ m2 o n T O T X V) i n t his gr o u p. I n sta n d ar d- ris k a n d hi g h-ris k 
g r o u ps, hi g h- d os e c ytara bi ne ( 2 g m/ m2) is i nc or p orate d i n re- i n d ucti o n II beca use 
T O T XII s u g geste d t hat T-cell cas es be nefit fr o m t his treat me nt 3 7 a n d a n a d ult B F M 
st u dy s h o we d t hat hi g h- d ose c yt ara bi ne ca n mar ke dl y i m pr o ve o utc o me, e v e n i n 
patie nts wit h t he t ( 4; 1 1) A L L 4 3. 
 
Ge n der has l o n g b ee n rec o g niz e d as a pr o g n ostic fact or i n c hil d h o o d A L L.  B o ys ha ve 
c o nsiste ntl y fare d w orse t ha n girls, gi ve n e q ui vale nt t hera p y. Male patie nts treate d o n 
C C G, B F M, a n d T O T X V pr ot oc ols recei ve d a n e xte n de d d urati o n of treat me nt (i.e. 3 
years). H o we v er, i n T O T XIII B (i n w hic h t h e d urati o n of c he m ot hera p y f or b ot h males 
a n d fe males was 2. 5 years) a n d i n T O T X V, wit h o verall 5- year e v e nt- free s ur vi val rates 
o ver 8 0 %, male p atie nts fare d as well as fe male p atie nts.  He nce, i n T O T X VI, t he 
d ura ti o n of t hera p y will be t he sa me f or b ot h ge n d ers ( 2 ½ years).  As i n T O T X V, 
co nti n uati o n treat me nt be y o n d 2 years i n T O T X VI c o nsists of merca pt o p uri ne a n d 
met h otre x ate o nl y ( n o de x a met has o ne a n d vi ncristi ne p ulses).  M ore o v er, 
de x a met has o ne d ose will be decreas e d t o 6 m g/ m 2 bet wee n wee k 6 9 a n d wee k 1 0 1 t o 
decrease t he m or bi dit y fr o m de xa met has o ne t hera p y. 
 
2. 1. 5  
S u b-cli nical C N S treat me nt 
 
S i nce C N S irra diati o n ca n i n d uce seri o us l o n g-ter m se q uelae, i ncl u di n g gr o wt h 
retar dati o n, i ntellect ual i m pair me nt a n d brai n t u m ors, a n d i n vie w of t he o utsta n di n g 
C N S c o ntr ol i n T O T XIII A & B,  C N S irra diati o n was eli mi nate d alt o get her i n 
T O T X V, e x ce pt i n patie nts w h o de vel o pe d C N S rela pse. 
 
T he o verall 5- year c u m ul ati ve ris k of C N S rela pse was 3. 7 % + 1. 3 % ( S E) i n T O T X V, 
w hic h is c o m para bl e t o r es ults i n st u dies still usi n g pre ve nti ve C N S irra di ati o n. We 
attri b ute t his s uccess t o earl y i nte nsifi cati o n of i ntrat hecal treat me nt, es p eci all y i n 
patie nts at hi g h ris k of rela pse, a n d effecti ve s yst e mic treat me nt i ncl u di n g t he use of 
de x a met has o ne.  M ost C N S e ve nts o n T O T X V occ urre d i n p atie nts wit h T-cell 
li nea ge ( wit h c u m ulati ve ris k of 1 1. 1 % + 4. 8 %), or wit h a n y a m o u nt of blasts i n t he 
C S F ( 1 1 % + 4. 3 %). A rece nt  a nal ysis of T otal T hera p y st u dies XIII A, XIII B, XI V, 
a n d X V f urt h er i n dicate d t hat patie nts wit h t( 1; 1 9)/ E 2 A- P B X 1 ha ve a l o wer 
c u m ulati ve i nci de nce of a n y h e mat ol o gical r ela ps e b ut a si g nifi ca ntl y hi g h er 
i nci de nce of C N S rela p se ( p = 0. 0 0 5; 1 2. 4 % + 5. 9 % vs. 2. 7 % + 0. 7 % at 5 years)4 4. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 of 1 1 1  
 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5   
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
N ota bl y, all patie nts wit h is olate d C N S rela pse were ali ve i n se c o n d re missi o n after 
recei vi n g t heir first c o urs e of irra di ati o n f or treat me nt of C N S rela pse, res ulti n g i n n o 
si g nifica nt differe nce i n s ur vi val bet wee n p atie nts wit h B-li nea ge or T-li nea ge A L L, 
or bet wee n t h os e wit h or wit h o ut blasts i n C S F at dia g n osis.  He n ce, is olate d C N S 
rela pse i n patie nts w h o di d n ot recei ve pre v e nti ve C N S irra diati o n are c ura ble wit h 
retrie val t hera p y.  I n T O T X VI, i ntrat hecal treat me nt will be i nte nsifie d d uri n g 
i n d ucti o n treat me nt wit h 2 a d diti o nal i ntrat hecal treat me nt o n d a ys 4 a n d 1 1 f or 
patie nts wit h T-cell A L L, t( 1; 1 9)/ E 2 A- P B X 1, or a n y a m o u nt of le u k e mic blasts 
i de ntifia ble i n t he cere br os pi nal fl ui d at dia g n osis (i ncl u di n g t h ose wit h cere br os pi nal 
fl ui d c o nta mi nate d wit h le u ke mic- blast cells d ue t o a tra u matic l u m bar p u n ct ure, 
beca use t h e y are at hi g her ris k of C N S rela pse a n d ha ve a p o orer e ve nt-free s ur vi val 
if treat me nt is n ot i nte nsifie d).  T hes e patie nts t he n recei v e a d diti o nal i ntrat hecal 
d ose s e ver y 4 wee ks d uri n g t he first 5 6 wee ks of c o nti n uati o n t hera p y, as d o patie nts 
wit h n o i de ntifia ble blasts i n t he cere br os pi nal fl ui d w h o were j u d ge d t o ha ve a n 
i ncreas e d ris k of C N S rel a pse base d o n ot h er feat ures (i.e., t h ose wit h W B C ≥1 0 0 x 
1 0 9/ L, a n d P hila del p hia- c hr o m os o me p ositi ve cas es). 
 
As i n T O T X V, pre v e nti ve C N S irra diati o n is eli mi nate d alt o get her i n t his st u d y, 
e x ce pt i n patie nts w h o d uri n g c o nti n uati o n tr eat me nt ha ve m or p h ol o gi c e vi de nce of 
l y m p h o blasts i n t he C S F, c o nfir me d b y i m m u n ol o gical testi n g (i. e., T d T) o n t w o 
separat e occasi o ns.  We e x pect t hat t hese e ve nts s h o ul d n ot occ ur i n m ore t ha n 5 % of 
t he patie nts.  Patie nts are ma na ge d acc or di n g t o Secti o n 9. 4. 
 
2. 1. 6  R ati o nale f or m o dificati o n of merca pt o p uri ne a d mi nistrati o n (re visi o n 5. 5) 
 
Pri or t o re visi o n 5. 5, t his pr ot oc ol sti p ulate d t hat merca pt o p uri n e s h o ul d be ta ke n o n a n 
e m pt y st o mac h (i.e., > 2 h o urs after m eal) at b e dti me; patie nts s h o ul d n ot dri n k mil k or 
ta ke dair y pr o d u cts t o get her wit h merca pt o p uri ne. 
 
H o we ver, base d o n literat ure re vie w s u m marize d bel o w, t his c ha n ge d wit h a me n d me nt 6. 0 
a n d n o w sti p ulates t hat merca pt o p uri ne s h o ul d be gi ve n dail y at a c o nsiste nt ti me t hat 
ma xi mizes a d here nce wit h t he prescri b e d treat me nt. If a d ose is i na d verte ntl y misse d, t he n 
it s h o ul d be gi ve n as s o o n as t he o missi o n is n ote d, as l o n g as it is at least 6 h o urs pri or t o 
t he ne xt sc he d ule d d ose of M P. 
 
Pri or st u dies assessi n g t h e p har mac ol o gi cal a n d t h era pe utic i m pact of gi vi n g oral 
merca pt o p uri n e ( M P) wit h f o o d or wit h dair y pr o d ucts, or gi vi n g 6 M P at differe nt ti mes of 
da y h a ve pr o d uce d v aria ble res ults.  All of t he earl y st u dies 4 5 -4 7 e nr olle d s mall n u m bers of 
pa tie nts a n d re v eale d tre n ds i n differe n ces i n pea k plas ma c o nce ntrati o ns of pare nt dr u g or 
plas ma area- u n der-t he-c o nce ntrati o n-ti me c ur ve ( A U C), b ut t hese res ults were n ot 
statisticall y si g nifica nt.  Ot her st u dies 4 8; 4 9 re p orte d statisticall y si g nifica nt differe n ces i n 
time of ma xi m u m dr u g c o nce ntrati o n i n plas ma (t ma x)  a n d A U C i n t he fasti n g state of 
pare nt dr u g 4 8 or c ha n ges i n A L L dise ase free s ur vi val4 9 ass ociate d wit h ti me of da y of oral 
6 M P a d mi nistrati o n ( wit h better res ults re p orte d f or ni g htti me dr u g a d mi nistrati o n i n t hat 
t he ris k of rela ps e was 4. 6 ti mes greater wit h t he m or ni n g a d mi nistrati o n s c he d ule).   
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
H o we ver, t hese ol der st u dies di d n ot assess t hese varia bles i n t he c o nt e xt of treat me nt 
pr ot oc ols t hat utiliz e er yt hr oc yt e t hi o g u a ni ne n ucl e oti des ( T G N) l e vels t o g ui de t hera p y 
a dj ust me nts, n or di d t he y i ncl u de t hi o p uri ne d osi n g as p art of m ulti variate a nal ys es f or 
o utc o me pre dict ors.   
 
A m ore rece nt st u d y of 5 3 2 patie nts b y Sc h mie gel o w, et al. use d a C o x m ulti variate m o del 
t o s h ow t hat t he circa di a n sc he d ule ( m or ni n g vs. e ve ni n g vs. mi x e d) of M T X/ 6 M P was n ot 
of pr o g n ostic si g nifica nce f or t he ris k of rela ps e, a n d t he 1 0- year c u m ulati v e rela ps e ris k 
was bel o w 2 0 % i n all gr o u ps 5 0.  
 
A se parate rece nt st u d y assesse d t he effects of “ pill-ta ki n g” h a bits o n treat me nt a d here n ce, 
er yt hr oc yte T G N le vels & rel a pse ris k i n 4 4 1 c hil dre n e nr olle d o n t h e C O G A A L L 0 3 N 1 
st u d y5 1.  T his st u d y re p orte d n o ass ociati o n bet wee n rela ps e ris k a n d w het her 6 M P was 
ta ke n wit h f o o d ( p = 0. 5), wit h dair y ( p = 0. 2), w het her ta blets were s w all o we d w h ole vs. 
cr us hi n g/ c he wi n g ( p = 0. 7); I V), or ti me of d a y: e v e ni n g/ ni g ht vs. m or ni n g/ mi d- da y 
( p = 0. 9), var yi n g ti mes vs. n o n- var yi n g ti mes ( p = 0. 9). T he 6 M P ta ki n g h a bits were als o n ot 
ass ociate d wit h DI- a n d a ge-a dj uste d T G N le vels.  T he a ut h ors c o n cl u de d t hat t he 
co m m o nl y practice d restricti o ns c o ncer ni n g a d mi nistrati o n wit h f o o d or at be dti me di d n ot 
si g nifica ntl y i nfl ue n ce o utc o me i n t heir pr ot oc ol a n d patie nt c o h ort. 
 
Base d o n t h ese lar ger a n d ne wer st u dies, t hat i ncl u de m ore caref ul atte nti o n t o 6 M P d osi n g 
t ha n was tr ue i n t he earli er st u dies, a n d o n t he fact t hat 6 M P d ose is a dj uste d t o desire d 
bl o o d c o u nts, we pr o p ose t o lift t he restricti o ns c o ncer ni n g a d mi nisteri n g M P at be dti me 
a n d o n a n e m pt y st o mac h t o all o w patie nts t o ta ke 6 M P at a ti me of da y w hi c h is m ost 
li kel y t o yi el d f ull a d here nce t o t he pres cri be d d ail y d osi n g of 6 M P.  As f or a n y d ail y dr u g, 
we rec o m me n d t hat pare nts a d mi nister a n d/ or patie nts ta ke 6 M P at a c o nsiste nt ti me e ver y 
da y. We als o str o n gl y rec o m me n d t hat er yt hr oc yte T G N le vels c o nti n ue t o be m o nit or e d 
t o g ui de 6 M P t hera p y ( detect n o n-a d here n ce a n d/ or i na p pr o priate d osi n g). Li ke wis e, 
T P M T p he n ot y pe/ ge n ot y pe s h o ul d c o nti n ue t o be assesse d f or eac h patie nt t o g ui de t he 
selecti o n of o pti mal 6 M P d osa ges f or eac h p atie nt.  Fi nall y, A L L c o nti n uati o n t hera p y 
s h o uld c o nti n ue t o be g ui de d b y m eas ure me nt of W B C t hr o u g h o ut t hera p y, wit h d osa ge 
a dj uste d ma de as sti p ulat e d i n t he pri mar y A L L tr eat me nt pr ot oc ol. 
 
2. 2  
P har mac ol o gic St u dies 
 
2. 2. 1  Ge r mli ne ge netic p ol y m or p his ms 
 
Usi n g ca n di date ge n e a p pr oac hes, we a n d ot h ers ha ve i de ntifie d m ulti ple p ol y m or p his ms 
ass ociate d wit h rel a pse ris k, ac ute t o xicit y, a n d lat e effects (s uc h as sec o n d ca ncers) 1 2; 5 2- 5 6.  
Re plicati o n of ass ociati o ns fr o m o n g oi n g st u dies are re q uire d t o use t his i nf or mati o n t o 
i n di vi d ualiz e d osi n g f or t he maj orit y of t hese ass o ciati o ns, wit h t he e x ce pti o n of 
t hio p uri ne met h yltra nsferase ( T P M T), w hic h is alr ea d y bei n g use d t o i n di vi d ualize t hera p y 
( Secti o n 7. 1 0). 
 
Ge n o me wi de a nal yses are als o bei n g i nc or p orate d i nt o st u dies of treat me nt-relate d 
o utc o mes f or A L L 5 7; 5 8.  T he s u bstrate f or t hese ge n o me wi de st u dies ca n be D N A or R N A, 
a n d ma y i n v ol ve t he A L L blast material or ger mli ne material. Alt h o u g h t he c h oice of 
tiss ue t o ser ve as t he s u bstrate f or ge n o me- wi de assess me nts of ge ne e x pressi o n is n ot 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
clear, peri p heral bl o o d le u k oc ytes are a reas o na ble a n d accessi ble s o urce of “ ger mli ne” 
R N A, a n d we  ha ve use d t his tiss ue f or preli mi nar y st u dies o n T O T X V. 
 
B eca use of t h e hi g h false disc o ver y rat e i n here nt i n ge n o m e- wi de ass ociati o n st u dies, t he 
critical c o nce pt i n ge neti c st u dies is re plicati o n i n m ulti ple cli nical trials.  T h us, t o s o me 
exte nt, ge netic st u dies i n T O T X VI will be re peati n g a n al ys es o n earlier St. J u de a n d ot he r 
A L L st u dies.  T h os e p he n ot y pe/ ge n ot y p e relati o ns hi ps t hat are re plicate d will ha ve great er 
g e n eraliza bilit y i n t he f ut ure; s o me ass ociati o ns t h at d o n ot re plicate are li k el y d u e t o 
treat me nt differe nces a m o n g pr ot o c ols, a n d s o me will ha ve bee n d u e t o false p ositi ve 
ass ociati o ns.  T h ose ass o ciati o ns of great est i m p orta nce are t he s u bject of la b orat or y 
f oll o w- u p st u dies i n t he la bs of P har mace utical, O nc ol o g y, a n d Pat h ol o g y De part me nt 
fac ult y, as w ell as ot her gr o u ps. 
 
T w o ge netic p ol y m or p his ms t hat ha ve be e n li n ke d t o o utc o me p he n ot y pes b y  St. J u de 
i n vesti gat ors will be teste d o n T O T X VI, t he T Y M S en ha ncer re peat p ol y m or p his m a n d a n 
I L 1 5 S N P 5 8.  T he f or mer c o mes fr o m a ca n di date ge n e a p pr oac h a n d has bee n li n ke d t o 
rela pse ris k5 3 a n d t o oste o necr osis ris k5 9; t he latter is base d o n o ur ge n o me- wi de a nal ysis 
of  ger mli ne p ol y m or p his ms t hat are si g nifica ntl y relate d t o M R D stat us6 0. 
 
Gi ve n t he pace wit h w hic h ge n ot y pi n g tec h n ol o gi es are e v ol vi n g, it is n ot realistic t o 
descri be w h at ge n o mic i nterr o gati o ns will act uall y be us e d t o e val uat e ge n o mic 
deter mi na nts of efficac y a n d a d verse e v e nts, b ut it is clear t hat ge n o m e- wi d e 
i nterr o gati o ns will c o nti n ue t o e v ol ve t o bec o m e less e x pe nsi ve a n d m ore feasi ble d uri n g 
t he years t hat T O T X VI will accr ue p atie nts. Gi ve n t he relati vel y l o w c ost of pr os pecti vel y 
o btai ni n g ge n o mic material f or f ut ure st u dies, w e will c o nti n ue t o c ollect peri p heral bl o o d 
f or ger mli ne D N A a n d R N A is olati o n, as we ha v e f or T O T X V, a n d e m pl o y state- of-t he-
art tec h ni q ues t o ass ess w het her ge n o mic v ariati o n pre dicts ris k fact ors f or rela pse, 
( hemat ol o gi c or C N S), p o or res p o nse ( M R D p ositi vit y), ac ut e t o xicities (e. g. 
oste o ne cr osis, ne ur ot o xicit y, i nfecti o n), i nter me diate p har mac ol o gic p he n ot y p es (e. g. 
plas ma met h otre x ate cleara nce, s er u m le vels of bi o mar kers s uc h as ser u m c h olester ol or 
c ortis ol), a n d l o n g-ter m c o m plicati o ns of t hera p y (e. g. s ec o n d ca ncers, oste o pe nia). 
Refere n ce s er u m at dia g n osis will als o be c ollecte d f or t he p ote ntial use t o meas ure 
s ol u ble fact ors i n f ut ur e researc h, as w ell as ser u m f or “ bi o mar kers” (as i n 1 0. 3 a n d 1 6. 3) 
d uri n g t hera p y. 
 
E x a m ples of ge n ot y pe/ p h e n ot y p e ass ociati o n st u dies t hat will be perf or me d e xte n d o ur 
earlier w or k i n A L L trials t o defi ne ger mli ne ge n o mic variati o n 5 3; 5 9; 6 1- 6 4 t hat pre dicts t o xic 
a n d t hera p e utic res p o ns e; ge n o m e- wi de ge ne e x pressi o n t hat reflects ger mli ne varia bilit y 
a n d c orres p o n ds wit h res p o nse p he n ot y pes 1 2; 5 2; 5 4; 5 7 a n d ac q uire d ge n o mic c ha n ges t hat 
ma y affect A L L ris k gr o u p a n d treat me nt r es p o ns e 6 5; 6 6.  Sa m ple p o wer esti mates are 
i ncl u ded i n t he Statistical Secti o n 1 7. 5. 
 
T P M T e x hi bits ge netic p ol y m or p his m, wit h < 1 % of t he p o p ulati o n h o m oz y g o us deficie nt 
a n d 1 0 % heter oz y g o us 6 6.  We ha ve bee n usi n g i nf or mati o n o n patie nts' T P M T stat us t o 
assist i n d osa ge i n di vi d u alizati o n f or c o nti n uati o n t hera p y si nce 1 9 9 1 i n p atie nts e nr olle d 
at St. J u de.  We will c o nti n ue t o assess patie nts f or T P M T p he n ot y pe a n d ge n ot y pe, a n d 
use t hese data (al o n g wit h data o n cli nical t olera n ce of c h e m ot hera p y a n d meas ure me nts of 
acti ve t hi o p uri ne meta b olites i n re d bl o o d cells) as part of o ur al g orit h m f or d osa ge 
a dj ust me nt d uri n g c o nti n uati o n t hera p y o n T O T X VI.  Patie nts w h o are T P M T 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
H E T/ deficie nt will recei v e merca pt o p uri ne as p er T O T X V d uri n g i n d ucti o n i nstea d of 
t hi o g ua ni ne 
 
2. 2. 2  As para gi nase 
 
T o a d dress t he ra n d o mize d as para gi nase q u esti o ns, plas m a as para gi nase will be meas ure d 
d uri n g i n d ucti o n a n d rei n d ucti o ns.  T here are s u bsta ntial data fr o m ot her i n vesti gati o ns 6 7; 6 8 
s u p p orti n g t hat a tr o u g h l e vel at 1 4 da ys is i n t he eli mi nati o n p hase of t he dr u g’s 
c o nce ntr ati o n-ti mes-ti me c ur ves e v e n w he n t h e dr u g is a d mi nistere d I M.  Wit h t he first 
d ose d uri n g i n d u cti o n, a t otal of 3- 5 p ost- d ose sa m ples will be o btai ne d, ti me d t o c oi nci de 
wit h cli ni c visits a n d bl o o d dra ws, t o better assess P K after I V d osi n g.  D ue t o t he ver y 
l o n g half-life, t here is fle xi bilit y as t o w h e n t he sa m ples are o btai ne d, a n d Ba yesi a n 
m o deli n g per mits li mite d sa m pli n g.  T he g o als of t hese st u dies is t o defi ne t he ra n ge of 
tr o u gh plas ma as para gi nase c o nce ntrati o ns ac hie va ble wit h I V d osi n g of P E G-
as para gi n ase, t o c o m pare c o nce ntr ati o ns i n t he 2, 5 0 0 u nits/ m 2 vs.  3, 5 0 0 u nits/ m 2 (a n d 
3, 0 0 0 u nits/ m 2 if used) gr o u ps, a n d t o e x pl ore w het her as para gi nase c o nce ntrati o ns relate 
t o as para gi ne d e pleti o n a n d a nti-as para gi nase a nti b o dies. 
 
Aller gi c reacti o ns occ ur c o m m o nl y wit h a d mi nistrati o n of as para gi nase (a n e nz y me n ot 
prese nt i n h u ma ns) a n d ca n li mit its use.  M ore i m p orta ntl y, de v el o p me nt of a nti-
as para gi n ase a nti b o dies ( wit h or wit h o ut cli nical h y p erse nsiti vit y) ma y i n acti vate 
as para gi n ase a n d t h us att e n uate its a bilit y t o de plete as para gi ne s yste micall y.  Beca use 
as para gi n ase pla ys s uc h a pr o mi ne nt r ole i n T O T X VI, we will o btai n sa m ples f or a nti-
as para gi n ase a nti b o dies a n d plas ma as para gi nase ( base d o n a bi ol o gical ass a y of acti vit y, 
w hic h will t here b y reflect a n y i nacti vati n g effects of c o nc o mita nt a nti b o dies), a n d C S F 
as para gi n e, a p har mac o d y n a mic m eas ure of as p ara gi n ase effect a n d o ne feasi bl y meas ure d 
i n t he cli nic. 
 
As pa ra gi ne d e pleti o n is wi del y us e d as a n i n de x of as para gi nase effect. C S F c o nstit utes a 
c o n ve nie nt tiss ue f or sa m pli n g, beca use C S F as p ara gi n e le vels r eflect s yste mic le vels a n d 
are n ot s u bject t o t he diffic ulties i n i m me diate sa m ple pr ocessi n g ca us e d b y as p ara gi n ase 
i n bl o o d.  I n T O T X VI, i ntra ve n o us P E G- as p ara gi nase is re placi n g n ati ve E. c oli L-
as para gi n ase ( Els par), a n d will be a d mi nistere d i n a ra n d o mize d fas hi o n at t w o d ose le vels 
p ost re missi o n i n d ucti o n.  We will meas ure a nti-as para gi nas e a nti b o dies, as well as C S F 
as para gi n e de pleti o n i n all patie nts at i de ntical ti me peri o ds d uri n g t hera p y, t o e x pl ore 
w het her m or e fa v ora ble res ults are ass o ciate d wit h t he hi g her d ose of P E G- as para gi n ase, 
a n d w het her t h ese varia bles are relate d t o treat me nt o utc o me, t o xicities, a n d t o eac h ot her. 
 
I n T O T X V, ser u m mar kers s uc h as li pi ds, c h olester ol, a n d c ortis ol were clearl y i nfl ue nce d 
b y b ot h as p ara gi nas e a n d de x a met has o ne, a n d relate d t o a d verse e ve nts; m ore o ver, 
as para gi n ase a p p eare d t o ha ve a pr o mi ne nt effect o n de x a met has o ne p har m ac o d y na mics 6 9.  
T o e sta blis h t his relati o n, ser u m sa m ples ti me d rel ati ve t o as para gi nase a n d ster oi ds will 
be o btai ne d as w as d o ne o n T O T X V (as detaile d i n Ta ble 1 1. 2). 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 2. 3  
Deter mi nati o n of A L L bl ast se nsiti vit y t o a nti-le u ke mic a ge nts, i n vitro  
 
We ha ve pre vi o usl y st u die d t he e x vi v o se nsiti vit y a n d resista nce t o a nti-le u ke mic a ge nts 
of pri mar y le u ke mia cells is olate d fr o m ne wl y dia g n ose d c hil dre n wit h A L L 1 2; 1 3.  Ex viv o  
dr u g  s e nsiti vit y h as pre di cte d l o n g-ter m r ela pse ris k, is ass ociate d wit h dr u g-s pecific ge ne 
e x pressi o n patter ns, a n d is bei n g c o u ple d wit h precli nical st u dies i n cell li nes a n d m uri ne 
m o dels t o i de ntif y deter mi na nts of dr u g s e nsiti vit y i n la b orat or y m o dels. O ur pre vi o us 
st u dy i de ntifie d 4 2, 5 9, 5 4 a n d 2 2 ge ne pr o bes (c orres p o n di n g t o 1 9 t o 4 0 k n o w n ge nes per 
dr u g) t hat were differe nti all y e x presse d i n B-li nea ge A L L cells t hat were eit her se nsiti ve 
or resista nt t o pre d nis ol o ne, vi ncristi ne, L-as p ara gi nase or da u n or u bici n, res pecti vel y 1 2.  I n 
ad diti o n, we ha ve i de ntifi e d 4 5 ge nes differe ntiall y e x presse d i n A L L e x hi biti n g cr oss 
resista nce t o pr e d nis ol o ne, vi ncristi ne, as para gi nase, a n d da u n or u bi ci n 1 3.  O ur st u dies ha ve 
i de ntifie d ge nes n ot pre vi o usl y ass oci ate d wit h dr u g resista nce i n c hil d h o o d le u ke mia; 
discri mi nati n g ge n es bel o n g t o n u mer o us f u ncti o nal gr o u ps, a n d s pecific f u ncti o nal 
cate g ories were si g nifi ca ntl y o ver- re prese nte d f or s o me a nti-le u ke mic a ge nts 1 2; 1 3.  T hese 
fi n di n gs d oc u me nt t hat resista nce t o mec h a nisticall y disti nct a nti-le u ke mic a ge nts is 
ass ociate d wit h differe nti al e x pressi o n of differe nt f u ncti o nal gr o u ps of ge n es, i n s u p p ort 
of c o m bi nati o n c he m ot hera p y as t he p ara di g m f or ca ncer treat me nt.  M ore o ver, t hese 
fi n di n gs p oi nt t o pre vi o usl y u nrec o g nize d p ote ntial tar gets f or d e vel o pi n g ne w a ge nts t o 
au g m e nt t he efficac y of c urre nt c he m ot hera p y f or ac ute l y m p h o blastic le u ke mia.  T his is 
ill ustrate d b y o ur fi n di n g of M C L 1 o ver-e x pressi o n i n ster oi d resista nt A L L, a n d t h e 
s u bse q ue nt w or k of t he Ar mstr o n g La b at H ar var d, w h o s h o we d t hat ra p a m yci n ca n d o w n-
re g ulate M C L 1 pr otei n, a n d e n ha nce A L L se nsiti vit y t o ster oi ds7 0.  O ur st u dies ha ve als o 
s h o w n t hat t here are dr u g-s pecific c ha n ges i n ge ne e x pressi o n i n A L L, after i n vi v o 
treat me nt, a n d t hat dr u g c o m bi nati o ns are disti nct fr o m t he s u m of si n gle a ge nt 
treat me nt7 1.   I n T O T X VI we will c o nti n ue t o st u d y e x vi v o dr u g se nsiti vit y of pri mar y 
A L L bl asts t o a d diti o nal a nti-le u ke mic a ge nts ( 6 M P, 6 T G), i n a d diti o n t o e xte n di n g o ur 
pre vi o us st u dies, a n d f urt her i n vesti gate t he n at ure of ge ne e x pressi o n patter ns ass ociate d 
wit h re sista nce t o si n gle a nti-le u ke mic a ge nts or t o m ulti- dr u g cr oss resista nce. O ur 
h y p ot hesis is t hat t here is a defi na ble s et of ge n es t hat are differe ntiall y e x presse d i n 
pri mar y A L L cells e x hi biti n g de n ov o resista nce t o c he m ot hera p y a n d t hat i de ntificati o n of 
t hese ge nes will pr o vi de i m p orta nt ne w i nsi g hts i nt o t he basis of A L L resista nce a n d 
re veal p ote ntial n e w tar gets f or o verc o mi n g resista nce t o t hese wi del y use d me dicati o ns. 
T he w or k w e pr o p ose i n T O T X VI differs fr o m pri or w or k i n t hat ( 1) we are pri oritizi n g 
st u dies of merca pt o p uri n e a n d t hi o g u a ni ne ( dr u gs f or w hic h fe w p atie nts w ere e v al ua ble 
pre vi o usl y) a n d ( 2) we will si m ulta ne o usl y deter mi ne t he se nsiti vit y of t hes e ne w cases t o 
t he a nti-le u ke mic a ge nts we ha ve pre vi o usl y st u die d ( pre d nis o n e, vi ncristi ne, da u n o m yci n, 
as para gi n ase)1 2   i n or der t o el uci date ge n o mic det er mi na nts of m ulti- dr u g cr oss resista nce 
f or all 6 me dicati o ns.  We ha ve pre vi o usl y s h o w n t hat ge n e e x pressi o n patter ns ass ociat e d 
wit h m ulti- dr u g cr oss resista nce are disti nct fr o m ge n es c o nferri n g resista nce t o si n gle 
a ge nts 1 3.  We will als o use ot her ge n o me- wi de a p pr oac hes, i n cl u di n g S N P a n d ha pl ot y pe 
anal ys es, t o i de ntif y ge nes a n d ge netic p ol y m or p his ms li n ke d t o resista nce t o eac h of t h ese 
me dicati o ns ( n ot pre vi o usl y d o ne), a n d t o t he m ulti- dr u g cr oss resista nce p h e n ot y p e.  O ur 
pri or  w or k w as li mite d pre d o mi na ntl y t o B-li nea ge A L L.  I n T O T X VI, we ai m t o e xte n d 
t his w or k t o T-li nea ge A L L.  T his s u bset has a w orse pr o g n osis i n ma n y tr eat me nt 
pr ot oc ols, a n d t heref ore it is i m p orta nt t hat we u n dersta n d t he ge n o mic b asis of dr u g 
resista nce i n t his c o m m o n s u bt y pe of c hil d h o o d A L L. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 2. 3  P las ma h o m oc ystei ne l e v els 
 
I n T O T XI V a n d T O T X V st u dies, C S F a n d plas ma h o m oc ystei ne l e vels were meas ure d i n 
c o nj u ncti o n wit h H D M T X a d mi nistrati o n d uri n g C o ns oli dati o n t hera p y. T he rati o nale f or 
assessi n g M T X-i n d uce d c ha n ges i n h o m oc ystei ne is base d o n e vi de nce li n ki n g M T X 
e x p os ure t o ne ur ot o xicities (e. g., seiz ures) 7 2; 7 3, w hic h ha ve bee n h y p ot hesize d t o be 
ma nif este d, at least i n part, b y M T X-i n d uce d ele vati o n i n plas ma h o m oc ystei ne le vels.  A n 
anal ysis of T O T XI V data re veal e d a tr e n d i n ass ociati o n bet wee n i ncreas e d plas ma 
h o m oc ystei ne l e vels a n d i nci de nce of seiz ures 6 3.  W hile n o c orrelati o ns were o bser ve d 
bet wee n plas ma h o m o c ystei ne ( or seiz ures) wit h pre vi o usl y i de ntifie d M T H F R ge n ot y pes 
as was p ost ulate d 7 4; 7 5, it is li kel y t hat ot her ge netic p ol y m or p his ms u n derlie t he o bser ve d 
H D M T X- i n d uc e d t o xicities a n d i nter patie nt varia bilit y i n plas ma h o m oc ystei ne 
co nce ntr ati o ns.  We will c o nti n ue t o pr os pecti vel y assess plas ma h o m oc yst ei ne i n 
H D M T X c o urs es 1 a n d 2 of c o ns oli dati o n i n T otal X VI. Dat a will be use d t o pi n p oi nt 
g e n etic bi o mar kers ass ociate d wit h differe ntial plas ma h o m oc ystei n e le vels b ot h bef ore, 
a n d f oll o wi n g tr eat me nt wit h H D M T X, as well as t h ose c orrel ate d wit h a n y o bser ve d 
t o xicities. 
 
2. 3  
Bi ol o gic St u dies 
 
2. 3. 1 
Mi ni mal resi d ual disease 
 
W e a n d ot hers ha ve s h o w n t hat detecti o n of s u b micr osc o pic (" mi ni mal") disease str o n gl y 
c orrel ates wit h le u ke mia rela pse 7 6.  Usi n g b ot h fl o w c yt o m etric detecti o n of a berra nt 
i mm u n o p he n ot y pes a n d p ol y merase c h ai n reacti o n ( P C R) a m plificati o n of 
i m m u n o gl o b uli n a n d T-cell rece pt or ge nes, w e were a ble t o m o nit or mi ni mal resi d ual 
le u ke mia i n all patie nts i n T O T X V wit h hi g hl y c o nc or da nt r es ults.  We als o deter mi ne d 
t he degree of c orrel ati o n bet wee n le vels of resi d u al le u ke mia i n bl o o d vers us b o ne marr o w 
b y st u d yi n g paire d s a m pl es fr o m patie nts e nr olle d i n t he st u d y. M R D res ults i n peri p heral 
bl o o d were c o nc or da nt i n T-cell diseas e, b ut n ot i n B- cell li nea ge2 0.  I n T O T X VI we will 
m o nit or M R D usi n g pri maril y fl o w c yt o metr y; i n patie nts w h ose le u ke mi c cells lac k a 
s uita ble i m m u n o p he n ot y pe (esti mate d t o be 5 % or less) we will use t he P C R met h o d 
a p plie d i n T O T X V.  M R D ca n als o be f oll o we d b y t he ne xt ge nerati o n dee p se q ue nci n g of 
t he I g H l oc us i n B- A L L a n d T C R l oci i n T- A L L.  T he se nsiti vit y a n d s pecificit y are b etter 
t ha n fl o w- bas e d or P C R met h o ds7 7. 
 
Patie nts w h o ac hie ve n e gati ve M R D at t he e n d of i n d ucti o n i n T O T X V were u nli kel y t o 
ha ve rea p peara n ce of bl asts o n f urt her f oll o w u p.  He nce, p ost re missi o n b o ne marr o w 
sa m ples will o nl y be o btai ne d f or se q ue ntial M R D m o nit ori n g i n patie nts wit h detecta ble 
M R D at t he e n d of i n d ucti o n.  H o we ver, we will c o nti n ue t o m o nit or M R D i n all patie nts 
wit h T -cell A L L irres pecti ve of t heir M R D stat us at t he e n d of re missi o n i n d ucti o n 
be ca use T-cell cases h a v e hi g h er ris k of earl y rela pse c o m pare d t o B-li nea ge cases. 
B eca use w e s h o we d t h at M R D i n patie nts wit h T- A L L ca n b e effecti vel y m o nit ore d i n 
peri p heral bl o o d, we will use t his less-i n vasi ve pr oce d ure i nstea d of b o ne marr o w 
as pirates f or t his p ur p os e. F or B- A L L, we will als o f oll o w M R D of t he b o ne marr o w a n d 
peri p heral bl o o d b y d ee p se q ue nci n g met h o d t o deter mi ne if t his m ore se nsiti ve a n d 
s pecific test will s h o w c o nc or da nce u nli ke t he fl o w a n d P C R base d M R D t ests.  If 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c o nc or da nt, t he n we ca n m o nit or B- A L L patie nt usi n g a less i n vasi ve t esti n g of t he 
peri p heral bl o o d si milar t o T- A L L patie nts. 
 
I n v esti gat ors of t he C hil dre n’s O n c ol o g y Gr o u p ( C O G) de m o nstrate d t he pr o g n ostic val ue 
of deter mi ni n g M R D o n da y 8 of i n d ucti o n. I n T O T X VI, we will e x pl ore w het her da y 8 
M R D i n peri p heral bl o o d is a practical a p pr oac h t hat mi g ht p ote ntiall y all o w earl y 
t hera pe utic i nter ve nti o n i n f ut ure st u dies. 
 
I n eff orts t o i de ntif y n e w mar kers of l e u ke mia t o use f or M R D m o nit ori n g, we c o m pare d 
t he gene e x pressi o n pr ofile of m ore t ha n 3 0 0 dia g n ostic sa m ples of B-li nea ge A L L t o t hat 
of s orte d C D 1 9 + C D 1 0 + cells fr o m 4 n or mal b o ne marr o w sa m ples.  Se v eral ge nes were 
f o u n d t o be differe ntiall y e x presse d i n le u ke mic cells a n d a nti b o dies s uit a ble f or fl o w 
cyt o metri c stai ni n g are a vaila ble f or a s u bset of t h ese.  I n T O T X VI, we will c o m pare t he 
usef ul ness of t hese n e w mar kers t o m o nit or M R D b y fl o w c yt o metr y. 
 
A rare blast i de ntifie d b y m or p h ol o gic e x a mi nati o n of t he C S F at dia g n osis c urre ntl y 
u p gra de t he C N S r ela pse ris k cate g or y res ulti n g i n e xtra i ntrat hecal treat me nt.  Of 3 4 9 
pa tie nts e nr olle d o n T O T X VI si nce 2 0 0 7, o nl y o n e has ha d a C N S r ela pse t o date. M R D 
anal ysis of t he C S F b y fl o w or P C R base d tests is n ot feasi ble beca use t he C S F lac ks 
s ufficie nt cells.  We will use a dee p s e q ue n ci n g t ec h ni q ue t o e val uat e M R D i n C S F i n 
or der t o st u d y w het her le vels of M R D i n t he C S F at dia g n osis a n d d y n a mics of earl y M R D 
re d ucti o n i n C S F c o ul d b e use d t o f urt her refi ne o ur c urre nt classificati o n f or ris k of C N S 
rela pse.  T his mi g ht p ote ntiall y all o w t he re d ucti o n of i ntrat hecal t hera p y i n f ut ure st u dies 
i n c hil dre n wit h rare i de ntifia ble blast b y m or p h ol o g y b ut l o w le vels of M R D. 
 
2. 3. 2  N K  cell rece pt or st u d y 
 
T he  n or mal p h ysi ol o gical r oles of N K  cells are t o c o ntr ol i nfecti o n a n d pre ve nt ca ncer. I n 
fact, N K  cells are t he o nl y i m m u ne cells t hat ha ve bee n s h o w n b y pr os pecti ve c o h ort st u d y 
i n health y pers o ns t o ha v e i m m u n os ur veilla nce ca pa bilit y a gai nst h u ma n ca ncer 7 8.  I n a 
pr os pe cti ve st u d y of m ore t ha n 3 0 0 0 healt h y v ol u nteers w h o were f oll o we d f or 1 1 years, 
t he ris k of ca ncer was ass ociate d wit h decreas e d N K cell c yt ot o xicit y a gai nst K 5 6 2 
le u ke mia cells, decrease d e x pressi o n of t he N K  rece pt or N K R P 1, a n d decrease d 
pr o d ucti o n of c yt o ki nes s uc h as T N F α a n d I F Nγ i n N K cells. 
 
T hree rece nt st u dies of a d ult le u ke mia ha ve de m o nstrate d a dir ect li n k bet wee n le u ke mia 
an d N K  cell. I n o ne st u d y of patie nts wit h ac ute m yel oi d le u ke mia, t he maj orit y ( 1 6 of 1 8) 
of bl o o d sa m ples s h o we d defecti ve e x pressi o n a n d f u ncti o n of N K  cell –tri g geri n g 
rece pt ors ( N C Rs) ( d ull) 7 9.  T he e x pressi o n of N K  cell s urface rece pt ors was l o w, a n d t he 
c yt ol ytic acti vit y a gai nst a ut ol o g o us le u ke mia cells, a ut ol o g o us B l y m p h o blasts, a n d  N K  
cell–se nsiti ve cell li nes was wea k. T he a b n or mal N C R ( d ull) p he n ot y pe was c o nfir me d i n 
an ot her st u d y of 7 1 patie nts wit h ac ute m yel oi d le u ke mia a n d was f o u n d t o be prese nt i n 
va ri o us m or p h ol o gic a n d ge n ot y pic s u bt y pes of le u ke mia8 0.  I n t he t hir d st u d y of 2 5 A M L 
an d 1 4 A L L cases, t he e x pressi o n of H L A class I was fre q ue ntl y d o w nre g ulate d a n d t hat 
of  t he N K  cell rece pt or li ga n ds P V R a n d Necti n- 2 were u pre g ulate d 8 1.  T o get her,  t hese 
res ults s u g gest t hat N K  rece pt or –li ga n d i nteracti o n ma y be cr ucial f or t he de vel o p me nt of 
le u ke mia. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he n or malizati o n of N K cell rece pt or e x pressi o n ma y b e of pr o g n ostic val ue as N K cells 
ma y b e i m p orta nt f or t he c o ntr ol of le u ke mia rela pse a n d i nfecti o n.  T hese r oles of N K 
cells ha ve bee n s h o w n b y killer cell i n hi bit or y rece pt or ( KI R)- mis matc he d all o ge nei c ste m 
cell tra ns pla ntati o n 8 2.  L o n git u di nal st u d y of a d ult A M L p atie nts s h o we d t h at t he N C R 
( d ull) p he n ot y p e ac q uire d d uri n g le u ke mia de vel o p me nt was re v ersi ble i n patie nts 
ac hie vi n g c o m plete re missi o n after i n d ucti o n c he m ot hera p y 8 0.  Re versi bilit y of t he N C R 
( d ull) p hen ot y p e aft er c o m plete re missi o n s u g gest e d t hat le u ke mia cells mi g ht be i n v ol ve d 
i n N C R d o w n-re g ulati o n. Alter nati vel y, t he rec o ver y of n or mal N C Rs ma y all o w t he 
rec o ver y of n or m al N K cell f u ncti o n t hat c o ntri b utes t o t he ac q uisiti o n of re missi o n stat us. 
I nteresti n gl y, a c orrelati o n was f o u n d bet w ee n t he N C R ( d ull) p he n ot y pe a n d p o or 
s ur vi val i n A M L p atie nts after c he m ot hera p y8 0, s u g gesti n g t hat N K- defici e nt acti vati o n 
ca use d b y N C R d o w n-re g ulati o n c o ul d pla y a r ole i n treat me nt o utc o me.  T heref ore, we 
will  st u d y N K cell rece pt or e x pressi o n at dia g n osis a n d bef ore rei n d u cti o n t o el uci date t he 
r ole of N K cell i n t he de v el o p me nt a n d treat me nt r es p o nse of c hil d h o o d A L L. 
 
2. 3. 3  Gl o ba l ge ne e x pressi o n 
 
All dia g n ostic sa m ples will be e x a mi ne d f or gl o bal ge n e e x pressi o n usi n g micr oarra y 
c hi ps.  T his will c o nti n ue t o e nric h o ur u ni q ue data base o n t he ge ne e x pressi o n of A L L 
cells w hic h has bec o me a n i n val ua ble res o urce f or A L L i n v esti gat ors w orl d wi de. I n 
a d diti o n, t his will pr o vi de us wit h a n o p p ort u nit y t o vali date pr os pecti vel y t he ma n y 
retr os pecti ve o bs er vati o ns ma de i n past c orrelati ve st u dies i ncl u di n g gl o bal ge n e 
e x pressi o n.  I n a d diti o n t o e x a m ples me nti o ne d i n Secti o n 2. 2, c orrel ati ve st u dies 
perf or me d wit h sa m ples of patie nts e nr olle d i n T O T X V i de ntifie d se v eral ge n es w h ose 
e x pressi o n i n le u ke mic cells at dia g n osis was str o n gl y ass oci ate d wit h M R D d uri n g ( da y 
1 9) or at t he e n d of re missi o n i n d ucti o n t hera p y ( da y 4 6)1 0; 1 1.  After e x cl u di n g ge n es 
ass ociate d wit h ge n etic s u b gr o u ps, we f o u n d t hat s o me of t hese ge n es were als o str o n g 
pre dict ors of o v erall treat me nt o utc o me i n a n i n de pe n de nt c o h ort of 9 9 p atie nts e nr olle d i n 
T O T XIII 1 0; 1 1.  A f ull listi n g of t he ge nes ca n be f o u n d i n t he c orres p o n di n g p u blicati o ns. 
O ne  of t he ge nes w h ose e x pressi o n was m ost hi g hl y pre di cti ve f or o utc o m e was 
C A S P 8 A P 2 , w hic h e nc o d e a pr otei n t hat pr o m otes a p o pt osis a n d gl uc oc ortic oi d si g nali n g 
an d was f o u n d t o be e x presse d at l o wer le vels i n p atie nts wit h M R D at t he e n d of 
i n d ucti o n a n d a hi g h er ris k of rela pse1 0.  A n ot her set of ge nes re p orte d t o b e ass ociate d 
wit h i n vitr o dr u g resista nce i n c hil d h o o d A L L 1 2; 1 3, was als o ass ociate d wit h M R D o n da y 
1 9 1 1.  Ge nes f o u n d t o be o vere x presse d i n cases wit h i n vitr o dr u g resista nce a n d wit h 
M R D o n da y 1 9 i ncl u d e d H N P R F, H M G B 2 , H 2 A F Z , K P N A 2 , S N R P G, KI A A 0 9 2 2 , U 2 A F 2 
a n d C C D C 1 0 9 B . Ge nes wit h l o wer e x pressi o n i n patie nts wit h i n vitr o dr u g-resista nce a n d 
wit h M R D o n da y 1 9 i ncl u de d S L C 2 A 3 , M A F F , C D 6 9 , E G R 1, C K S 1 B a n d O T U B 1 . 
F i nall y, we i de ntifie d ge nes t hat were str o n gl y ass ociate d wit h M R D o n da y 1 9 or da y 4 6, 
a n d were als o i n de pe n d e nt pre dict ors of o utc o me i n a n i n de pe n de nt c o h ort, a n d e nc o d e d 
pr otei ns wit h k n o w n re g ulat or y f u ncti o ns i n cell c ycl e pr o gressi o n: C C N B 2 , C D C 2 , 
C K S 1 B , K L F 7, B R R N 1 , T O P 2 A, M A D 2 L 1 , B U B 3 , N U S A P 1 , P O L A 2 , E X O 1 , R N A S A H 2, 
M KI 6 7, a n d Z WI N T 1 1.  I n T O T X VI, we will st u d y t he ass ociati o n of t hese ge n es’ 
ex pressi o n wit h M R D o n da ys 1 5 a n d 4 2, a n d wit h i nci de nce of rela ps e. If t here are 
a nti b o dies a vaila ble f or t he pr otei ns e nc o d e d b y t he ge nes f o u n d t o b e ass ociate d wit h 
M R D a n d rela pse i n t he pre vi o us st u dies, t he e x pressi o n of t he pr otei ns will be m o nit ore d 
b y fl o w c yt o metr y a n d t h eir e x pressi o n will be rel ate d t o M R D o n da ys 1 5 a n d 4 2, a n d 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
cli nical o utc o me.  
 
2. 4  
Ne ur oi ma gi n g St u dies 
 
2. 4. 1 
I ma gi n g st u dies 
 
O n T O T XI V, M R i ma gi n g of t he brai n w as pr os p ecti vel y st u die d i n all patie nts at wee k 6 
of re missi o n i n d ucti o n, wee k 7, wee k 3 1 a n d wee k 1 2 0 of c o nti n uati o n treat me nt. We 
e val uate d t he l o n git u di nal pre vale nce of le u k o e nce p hal o pat h y i n 4 5 s u bjects b y treat me nt 
ris k ar m (l o w- a nd st a n dar d/ hi g h-ris k) 8 3.  Hi g her d oses a n d m ore c o urses of I V- M T X 
corres p o n d e d t o a hi g her ris k f or le u k oe n ce p hal o p at h y.  H o we ver, ma n y of t he c ha n ges 
res ol ve d aft er t he c o m pleti o n of t hera p y a n d t he effect of t hes e c ha n ges o n ne ur oc o g niti ve 
f u ncti o ni n g a n d q u alit y of life i n s ur vi v ors was n ot deter mi ne d.  A sec o n d st u d y of t his 
same patie nt c o h ort w as c o n d ucte d t o assess t he e xte nt of L E ( pr o p orti o n of w hite matter 
i mpacte d) t hr o u g h tiss ue se g me nt ati o n a n d t he r elati ve i nte nsit y of L E t hr o u g h relati ve 
ele vati o ns i n T 1 a n d T 2 rela x ati o n rates 8 4.   T he  pr o p orti o n of w hite matter affecte d i n 
b ot h treat me nt ris k gr o u ps i ncrease d si g nifica ntl y wit h a d diti o nal c o urses of I V- M T X, 
w hereas t he i nte nsit y of L E als o i ncrease d stea dil y; h o we v er, b ot h t he i nte nsit y a n d e xte nt 
of L E d ecli ne d si g nifica ntl y b y e n d of t hera p y. I n creases i n t he T 1 a n d T 2 rela xati o n rates 
a b o ve n or mal- a p peari n g w hite matter were si g nifi ca ntl y c orrelate d wit h eac h ot her a n d 
were d e pe n de nt o n t he pr o p orti o n of w hite matter affecte d. 
 
I n T O T X V, M RI of t h e brai n was pr os p ecti vel y st u die d i n all patie nts at wee k 6 of 
re missi o n i n d ucti o n, at first rei n d ucti o n, at wee k 4 8 a n d wee k 1 2 0 of c o nti n uati o n 
treat me nt. Preli mi nar y a n al ysis of t he first 2 2 9 patie nts t o c o m plete t hera p y s h o we d t hat 
w hite matter c ha n ges were f o u n d i n 2 9 % of b ot h l o w- a n d sta n dar d/ hi g h-ris k patie nts at 
first rei n d ucti o n. B y w ee k 1 2 0 of c o nti n uati o n, t he pre val e nce i n t he l o w-ris k patie nts ha d 
decrease d t o 2 4 % w hile 2 9 % of sta n dar d/ hi g h-ris k patie nts c o nti n ue d t o de m o nstrate w hite 
matter a b n or malit y. T he a vera ge pr o p orti o n of w hite matter affecte d b y t h ese 
a b n or malities was greater f or sta n dar d/ hi g h-ris k p atie nts ( 9. 2 %) t ha n f or l o w-ris k ( 6. 6 %) 
at first rei n d ucti o n b ut decreas e d b y m ore t ha n half b y wee k 1 2 0 of c o nti n u ati o n f or b ot h 
gr o u ps ( 4. 4 % sta n dar d/ hi g h a n d 2. 8 % l o w). 
 
Ne w ne ur oi ma gi n g te c h ni q ues a n d i ma ge pr ocessi n g met h o ds n o w e na ble researc hers t o 
i n vesti gate t he c o m ple x mat urati o n of t he h u ma n brai n8 5.  A l o n git u di nal i ma gi n g st u d y of 
4 5 c hil dre n bet wee n 5 a n d 1 1 years of a ge i ma ge d t wice, t w o years a part, was c o n d ucte d 
a n d pr ocess e d wit h t he Free S urfer s oft w are ( htt p://s urfer. n mr. m g h. har var d.e d u/ ) t o assess 
w h ole brai n c ortical t hic k ness 8 6.  T he brai n gre w at a rate of a p pr o xi matel y 0. 4 t o 1. 5 m m 
pe r year i n ma n y areas, pr o mi ne ntl y i n t he fr o nt al a n d occi pital re gi o ns.  C ortical t hi n ni n g 
wa s n ote d of a p pr o xi matel y 0. 1 5 t o 0. 3 m m per year i n ri g ht d orsal fr o ntal a n d bilateral 
pa rietal re gi o ns.  T hese n e w tec h n ol o gies e n a ble researc hers t o assess at y pi cal c ortical 
bra i n mat urati o n acr oss t he e ntire brai n t o i de ntif y s pecific ne ur oa nat o mical re gi o ns w hi c h 
ma y b e at i ncrease d ris k of i nj ur y a n d relat e t hese c ha n ges t o s pecific ne ur oc o g niti ve 
d o mai ns w hic h ma y b e n e gati vel y i m pacte d b y t h era p y. 
 
T he use of Diff usi o n Te ns or I m a gi n g ( D TI) i n as y m pt o matic patie nts d uri n g or after 
treat me nt f or A L L is a m ore rece nt de vel o p me nt.  K h o n g et al. pr os pecti vel y teste d t he 
ass ociati o n of w hite matt er fracti o nal a nis otr o p y ( F A) a n d i ntelli ge n ce q u otie nt (I Q) i n 1 8 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A L L s ur vi v ors a n d a ge- matc he d healt h y c o ntr ols 8 7.  A m o n g t he A L L s ur vi v ors, ni ne 
recei v e d H D M T X a n d ni ne u n der we nt cra nial irra diati o n wit h a tre n di n g differe nce 
bet we e n t he t w o gr o u ps. T he F A i n t he w hite matter of A L L s ur vi v ors was ofte n l o wer 
t ha n t hat i n t he a ge- mat c he d c o ntr ols, a n d t he differe ntial bet wee n t he F A i n patie nts 
relati ve t o t hat i n c o ntr ols was directl y pr o p orti o nal t o t he f ull-scale, perf or ma nce, a n d 
ver bal I Q s c ores of t he s ur vi v ors. T hese preli mi nar y fi n di n gs s u g geste d t h at w hite matter 
F A is a cli nicall y usef ul bi o mar ker f or t he assess me nt of treat me nt- relate d a berra nt brai n 
mat urati o n. 
 
As a n a ncillar y m eas ur e of m yeli n de gra d ati o n, q ua ntitati ve m ulti ple e x p o ne ntial T 2 
meas ure me nts ha v e t he a d va nta ges of pr o vi di n g b ot h m yeli n water fracti o n ( M W F) ma ps 
w hic h are n ot s e nsiti ve t o fi ber cr ossi n gs or de nsit y, a n d l o n g- T 2 water fracti o n ( L W F) 
ma ps w hic h are belie ve d t o s u g gest m ore s e vere d a ma ge. M W F ma ps ha v e bee n s h o w n t o 
c orrel ate str o n gl y wit h b ot h hist ol o gical stai ni n g f or m yeli n a n d wit h D TI meas ures of F A 
a n d ra dial diff usi vit y 8 8; 8 9.  Si g nals o n L W F ma ps s u g gest i nfla m mati o n, e xte nsi ve cell ular 
de str ucti o n wit h i ncreas e d e xtracell ular water, a n d se vere a x o nal da ma ge i n t he w hite 
matter 9 0. 
 
2. 4. 2  Ge netic p ol y m or p his ms 
 
Alt h o u g h se v eral c h e m ot hera pe utic a ge nts i n A L L t hera p y ma y c o ntri b ute t o ne ur ot o xicit y 
a n d ne gati ve n e ur oc o g niti ve o utc o mes, met h otre x ate has bee n t he pri mar y f oc us of ma n y 
st u dies9 1 -9 3.  T he d ose, c u m ulati ve e x p os ure, a n d i nf usi o n rate of met h otr e x ate ha ve b ee n 
ass ociate d wit h t he de gree of ne ur oc o g niti ve deficit 9 1; 9 4.  T hese sa me fact ors ha ve bee n 
ass ociate d wit h pre v ale n ce a n d i nte nsit y of w hite matter c ha n ges partic ularl y i n t he fr o nt al 
l o bes w hic h are ofte n ass ociate d wit h atte nti o n pr ocesses9 5; 9 6.  Met h otre x ate a n d its 
meta b olites i n hi bit f olate pat h wa y e nz y m es s uc h as 5, 1 0- met h yle netetra h y dr ore d uct ase 
( M TH F R) 9 7.  T he M T H F R e nz y m e has t w o p ol y m or p his ms, c haracterize d b y C 6 7 7 T a n d 
A 1 2 9 8 C, w hic h a lter t he f u ncti o n of t he e nz y m e, l ea di n g t o i ncrease d h o m oc ystei n e a n d 
re d uce d f olate. H o m o c ystei ne is c o n verte d t o met hi o ni ne b y met hi o ni ne s y nt hase ( M S), 
an d i n di vi d uals wit h M S deficie nc y h a ve ele vate d plas ma h o m oc yst ei ne le v els 9 8.  
A d diti o nal ke y e nz y mes t o c o nsi der i ncl u de t h y mi d ylate s y nt has e ( T S) a n d c ystat hi o ni ne 
beta s y nt h ase ( C B S). T S utilize circ ulati n g f olate t o c o n vert de o x y uri di ne m o n o p h os p hate 
t o de o x yt h y mi di ne m o n o p h os p hate, w hic h is esse ntial f or D N A s y nt hesis. C B S deficie nc y 
res ults i n classical h o m oc ystei n uria 9 9.  M S, T S, a n d C B S eac h h a ve p ol y m or p hic varia nts 
ca pa ble of i m pacti n g le v els of f olate a n d/ or h o m oc ystei n e. Alterati o ns i n t he f u ncti o n of 
f olate pat h wa y e nz y mes ma y i m pact c he m ot hera p y-relate d t o xic effects. 
 
O ne rece nt st u d y teste d t he h y p ot h esis t hat t hese p ol y m or p his ms ma y partiall y e x plai n t he 
i n di vi d ual variati o n i n c hil dre n de vel o pi n g atte nti o n deficits after treat me nt f or A L L1 0 0.  
F ort y-ei g ht s ur vi v ors of A L L were e val u ate d f or atte nti o n deficits a n d peri p heral bl o o d 
D N A was c ollecte d a n d ge n ot y p e d f or M T H F R p ol y m or p his ms.  Patie nts wit h t he C 6 7 7 T 
an d A 1 2 9 8 C ge n ot y pes were m or e li kel y t o ha ve atte nti o n deficits ( P = 0. 0 7). W hile t his 
st u d y di d pr o vi de str o n g preli mi nar y e vi de nce t hat M T H F R p ol y m or p his ms ma y pla y a n 
i nfl ue ntial r ole i n deter mi ni n g w hic h patie nts will de vel o p atte nti o n deficits after t hera p y 
f or A L L, t he s a m ple size was s mall a n d i nf or mati o n o n c u m ulati ve met h otre x ate e x p os ure 
a n d ster oi d d ose w as n ot a vaila ble.  T hes e res ults still nee d t o be re plicate d i n a lar ger 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c o h ort, w hic h w o ul d als o per mit t he i ncl usi o n of pr os pecti ve ne ur oi ma gi n g. 
 
2. 4. 3  Ima gi n g c ha n ges ass ociat e d wit h ne ur oc o g niti ve perf or ma n ce 
 
E val uati o n of ne ur o ps yc h ol o gical f u n cti o n of l o n g-ter m s ur vi v ors fr o m T O T XIII A 
s h o we d t hat 4 1 % ( 1 8/ 4 4) of t he patie nts treat e d wit h o ut cra nial irra di ati o n ha d F ull- Scale 
I Q sc ores at least 1 sta n d ar d de viati o n bel o w n or mal b ut o nl y 1 0 % ( 4/ 4 4) ha d s ufficie nt 
aca d e mic a n d atte nti o n d eficits t o q ualif y f or a n i nter ve nti o nal feasi bilit y st u d y 
( M E M FI X). Ni netee n of t he 4 4 patie nts ha d M RI e x a mi nati o ns s uita ble f or se g me nt ati o n 
a nal ysis a n d t hree of t hes e l o n g-t er m s ur vi v ors ( 1 6 %) ha d le u k oe nce p h al o p at h y o n t he 
e x a mi nati o ns. A direct relati o ns hi p bet wee n n or m al a p peari n g w hite matter v ol u me a n d 
ne ur oc o g niti ve perf or ma nce ( F ull- Scale I Q [r = 0. 3 3, p = 0. 1 6 5] a n d C P T Hits Reacti o n 
Ti me [r = 0. 4 4, p = 0. 0 5 9]) was als o de m o nstrate d i n t his pil ot st u d y. 
 
T o e x pa n d o n t hese fi n di n gs, w e rece ntl y e x a mi ne d 1 1 2 A L L s ur vi v ors treate d wit h eit her 
c he m ot hera p y al o ne ( n = 8 4) or i n c o m bi nati o n wit h irra diati o n ( n = 2 8) 1 0 1.  A gr o u p of 3 3 
he alt h y si bli n g c o ntr ols 6 t o 1 6 years ol d was als o recr uite d a n d i ma ge d. Perf or ma nce o n 
m ost  ne ur oc o g niti ve meas ures i n A L L s ur vi v ors d e m o nstrate d si g nifica nt d eficits fr o m 
n or mati ve test sc ores, b ut o nl y perf or ma nce o n t he atte nti o n meas ures e x cee de d o ne 
sta n dar d de viati o n fr o m t he n or mati ve mea n.  Perf or ma nce o n meas ures of aca d e mic 
ac hie ve m e nt differe d bet wee n t he t w o patie nt gr o u ps, a n d deficits e x cee di n g o ne st a n dar d 
de viati o n fr o m t he n or mati ve mea n were see n o nl y i n patie nts w h o recei ve d irra diati o n.  
Patie nts treate d wit h c he m ot hera p y al o ne ha d si g nifica ntl y s maller v ol u mes of w hite 
matter t ha n a ge- a n d se x- matc he d healt h y si bli n g c o ntr ols ( P = 0. 0 3), a n d p atie nts w h o 
recei v e d c he m ot hera p y a n d irra diati o n ha d e v e n s maller w hite matter v ol u mes t ha n t h ose 
treate d wit h c h e m ot hera p y al o n e ( P = 0. 0 2).  M ore o ver, s maller w hite matter v ol u mes 
corres p o n d e d t o lar ger deficits i n atte nti o n, i ntelli ge nce, a n d aca de mic ac hie ve me nt. 
 
In T O T X V, w e pr os pecti vel y teste d t h e ass ociati o n of w hite matter a b n or malit y wit h 
ne ur oc o g niti ve perf or ma nce.  We a nal yze d t he ass ociati o n bet wee n t he q ua ntitati ve 
mea s ures of n or mal a p peari n g w hite matter v ol u m e, T 1 a n d T 2 of w hite matter, o n wee k 
1 2 0 c o nti n uati o n treat me nt a n d t he ne ur oc o g niti ve perf or ma n ce of t he first 2 2 9 patie nts at 
t his sa me ti me p oi nt.  O nl y 1 4 0 s u bjects ha d n e ur oc o g niti ve testi n g a n d c orres p o n di n g 
ne ur oi ma gi n g p erf or me d. L o w er v ol u mes of n or mal a p peari n g w hite matter were 
si g nifica ntl y ass o ciate d wit h l o wer perf or ma nce i n mat h a n d s pelli n g i n l o w-ris k patie nts.  
A s u bsta ntial ass ociati o n als o e xiste d bet wee n n or mal a p peari n g w hite m atter v ol u me a n d 
rea di n g i n t hese sa m e patie nts.  Ele vate d T 1 rela xati o n rates i n t he sta n dar d/ hi g h ris k 
pa tie nts were ass ociate d wit h l o wer f ull-scal e, ver bal a n d perf or ma nce I Q as well as l o wer 
perf or ma n ce i n r ea di n g a n d s pelli n g.  Ele vat e d T 2 rela xati o n rates i n t he sta n dar d/ hi g h ris k 
patie nts were als o ass oci ate d wit h l o wer f ull-s cale, ver bal a n d perf or ma nce I Q as well as 
l o wer perf or ma n ce i n l o n g ter m me m or y. 
 
Differe nces i n n e ur oc o g niti ve perf or ma n ce bet w ee n ris k ar ms f or t hes e patie nts ca n best 
be a p preciate d b y e x a mi ni n g t he pr o p orti o n of s u bjects at least o ne sta n dar d de viati o n 
bel o w t he n or mati ve mea n o n eac h meas ure.  L o w-ris k s u bjects perf or me d relati vel y well 
o n i ntellect ual meas ures of f ull-scale, perf or ma nce, a n d ver bal I Q ( 1 7 %, 2 0 %, a n d 1 1 % 
m ore t ha n o ne sta n d ar d de viati o n bel o w t he n or mati ve mea n) w hile greater pr o p orti o ns of 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
sta n dar d/ hi g h-ris k s u bjects were m ore t h a n o ne sta n dar d de viati o n bel o w t h e n or mati ve 
mea n ( 3 2 %, 3 0 %, a n d 2 6 %). T his sa me patter n ca n be see n i n aca de mic p erf or ma nce 
mea s ures of m at h, rea di n g, a n d s p elli n g ( 5 %, 2 %, a n d 5 % f or l o w-ris k; a n d 2 6 %, 2 3 %, 
a n d 2 6 % f or sta n d ar d/ hi g h-ris k). 
 
B ase d o n t h ese ass o ciati o ns bet wee n w hite matter v ol u me a n d rela xati o n c h a n ges i n t hese 
patie nts a n d t he ass ociati o n of t hese c h a n ges wit h deficits i n ne ur oc o g niti ve perf or ma n ce, 
we pr o p ose t o c o nti n ue pr os pecti ve q ua ntitati ve i ma gi n g of t he d e vel o p me nt of patie nts 
treate d o n T O T X VI. T o refi ne o ur u n d ersta n di n g of t he i m pact of t hera p y o n t he 
de vel o pi n g brai n a n d t he mec ha nis ms t hat ma y be res p o nsi ble, we h a ve pr o p ose d t o 
i n vesti gate t he i nte grit y of t he w hite matter m yeli n usi n g D TI a n d de v el o p me ntal c ha n ges 
i n c ortical t hic k ness usi n g hi g h-res ol uti o n m ultis pectral i ma gi n g. T his will be t he first 
o p p ort u nit y t o directl y c o m pare ne ur oi ma gi n g of patie nts d uri n g tr eat me nt f or A L L wit h 
t h ose of healt h y c hil dre n matc he d o n selecte d c h aracteristics. T he n e ur o ps yc h ol o gic al 
batter y has als o be e n refi ne d t o be ma xi mall y s e nsiti ve t o t h ose brai n re gi o ns i de ntifie d as 
m ost  v ul nera ble i n rece nt ne ur oi ma gi n g st u dies. 
 
We ha ve rece ntl y i m ple me nte d a pr ot ot y pical N- bac k w or ki n g me m or y t as k f or f M RI, a n d 
ha ve pil ot st u dies wit h t he tas k u n der wa y i n 4 8 l o n g-ter m s ur vi v ors of A L L ( > 1 0 years 
p ost-t hera p y) a n d 2 5 a ge-si milar healt h y c o ntr ols.  Preli mi nar y ra n d o m effects gr o u p 
anal ysis h as de m o nstrate d acti vati o n i n t he t y pical net w or k of brai n re gi o ns t hat ha ve bee n 
re p orte d i n f M RI st u dies of t he N- Bac k tas k1 0 2 i ncl u di n g a nteri or ci n g ulate/ me dial fr o ntal, 
d ors olateral pr efr o nt al, ve ntr olateral prefr o ntal, fr o ntal p olar a n d parietal areas. A cti vati o n 
i n ri g ht d ors olateral prefr o ntal a n d ri g ht p arietal i n creas e d wit h i ncreasi n g w or ki n g 
me m or y l oa d, a n d bilateral acti vati o n i n ve ntr olateral prefr o ntal areas w as d etecte d o nl y i n 
t he 2- bac k c o n diti o n. I n t he A L L s ur vi v or gr o u p, we ha ve als o ac q uir e d resti n g state 
f M RI d ata wit h ac q uisiti o n para meters as re p orte d b y S or g et al1 0 3.  I n de p e n de nt 
co m p o ne nt a nal ysis (I C A) of t he resti n g state d ata re veal e d ne ural net w or ks wit h 
te m p orall y c orrelate d resti n g B O L D si g nal fl uct uati o ns, i ncl u di n g t he fr o nt al- pariet al a n d 
ve ntral fr o ntal n et w or ks i de ntifie d wit h t he ge neral li near m o del a nal ysis of data fr o m t he 
N- bac k tas k. I C A a nal ysis of t he resti n g state a n d N- bac k d ata als o r e veal e d ot her 
ne t w or ks t hat ma y be i nf or mati ve a b o ut t he ne ural c orrelat es of c o g niti ve deficits i n A L L 
s ur vi v ors, i ncl u di n g t he pri mar y se ns or y c ortices a n d t he defa ult m o de net w or k 1 0 3.  T he 
f M RI p ara di g m bas e d o n t he N- bac k t est of w or ki n g me m or y was desi g ne d a n d t he 
pr oce d ures were o pti mize d s pecificall y t o a d dress k n o w n ne ur oc o g niti ve deficits i n t he 
hi g hl y v ul nera bl e y o u n g p o p ulati o n of c hil d h o o d ca ncer s ur vi v ors.  F u ncti o nal M RI is a n 
i m p orta nt c o m ple me nt t o t he str uct ural i ma gi n g meas ures we pr o p os e t hat will hel p t o 
c haracteriz e t he f u n cti o nal c o nse q ue n ces of t hera p y-i n d uce d c h a n ges i n t h e gra y matter 
a n d w hite matter t hat c o nstit ute t he ne ural net w or ks i n t he brai n. 
 
2. 5  
P hila del p hia C hr o m os o me ( P h)- P ositi ve A L L 
 
P atie nts wit h P h + A L L, a gr o u p w hic h c o nstit utes less t ha n 5 % of c hil d h o o d A L L, h a ve a 
dis mal pr o g n osis w he n tr eate d wit h c h e m ot hera p y al o ne 2 4.  T he t( 9; 2 2) tra nsl ocati o n 
j u xta p oses t he brea k p oi nt cl uster re gi o n ( B C R) ge ne wit h t he A bels o n le u k e mia vir us 
pr ot o- o nc o ge n e ( A B L).  T he res ulta nt f usi o n pr ot ei n is a c o nstit uti vel y acti ve t yr osi n e 
ki nase t hat acti vates m ol ec ular casca des le a di n g t o cell pr oliferati o n, e n ha nce d cell 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
s ur vival, a n d alterati o ns i n cell a d hesi o n. T he t yr osi ne ki nase acti vit y of B C R- A B L is 
req uire d f or tra nsf or mati o n i n vitr o a n d i n m uri ne m o dels. I mati ni b was t he first t yr osi ne 
ki nase i n hi bit or de vel o pe d f or treat me nt of P h + le u ke mia 1 0 4- 1 0 8.   
 
B et wee n J u ne 2 0 0 0 a n d J u ne 2 0 0 4, fi ve patie nts wit h P h + A L L were e nr oll e d o n T O T X V.  
O ne patie nt was refract or y t o treat me nt a n d 2 s ustai ne d a he m at ol o gic rela pse. W he n 
i mati ni b beca me c o m merciall y a vaila ble, T O T X V was c o nse q u e ntl y a me n de d t o 
i nc or p orate i mati ni b i n t he treat me nt r e gi me n of P h + A L L patie nts.  All 4 P h + A L L 
pa tie nts e nr olle d aft er t he a me n d me nt re mai n i n c o nti n u o us c o m plete re missi o n. I mati ni b 
was well t olerat e d w he n i nc or p orat e d i nt o T O T X V bac k b o ne, wit h n o si g nifica nt a d de d 
t o xicit y, ma ki n g t he ris k- be nefit of i nc or p orati n g a t yr osi n e ki nase i n hi bit or i nt o t he 
t hera p y of t his hi g h ris k gr o u p w ort h w hile. 
 
T he rece ntl y a p pr o ve d dasati ni b is a p ote nt, br oa d s pectr u m A T P-c o m petiti ve i n hi bit or of 
se veral t yr osi ne ki n ases i ncl u di n g B C R- A B L a n d S R C. Dasati ni b is ~ 5 0 0-f ol d m ore 
p ote nt t ha n i mati ni b i n i n hi biti n g B C R- A B L a n d bi n ds t o b ot h acti ve a n d i nacti ve 
c o nf or mati o ns of c- A B L, w hereas i mati ni b o nl y bi n ds t o t he i nacti ve state. Dasati ni b 
de m o nstrate d si g nifica nt acti vit y a gai nst se veral a d va nce d h u ma n c hr o nic m yel oi d 
le u ke mia ( C M L) xe n o grafts, i ncl u di n g a n i mati ni b ac q uire d-resista nce m o d el c o m pletel y 
i nse nsiti ve t o i mati ni b1 0 9; 1 1 0.  F urt her m ore, earl y cli nical st u dies of dasati ni b ha ve 
de m o nstrate d its hi g h acti vit y a n d li mite d t o xicit y i n treati n g p atie nts wit h P h + le u ke mias, 
i ncl u di n g patie nts wit h refract or y P h + A L L2 5 -2 7.  He mat ol o gi c t o xicities a n d ple ural 
eff usi o ns are t he m ost c o m m o n a d verse e v e nts ass ociate d wit h dasati ni b. A d verse e v e nts 
are ma n a gea bl e wit h s u p p orti ve care a n d d ose re d ucti o n. A d ult patie nts wit h P h + le u ke mia 
treate d wit h das ati ni b at 1 0 0 m g o nce dail y ha d l o wer i nci de nce of a d verse e ve nts 
c o m pare d t o t h ose tr eate d wit h 5 0 m g t wice d ail y, 1 4 0 m g o nce dail y, or 7 0 m g t wice 
dail y.  M ost i m p orta ntl y, effic ac y was si milar wit h all d ose sc he d ules 1 1 1.  M. D. A n ders o n 
Ca ncer Ce nter i n vesti gat ors ha ve i nc or p orate d d asati ni b i nt o fr o ntli ne P h + A L L re gi me ns, 
a n d t he C O G is i nc or p orati n g it i nt o t heir fr o ntli ne P h + A L L pr ot oc ol. T h e c urre nt 
sta n dar d a d ult d ose is 7 0 m g gi ve n t wice dail y2 5.  I n t he o n g oi n g C O G P has e I trial, a 
starti n g d ose of 5 0 m g/ m2 t wice dail y was well t olerate d i n c hil dre n wit h s oli d t u m ors. 
 
In T O T X VI, we will b uil d o n t he e x perie nce of T O T X V w hic h safel y i nc or p orate d 
i mati ni b i nt o a n i nte nsi ve c he m ot hera p y b ac k b o n e f or patie nts wit h P h+ A L L. Dasati ni b 
wi ll be s u bstit ute d f or i mati ni b i n t he c he m ot hera p y bac k b o ne, starti n g at da y 2 2 of 
i n d ucti o n u ntil t he e n d of t hera p y. We will use t he e q ui vale nt of t he sta n d ar d a d ult d osa ge 
of 7 0 m g b.i. d., w hic h is 4 0 m g/ m 2 b.i. d. (see secti o n 8. 3 f or d ose m o dificati o n). F or 
pa tie nts w h o u n der g o he mat o p oietic ste m cell tra ns pla ntati o n, dasati ni b will be hel d 
d uri n g t he tra ns pla nt peri o d, a n d t he n res u me d aft er rec o ver y of marr o w f u ncti o n u ntil 1 
year p ost tra ns pla nt d ate or c o m pleti o n of 6 m o nt hs dasati ni b t hera p y p ost-tra ns pla nt, 
w hic he ver pr o vi des l o n ger e x p os ure t o dasati ni b p ost-tra ns pla nt. T he reas o n f or starti n g 
dasati ni b o n da y 2 2 of i n d ucti o n is t hat dasati ni b is b ot h a n i n hi bit or a n d s u bstrate f or 
c yt o c hr o me P 4 5 0 3 A 4. T heref ore, it is best t o a v oi d t he use of t his a ge nt d uri n g pr ol o n ge d 
treat me nt wit h pre d nis o n e a n d vi ncristi ne i n t he first t hree wee ks of i n d ucti o n. Als o, t his 
will still all o w us t o assess earl y res p o ns e t o c he m ot hera p y, w hic h is a n i m p orta nt fact or i n 
deter mi ni n g w h et her tr a ns pla nt is i n dicate d or n ot f or certai n P h + A L L. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2. 6   
I nfa nt A L L 
 
I nfa nt A L L c o nstit utes a b o ut 4 % of c hil d h o o d A L L, a n d is ass ociate d wit h a hi g h W B C at 
prese ntati o n, a hi g h fre q u e nc y of a n i m mat ure prec urs or B-li nea ge c haracterize d b y t he 
lac k of C D 1 0 e x pressi o n a n d t he pres e nce of M L L ge n e ( 1 1 q 2 3) rearra n ge m e nts. W hereas 
t he o utc o me of i nfa nts wit h a M L L ger mli ne A L L (i ncl u de 1 5- 2 0 % of i nfa nt A L L) is 
c o m para ble t o t hat of ol der c hil dre n wit h A L L, i nf a nts wit h M L L rearra n ge d A L L h a ve a 
dis mal pr o g n osis, es peciall y t h ose wit h a ge < 6 m o nt hs or W B C > 3 0 0 at dia g n osis 1 6; 1 7. 
 
I nfa nts wit h A L L w ere i n cl u de d i n T O T XII a n d T O T XIII. I n 1 9 9 9, a lar ge i nter nati o nal 
c olla b orati ve st u d y gr o u p de vel o pe d a c o m m o n treat me nt pr ot oc ol (I nterfa nt- 9 9) f or i nfa nt 
A L L t o tr y t o i m pr o ve t h e o utc o me f or t h ese ver y y o u n g c hil dre n.  St J u de j oi ne d t hat 
g r o u p, a n d i nfa nts w ere e nr olle d o n I nterfa nt- 9 9 w hile T O T X V e x cl u de d c hil dre n y o u n ger 
t ha n 1 year of a ge. 
 
Beca use t he res ults of I nt erfa nt- 9 9 pr ot oc ol were n ot s u peri or t o t hat of T O T XIII B, i nfa nts 
will  be e nr olle d i n T O T X VI. T h ose wit h o ut ger mli ne M L L ( 1 5 t o 2 0 % of i nfa nt A L L) will 
recei v e t he sa me ris k- dir ecte d treat me nt pla n as ol der c hil dre n.  T h e re mai ni n g 8 0 t o 8 5 % 
of i nf a nts wit h M L L rearra n ge me nt nee d i n n o vati ve t hera p y t o i m pr o ve t h eir dis mal 
o utc o me.  All i nfa nts wit h rearra n ge d M L L will be treate d o n t he sta n d ar d-/ hi g h-ris k ar m 
of T O T X VI. Cl of ara bi n e is a rece ntl y a p pr o ve d n o vel n ucle osi de a n al o g w hic h has s h o w n 
si gnifica nt acti vit y i n c hil dre n wit h A L L w h ose disease was refract or y t o sta n dar d 
a ge nts 1 7; 1 1 2; 1 1 3.  W he n gi ve n i n c o m bi nati o n wit h c ycl o p h os p ha mi de a n d et o p osi de, 
cl ofara bi ne i n d uce d re missi o ns i n o ver 2/ 3 of rela pse d a n d refract or y c hil dre n wit h 
A L L 1 1 4.  T his c o m bi nati o n will t heref ore b e gi ve n t o i nfa nts wit h M L L rearra n ge me nt o n 
da y 2 2 of re missi o n i n d ucti o n (re placi n g t h e c ycl o p h os p ha mi de, c yt ara bi ne, t hi o g ua ni ne). 
It will als o be a d mi nistere d i n c o m bi nati o n wit h de x a met has o ne a n d P E G- as para gi n ase o n 
wee ks 7 t o 9 of c o nti n uati o n re placi n g rei n d ucti o n I. 
 
2. 7  
Bac k gr o u n d a n d R ati o nale f or I ntesti nal Micr o bi o me O bjecti ves 
 
In crease d s usc e pti bilit y t o a n u m ber of pat h o ge ns i n c hil dre n wit h A L L ca n res ult i n 
si g nifica nt m or bi dit y a n d treat me nt dela ys, t h us c o m pr o misi n g o utc o me 1 1 5; 1 1 6.  Ac ute 
g astr o e nteritis is o ne of t he m ost c o m m o n diseases affec ts, partic ularl y i n c hil dre n.  Si nce 
t he N or wal k vir us was i de ntifie d as a ca use ti n g c hil dre n w orl d wi de.  Vir uses are 
rec o g niz e d as a m aj or ca use of t he gastr o e nteritis, t he n u m ber of viral a ge nts ass ociate d 
wit h diarr heal disease i n h u ma ns has pr o gressi vel y i ncreas e d.  U ntil t he rel ease of a 
vacci ne, r ota vir us was t h e m ost c o m m o n ca use of se vere di arr h ea i n c hil dre n u n der 5 years 
of a ge.  H u ma n astr o vir uses, calici vir uses a n d e nt eric a d e n o vir us are als o i m p orta nt 
eti ol o gic a ge nts of ac ute gastr o e nteritis. Ot her vir uses s uc h as t or o vir uses, c or o na vir uses, 
pic o bir na vir uses, Aic hi vir us a n d h u ma n b oca vir us are als o i ncreasi n gl y bei n g i de ntifie d 
as ca usati ve a ge nts of diarr hea.  Little is k n o w n a b o ut t he pre vale nce of e nt eric vir uses i n 
i mm u n oc o m pr o mise d c hil dre n.  Se veral st u dies fr o m t he 1 9 8 0’s ha ve s h o w n t hat c hil dre n 
wit h HI V or T- cell defici e ncies ca n de vel o p c hr o nic i nfecti o ns wit h se veral e nteric vir uses 
leadi n g t o p ersiste nt diarr hea, w hic h ca n ca use c o nsi dera ble pr o ble ms of m a na ge me nt.  B y 
e val uati n g t he p o p ulati o n d y na mics of t hese e nteric vir uses pri or t o a n d after 
che m ot hera p y, w e  will o btai n a greater u n dersta n di n g of  t he pre vale nce of t hese vir uses i n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t his patie nt p o p ulati o n wit h t he e ve nt ual g oal of i m pr o ve d dia g n ostics a n d pre dicti o ns of 
cli nical c o m plicati o ns. 
 
W e will st u d y t he i m pa ct of A L L t hera p y o n t he i ntesti nal micr o bi o me, a n d t he 
relati o ns hi p bet wee n t h e i ntesti nal micr o bi o me a n d t he i ncreas e d s usce pti bilit y of c hil dre n 
wit h A L L t o i nfecti o ns, i ncl u di n g gaster oe nteritis. T he i ntesti nal micr o bi o me c o nsists of 
all t he i ntesti nal micr o- or ga nis ms a n d t heir ass ociate d ge netic ele m e nts. Se veral li nes of 
e vi de nce s u g gest t hat t he i nteracti o ns bet wee n t he h ost's e nteric micr o bi ota a n d t h e i n nate 
i m m u ne s yste m are i m p orta nt i n m o d ulati n g t he i ntesti nal res p o nse t o ca n cer t hera p y1 1 7.  
Alterati o ns i n t he h ost micr o bi ota ca n tra nslate i nt o alterati o ns i n t he s usce pti bilit y of t he 
h os t t o i nfecti o n1 1 8.  Cl ostri di u m difficile is a co m m o n ca use of a nti bi otic-ass ociate d 
diarr hea i n t his patie nt p o p ulati o n.  As pert ur bati o ns of t he n or mal g ut micr ofl ora are 
t h o u ght t o pre dis p ose patie nts t o i nfecti o ns ca use d b y C. difficile , t hese i n vesti gati o ns will 
als o a d dress w h at alterati o ns i n t he micr ofl ora c orrelate wit h t he pre d o mi na nce of C. 
difficile i n t he gastr oi ntesti nal tract.  T he g ut micr o bi ota pla ys a cr ucial r ole i n t he 
de vel o p me nt of a n effecti ve i m m u ne res p o nse. 
 
Alter ati o ns i n t he g ut micr o bi ota ca n ha v e pr of o u n d c o nse q ue nces n ot o nl y f or i ntesti nal 
diseases b ut als o f or m o u nti n g a n effecti ve i m m u ne res p o nse a gai nst i n va di n g pat h o ge ns 
at vari o us sites i n t he h u ma n b o d y 1 1 9.  Rece nt st u dies ha ve s h o w n t hat cert ai n bacteri al 
s pecies i n t he g ut ca n b e utilize d t o esti mate t he ris k of a nti bi otic-ass ociate d diarr hea wit h 
a n err or rat e of 2 %, e m p hasizi n g t he rele va nt a p plicati o n of t hese data f or i m pr o ve d 
pre dicti o n of cli nical o ut c o mes 1 2 0.  I n s u m mar y, e xisti n g literat ure s u g gests t hat t he h u ma n 
mi cr o bi o me pla ys a vari et y of i m p orta nt r oles i n i m m u n ol o g y a n d i nfecti o us diseases. 
Alterati o ns i n t he h ost micr o bi ota ca n h a ve pr of o u n d effects o n t he t y p e a n d ma g nit u de of 
t he i m m u ne res p o nse a gai nst i n va di n g pat h o ge ns a n d t h us o n t he i nfecti o us c o m plicati o ns. 
W e w o ul d li ke t o i n vesti gat e t he effect of t he c h e m ot hera pe utic re gi me ns f or pe diatric 
A L L o n t h e g ut micr o bi o me, a n d w het her alterati o ns of t heir micr o bi o me ha ve s u bse q ue nt 
effects o n i nfecti o n-relat e d cli nical o utc o mes. 
 
2. 8  
I n cl usi o n of W o me n a n d Mi n orities 
 
Ac c or di n g t o i nstit uti o n al a n d NI H p olic y, t he st u d y will accessi o n res earc h partici pa nts 
re gar dl ess of ge n d er a n d et h nic bac k gr o u n d.  I nstit uti o nal e x perie nce c o nfir ms br oa d 
re pres e ntati o n i n t his re gar d. 
 
3. 0  
E LI GI BI LI T Y C RI T E RI A A N D S T U D Y E N R O L L M E N T  
 
3. 1  
I n cl usi o n Criteria 
 
3. 1 . 1 Di a g n osis of prec urs or B-cell or prec urs or T-cell A L L 
b y  i m m u n o p he n ot y pi n g. 
 
3. 1. 2  A ge < 1 8  years (i ncl usi ve). 
 
3. 1. 3  Li mite d pri or t hera p y, i ncl u di n g s yste mic gl uc oc ortic oi ds f or o ne wee k 
or  less, o ne d ose of vi ncristi ne, e mer ge nc y ra diati o n t hera p y t o t he 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
me diasti n u m a n d o ne d ose of i ntrat hecal c he m ot hera p y. Ot her 
circ u msta nces m ust be cleare d b y  PI  or c o- PI. 
 
3. 1. 5 
Writte n, i nf or me d c o nse nt a n d asse nt f oll o wi n g I nstit uti o nal 
R e vie w B oar d, N CI, F D A, a n d O H R P G ui deli nes. 
 
3. 2  
E x cl usi o n Criteria 
 
3. 2. 1  P artici pa nts wit h pri or t hera p y, ot her t ha n t hera p y s pecifie d i n 3. 1. 3. 
 
3. 2. 2  P artici pa nts w h o are pre g na nt or lactati n g. 
 
3. 2. 3  In a bilit y or u n willi n g ness of researc h partici pa nt or le gal 
g uar dia n/re prese ntati ve t o gi ve writte n i nf or me d c o nse nt. 
 
3. 3  
Researc h Partici pa nt Recr uit me nt a n d Scree ni n g  
 
R esearc h partici pa nts will be recr uite d b y  st u d y i n vesti gat ors t hr o u g h re g ular 
cli nical practice. 
 
3. 4  
E nr oll me nt O n  St u d y 
 
A me m ber of t he st u d y tea m will c o nfir m p ote ntial partici pa nt eli gi bilit y as 
de fi ne d i n Secti o n 3. 1 - 3. 2, c o m plete a n d si g n t he ‘ Partici pa nt Eli gi bilit y 
C hec klist’.  T he c o m plete d c hec klist will be fa xe d t o t he Ce ntral Pr ot oc ol a n d 
Da ta M o nit ori n g Office ( C P D M O) at 
; f oll o we d b y  a p h o ne call t o e xt. 
 t o e ns ure t hat t he fa x is recei ve d. Eli gi bilit y will be re vie we d, a n d e ntere d 
i nto t he Patie nt Pr ot oc ol Ma na ger ( P P M) s yste m. A researc h partici pa nt-s pecific 
co nse nt f or m a n d asse nt d oc u me nt, w here a p plica ble, will be ge nerate d. T he 
pr o t oc ol (if a p plica ble), a n d c o nse nt/asse nt d oc u me nt will be deli vere d t o t he 
area desi g nate d o n t he c hec klist. T he e ntire si g ne d i nf or me d c o nse nt/asse nt f or m 
m ust  be fa x e d t o t he C P D M O t o c o m plete t he e nr oll me nt pr ocess. 
 
T he  C P D M O is staffe d 7: 3 0 a m- 5: 0 0 p m C S T, M o n da y t hr o u g h Fri da y. A staff 
me m ber is o n call Sat ur da y, S u n da y, a n d h oli da ys fr om  8: 0 0 a. m. t o 5: 0 0 p. m. 
 
4. 0  
RI S K C L A S SI FI C A TI O N  
 
P atie nts are classifie d i nt o o ne of t hree cate g ories (l o w-, sta n dar d-, or hi g h-ris k) base d 
o n  t he prese nti n g a ge, le u k oc yte c o u nt, prese nce or a bse nce of C N S- 3 stat us or 
testic ular le u ke mia, i m m u n o p he n ot y pe, c yt o ge netics a n d m olec ular ge netics, D N A  
i n de x, a n d earl y res p o ns e t o t hera p y. He nce, defi niti ve ris k assi g n me nt (f or pr o visi o nal 
l o w-ris k or sta n dar d-ris k cases base d o n prese nti n g feat ures) will be ma de after 
co m pleti o n of re missi o n i n d ucti o n t hera p y.  T he criteria a n d t he esti mate d pr o p orti o n  of 
patie nts i n eac h cate g or y ( base d o n data fr o m T O T X V st u d y) are pr o vi d e d bel o w. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
4. 1  
Criteria f or L o w- Ris k A L L (a p pr o xi matel y 4 8 % of patie nts) 
 
 B -cell prec urs or A L L wit h D N A i n de x ≥1. 1 6, T E L- A M L 1 f usi o n, O R  a ge 1 t o 
9. 9 years a n d prese nti n g W B C < 5 0 x 1 0 9 / L. 
 M ust  n ot ha ve: 
o  C N S 3 stat us ( ≥ 5 W B C/ μ L of cere br os pi nal fl ui d wit h 
m or p h ol o g icall y i de ntifia ble blasts or cra nial ner ve pals y). 
o  O ve rt testic ular le u ke mia (e vi de nce d b y  ultras o n o gra m). 
o  A d ve rse ge netic feat ure s: t( 9; 2 2) or B C R- A B L f usi o n; t( 1; 1 9) wit h 
E 2 A- P B X 1 f usi o n; rearra n ge d M L L (as meas ure d b y  FI S H a n d/ or 
P C R) ; or h y p o di pl oi d y ( < 4 4 c hr o m os o mes). 
o  P o or earl y res p o ns e ( ≥1 % l y m p h o blasts o n da y 1 5  of re missi o n i n d ucti o n, 
≥0. 0 1 % l y m p h o blasts b y  i m m u n ol o gic or m olec ular met h o ds o n 
re missi o n date). 
 
4. 2  
Criteria f or Sta n dar d- Ris k A L L (a p pr o xi matel y 4 4 % of patie nts) 
 
 
All cases of T-cell A L L a n d t h ose of B-cell prec urs or A L L t hat d o n ot 
meet t he criteria f or l o w-ris k or hi g h-ris k A L L. 
 
4. 3   
Criteria f or Hi g h- Ris k A L L (a p pr o xi matel y 8 % of patie nts) 
 
 t( 9; 2 2) or B C R- A B L f usi o n. 
 Infa nts wit h t( 4; 1 1) or M L L f usi o n. 
 I n d ucti o n fail ure or > 1 % le u ke mic l y m p h o blasts i n t he b o ne marr o w 
o n  re missi o n date. 
 > 0. 1 % le u ke mic l y m p h o blasts i n t he b o ne marr o w i n wee k 7 of 
c o nti n uati o n treat me nt (i.e. bef ore rei n d ucti o n  I, ~ 1 4 wee ks p ost re missi o n 
i n d ucti o n). 
 Re -e mer ge nce of le u ke mic l y m p h o blasts b y  M R D (at a n y le vel) i n 
patie nts pre vi o usl y M R D ne gati ve. 
 P ersiste ntl y detecta ble M R D at l o wer le vels 
 Ea rl y T-cell prec urs or ( E T P) A L L, defi ne d  b y  l o w e x pressi o n of T-cell 
mar kers t o get her wit h a berra nt e x pressi o n of m yel oi d mar kers (as descri be d 
i n secti o n 2. 1. 1).  T he f oll o wi n g feat ures c haracterize E T P T- A L L: 
 
1)  L e vels of C D 5 e x pressi o n at least 1 0 f ol d l o wer t ha n t hat of n or mal 
pe ri p heral bl o o d T-l y m p h oc ytes. I n t he st u d y t h at i de ntifie d t his s u bset of 
T - A L L, we f o u n d t hat C D 5 e x pressi o n was 1 0  - > 2 0 0-f ol d l o wer t ha n t hat 
of  n or mal l y m p h oc ytes a n d me dia n perce nt le u ke mic cells e x pressi n g 
C D 5 i n t he 1 7 at y pical cases was 4 5 %, i n c o ntrast t o > 9 8 % f or t he 1 2 2 
of  t he t y pical gr o u p. 
2)  A bse nce ( < 1 0 %) of C D 1a a n d C D 8 e x pressi o n. 
3)  E x pressi o n of c yt o plas mic C D 3 t o get her wit h t he e x pressi o n of 1 or 
m ore  mar kers ass ociate d wit h m yel oi d le u ke mia s uc h as H L A- Dr, 
C D 3 4, C D 1 3, C D 3 3 or C D 1 1 b, w hile m yel o per o xi dase is < 3 % b y  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c yt o c he mistr y a n d/ or fl o w c yt o metr y. 
 
5. 0  
T R E A T M E N T P L A N  
 
Tr eat me nt will c o nsist of t hree mai n p hases: Re missi o n I n d ucti o n, C o ns oli dati o n, 
an d C o nti n uati o n. 
 
5. 1   
I ntrat hecal C he m ot hera p y 
 
As a tra u matic l u m bar p u nct ure at dia g n osis ma y res ult i n a p o orer o utc o me a n d 
t he nee d f or e xtra i ntrat hecal t hera p y s u bse q ue ntl y, all dia g n ostic l u m bar 
p u nc t ures will be perf or me d b y e x perie nce d pers o n nel, prefera bl y u n der ge neral 
anest hesia or dee p se dati o n. Tri ple i ntrat hecal c he m ot hera p y ( M H A) will be  
ad mi nistere d i m me diatel y after cere br os pi nal fl ui d is c ollecte d f or dia g n osis, a n d 
t he d osa ge is a ge- de p e n d e nt as f oll o wi n g: 
 
A ge  ( m o nt hs) Met h otre x ate  ( m g) H y dr oc ortis o ne ( m g) C ytara bi ne( m g)  V ol u me ( ml) 
< 1 2  
6  
1 2  
1 8  
6  
1 2 -2 3  
8  
1 6  
2 4  
8  
2 4 -3 5  
1 0  
2 0  
3 0  
1 0  
≥3 6  
1 2  
2 4  
3 6  
1 2  
 
Fre q u e nc y a n d  t otal n u m ber of tri ple i ntrat hecal treat me nts f or Re missi o n 
In d ucti o n is base d o n t he patie nt's ris k of C N S rela pse, as f oll o ws: 
 All patie nts wil l recei ve tri ple i ntrat hecal treat me nt o n da ys 1  a n d 1 5. 
 Patie nts wit h a n y of t he f oll o wi n g feat ures will recei ve a d diti o nal tri ple 
i ntrat hecal treat me nt o n da ys 8 a n d 2 2: 
- 
P hila del p hia c hr o m os o me 
- 
M L L rearra n ge me nt 
- 
H y p o di pl oi d y ( < 4 4) 
- 
W B C > 1 0 0  x 1 0 9/ L at prese ntati o n 
 P atie nts wit h a n y of t he f oll o wi n g feat ures will recei ve a d diti o nal tri ple 
i ntrat hecal treat me nt o n da ys 4, 8, 1 1, a n d 2 2: 
- 
T -cell A L L  
- 
t ( 1; 1 9)/E 2 A- P B X 1  
- 
C N S- 3 stat us (i.e., ≥5 W B C/ µ L of C S F wit h blasts or cra nial 
ne r ve pals y) 
- 
C N S- 2 stat us ( < 5 W B C/ µ L of C S F wit h blasts) 
- 
Tra u matic L P  ( > 1 0 R B C/ µ L of C S F wit h blasts) 
Le uc o v ori n resc ue ( 5 m g/ m2/ d ose, ma x 5 m g) P O will be gi ve n at 2 4 a n d 3 0 h o urs 
after eac h tri ple i ntrat hecal treat me nt d uri n g i n d ucti o n. F oll o w plas ma 
met h otre x ate le vels (starti n g 2 4 h o urs after i ntrat hecal t hera p y a n d u ntil le vel 
be c o mes u n detecta ble) i n patie nts wit h re nal d ysf u ncti o n or e xtra fl ui d i n t hir d 
s pace, a n d resc ue wit h le uc o v ori n acc or di n g t o P har m. D rec o m me n dati o n. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 2   
Re missi o n I n d ucti o n C he m ot hera p y ( 6 t o 7 wee ks) 
 
In d u cti o n treat me nt will be gi n wit h pre d nis o ne, vi ncristi ne, da u n or u bici n, P E G- 
as para gi n ase a n d tri ple i ntrat hecal treat me nt, f oll o we d b y c ycl o p h os p h a mi de pl us c yt ara bi n e 
pl us t hi o g ua ni ne .  De x a met has o ne will be s u bstit ute d f or pre d nis o n e i n patie nts wit h E T P 
i m m u n o p he n ot y pe.  Merca pt o p uri ne will be s u bstit ute d f or t hi o g ua ni n e i n T P M T 
H E T/ deficie nt patie nts.  Da u n or u bici n ma y be d el a ye d i n patie nts wit h fe brile ne utr o pe nia, 
e vi de nce of m uc ositis or i ncreas e d h y per bilir u bi ne mia (i.e., t otal bilir u bi n ≥2. 0 m g/ dl a n d 
direct bilir u bi n > 1. 4 m g/ dl).  Patie nts wit h m uc ositis s h o ul d be e val uate d f or her pes si m ple x 
i nfecti o n a n d treate d wit h ac ycl o vir or fa mcicl o vir if w or k- u p is p ositi ve. 
 
5. 2. 1 
Dr u g d osa ges (s ee secti o n 5. 2. 1. 1 f or d osi n g of i nfa nts a n d Secti o ns 
7. 0 a n d 8. 0 f or d ose m o dificati o n) 
Partici pa nts  
A ge nts  
D osa ges a n d r o utes  
# D ose  Sc he d ules  
All p artici p a nts  
 
Pre d nis o ne § or  
Pre d nis ol o ne §  
 
De x a met has o ne ( f or  
E T P i m m u n o p he n ot y p e 
o nl y)   
4 0 m g/ m 2/ da y P O ( di vi d e d t.i. d.) 
 
 
1 0 m g/ m 2/ da y P O di vi de d t.i. d.) 
4 m g/ m 2/ da y P O ( di vi de d t.i. d) 
2 m g/ m 2/ da y P O( di vi de d t.i. d) 
8 4  
 
 
6 3  
 
9  
 
1 2  
Da ys 1 –  2 8  
 
 
Da ys 1 -2 1  
 
Da ys 2 2 -2 4  
 
Da ys 2 5 -2 8  
 
Vi ncristi ne  
1. 5 m g/ m 2  I V ( ma x 2 m g) 
4  
Da ys 1, 8, 1 5, 2 2  
 
Da u n or u bici n *  
2 5 m g/ m 2   I V 
2  
Da ys 1 a n d 8  
 
P E G -as para gi nase  
3, 0 0 0 u nits/ m 2 I V 
1  
Da y 3  
D a y 1 5 M R D >  1 %  
 
P E G -as para gi nase  
3, 0 0 0 u nits/ m 2 I V 
1  
Da y 1 5  
D a y 1 5 M R D < 5 % (e xcl u di n g M L L + i nf a nts)  
 
C ycl o p h os p ha mi de †  
1 0 0 0 m g/ m 2 I V  
1  
Da y 2 2  
 
C yt ara bi ne  
7 5 m g/ m 2/ d ose I V  
8  
Da ys 2 3 -2 6, 3 0 -3 3  
 
T hi o g ua ni ne  
Merca pt o p uri n e ( T P M T 
H E T/ deficie nt patie nts o nl y)  
6 0 m g/ m 2/ d ose  P O 
1 4  
Da ys 2 2 -3 5  
 
Dasati ni b ( ‡) (P h + 
p artici p a nts o nly ) 
4 0 m g/ m 2 b.i. d  
Dail y  
Starti n g Da y 2 2 of 
i n d ucti o n t o 
c o nti n ue u ntil e n d of 
treat me nt 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
D a y 1 5 M R D >  5 % (e xcl u di n g M L L + i nf a nts)  
 
C ycl o p h os p ha mi de †  
3 0 0 m g/ m 2 I V  
4  
q 1 2 hrs , Da ys 2 2 -2 3  
C yt ara bi ne  
7 5 m g/ m 2/ d ose I V  
8  
Da ys 2 3 -2 6, 3 0 -3 3  
T hi o g ua ni ne  
Merca pt o p uri n e ( T P M T 
H E T/ deficie nt patie nts 
o nl y)  
6 0 m g/ m 2/ d ose  P O 
1 4  
Da ys 2 2 -3 5  
Dasati ni b ‡ (P h + 
p artici p a nts o nly ) 
4 0 m g/ m 2 b.i. d  
Dail y  
Starti n g Da y 2 2  of 
i n d ucti o n a n d 
c o nti n ue u ntil e n d of 
treat me nt 
Partici pa nts  
A ge nts  
D osa ges a n d r o utes  
# D ose  Sc he d ules  
I nf a nts wit h M L L +  
 
Cl ofara bi ne  
4 0 m g/ m 2/ d ose I V 
5  
Da ys 2 2 -2 6  
Et o p osi de  
1 0 0 m g/ m 2/ d ose I V 
5  
Da ys 2 2 -2 6  
C ycl o p h os p ha mi de  
3 0 0 m g/ m 2/ d ose I V 
5  
Da ys  2 2 -2 6  
* First d ose of  d a u n or u bici n m ay be  del aye d u ntil d ay  2 i n p atie nts wit h or  at  hi g h risk of  t u m or lysis sy n dr o me. 
Sec o n d d ose of  d a u n or u bici n c o ul d be  del aye d u p  t o o ne week if cli nic ally i n dic ate d. 
Sec o n d d ose of  P E G - as p ar a gi n ase t o be  give n as  s oo n  as  M R D > = 1 % is c o nfir me d a n d  n o  l ater t h a n d ay 2 1.  
†See 5. 2. 3. 2 f or t he nee d of  b o ne m arr o w ex a m a n d  t he criteri a of  st arti n g cycl o p h os p h a mi de pl us 
t hi o g u a ni ne o n  d ay  2 2.  § Or al pre d nis o ne c a n be  s u bstit ute d wit h met hyl pre d nis ol o ne at  2 0  m g/ m2/ d ay 
I V (t.i. d.) f or p atie nts w h o c a n n ot t oler ate t he or al me dic ati o n. 
D ay 2 2  vi ncristi ne will be  o mitte d f or i nf a nts wit h M L L +  
( ‡)St art d as ati ni b o n  d ay  2 2  f or P h + c ases. See Secti o n 7. 1 2. 
 
5. 2. 1. 1 D ose a dj ust me nt f or i nf a nts  
 
Wit h t he e x ce pti o n of vi ncristi ne, all d osa ges gi ve n t o i nfa nts ( < 1 year) will be base d o n 
b o d y s urface area. F or i nfa nts < 1 m o nt h of a ge, or f or i nfa nts < 3 m o nt hs of a ge b or n 
si g nifica ntl y pre mat urel y, a 5 0 % re d u cti o n i n d osa ges of da u n o m yci n, as p ara gi n ase, 
et o p osi de, met h otre x ate, t hi o p uri nes, c ycl o p h os p ha mi de, cl ofara bi ne, a n d c yt ara bi ne 
s h o ul d be ma de.  T he vi n cristi ne d osa ge f or patie nts < 1 2 m o nt hs of a ge or < 1 0 k g wei g ht 
is 0. 0 5 m g/ k g/ d ose. 
 
5. 2. 2  R e missi o n i n d ucti o n d ose m o dificati o ns 
 
See Secti o n 7. 0 f or treat me nt m o dificati o ns f or vi n cristi ne, da u n or u bici n, a n d P E G-
as para gi n ase a n d s ecti o n 7. 1 0 f or s u bstit uti o n of merca pt o p uri ne a n d m o difi cati o n of 
t hi o p uri ne d osi n g base d o n T P M T stat us.  F oll o wi n g Da y 2 2 treat me nt, c yt ara bi ne a n d 
t hi o g ua ni ne ma y b e hel d if patie nt de vel o ps fe brile ne utr o pe nia or gra d e 3 or 4 m uc ositis.  
If C-reacti ve pr ot ei n is n or mal, fe ver s u bsi des, c ult ures are n ot si g nifica nt a n d m uc ositis 
res ol ves, c ytara bi ne a n d t hi o g ua ni ne m a y be res u me d.  D oses ma y be c o m pletel y o mitte d 
if t he patie nt is be y o n d d a y 3 0 of re missi o n i n d ucti o n (i.e., half or m or e d oses of 
t hi o g ua ni ne ( or merca pt u p uri ne) a n d c yt ara bi n e ha ve bee n gi ve n), all o wi n g earl y b o ne 
marr o w rec o ver y a n d earl y i nitiati o n of c o ns oli dati o n t hera p y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 2 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 2. 3  B o ne marr o w e val uati o ns 
 
Da y 1 5:  A b o ne marr o w as pirate will be d o ne o n da y 1 5 of re missi o n i n d ucti o n t o assess 
a nti-le u ke mic res p o ns e. T he prese n ce of > 1 % of le u ke mic blasts i n t he b o ne marr o w b y 
m or p h ol o gic e x a m or b y M R D st u d y is a n i n dicati o n f or a n a d diti o nal d ose of P E G-
as para gi n ase t o be a d mi nistere d bet wee n da ys 1 5 a n d 2 1 (f or m o dificati o ns d ue t o P E G-
as para gi n ase aller gic reacti o ns, see Secti o n 7. 9). 
 
Da y 2 2:  B o n e marr o w as pirate o n da y 2 2 will be perf or me d i n p atie nts w h o ha d recei ve d 
a n e xtra d ose of P E G- as para gi nas e d ue t o t he pres e nce of 1 % or m ore le u ke mic blasts i n 
t he b o ne marr o w o n da y 1 5.  Patie nts wit h resi d ual le u ke mia i de ntifie d o n da y 2 2 recei ve 
c ycl o p h os p ha mi de, t hi o g ua ni ne, a n d c yt ara bi ne as sc he d ule d if t heir cli nical c o n diti o n 
per mits, re gar dl ess of t heir A N C.  F or ot her patie nts, t he treat me nt ma y be dela ye d f or 3 t o 
7 da ys t o all o w s o me de gree of he mat o p oietic rec o ver y if A P C ( A N C + m o n oc yt e) 
< 3 0 0/ m m 3. 
 
E n d of i n d ucti o n- M R D res p o nse:  A b o ne marr o w as pirate will be perf or m e d o n da y 3 8-
4 2 of re missi o n i n d ucti o n, de pe n di n g o n w he n A N C has rec o v ere d t o > 3 0 0/ m m 3, W B C t o 
> 1, 0 0 0/ m m 3, a n d platelet c o u nt t o > 5 0 x 1 09/ L.  If t he date falls o n a wee k-e n d or h oli da y, 
t he pr oce d ure ma y b e perf or me d o n cl osest w or ki n g da y. M R D le v el will be deter mi ne d i n 
t his b o ne marr o w sa m ple. P o or res p o nse will be defi ne d as M R D le v el > 0. 0 1 % ( o ne or 
m ore l y m p h o blasts a m o n g 1 0 4 b o ne marr o w m o n o n uclear cells) b y eit her i m m u n ol o gic or 
m olec ular assa y. If t he res ult of M R D is p ositi ve, pr o visi o nal l o w-ris k cases will t he n be 
re-cl assifie d as sta n dar d-ris k ( M R D > 0. 0 1 % b ut less t ha n 1 %) or hi g h-ris k ( M R D > 1 %), 
a n d will recei v e s u bse q u e nt 3 d oses of H D M T X at a hi g her d osa ge (i.e., 5 g m/ m 2).  ( T hese 
patie nts w o ul d ha ve recei ve d t he first H D M T X of c o ns oli dati o n t hera p y at 2. 5 g m/ m 2.) 
 
5. 3  
C o ns oli dati o n Treat me nt ( 8 wee ks) 
 
5. 3 . 1 Dr u g d osa ges 
 
A ge nt  
D osa ge a n d  R o ute  
# D oses  Sc he d ule  
Hi g h  D ose  
Met h otre x ate  
( H D M T X) 
2. 5 g m/ m 2 (l o w ris k), or  
tar gete d 6 5 μ M (st d/ hi g h-ris k) 
4  
da ys  1, 1 5, 2 9  a n d 4 3  
Merca pt o p uri ne  
5 0 m g/ m 2/ da y 
5 6  
Da ys  1 t o 5 6  
 
W he n A N C > 3 0 0/ m m
3, > W B C 1, 0 0 0/ m m3, an d platelet c o u nt > 5 0 x 1 0 9/ L, c o ns oli dati o n 
treat me nt will be starte d, c o nsisti n g of hi g h d ose met h otre x ate (e ver y ot h er wee k f or 4 
d oses), dail y merca pt o p uri ne a n d I T c he m ot hera p y o n t he s a me dates of hi g h d ose 
met h otre x ate (see secti o n 5. 3. 4). 
 
See secti o n 5. 3. 5 (I nteri m C o nti n uati o n Treat me nt) a n d secti o n 7. 0 f or d ose a dj ust me nts. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 3. 2  Me rca pt o p uri n e a d mi nistrati o n 
 
Merca pt o p uri n e s h o ul d be gi v e n dail y at a c o nsiste nt ti me t hat ma xi mizes a d here n ce wit h 
t he prescri b e d treat me nt.  If a d ose is i na d v erte ntl y misse d, t he n it s h o ul d be gi ve n as s o o n 
as t he o missi o n is n ote d, as l o n g as it is at least 6 h o urs pri or t o t he ne xt sc he d ule d d ose.  
I n p atie nts f or w h o m hi g h d ose met h otre x ate treat me nt is dela ye d, merca pt o p uri ne ma y be 
c o nti n ue d u ntil 1 4 da ys after t he last c o urse of hi g h d ose met h otre x ate.  Merca pt o p uri ne 
ma y b e hel d i n t he pres e nce of A N C < 3 0 0/ m m 3, W B C < 1, 0 0 0/ m m3, platelet c o u nt 
< 5 0, 0 0 0/ m m 3 or gra d e 3 or 4 m uc ositis.  D osa ge of merca pt o p uri ne i n s u bse q ue nt c o urs es 
ma y b e re d u ce d t o 2 5 m g/ m 2/ da y i n patie nts w h o h a ve pr ol o n ge d n e utr o pe ni a after hi g h 
d ose met h otre x ate a n d m erca pt o p uri ne treat me nt.  See secti o n 7. 1 0 f or m o dificati o ns of 
merca pt o p uri n e base d o n T P M T stat us. 
 
5. 3. 3  Hi g h- d os e met h otre x ate ( H D M T X) a d mi nistrati o n 
 
T he d osa ge of hi g h d os e met h otre x ate de pe n ds o n t he ris k classificati o n of i n di vi d ual 
patie nts. Patie nts wit h sta n dar d- or hi g h-ris k A L L will recei ve 5 g m/ m 2, ( or a d ose 
targete d t o ac hie ve a stea d y-stat e plas ma c o n ce ntr ati o n of 6 5 M) a n d t h ose wit h l o w-ris k 
A L L 2. 5 g m/ m 2, ( or, w he n re q ueste d, a d ose tar get e d t o ac hie ve a stea d y-state 
c o nce ntr ati o n of 3 3 M) a d mi nistere d o ver 2 4 hr i ntra ve n o usl y. T he s u bse q ue nt d ose of 
hi g h d ose met h otr e x ate, merca pt o p uri n e a n d i ntrat hecal treat me nt will be dela ye d if A N C 
< 3 0 0/ m m 3, W B C < 1 0 0 0/ m m3, platelet c o u nt < 5 0 x 1 09/ L, S G P T > 5 0 0 U/ L, t otal bilir u bi n 
> 2 m g/ dl a n d dir ect bilir u bi n > 1. 4 m g/ dl, or m uc ositis is prese nt. S o di u m bicar b o nate m a y 
be gi v e n orall y at 1 g m/ m 2 e ver y 6 h o urs or i ntra ve n o usl y wit h pr e- h y drati o n fl ui d starti n g 
t he da y bef ore hi g h d ose met h otre x ate.  F or patie nts wit h D o w n s y n dr o me, hi g h d ose 
met h otre x ate a d mi nistrati o n will be m o difie d ( See Secti o n 7. 1. 1).  Ba se d o n pri or 
e x perie nce i n T O T X V, we a ntici pate t hat 2. 5 g/ m 2 s h o ul d ac hie ve t he tar get c o nce ntr ati o n 
of 3 3 M + 2 0 % i n 7 0 % of t he L R c o urses (see Secti o n 2. 1. 3 f or details a n d rati o nale).  
Cleara nce is esti mate d fr o m t he plas ma c o nce ntrati o ns u p t hr o u g h 4 8 h o urs fr o m 
met h otre x ate i nf usi o n, usi n g n o nli near c ur ve fitti n g a n d a Ba yesia n esti mati o n strate g y as 
i m ple me nte d i n A D A P T. 1 0 % of t he t otal d ose is a d mi nistere d as a l oa di n g d ose o ver 1 
h o ur a n d t he re mai n der o ver 2 3 h o urs. 
 
D osa ge i n di vi d ualiz ati o n ma y b e cli nicall y i n dicat e d i n select L R patie nts. I n t hese cas es, 
t he precise m et h o d f or tar geti n g will be d o c u me nt e d i n t he researc h d ata base f or eac h d ose 
of hi g h d ose m et h otre x ate gi v e n, al o n g wit h t he reas o n(s) t he d ose was tar gete d. 
 
Base d o n pri or e x perie nce i n T O T X V, we a ntici pate t hat 5 g/ m 2 s h o ul d ac hie ve t he 
tar gete d c o n ce ntr ati o n of 6 5 M + 2 0 % i n o nl y 6 2 % of t he c o urses (see Secti o n 2. 1. 3 f or 
details a n d rati o nale).  Cleara n ce is esti mate d fr o m t he plas ma c o nce ntrati o ns u p t hr o u g h 
4 8 h o urs fr o m met h otre x ate i nf usi o n usi n g n o nli n ear c ur ves fitti n g a n d a Ba yesia n 
esti mati o n strate g y b ase d o n pre dicti ve c h aracteristics (s uc h as ser u m creati ni ne a n d 
S G P T) as i m ple me nte d i n A D A P T. Te n perce nt of t he t otal d ose is a d mi nistere d as a 
l oa di n g d ose o v er 1 h o ur a n d t he re mai n d er o ver 2 3 h o urs. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 3. 3. 1  Pre - hy dr ati o n 
 
At least t w o h o urs bef ore hi g h d ose met h otr e x ate, pre h y drati o n I V fl ui d ( D 5 W + 4 0 m E q 
Na H C O 3/ L + 2 0 m E q K Cl/ L) will be a d mi nistere d at t he rate of 2 0 0 ml/ m2/ hr. At start of 
pre h y drati o n, o ne I V d os e of Na H C O 3 (u nless ot her wise cli nicall y i n dicat e d, 1 2 m E q/ m 2 
f or l o w-ris k patie nts a n d 2 5 m E q/ m2 f or sta n dar d-/ hi g h-ris k p atie nts) dil ute d i n 5 0 ml 
D 5 W will be gi ve n o ver 1 5 mi n utes.  Pre h y drati o n fl ui d ma y als o b e gi ve n o ver ni g ht at a 
rate of at least 1 0 0 ml/ m2/ hr. Hi g h d ose m et h otre x ate treat me nt will f oll o w, pr o vi de d t hat 
uri nar y p H is > 6. 5; e x ce pti o ns m ust be cleare d wit h t he p har mac o ki n etics ser vice a n d t he 
atte n di n g p h ysicia n. 
 
5. 3. 3. 2  Hi g h - d ose met h otrex ate i nf usi o n 
 
Met h otre x ate l oa di n g d os e will be gi v e n o ver 1 h o ur, f oll o we d i m me diatel y b y 
mai nte na nce i nf usi o n o v er 2 3 h o urs.  D uri n g t he met h otre x ate i nf usi o n, patie nts s h o ul d 
recei v e h y drati o n fl ui d wit h D 5 W + 4 0 m E q/ L Na H C O3 + 2 0 m E q K Cl/ L at 1 0 0- 1 5 0 
ml/ m 2/ hr. Uri ne p H will be m o nit ore d wit h eac h v oi d d uri n g i nf usi o n. A n I V b ol us of 1 2 
m E q/ m 2 Na H C O 3 will be gi ve n if uri ne p H is 6. 0; a n d 2 5 m E q/ m 2 will be gi ve n if uri ne 
p H is < 6. 0.  Acet az ola mi de 5 0 0 m g/ m 2 orall y e ver y 6 t o 8 h o urs ma y b e us e d if s yst e mic 
al kal osis li mits t he a d mi nistrati o n of bicar b o nat e f or uri n ar y al kali nizati o n.  Patie nts wit h 
e vi de nce of re n al d ysf u ncti o n or dela ye d cleara nce d uri n g t h e met h otre x ate i nf usi o n ma y 
recei v e less t ha n a 2 4 h o ur met h otre x ate i nf usi o n.  Bl o o d sa m ples f or met h otre x ate 
p ha r mac o ki netics will be dra w n acc or di n g t o Secti o n 1 0. 1. 
 
5. 3. 3. 3  L e uc ov ori n resc u e  
 
Le u c o v ori n, 1 5 m g/ m 2 (I V or P O) f or sta n d ar d-/ hi g h-ris k or 1 0 m g/ m2 ( P O or I V) f or l o w-
ris k cases, will be start e d at 4 2 h o urs after t he start of met h otre x ate a n d re p eate d e ver y 6 
h o urs f or a t otal of t hr ee d oses, as descri be d b y Reiter, et al 3 0.  T he d osa ge of le uc o v ori n 
will  be i ncreas e d i n patie nts wit h hi g h plas ma met h otre x ate c o nce ntr ati o ns ( > 1. 0 M at 4 2 
h o urs) a n d c o nti n ue d u ntil t he met h otre x ate c o nce ntrati o n is less t ha n 0. 1 0 M.  
A d diti o nal meas ures, s uc h as h y drati o n, he m o perf usi o n, or car b o x y p e pti dase will be 
c o nsi dere d i n patie nts wit h 4 2- h o ur met h otre x ate le vels > 1 0 M.  Patie nts wit h a hist or y of 
dela ye d Gra de 3 or 4 gastr oi ntesti nal t o xicit y wit h pri or met h otre x ate or a hist or y of 
t y p hlitis wit h a n y c h e m ot hera p y s h o ul d ha v e le uc o v ori n c o nti n ue f or 5, rat h er t ha n 3 
d oses; t h ose wit h earl y t o xicit y s h o ul d ha ve le uc o v ori n be gi n at 3 6 h o urs wit h s u bse q ue nt 
met h otre x ate; if t o xicit y rec urs, t he b aseli ne le uc o v ori n d osa ge s h o ul d als o be i ncrease d. 
 
5. 3. 4  IT c he m ot hera p y 
 
All patie nts will recei ve tri ple i ntrat hecal t hera p y e ver y ot her wee k f or f o ur d oses o n Da ys 
1, 1 5, 2 9, a n d 4 3 ( d osa ges are bas e d u p o n a ge, acc or di n g t o Secti o n 5. 1).  T he i ntrat hecal 
treat me nt s h o ul d be gi ve n o n t he sa me da y of t h e hi g h d ose met h otr e x ate a d mi nistrati o n.  
C o ns ult t he PI or P har ma c o ki netics if t he I T a n d hi g h d ose met h otr e x ate bec o me se parate d 
b y m ore t h a n 1 2 h o urs. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 3. 5  Interi m c o nti n uati o n treat me nt 
 
I nteri m c o nti n uati o n treat me nt will be gi ve n t o t he occasi o nal patie nts w h o, u p o n attai ni n g 
c o m plete re missi o n, are dee me d u na bl e t o t olerat e hi g h d os e met h otre x ate.  S pecific 
criteria t o use i nteri m c o nti n uati o n t hera p y i n cl u de disse mi nate d f u n gal i nfecti o n re q uiri n g 
s yste mic a ntif u n gal t hera p y, rece nt d e vel o p me nt of cere bral t hr o m b osis, or gra de 3 or 4 
re nal or h e patic d ysf u n cti o n. T here ma y b e ot her u nf oresee n reas o ns t hat w arra nt 
te m p orar y wit h h ol di n g of hi g h d ose m et h otre x ate. 
 
I nteri m treat me nt will c o nsist of oral merca pt o p uri ne 7 5 m g/ m2 per da y ( 5 0 m g/ m 2 per da y 
i n t h ose wit h A N C < 5 0 0) a n d i ntra ve n o us met h otre x ate 4 0 m g/ m2 per wee k; i ntrat hecal 
t hera p y ma y be gi v e n e v er y ot her wee k d uri n g t his peri o d of ti me a n d c o nti n ue d d uri n g 
t he s u bse q ue nt hi g h d os e met h otre x ate treat me nt f or a t otal of 4 d oses. Hi g h d ose 
met h otre x ate will be starte d w he n t he patie nt’s p h ysical c o n diti o n all o ws.  I n t he e ve nt t hat 
t he i nteri m t hera p y is l o n ger t ha n 4 wee ks, a n e xtra i ntrat hecal t hera p y ma y be gi v e n wit h 
t he last c o urse of hi g h d ose met h otre x ate. Patie nts wit h a defecti ve T P M T stat us ma y 
recei v e l o wer d os es of m erca pt o p uri ne. 
 
5. 4  
Rei nte nsificati o n Treat m e nt (f or Hi g h- Ris k A L L) 
 
Patie nts wit h hi g h-ris k le u ke mia ma y recei ve rei nte nsificati o n t hera p y a n d t he n will be 
offere d t he o pti o n of tra ns pla nt. T his treat me nt will atte m pt t o ma xi mize le u ke mic cell kill 
bef ore all o ge neic h e mat o p oietic ste m cell tra ns pla ntati o n ( H S C T).  F or pati e nts wit h 
P hila del p hia c hr o m os o me p ositi ve A L L, E T P T- A L L, a n d t h ose wit h i n d ucti o n fail ure or 
> 1 % le u ke mic l y m p h o bl asts ( deter mi ne d b y M R D st u d y) i n b o ne m arr o w at t he e n d of 
re missi o n i n d ucti o n, treat me nt will be gi ve n after c o ns oli dati o n t hera p y.  H o we ver, 
c o ns oli dati o n t hera p y ma y be s h orte ne d, d e pe n di n g o n patie nt’s res p o nse t o t hera p y a n d 
o n t he ti mi n g of tra ns pla ntati o n. F or patie nts wit h > 0. 1 % le u ke mic l y m p h o blasts 
( deter mi ne d b y M R D st u d y) i n b o n e marr o w i n wee k 7 of c o nti n uati o n tr eat me nt, t his 
treat me nt will be gi ve n after t he rei n d ucti o n I.  U p o n marr o w rec o ver y (i.e., A N C 
3 0 0/ m m 3, W B C 1 0 0 0/ m m 3 a n d platelet c o u nt 5 0 x 1 0 9/ L) after eac h c o urse of 
rei nte nsificati o n, b o ne m arr o w e x a mi nati o n wit h M R D st u d y will be re p eate d. 
 
T his treat me nt c o urse m a y be re peate d o nl y o nce if t he patie nt still has persiste ntl y 
p ositi ve M R D (i.e. > 0. 0 1 % blasts). All o ge neic he mat o p oietic ste m cell tra ns pla nt ati o n 
ma y pr ocee d aft er 1 c o urse of t he treat me nt if M R D bec o mes ne gati ve wit h t he first c o urse 
of treat me nt; ot her wis e, tra ns pla nt will be perf or m e d after t w o c o urses of treat me nt.  
Patie nts dee me d u ns uita ble f or t he tra ns pl a nt or w h o decli ne t he pr o ce d ur e or w h ose d o n or 
has yet t o b e i de ntifie d, will re mai n o n st u d y a n d recei v e s u bse q ue nt c he m ot hera p y as 
sc he d ule d.   
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he treat me nt sc h e me a n d d osa ge of c h e m ot hera p y are s u m marize d bel o w. 
 
A ge nt  
D osa ge a n d  r o ute 
# D oses  
Sc he d ule  
De x a met has o ne  
2 0 m g/ m 2/ da y P O or I V 
( di vi de d t.i. d) 
1 8  
Da ys  1 -6  
C ytara bi ne  
2 gra ms/ m 2, 3 -h o ur  I V 
i nf usi o n e ver y 1 2 h o urs  
4  
Da ys  1 -2  
Et o p osi de  
1 0 0 m g/ m 2, 1 -h o ur  I V 
i nf usi o n e ver y 1 2 h o urs  
5  
Da ys  3 -5  
I T M H A 
See Secti o n  5. 1 f or a ge- 
s pecific d ose  
1  
D a y  5  
P E G -as para gi nase 
3, 0 0 0 u nit s/ m2 I V 
1  
D a y  6  
 
Patie nts wit h s u b o pti mal res p o nse t o rei nte nsificati o n ma y recei ve o ne t o t w o c ycles 
of  cl ofara bi ne/c ycl o p h os p ha mi de/et o p osi de/ de x a met has o ne: 
 
A ge nt  
D osa ge a n d  r o ute 
# D oses  
Sc he d ule  
Cl ofara bi ne  
4 0 m g/ m 2/ da y, 2 -h o ur  I V 
i nf usi o n 
5  
Da ys  1 -5  
Et o p osi de  
1 0 0 m g/ m 2/ da y, 2 -h o ur  I V 
i nf usi o n 
5  
Da ys  1 -5  
C ycl o p h os p ha mi de  
3 0 0 m g/ m 2/ da y, 3 0 -6 0  
mi n ute  I V i nf usi o n 
5  
Da ys  1 -5  
De x a met has o ne  
8 m g/ m 2/ da y ( di vi de d t.i. d) 1 5  
Da ys  1 -5  
 
See Secti o n 5. 2. 1. 1 f or d osi n g f or i nfa nts. 
 
T his cl ofara bi ne/c ycl o p h os p ha mi de/et o p osi de/ de xa met has o ne c ycle ca n s u bstit ute 
f or t he sec o n d rei nte nsificati o n i n patie nts wit h hi g h ris k pr ocee di n g t o tra ns pla nt. 
P atie nts w h o are eli gi ble t o N K H E M c o ul d i nstea d be tra nsferre d t o tra ns pla nt t o 
recei ve N K H E M f oll o we d b y  all o ge neic H S C T.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5   
C o nti n uati o n Treat me nt ( 1 2 0 wee ks) 
 
P ost-re missi o n c o nti n uati o n treat me nt be gi ns after t he c o m pleti o n of 
co ns oli dati o n, pr o vi de d t hat t he A N C  3 0 0/ m m 3, W B C 1 0 0 0/ m m 3 a n d 
pla telet c o u nt 5 0 x 1 0 9/ L as well as n o e vi de nce of gra de 3 or 4 
m uc osit is. C o nti n uati o n treat me nt ( 1 2 0 wee ks) differs acc or di n g t o t he 
ris k classificati o n, as f oll o ws (a b bre viati o ns as defi ne d bel o w). 
 
Wee k  
Sta n dar d -/ Hi g h-Ris k  ( ‡) 
L o w -Ris k  
1  
D E X + D O X + V C R + M P  +  P E G -A S P  
M P +  D E X  +  V C R  
2  
M P  
M P +  M T X  
3  
¥ M P  +  P E G -A S P  
¥ M P +  M T X  
4  
D E X  +  D O X  +  V C R +  M P  
M P +  D E X  +  V C R  
5  
M P +  P E G -A S P  
M P +  M T X  
6  
M P  
M P +  M T X  
7  
* † Rei n d ucti o n I § 
* Rei n d ucti o n  I 
8  
Rei n d ucti o n  I 
Rei n d ucti o n  I 
9  
Rei n d ucti o n  I 
Rei n d ucti o n  I 
1 0  
M P  
M P +  M T X  
1 1  
D O X  +  V C R + M P  +  P E G -A S P  
M P +  M T X  
1 2  
* M P  
* M P +  M T X  
1 3  
M P +  P E G -A S P  
M P +  M T X  
1 4  
D E X  +  D O X  +  V C R + 6 M P  
M P +  D E X  +  V C R  
1 5  
M P +  P E G -A S P  
M P +  M T X  
1 6  
M P  
M P +  M T X  
1 7  
* † Rei n d ucti o n II  
* Rei n d ucti o n  II 
1 8  
Rei n d ucti o n  II 
Rei n d ucti o n  II 
1 9  
Rei n d ucti o n  II 
Rei n d ucti o n  II 
2 0  
N o c he m ot hera p y  
M P +  M T X  
¥Tri ple i ntr at hec al tre at me nt will be give n c ases wit h W B C 1 0 0 x 1 0 9/ L, T-cell A L L, t( 1; 1 9)/ E 2 A-
P B X, prese nce of P hil a del p hi a c hr o m os o me, M L L re arr a n ge me nt, hy p o di pl oi dy < 4 4, or C N S- 3 
st at us, wit h C N S- 2 or tr a u m atic l u m b ar p u nct ure wit h bl asts at di a g n osis.. 
*I T M H A ( met h otrex at e + h y dr oc ortis o ne + cyt ar a bi ne; see secti o n 5. 1 f or d os a ge) 
† M R D st u dy i n b o ne m arr o w f or p atie nts wit h p ositive M R D at e n d of re missi o n i n d ucti o n, a n d f or 
p atie nts wit h aty pic al T-li ne a ge A L L. F or ot her T-li ne a ge p atie nts peri p her al bl o o d c a n be use d 
i nste a d. 
§ P atie nts wit h M R D > 0. 1 % at week 7 receive rei nte nsific ati o n tre at me nt after Rei n d ucti o n I (see 
Secti o n 5. 4) 
See Secti o n 5. 5. 2 f or det ails o n Rei n d ucti o n tre at me nt. 
Dex a met h as o ne, vi ncristi ne a n d P E G- as p ar a gi n ase c a n be give n re g ar dless of bl o o d c o u nts, 
pr ovi de d t h at t he p atie nt is n ot sick.  Met h otrex ate, merc a pt o p uri ne a n d d ox or u bici n will be hel d if 
A N C < 3 0 0/ m m 3, W B C < 1 0 0 0/ m m3, or pl atelet c o u nt < 5 0 x 1 09/ L (see secti o n 8. 0 f or ot her d ose 
m o dific ati o ns). 
( ‡)C o nti n ue d as ati ni b i n P h +  c ases 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 1. 1  Dr u g d os a ges, sc he d ules a n d r o utes f or c o nti n u ati o n t her a py weeks 1 t o 6 
a n d 1 0 t o 1 6  
 
D E X ( de x a met has o ne) 
1 2 m g/ m 2 (st d/ hi g h ris k) or 8 m g/ m2 
(l o w ris k) P O  dail y ( di vi de d t.i. d.) f or 
5 da ys, Da ys 1- 5 
 
D O X ( d ox or u bici n) 
3 0 m g/ m 2 IV, Da y 1 
 
V C R ( vi ncristi n e) 
2 m g/ m 2  I V p us h ( ma x. 2 m g), Da y 1 
( 0. 0 5 m g/ k g f or patie nts < 1  year of a ge 
or  < 1 0 k g i n wei g ht) 
 
M P  ( merca pt o p uri ne) 
5 0 m g/ m 2 P O dail y at c o nsiste nt ti me * 
f or 7 da ys (st d/ hi g h ris k), Da ys 1- 7 
7 5 m g/ m 2 P O dail y at c o nsiste nt ti me * 
f or 7 da ys (l o w ris k), Da ys 1- 7 
 
P E G- A S P ( P E G-as para gi nase) 
2, 5 0 0 vs. 3, 5 0 0 u nits/ m 2 I V 
ran d o mizati o n, 
Da y 1 
 
M T X ( met h otre x ate) 
4 0 m g/ m 2  
I V Da y 1  
 
Se e Secti o n 5. 2. 1. 1 f or d osi n g f or i nf a nts . 
 
De x a met has o ne, vi ncristi ne, a n d as para gi nase will be gi ve n re gar dless of bl o o d 
c o u nts, pr o vi de d t hat t he patie nt is cli nicall y well.  D o x or u bici n, merca pt o p uri ne 
an d met h otre x ate will be hel d if W B C < 1 0 0 0/ m m 3 or  A N C < 3 0 0/ m m 3.  See 
S ecti o n 8. 0 f or f urt her details.  * Merca pt o p uri ne s h o ul d be gi ve n dail y at a 
co nsiste nt ti me t hat ma xi mizes a d here nce wit h t he prescri be d treat me nt.  If a d ose 
is i na d verte ntl y misse d, t he n it s h o ul d be gi ve n as s o o n as t he o missi o n is n ote d, as 
l o n g as it is at least 6 h o urs pri or t o t he ne xt sc he d ule d d ose. 
 
5. 5. 2  
R ei n d ucti o n treat me nt 
 
T his p hase of treat me nt will be starte d at wee ks 7 a n d 1 7 after b o ne marr o w 
e x a mi nati o n c o nfir ms c o m plete re missi o n.  D o x or u bici n a n d H D- c yt ara bi n e will 
be hel d if A N C < 3 0 0/ m m 3 or W B C < 1 0 0 0/ m m 3.  It is prefera ble t o start H D-
c yt ara bi ne w he n W B C > 1 8 0 0/ m m 3 a n d A N C > 3 0 0/ m m 3 
 
Rei n d ucti o n treat me nt will be gi ve n t wice: wee ks 7 t o 9 a n d wee ks 1 7 t o 1 9 f or all 
patie nts. 
 
I ntr at hecal treat me nt will be f oll o we d b y le uc o v ori n resc ue ( 5 m g/ m2/ d ose P O, 
ma x 5 m g) at 2 4 a n d 3 0 h o urs o nl y i n patie nts wit h pri or C N S t o xicities or i n 
patie nts wit h W B C < 1 5 0 0/ m m 3, or A N C < 5 0 0/ m m3 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 2. 1  R ei n d ucti o n I f or sta n dar d/ hi g h-ris k A L L e x cl u di n g M L L + i nfa nts ( ‡) 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O ( di vi de d t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V 
0. 0 5 m g/ k g f or i nf a nts  < 1 yr  or 
< 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
D o x or u bici n  
3 0 m g/ m 2 I V 
2  
Da ys 1, 8  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne + 
Ara -C  
A ge -de p e n de nt, I T 
(secti o n 5. 1) 
1  
Da y 1  
 
5. 5. 2. 2  Rei n d ucti o n II f or sta n dar d/ hi g h-ris k A L L i n cl u di n g M L L + i nfa nts (‡)  
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O (t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V  
0. 0 5 m g/ k g f or i nf a nts < 1 yr or  
< 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
P E G -as para gi nase  
2, 5 0 0 or  3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne +  
Ara -C  
A ge -de p e n de nt, I T  
1  
Da ys 1  
Hi g h -d os e 
c yt ara bi ne  
2 g m/ m 2 I V q 1 2 hr 
4  
Da ys 1 5, 1 6  
( ‡)P h + c ases c o nti n ue d as ati ni b  
 
5. 5. 2. 3  Rei n d ucti o n I f or l o w-ris k A L L 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc h e d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O  
( di vi de d t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V  
0. 0 5 m g/ k g f or < 1 yr or  
< 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
D o x or u bici n  
3 0 m g/ m 2/ I V 
1  
Da y 1  
M et h otre x ate + 
h y dr oc ortis o ne + 
Ara -C  
A ge -de p e n de nt, I T  
1  
Da y 1  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 2. 4  R ei n d ucti o n II f or L o w Ris k A L L 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O 
( di vi de d t.i. d.) 
4 5  
Da ys 1 -8, 1 5 -2 1  
Vi ncristi ne  
1. 5 m g/ m 2/ wee k I V 
0. 0 5 m g/ k g f or < 1 y r 
or < 1 0 k g ( ma x 2 m g)  
3  
Da ys 1, 8, 1 5  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne 
+ Ara -C  
A ge -de p e n de nt, I T  
1  
Da y 1  
 
5. 5. 2. 5 Rei n d ucti o n I f or M L L + i nfa nts 
 
A ge nts  
D osa ges a n d r o utes  
# D oses  Sc he d ules  
De x a met has o ne  
8 m g/ m 2/ da y P O ( di vi de d t.i. d.) 
4 5  
Da ys 1 -8 a n d   
1 5 -2 1  
Cl ofara bi ne  
4 0 m g/ m 2/ da y, 2-h o ur I V  
5  
Da ys 1 -5  
Et o p osi de  
1 0 0 m g/ m 2/ da y, 2-h o ur I V  
5  
Da ys 1 -5  
C ycl o p h os p ha mi de  
3 0 0 m g/ m 2/ da y, 1-h o ur I V  
5  
Da ys 1 -5  
P E G -as para gi nase  
2, 5 0 0 or 3, 5 0 0 u nits/ m 2 I V 
2  
Da ys 1, 1 5  
Met h otre x ate + 
h y dr oc ortis o ne 
+ Ara -C  
A ge -de p e n de nt, I T  
1  
Da ys 1  
F or i nfa nts < 1 m o nt h of a ge, or f or i nfa nts < 3 m o nt hs of a ge b or n si g nifica ntl y 
pre mat urel y, a 5 0 % re d u cti o n i n d osa ges of as para gi n ase, et o p osi de, 
c ycl o p h os p ha mi de, d o x or u bici n, a n d cl of ara bi ne s h o ul d be ma de. 
 
5. 5. 3  Intr at hecal c he m ot hera p y 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o l o w-ris k cases wit h C N S- 1 
stat us ( n o i de ntifia ble blasts i n C S F) o n wee ks 7, 1 2, 1 7, 2 5, 3 3, 4 1, a n d 4 9. 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o l o w-ris k cases wit h C N S- 2, 
tra u matic C S F wit h blasts stat us, or W B C 1 0 0 x 1 0 9/ L at prese nt ati o n o n 
wee ks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o sta n dar d/ hi g h-ris k cases o n 
wee ks 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tr i ple i ntrat hecal treat me nt will be gi ve n t o ot her sta n dar d/ hi g h-ris k cases 
wit h W B C 1 0 0 x 1 0 9/ L at prese ntati o n, , T-cell A L L, t ( 1; 1 9)/ E 2 A- P B X 1, 
prese nce of P hila del p hia c hr o m os o me, M L L  rearra n ge me nt, h y p o di pl oi d y 
< 4 4, C N S- 2 or C N S- 3 stat us, or tra u matic l u m bar p u nct ure wit h blasts o n 
wee ks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5, 4 9, 5 7, 6 5, 7 3, 8 1, 8 9 a n d 9 7 .
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T O T X VI I ntrat he cal t hera p y 
 
I n d u cti o n 
C o ns oli dati o n  
C o nti n uati o n Wee k 1 -2 0  C o nti n uati o n Wee ks 2 1 -9 7  
All P hases  
Ris k -gr o u p  
C N S Stat us  
Da ys  
T otal  
Da ys  
T otal  
Wee ks  
T otal  
Wee ks  
T otal  
T ot al  
L o w -ris k, 
W B C < 1 0 0 x 
1 0 9/ L 
C N S 1  
1, 1 5  
2  
1, 1 5, 2 9, 
4 3  
4  
7, 1 2, 1 7  
3  
2 5, 3 3, 4 1, 4 9  
4  
1 3  
L o w -ris k, 
W B C > 1 0 0 x 
1 0 9/ L 
C N S 1  
1, 8, 1 5, 
2 2  
4  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9  
7  
1 9  
L o w -ris k 
C N S 2 or 
Tra u matic 
Blasts  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9  
7  
2 1  
St d -/ hi g h-ris k 
W B C x > 1 0 0 x 
1 0 9/ L,  
h y p o di pl oi d y,  
P h +, or M L L +  
C N S 1  
1, 8, 1 5, 
2 2  
4  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3,  3 7, 4 1, 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 5  
St d -/ hi g h-ris k, 
ot her  
C N S 1  
1, 1 5  
2  
1, 1 5, 2 9, 
4 3  
4  
7, 1 2, 1 7  
3  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9  
7  
1 6  
St d -/ hi g h-ris k  
C N S 2 or 
Tra u matic 
Blasts  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1 , 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 7  
T -cell 
t( 1; 1 9)/E 2 A -
P B X 1  
C N S 1, C N S 
2, or C N S 3  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 7  
St d -/ hi g h-ris k  
C N S 3  
1, 4, 8, 
1 1, 1 5, 
2 2  
6  
1, 1 5, 2 9, 
4 3  
4  
3, 7, 1 2, 1 7  
4  
2 5, 2 9, 3 3, 3 7, 4 1, 
4 5, 4 9, 5 7, 6 5, 7 3, 
8 1, 8 9, 9 7  
1 3  
2 7  
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 3 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T h us, t he t otal n u m bers of i ntrat hecal treat me nts f or vari o us s u b gr o u ps of p atie nts are 1 3 
(l o w-ris k cas es wit h W B C < 1 0 0 x 1 09/ L at pres e ntati o n a n d C N S 1 stat us), 1 9 (l o w-ris k 
cases wit h W B C > 1 0 0 x 1 0 9/ L at prese nt ati o n), 2 1 (l o w-ris k cas es wit h C N S 2 stat us or 
tra u matic C S F wit h blast stat us), 1 6 (st d-/ hi g h-ris k cases wit h C N S 1 stat us), 2 5 (st d-/ hi g h-
ris k cases wit h W B C > 1 0 0 x 1 0 9/ L at prese nt ati o n, prese nce of P hila del p hia c hr o m os o me, 
M L L rearra n ge me nt, or h y p o di pl oi d y < 4 4), 2 7 (st d-/ hi g h-ris k cases wit h T-cell 
p he n ot y p e, t( 1; 1 9)/ E 2 A- P B X 1, or C N S- 2 or C N S- 3 stat us, or tra u matic l u m bar p u nct ure 
wit h bl ast). T he n u m ber of i ntrat hecal treat me nts f or hi g h ris k patie nts will de pe n d o n 
w het her a n d w he n t he p atie nts will recei ve ste m cell tra ns pla ntati o n.  Le uc o v ori n will n ot 
be gi v e n after i ntrat he cal treat me nt d uri n g c o nti n u ati o n treat me nt u nless t he patie nt has a n 
a d verse reacti o n wit h pre vi o us i ntrat hecal or met h otre x ate treat me nt, e. g., s eiz ure or 
e nce p h al o pat h y, has r e nal d ysf u ncti o n res ulti n g i n hi g h plas ma met h otr e x ate 
c o nce ntr ati o n, or is D o w n s y n dr o me a n d has u n acce pta ble t o xicit y des pite d osa ge 
decreases.  Le uc o v ori n m a y b e gi ve n w h e n patie nt is ne utr o pe nic, at treati n g p h ysicia n’s 
discreti o n.  D o w n s y n dr o me patie nts will recei ve l e uc o v ori n wit h e ver y L PI T.  W hile 
i ntrat hecal treat me nts ma y be gi v e n at SJ C R H affiliate i nstit uti o ns, all patie nts m ust ha ve 
i ntrat hecal treat me nt gi ve n at St. J u de at least e ver y 1 6 wee ks, beca us e cl os e m o nit ori n g of 
cere br os pi nal fl ui d is a n esse ntial c o m p o ne nt of t hera p y. 
 
5. 5. 4  Tr eat me nt ( wee ks 2 1 t o 2 9) 
 
Wee k  
Sta n dar d/ Hi g h  Ris k  
L o w  Ris k  
2 1  
M P +  P E G - 
A S P + ‡ Dasati ni b  
M P +  M T X  
2 2  
M P  + ‡ Dasati ni b  
M P +  M T X  
2 3  
M P +  P E G -A S P + ‡ Dasati ni b  
M P +  M T X  
2 4  
C ycl o  +  Ara -C + ‡ Dasati ni b  
M P +  M T X  
2 5  
* D E X  +  V C R +  P E G - 
A S P + ‡ Dasati ni b  
* M P +  D E X  +  V C R  
2 6  
M P + ‡ Dasati ni b  
M P +  M T X  
2 7  
M P +  P E G -A S P + ‡ Dasati ni b  
M P +  M T X  
2 8  
C ycl o  +  Ara -C + ‡ Dasati ni b  
M P +  M T X  
2 9  
* D E X  +  V C R +  P E G - 
A S P + ‡ Dasati ni b  
( *) M P +  D E X  +  V C R  
*I T M H A ( m et h otrex a te + hy dr o c ortis o ne + cyt ar a bi ne; see secti o n 5. 1 f or 
d os a ge ) ( *)I T M H A f or l o w-risk c ases wit h W B C > 1 0 0 x 1 09/ L , C N S- 2 or 
tr a u m atic l u m b ar p u nct ure wit h bl ast.  
‡ O nly f or P h + p atie nts 
Merc a pt o p uri ne s h o ul d be give n d aily at a c o nsiste nt ti me t h at 
m axi mize s 
a d here nce wit h t he pres cri be d tre at me nt.  If a d os e is i n a dverte ntly misse d, t he n it 
s h o ul d be give n as s o o n as t he o missi o n is n ote d, as l o n g as it is at le ast 6 h o urs 
pri or t o t he next sc he d ule d d ose. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5. 5. 5  Treat me nt ( wee ks 3 0 t o e n d of t hera p y) 
 
Wee k  
Sta n dar d/ Hi g h  Ris k  
L o w  Ris k  
3 0  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 1  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 2  
C ycl o  +  Ara -C + ‡ Dasati ni b  
M P +  M T X  
3 3  
* D E X  +  V C R + ‡ Dasati ni b  
* M P +  D E X  +  V C R  
3 4  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 5  
M P +  M T X + ‡ Dasati ni b  
M P +  M T X  
3 6  
C ycl o  +  Ara -C + ‡ D asati ni b 
M P +  M T X  
3 7  
* D E X  +  V C R + ‡ Dasati ni b  
( *) M P +  D E X  +  V C R  
*I T M H A ( met h otrex ate + hy dr oc ortis o ne + cyt ar a bi ne; see secti o n 5. 1 f or 
d os a ge)  ( *)I T M H A f or l o w-risk c ases wit h W B C > 1 0 0 x 1 09/ L, C N S- 2 or  
tr a u m atic l u m b ar p u n ct ure wit h bl ast.  
‡O nly f or P h + p atie nts.  
Merc a pt o p uri ne s h o ul d b e give n d aily at a c o nsist e nt ti me t h at m axi mizes 
a d here nce wit h t he pres cri be d tre at me nt.  If a d ose is i n a dverte ntly misse d, t he n it 
s h o ul d be give n as s o o n as t he o missi o n is n ote d, as l o n g as it is at le ast 6 h o urs 
pri or t o t he next sc he d ule d d ose. 
 
5. 5. 5. 1  Dr u g d osa ges, sc h e d ules a n d r o utes f or c o nti n uati o n t hera p y fr o m wee k 2 1 t o 
e n d of t hera p y 
 
M P ( merca pt o p uri ne) 
7 5 m g/ m 2 P O dail y f or 7 da ys, Da ys 1- 7  
 
M T X ( met h otre x ate) 
4 0 m g/ m 2 I V or I M, Da y 1 
 
C ycl o ( C ycl o p h os p ha mi de)  
3 0 0 m g/ m 2 IV, Da y 1  
 
Ara- C ( C ytara bi ne) 
3 0 0 m g/ m 2 I V, Da y 1 
 
D E X ( de x a met has o ne) 
1 2 m g/ m 2 (st d/ hi g h ris k) or 8 m g/ m2 (l o w 
ris k) P O dail y ( di vi de d t.i. d.) f or 5 da ys, 
Da y 1- 5 bet w ee n wee k 2 1 a n d wee k 6 8 
 
6 m g/ m 2 P O  dail y ( di vi de d t.i. d.) x 5 da ys, 
Da y 1- 5 bet w ee n wee k 6 9 a n d wee k 1 0 1 f or 
all ris k gr o u ps 
 
V C R ( vi ncristi ne) 
2 m g/ m 2 I V p us h ( m a x 2 m g), Da y 1 
( 0. 0 5 m g/ k g f or patie nts < 1 yr or < 1 0 k g) 
 
P E G- A S P 
2, 5 0 0 vs. 3, 5 0 0 u nits/ m 2 IV ra n d o mizati o n 
( u ntil wee k 3 0) 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
De x a met has o ne, vi ncristi ne, a n d as para gi nas e will be gi v e n re gar dless of bl o o d c o u nts, 
pr o vi de d t hat t he patie nt is cli nicall y well. C ycl o p h os p ha mi de, c yt ara bi ne, merca pt o p uri n e 
a n d met h otre x ate will be hel d if W B C < 1 0 0 0/ m m 3, platelet c o u nt t o < 5 0 x 1 09/ L, or A N C 
< 3 0 0/ m m 3 (see Secti o n 8. 0 f or f urt her details).  M erca pt o p uri ne s h o ul d be gi ve n dail y at a 
co nsiste nt ti me t hat ma xi mizes a d here nce wit h t he prescri be d treat me nt.  If a d ose is 
i na d verte ntl y misse d, t he n it s h o ul d be gi ve n as s o o n as t he o missi o n is n ote d, as l o n g as it 
is at least 6 h o urs pri or t o t he ne xt sc he d ule d d ose. 
 
 
Merca pt o p uri n e a n d met h otre x ate will be re d uce d f or if W B C a n d A N C d o n ot i ncrease b y 
at least 2 f ol ds a wee k after t he start dat e of de x a m et has o ne p ulse.  E x ce pti o ns ca n be 
ma de  i n patie nts wit h W B C a n d A N C t hat d oes n ot d o u ble, b ut is o ver 3 0 0 0 a n d 1 2 0 0, 
res pecti vel y, wit h n o hist or y of pri or c h e m ot hera p y i nterr u pti o n or m yel os u p pressi o n (see 
Secti o n 8. 0 f or f urt her details). 
 
D oses of c ycl o p h os p h a mi de a n d c ytara bi ne ma y n ee d t o be re d uce d if patie nt misses 2 5 % 
of c he m ot hera p y a n d if t he l o w c o u nts dee m t o be relate d t o t his c o m bi nati o n. 
 
T he sa me treat me nt ( wee ks 3 0- 3 7) will be re p eate d f or a t otal of 5 ti mes, u ntil wee k 6 9 
(see Secti o n 5. 5. 3 f or i ntrat hecal t hera p y).  After wee k 6 9, all patie nts will recei v e dail y 
merca pt o p uri n e a n d w ee kl y met h otre x ate i nterr u pte d wit h p ulses of de x a met has o ne, 
vi ncr isti ne, a n d merca pt o p uri ne e ver y 4 wee ks. 
 
T he d ose of de x a met h as o ne will be decre ase d t o 6 m g/ m 2 bet wee n wee k 6 9 a n d wee k 
1 0 1, after w hic h o nl y merc a pt o p uri ne a n d met h otre x ate will be gi ve n. Intr at hecal 
treat me nt will be gi ve n e ver y 8 wee ks o nl y t o p atie nts at ris k of C N S rela pse after wee k 4 9 
a n d will be disc o nti n ue d after wee k 9 7. C o nti n uati o n t hera p y will be disc o nti n ue d after 
1 2 0 wee ks. 
 
5. 6  
He mat o p oietic Ste m Cell Tra ns pla ntati o n 
 
P atie nts w h o meet t he criteria of hi g h-ris k A L L are ca n di dates f or all o ge neic 
he mat o p oietic ste m cell tra ns pla ntati o n.  H o we ver, if t he o pti o n is decli ne d b y  t he 
patie nts or g uar dia ns, or t he pr oce d ure is dee me d u ns uita ble b y  t h e atte n di n g p h ysicia n 
an d t he pri nci pal i n vesti gat or, t he patie nt will re mai n o n st u d y a n d c o nti n ue t o recei ve 
che m ot hera p y. 
 
6. 0 
D R U G  I N F O R M A TI O N 
 
See A p pe n di x II f or i nf or mati o n o n t he i n di vi d ual dr u gs t o be use d i n t his pr ot oc ol. 
 
6. 1  
Dr u g S h orta ges a n d U n a vaila bilit y 
 
I n t he case of dr u g s h orta ges a n d u na vaila bilit y of a n y a ge nt use d i n t his pr ot oc ol, 
treati n g i n vesti gat ors are ur ge d t o c o ns ult wit h t he PI  or  c o -PI  a n d use t heir best cli nical 
j u d gme nt i n o pti mizi n g t hera pe utic i nte nt a n d e ns uri n g patie nt safet y i n ma na gi n g t he 
pr ot oc ol-s pecifie d t hera p y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Alt h o u g h  t hese decisi o ns ma y c o nstit ute “ Pr ot oc ol Vi olati o ns,” t he y are u na v oi da ble 
an d ma de i n c o nsi derati o n of t he best i nterest of a n i n di vi d ual patie nt.  T hese will N O T  
be  c o nsi dere d m o nit ori n g/a u dit fi n di n gs if a p pr o priatel y d oc u me nte d.  M ost 
i mp orta ntl y, all pr ot oc ol de viati o ns m ust be n ote d i n t he researc h data base a n d t he 
alterati o ns i n t hera p y d ue t o t he a ge nt s h orta ge will be ca pt ure d.  T his s h o ul d be 
acc o m plis he d b y  e nteri n g “ d ose m o difie d” a n d details n ote d i n t he c o m me nts fiel d. 
 
7. 0 
T R E A T M E N T M O DI FI C A TI O N S  
 
7. 1  
D o w n S y n dr o m e P artici p a nts 
 
P artici pa nts wit h D o w n s y n dr o me are eli gi ble f or e nr oll me nt, wit h t he f oll o wi n g 
m o dificati o ns. 
 
7. 1. 1  H D M T X:  D osa ges of hi g h- d os e M T X will be m o difie d d ue t o t heir well- 
d oc u me nte d altere d p har mac o ki netics a n d e n h a nce d tiss ue se nsiti vit y t o M T X’s effects.  
T heir h y drati o n a n d al kali nizati o n re gi me n s h o ul d be t he sa me as o utli ne d i n Secti o n 
5. 3. 3.  H o we ver, t he d ose of H D M T X is 5 0 0 m g/ m 2 ( 5 0 m g/ m2  
o ver 1 h o ur a n d 4 5 0 
m g/ m 2 gi ve n o ver 2 3 h o urs). 
 
T he baseli ne le u c o v ori n resc ue will be gi n earl y (at h o ur 3 0 at 3 0 m g/ m 2 I V q 6 h o urs x 2 
d oses, f oll o we d b y 1 0 m g/ m 2   I V q 6 h o urs x 6 d oses).  If M T X pl as ma le v els are ele vate d, 
i ncreas e d le uc o v ori n resc ue will be rec o m me n d e d b y t he P har mace utical D e part me nt.  
Vi g or o us h y drati o n s h o ul d be ass ure d u ntil t he 4 2 h o ur M T X le vel is k n o w n. 
 
7. 1. 2  C o nti n uati o n l o w- d ose M T X:  T he l o w- d ose wee kl y M T X ( 4 0 m g/ m 2) d osa ge 
s h o ul d be a d mi nistere d at f ull d osa ge if p ossi ble.  If t he patie nt has s e vere ne utr o pe nia or 
le uc o pe nia ( w hic h dela ys s u bse q ue nt t hera p y) or gra de 4 m uc ositis ( or m uc ositis w hic h 
dela ys s u bs e q ue nt t hera p y) f oll o wi n g t he d os e of 4 0 m g/ m 2, t he d osa ge s h o ul d be 
decrease d t o 3 0 m g/ m 2.  If t hat d osa ge is si milarl y n ot t olerate d, t he n t he d osa ge ma y be 
f urt her decrease d t o 2 0 m g/ m2 a n d fi nall y t o 1 0 m g/ m 2, if necessar y.  If 1 0 m g/ m2 is als o 
n ot t olerate d, t he n le uc o v ori n s h o ul d be a d de d at 5 m g/ m 2 e ver y 6 h o ur f or 4 d oses starti n g 
4 2 h o urs fr o m t he M T X d osa ge, wit h titrati o n t o acce pta bl e t o xicit y. 
 
7. 1. 3  I ntr at hecal t hera p y:  I ntrat hecal treat me nt s h o ul d be a d mi nistere d as o utli ne d i n 
Secti o n 5. 1. 
 
7. 1. 4  P E G-as para gi nase: Patie nts wit h D o w n’s s y n dr o me will n ot be ra n d o mize d, a n d 
will all recei ve 2, 5 0 0 u nits/ m 2 P E G-as para gi nas e p ost re missi o n i n d ucti o n. 
 
7. 1. 5  D o w n s y n dr o me patie nts s h o ul d be cl osel y m o nit ore d.  D ose re d ucti o n ( 3 0 % t o 
5 0 %) s h o ul d be a p plie d as cli nicall y i n dicat e d (es p eciall y t o de xa met has o ne a n d hi g h- d ose 
c yt ara bi ne f or t he fe w p atie nts w h o w o ul d be treat e d o n t he sta n dar d ar m, a n d w h o are 
n ote d t o ha ve hi g her t ha n e x pecte d t o xicit y i n earlier p hases)  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
7. 2   
Re nal D ysf u ncti o n 
 
S u bcli nical re nal i m pair me nt ( n or mal ser u m creati ni ne b ut decreas e d G F R) ma y b e 
prese nt i n patie nts recei vi n g c o n c urre nt ne p hr ot o xic dr u gs (e. g. I V ac ycl o vir) w hic h, if 
p ossi ble, s h o ul d be hel d d uri n g a n d f or 2 0 h o urs after H D M T X i nf usi o ns or u ntil a de q uate 
M T X c leara nce has bee n d oc u me nte d. C o nsi derati o n t o dela yi n g M T X s h o ul d be gi ve n if 
a patie nt's ser u m creati ni ne i n dicates re nal i m pair me nt. 
 
7. 3  
He patic D ysf u n cti o n 
 
A nt hrac ycli nes a n d vi ncristi ne d osa ges s h o ul d be m o difie d i n patie nts wit h ele vate d direct 
bil ir u bi n c o nce ntrati o ns or ot her e vi de nce of biliar y o bstr ucti o n. ( M ore c o nser vati ve 
criteria will be use d f or a nt hrac ycli ne treat me nt d uri n g i nitial re missi o n i n d ucti o n, See 
S ecti o n 5. 2.) 
 
Dire ct bilir u bi n 2- 4 m g/ dl: 
5 0 % d osa ge decrease  
Dire ct bilir u bi n 4- 6 m g/ dl: 
7 5 % d osa ge decrease  
Dire ct bilir u bi n > 6  m g/ dl: 
wit h h ol d d ose 
 
P E G-as para gi nase ma y n ee d t o be wit h hel d i n pati e nts wit h ele vate d direct bilir u bi n 
c o nce ntrati o ns, es peciall y if t here is e vi de n ce of  m uc ositis. 
 
H D M T X s h o ul d be wit h hel d if t here is e vi de nce of e xisti n g m uc ositis or if t otal 
bilir u bi n > 2  m g/ dl a n d direct bilir u bi n > 1. 4 m g/ dl. 
 
S u bcli nical h y pertra nsa mi nase mia ( S G P T > 5 0 0 I U/ L) is a n i n dicati o n t o dela y o nl y 
hi g h- d ose met h otre x ate b ut n ot f or ot her c he m ot hera p y. 
 
7. 4  
O besit y 
 
Ac t ual b o d y wei g ht will be use d t o calc ul ate b o d y s urface area i n all patie nts a n d use d f or 
d osa ge cal c ulati o ns ( wit h t he e x ce pti o n t hat vi ncristi ne d osa ge is ca p pe d at 2 m g). 
 
7. 5 
Te stic ular Le u k e mia at Dia g n osis 
 
O vert testic ular le u k e mia occ urs i n 2 % of b o ys at dia g n osis, ge n erall y i n i nfa nts or 
a d olesce nts wit h h y perl e u k oc yt osis.  Ultras o n o gra m s h o ul d be perf or me d t o differe ntiate 
testic ular le u ke mia fr o m h y dr ocele a n d t o meas ure t he testic ular v ol u me.  O vert testic ular 
le u ke mia at dia g n osis per se is n ot a n i n dicati o n f or testic ular irra diati o n, as ma n y p atie nts 
ca n be s uccessf ull y treate d wit h c he m ot hera p y, i ncl u di n g hi g h- d ose met h otr e x ate.  
Ultras o n o gra m s h o ul d a gai n be perf or me d u p o n c o m pleti o n of re missi o n i n d ucti o n.  If 
testic ular size is still a b n or mall y e nl ar ge d, t h e s o n o gra m s h o ul d be re p eate d after 
c o ns oli dati o n treat me nt wit h hi g h- d ose met h otr e x ate a n d merca pt o p uri n e. Persiste ntl y 
e nlar ge d test es after c o ns oli dati o n treat m e nt will be bi o psie d.  Testic ular irra diati o n ( 2 4 
G y) will be a d mi nistere d i n t he rare p atie nts wit h p ositi ve bi o psies, after c o ns ultati o n wit h 
a ra diati o n o nc ol o gist. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
7. 6   
Vi ncristi ne Ne ur ot o xicit y 
 
T he  ma xi m u m si n gle d ose of vi ncristi ne m ust n ot e xcee d 2 m g. Mil d vi ncristi ne 
t o xicities (ja w pai n, c o nsti pati o n, a n d decrease d d ee p te n d o n refle x es) are a ntici pate d.  
L oss of v oice d ue t o v oc al c or d paral ysis ma y be a c o m plicati o n of vi ncristi ne t o xicit y 
b ut it m ust be differe ntiate d fr o m p har y n gitis or C a n di d a i nfecti o n of t h e c or d.  If 
persiste nt, se vere a b d o mi nal cra m ps, gait i m pair m e nt, se vere pai n (re q uiri n g narc otic 
treat me nt), or SI A D H de vel o p, t he d ose ma y be re d uce d t o 1 m g/ m2.  O nl y m ot or 
paral ysis or t y p hlitis warra nts wit h h ol di n g vi ncristi ne. 
 
7. 7  
Ve n o us T hr o m b oe m b olis m 
 
P atie nts w h o de vel o p cere bral or ot her ve n o us t hr o m b osis will recei ve l o w m olec ular 
wei g ht h e pari n t hr o u g h o ut treat me nt wit h As para gi nase ( d uri n g Rei n d ucti o n I a n d 
Rei n d ucti o n II i n l o w-ris k patie nts, d uri n g t he first 3 0 wee ks of c o nti n uati o n treat me nt i n 
sta n dar d-/ hi g h-ris k cases, a n d d uri n g rei nte nsificati o n I i n hi g h-ris k patie nts). Ac ute 
ma na ge me nt of t hr o m b osis will f oll o w t he St. J u de g ui deli nes o n t he use of t hr o m b ol ysis 
a n d a ntic oa g ulati o n; q uesti o ns s h o ul d be referre d t o t he PI or c o- PI. 
 
7. 8  
A vasc ular Necr osis of B o ne 
 
M R I e x a ms will be i nter prete d b y t he ra di ol o gist. If t here is e vi de nce of e pi p h yseal or 
meta p h ys eal hi p lesi o ns, k nee e pi p h yseal or meta p h yseal lesi o ns, or lesi o ns of tal us 
c o nsiste nt wit h a vasc ular necr osis of t he b o ne, t he patie nt will be referre d t o t he 
ort h o pe dic s ur ge o n, w h o will e val uate s y m pt o ms, a n d will assess t he se verit y a n d 
esti mate d ris k of pr o gressi o n. P h ysic al t hera p y, acti vit y m o dificati o ns, a n d s ur gical 
pr oce d ures will be rec o m me n de d as nee de d. Patie nts wit h hi p e pi p h ys eal lesi o ns or tal us 
lesi o ns affecti n g > 3 0 % of wei g ht- beari n g area will ha ve a n X-ra y of t he affecte d area, a n d 
will be assesse d at hi g her ris k f or pr o gressi o n. S y m pt o matic patie nts wit h s uc h fi n di n gs 
will li kel y h a ve t heir d e x a met has o ne st o p pe d, es peciall y if t he y are past r ei n d ucti o n II i n 
t hera p y. 
 
As y m pt o matic patie nts wit h s uc h fi n di n gs will li kel y ha v e t heir de x a met has o ne d ose 
hal ve d, es peciall y if t he y are past r ei n d ucti o n II i n t hera p y.  A n y p atie nts wit h X-ra y 
fi n di n gs of A V N are ca n di dates f or de x a met has o n e m o dificati o n, re gar dless of s y m pt o ms. 
All m o dificati o ns ( or lac k t here of) of d osa ge will be rec or de d i n t he researc h data bas e. 
Patie nts wit h pr o gressi o n of a n y lesi o ns or wit h w orse ni n g s y m pt o ms will be re-e val uat e d 
b y i ma gi n g a n d, if a p pr o priate, b y a d diti o nal ort h o pe dic f oll o w- u p.  If t he de x a met has o ne 
is disc o nti n ue d, t he, first c h oice will be t o re pl ace eac h wee k’s d osi n g wit h o ne d ose of 
met h otre x ate ( 4 0 m g/ m 2), if t olerate d.  See Secti o n 1 3. 4 f or a d diti o nal g ui deli nes. 
 
7. 9  
P E G- As para gi n ase 
 
P atie nts wit h aller gic reacti o ns or i nt olera nce t o P E G-as para gi nase s u bs e q ue ntl y will be 
gi ve n Er wi ni a L-as p ara gi nase i ntra m usc ularl y or i ntra ve n o usl y o ver 3 0- 6 0 mi n utes 
d urati o n. If aller g y occ urs wit h t he first P E G d ose a n d t h e patie nt re q uires a da y 1 5 d os e 
d uri n g  re missi o n i n d ucti o n, Er wi ni a L-as para gi nase will be gi ve n at 2 0, 0 0 0 u nits/ m 2/ d ose 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hrice wee kl y f or 2 w ee ks (t otal of 6 d oses).  Aft er c o ns oli dati o n, i n patie nts ra n d o mize d 
t o 2, 5 0 0 u nits/ m2, eac h d ose of P E G will be re place d b y Er wi nia at 3 0, 0 0 0 u nits/ m2/ d ose 
t wice wee kl y ( 3 t o 4 da ys a part) f or 4 d oses. I n p atie nts ra n d o mize d t o 3, 5 0 0 u nits/ m2 or 
3, 0 0 0 u nits/ m 2, eac h d os e of P E G will be re place d b y Er wi nia at 4 2, 0 0 0 u nits/ m2/ d ose or 
3 6, 0 0 0 u nits/ m 2/ d ose, res pecti vel y, t wice wee kl y ( 3 t o 4 da ys a part) f or 4 d oses.  D uri n g 
R ei nte nsificati o n, Er wi nia will be gi v e n 3 6, 0 0 0 u nits/ m 2/ d ose, t wice wee kl y ( 3 t o 4 d a ys 
apart) f or 2 d oses.  N ati ve E. c oli as para gi nase ca n als o be gi ve n w he n cli nicall y i n dicat e d, 
b ut t his s h o ul d be disc usse d a n d a p pr o ve d b y t he PI or c o- PI. 
 
As para gi nas e treat me nt s h o ul d be dela ye d u ntil at least 2 h o urs after i ntrat h ecal treat me nt. 
 
If si g nifi ca nt i ncrease i n t o xicit y is n ote d i n t he ar m ra n d o mize d t o 3, 5 0 0 u nits/ m2 P E G-
as para gi n ase c o m pare d t o t he c o n ve nti o nal d ose ar m, P E G-as para gi nase d ose will be 
re d uce d t o 3, 0 0 0 u nits/ m2.  If si g nifica nt i ncreas e i n t o xicit y is n ote d wit h t he re d uce d 
d ose , ra n d o mizati o n will cease, a n d all patie nts will be treate d at t he c o n ve nti o nal d ose of 
2, 5 0 0 u nits/ m 2 (see secti o n 1 7. 0 f or details a n d st atistical a nal ysis). 
 
Patie nts w h o are i nt olera nt t o all as para gi nase f or m ulati o ns ca n ha ve as p ara gi n ase 
s u bstit ute d wit h met h otre x ate 4 0 m g/ m 2 I V o n wee ks 2 1, 2 2, 2 3, 2 6, a n d 2 7. 
 
7. 1 0  
T P M T Stat us a n d T hi o p uri ne D osa ge 
 
T P M T defects ha v e bee n li n ke d t o ac ute m yel os u p pressi o n a n d t o t he l o n g-ter m ris k of 
t hera p y-relate d A M L (t- A M L), e ve n i n t he c o nte xt of A L L t hera p y c o nsisti n g pri maril y of 
a nti meta b olites. St u dies re p orti n g a n ass ociati o n of T P M T defects wit h ris k of t- A M L 
i nc or p orate d m erca pt o p uri ne at a d osa ge of 7 5 m g/ m2/ da y, w hereas ma n y A L L tr eat me nt 
gr o u ps us e a starti n g d os a ge of 6 0 m g/ m 2/ da y a n d t he n titrate u p.  Alt h o u g h t he 
mec ha nis m is n ot k n o w n, patie nts wit h T P M T defects ha ve hi g her c o n ce ntr ati o ns of 
t hi o g ua ni ne n u cle oti des, a n d s u bstit uti o n of t hi o g ua ni ne f or g u a ni ne i n D N A ca n affect 
t o p ois o merase II- i n d uce d clea va ge of D N A i n t he prese n ce a n d a bse n ce of a 
t o p ois o merase II i n hi bit or. T o get her, t he cli nical a n d precli nical e vi d e nce s u g gest t hat t he 
1 0 %  of patie nts w h o carr y a v aria nt T P M T allele ma y b e at hi g her ris k f or sec o n dar y 
t u m ors.   Beca use s uc h p atie nts ofte n re q uir e d osa ge d ecreas es of t hi o p uri nes, a n d beca use 
(i n a setti n g i n w hic h d os a ge was a dj uste d i n a b o ut 1/ 3 of patie nts wit h T P M T defects) 
o verall le u ke mia-free s ur vi val was o utsta n di n g a m o n g patie nts wit h T P M T defects, w e are 
rec o m me n di n g t hat patie nts wit h p he n ot y pe or ge n ot y pe c o nsiste nt wit h at least o ne 
varia nt T P M T allele recei ve n o m ore t ha n 6 0 m g/ m 2/ da y of merca pt o p uri n e or t hi o g u a ni ne 
u nless it is clearl y d o c u m e nte d t hat c o m plia nce h as bee n g o o d a n d meta b olite le vels 
re mai n l o w ( < 1 0 0 p m ol/8 x 1 0 8 re d cells) (see secti o ns 8. 1 a n d 8. 2).  F urt h er c ha n ges i n 
merca pt o p uri n e d ose s h o ul d be titrate d base d o n W B C a n d A N C. E ver y eff ort s h o ul d be 
ma de t o kee p ot her a ntica ncer a ge nt d oses at pr ot oc ol le vels f or t hes e patie nts. A bl o o d 
sa m ple ( 5 ml) will be dra w n al o n g wit h r o uti ne la b w or k at Da y 3 of re missi o n i n d ucti o n 
t o all o w f or ti mel y T P M T ge n ot y pi n g. 
 
Assessi n g T P M T stat us: T P M T ge n ot y pe will be deter mi ne d b y allele-s pecific ge n ot y pi n g, 
directe d a gai nst t he 3 m ost c o m m o n i nacti vati n g p ol y m or p his ms at p ositi o ns 2 3 8, 4 6 0, 
a n d 7 1 9 of t he c D N A.  T hese 3 p ol y m or p his ms acc o u nt f or > 9 0 % of all varia nt alleles.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Ge n ot y pi n g will be e val u ate d t o assi g n p atie nts as ha vi n g h o m oz y g o us wil d-t y pe, 
heter oz y g o us, or h o m oz y g o us varia nt T P M T stat us.  As s pecifie d i n secti o n 8. 2, all 
pa tie nts als o ha ve 6 T G N t hi o p uri ne meta b olite meas ures at t he start of rei n d ucti o n I a n d 
T P M T acti vit y i n R B Cs assesse d at least b y wee k 1 7.  T he t hres h ol d f or o n-t hera p y, n o n-
transf use d T P M T acti vit y t hat is c o nsi dere d t he u p per b o u n ds f or h eter oz y g o us stat us ( 1 4 
u nits/ ml) is hi g her t ha n t hat f or off-t hera p y, n o n-tra nsf use d p atie nts ( 1 0 u nits/ ml). T he 
rati o of met h yl t hi o p uri n e meta b olites t o T G Ns ca n als o be use d t o assist i n p he n ot y pi n g 
t he patie nt if ge n ot y pe a n d acti vit y p he n ot y p e data are c o nflicti n g. If T P M T ge n ot y p e or 
acti vit y or met a b olite meas ures are c o nsiste nt wit h heter oz y g o us stat us, t h e patie nt will be 
c o nsi dere d h eter oz y g ot e; usi n g t hese criteria, a p pr o xi matel y 1 0 % of patie nts are e x pecte d 
t o be heter oz y g ot e or h o m oz y g o us v aria nts, i n a gree me nt wit h p o p ulati o n st u dies f or 
T P M T stat us. 
 
T h us, a p pr o xi matel y 1 0 % of patie nts are e x pecte d t o re q uire s u bstit uti o n of merca pt o p uri ne 
f or t hi o g u a ni ne o n t he basis of T P M T stat us.  See Secti o n 8. 2 f or a d diti o nal i nf or mati o n. 
 
7. 1 1 
Pa ncreatitis 
 
Ac ute he m orr ha gic p a ncreatitis is a c o ntrai n dicati o n t o c o nti n ue as para gi nase treat me nt. I n 
t he case of mil d t o m o derate pa ncreatitis, as para gi nase s h o ul d be hel d u ntil s y m pt o ms a n d 
si gns s u bsi de, a n d a m ylase a n d li pase le vels ret ur n t o n or mal a n d t he n res u me d. A n y 
patie nts wit h a b d o mi nal pai n s us pecte d of p a ncreatitis s h o ul d ha ve ser u m a m ylas e a n d 
li pase meas ure d as well as a n a b d o mi nal s o n o gra m or C T sca n d o ne.  I n t h e case of se vere 
pa ncreatitis (i.e. a b d o mi nal pai n of 7 2 h o urs or m ore, a m ylase l e vel t hree ti mes or m ore of 
t he u p per li mit of n or mal, a n d s o n o gra p hic or C T sca n e vi de nce of pa ncreatitis), 
as para gi n ase ma y be dis c o nti n ue d per ma ne ntl y w h e n t he p ossi bilit y of gl uc oc ortic oi d- or 
mer ca pt o p uri n e-i n d uce d pa ncreatitis is e x cl u de d. I n cases wit h mil d t o m o derate 
pa ncreatitis (a b d o mi nal pai n less t ha n 7 2 h o urs a n d a m ylas e a n d li pase l e vel less t ha n 
t hree ti mes t he u p per li mit of n or mal), as para gi nas e s h o ul d be hel d a n d res u me d o nce 
s y m pt o ms a n d si g ns s u bsi de d.  Call t he PI or c o- PI t o disc uss t he ma na ge m e nt if t he 
patie nt is as y m pt o matic ( wit h o ut a b d o mi nal pai n) a n d has o nl y ele vat e d a m yl ase or li pase 
le vels. C o nsi derati o n s h o ul d als o be gi ve n t o d e x a met has o ne- or merca pt o p uri ne- rel ate d 
pa ncreatitis. C o ntact t he PI or c o- PI t o disc uss t he ma na ge m e nt if t here is a p ossi bilit y 
t hat t he pancreatitis is d ue t o eit her of t hes e t w o dr u gs. 
 
7. 1 2 
P hila del p hia C hr o m os o me P ositi ve ( P h +) A L L 
 
P atie nts wit h P h + A L L will recei ve das ati ni b ( 4 0 m g/ m 2 b.i. d.), star ti n g o n da y 2 2 of 
i n d ucti o n c he m ot hera p y. Patie nts ma y recei v e 8 0 m g/ m2 dail y if better t olerate d. T his is 
e q ui vale nt t o t he sta n dar d a d ult d osa ge of 7 0 m g b.i. d., a n d is e q ual t o t he pr o p ose d 
dasati ni b d ose i n t he u pc o mi n g fr o ntli ne C O G re gi me n f or P h + A L L. If ple ural eff usi o n 
occ urs, or if d asati ni b i n d uce d m yel os u p pressi o n ( or ot her t o xicit y) i nterferes wit h t he 
a bilit y t o a d mi nister it c o nti n u o usl y wit h c he m ot hera p y, t he dasati ni b d ose will be 
decrease d b y 2 5 % t o 6 0 m g/ m 2 dail y w hic h is e q ui vale nt t o t he 1 0 0 m g dail y d ose t hat has 
bee n ass oci ate d wit h e q u al efficac y a n d better t olera nce i n a d ults 1 1 1; 1 2 1.  If 
m yel os u p pressi o n res ults i n t hera p y i nterr u pti o n at t he re d uce d dasati ni b d ose of 6 0 m g/ m 2 
da il y, das ati ni b will be re place d wit h i mati ni b ( 3 4 0 m g/ m2 dail y as gi ve n i n T O T X V). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
8. 0  
D O S E M O DI FI C A TI O N S D U RI N G C O N TI N U A TI O N T H E R A P Y  
 
D osa ge of c o nti n uati o n treat me nt s h o ul d be titrate d t o kee p W B C bet wee n 1 8 0 0  a n d 
3 0 0 0/ m m 3, A N C bet wee n 5 0 0 a n d 1 2 0 0/ m m3 ( wit h t he e x ce pti o n of t he c o u nt o ne wee k 
after de x a met has o ne treat me nt), a n d platelet c o u nt 5 0 x 1 0 9/ L. 
 
F ull d ose of treat me nt will be a d mi nistere d w he n W B C 1 5 0 0/ m m 3, A N C is 3 0 0 / m m3 
a n d platelet c o u nt 5 0 x  1 0 9/ L; e x ce pt w he n d ose re d ucti o n is cli nicall y i n dicate d.  If 
patie nt is cli nicall y w ell a n d A N C < 3 0 0/ m m 3, f ull d ose of treat me nt ca n be a d mi nistere d if 
W B C > 1 5 0 0/ m m 3, platelet c o u nt > 5 0 x 1 0 9/ L, a n d A P C > 5 0 0/ m m 3. 
 
D o x or u bici n, c ycl o p h os p ha mi de, c ytara bi ne, met h otre x ate a n d merca pt o p uri ne ma y b e  
red uce d b y  3 0 t o 5 0 % if W B C is bet wee n 1 0 0 0 a n d 1 5 0 0/ m m 3 wit h A N C 3 0 0/ m m 3 a n d 
pla telet c o u nt 5 0 x 1 0 9/L.  Dis pr o p orti o nate d ose re d ucti o n of o ne a ge nt c o m pare d t o 
an ot her s h o ul d be a v oi de d u nless cli nicall y i n dicat e d. Fre q ue nt (e. g., wee kl y) c ha n ges of 
mer ca pt o p uri ne d oses s h o ul d be a v oi de d.  Patie nts w h o recei ve merca pt o p uri ne at a 
red uce d d ose f or l o n ger t ha n 2 wee ks s h o ul d ha ve a T G N le vel c hec ke d after at least 1 4 
da ys of  u ni nterr u pte d merca pt o p uri ne if t he pla n is t o c o nti n ue at re d uce d d oses. 
 
Merca pt o p uri ne a n d met h otre x ate will be re d uce d if W B C a n d A N C  d o n ot i ncrease b y  at 
least 2 f ol ds a wee k after t he start date of de x a met has o ne p ulse. E x ce pti o n ca n be ma de i n 
pa tie nts w h ose W B C a n d A N C  d o n ot d o u ble b ut are o ver 3 0 0 0 a n d 1 2 0 0 res pecti vel y 
wit h n o hist or y of pri or c he m ot hera p y i nterr u pti o n or m yel os u p pressi o n.  I n Sta n dar d Ris k 
patie nts c o nsi der re d uci n g c ycl o p h os p ha mi de a n d c ytara bi ne d ose if s us pecte d t o 
co ntri b ute t o m yel os u p pressi o n. De x a met has o ne, vi ncristi ne, a n d as para gi nase will be 
g i ve n re gar dless of bl o o d c o u nts, pr o vi de d t hat t he patie nt is cli nicall y well. O n t he wee ks 
of vi nc risti ne a n d de xa met has o ne p ulses, merca pt o p uri ne ma y be re d uce d b y  3 0 % t o 5 0 % 
i n patie nts wit h 
W B C < 1 5 0 0/ m m3 t he wee k after pri or de x a met has o ne p ulse. I n Sta n dar d 
Ris k patie nts c o nsi der re d uci n g c ycl o p h os p ha mi de a n d c ytara bi ne d ose if s us pecte d t o 
co ntri b ute t o m yel os u p pressi o n.  A dj ust me nts of d osa ges s h o ul d be ma de i n t he f oll o wi n g 
circ u msta nces, wit h re-e v al uati o n of t olera nce a n d t o xicities e ver y 8 t o 1 6 wee ks ( See 
secti o n 8. 3 f or das ati ni b m o dificati o n). 
 
8. 1  
D ose M o dificati o ns f or I na de q uate M yel os u p pressi o n 
 
Patie nts w h o miss less t ha n 2 5 % of t hera p y b ut ha ve persiste ntl y ( > 5 0 % of ti me; n ot 
c o u nti n g t he wee k after de x a met has o ne/ vi ncristi ne) hi g h W B C ( > 3 x 1 0 9/ L) a n d hi g h 
A N C ( > 1 0 0 0/ m m 3) s h o ul d be c o u nsele d o n c o m plia nce, p artic ularl y if 6 T G N le vels are 
< 1 0 0 p m ol/ 8 x 1 0 8 R B Cs.  If t he W B C re mai ns hi g h, merca pt o p uri n e a n d met h otre x ate 
d osa ges s h o ul d be i ncrease d b y 3 0 % (e. g., t o 1 0 0 m g/ m 2 a n d 5 0 m g/ m 2, res pecti vel y), 
usi n g a ste p wis e a p pr oac h if nee de d.  If patie nts h a ve a T P M T defect, merca pt o p uri ne 
d osa ge s h o ul d n ot be i ncrease d u nless t he T G N le vels are < 1 0 0 p m ol/ 8 x 1 0 8 R B Cs. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
8. 2   
D ose Decreases Base d o n Merca pt o p uri ne P har m ac ol o g y 
 
L o w ris k a n d sta n dar d/ hi g h ris k 
 
All patie nts o n b ot h ar ms will ha ve 6 T G N meas ure d at t he start of rei n d ucti o n I (i. e., wee k 
7). T P M T will be meas ur e d at t he start of rei n d ucti o n II ( wee k 1 7) or earlier if T P M T 
defects are s us pe cte d.  T P M T ge n ot y pe ma y b e use d t o i de ntif y T P M T varia nt alleles. 
6 T G N a n d T P M T will be meas ure d s u bse q ue ntl y i n patie nts wit h hi g h 6 T G N le vel, 
s us pecte d n o nc o m plia nce, pr o ble ms wit h t o xicities or hi g h bl o o d c o u nts. 
 
Patie nts missi n g 2 5 % of t hera p y w h o ha ve 6 T G N le vels > 1 0 0 0 p m ol/ 8 x 1 0 8 R B Cs will 
ha ve merca pt o p uri ne d os a ge re d u ce d t o ac hie ve a stea d y-state 6 T G N le vel bet wee n 2 0 0 t o 
1 0 0 0; t h ose wit h 6 T G N le vel < 1 0 0 0 will ha ve b ot h merca pt o p uri n e a n d met h otre x ate 
d osa ges re d u ce d b y 3 0 %. 
 
D osa ges will be re-e v al uate d e ver y 8 t o 1 6 wee ks.  Ot her ca us es of l o w bl o o d c o u nts 
s h o ul d als o be c o nsi dere d (see Secti o n 1 3. 5). 
 
Patie nts missi n g less t ha n 2 5 % of t hera p y a n d wit h W B C < 3 x 1 0 9/ L a n d A N C 
< 1 0 0 0 d o n ot nee d a n y c ha n ge i n d osa ge, re gar dless of 6 T G N le vel. See s ecti o n 7. 1 0 f or 
merca pt o p uri n e d osa ge a dj ust me nts.  
 
8. 3  
Dasati ni b D osa ge A dj ust me nts ( P h + A L L Patie nts O nl y) 
 
C o nsi der h ol di n g dasati ni b f or gra de III-I V n o n- h e mat ol o gical t o xicit y u ntil res ol uti o n t o 
gra de 1 or l ess. H ol d das ati ni b f or ple ural eff usi o n.  Ma y c o nsi der res u mi n g at r e d uce d ( 6 0 
m g / m2 dail y).  D os e ca n be escal ate d bac k t o 4 0 m g/ m 2 b.i. d. i f well t olerate d. Patie nts 
ma y recei ve 8 0 m g/ m 2 dail y if better t olerate d. C o nsi der re placi n g wit h i mati ni b 3 4 0 
m g/ m 2 dail y (as gi ve n o n T X V) if t o xicit y p ersists at re d uce d d osa ge.  All m o dificati o ns 
s h o uld be disc usse d wit h PI or c o- PI. 
 
C o nsi der re d uci n g das ati ni b d ose t o 6 0 m g/ m 2 dail y if m yel os u p pressi o n i nterferes wit h 
t he a bilit y t o a d mi nister t hera p y wit h o ut i nterr u pti o n. D ose ca n b e escalate d bac k t o 4 0 
m g/ m 2 BI D if t olerate d. Patie nts ma y recei v e 8 0 m g/ m 2 dail y if better t olerate d.  C o nsi der 
re placi n g wit h i mati ni b 3 4 0 m g/ m2 (as gi v e n o n T X V) if i nterr u pti o ns persist at re d uce d 
d osa ge. All m o dificati o ns s h o ul d be disc usse d wit h t he Pri nci pal I n vesti gat or. 
 
C o nsi der h ol di n g dasati ni b d uri n g peri o ds of m yel os u p pressi o n, u ntil A N C 3 0 0/ m m 3 a n d 
platelet c o u nt 5 0 x 1 0 9/ L. 
 
A v oi d c o nc urre nt use of dr u gs t hat are ge nerall y acce pte d t o h a ve a ris k of ca usi n g 
T orsa des de P oi ntes (i ncl u di n g: er yt hr o m yci n, ps e u d oe p he dri ne), a n d dr u gs k n o w n t o be 
i nterfere wit h C Y P 3 A 4. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 4 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
9. 0  
C O N TI N G E N C Y P L A N S F O R R E F R A C T O R Y DI S E A S E O R R E L A P S E  
 
9. 1   
I n d u cti o n Fail ures 
 
P atie nts w h o d o n ot attai n c o m plete re missi o n ( ≥5 % le u ke mic blasts i n b o ne marr o w) aft er 
re missi o n i n d ucti o n, c o ns oli dati o n treat me nt a n d rei nte nsificati o n treat me nt will be 
re m o ve d fr o m t he pr ot oc ol. T h ose w h o d o n ot ac hie ve a re missi o n after i n d ucti o n t h era p y, 
b ut s u bse q ue ntl y attai n c o m plete re missi o n after c o ns oli dati o n or rei nte nsificati o n 
treat me nt, are ca n di d ates f or all o ge nei c he mat o p oi etic ste m cell tra ns pla ntati o n. 
 
9. 2  
He mat ol o gi c Rela pse 
 
P atie nts wit h 2 5 % l y m p h o blasts i n marr o w as pir ate will b ec o me eli gi ble f or rela pse 
pr ot oc ols. 
 
9. 3  
E x tra me d ullar y Rela ps e 
 
Patie nts wit h a n y f or m of e xtra me d ullar y rela ps e (testes, o varia n, et c.) e x ce pt t hat of C N S 
will bec o me eli gi ble f or rela pse pr ot oc ols.  Patie nts wit h o vert C N S rela pse (i.e. 5 
W B C/ µ L of C S F wit h blasts) will re mai n o n st u d y a n d recei ve treat me nt o utli ne d i n 
Secti o n 9. 4.  Patie nts w h o ha ve < 5 W B C/ µ L of C S F wit h i de ntifia ble blasts are n ot 
co nsi dere d t o ha v e o vert C N S rela pse a n d will be treate d as o utli ne d i n Secti o n 9. 4. 
 
9. 4  
E mer ge nce of C S F L y m p h o blasts d uri n g Re missi o n Re q uiri n g C N S R a diati o n 
 
P re ve nti ve cra nial irra diati o n will n ot be gi ve n pr o p h ylacticall y t o p atie nts wit h C N S 
le u ke mia at dia g n osis or t o t h ose wit h hi g h-ris k le u ke mia. O nl y p atie nts wit h 
i m m u n ol o gicall y pr o ve n le u ke mic l y m p h o blasts i n C S F (re gar dless of cell c o u nt) d uri n g 
he mat ol o gic re missi o n o n t w o occasi o ns i n t he st u d y will recei ve t hera p e utic C N S 
irra diati o n i n c o ns ultati o n wit h ra di ot hera pists a n d after recei vi n g a sec o n d re missi o n 
i n d ucti o n (as i n Secti o n 5. 2) f oll o we d b y 1- 2 c ycles of rei nte nsificati o n (as i n Secti o n 5. 4) 
t o c o ns oli date b o ne marr o w re missi o n after i n d ucti o n. W het her 1 or 2 c ycles are t o be 
gi ve n will de p e n d o n ris k gr o u p, ti me t o e mer ge n ce of blasts i n C S F, i m m u n o p he n ot y p e of 
blasts, a n d i n di vi d ual patie nt t olera nce. I n ge neral, sta n dar d/ hi g h ris k partici pa nts or t h ose 
wit h earl y occ urre n ce ( < 1 8 m o nt hs) will recei ve 2 c ycles.  T his s h o ul d be disc usse d wit h 
t he pri nci pal i n vesti gat or. Tri ple i ntrat hecal t hera p y will be c o nti n ue d e ver y 3 t o 4 wee ks. 
 
C N S irra diati o n f or patie nts wit h C N S rela pse is i n dicate d as f oll o ws: cr a nial irra diati o n 
( 2 4 G y i n 1 6 fracti o ns) f or patie nts wit h < 5 W B C/ μ L of C S F occ urri n g wit hi n t he first 1 8 
m o nt hs of re missi o n; cra nial irra diati o n ( 1 8 G y i n 1 2 fracti o ns) f or t h ose wit h a n y n u m ber 
of le u ke mic l y m p h o bl asts i n C S F after 1 8 m o nt hs of i nitial re missi o n; a n d cra ni os pi nal 
irra diati o n ( 2 4 G y cra nial irra diati o n i n 1 6 fracti o ns pl us 1 5 G y s pi nal irra diati o n i n 1 0 
fracti o ns) f or patie nts wit h > 5 W B C/ μ L of C S F occ urri n g wit hi n t he first 1 8 m o nt hs of 
re missi o n. T h ose patie nts recei vi n g cra nial irra di ati o n o nl y s h o ul d recei ve 4 t o 5 tri ple 
i ntrat hecal t hera p y wit h le uc o v ori n resc ue d uri n g irra diati o n.  Merca pt o p uri ne a n d 
met h otre x ate will be wit h hel d f or at least o ne wee k pri or t o a n d d uri n g irra diati o n; 
s yste mic c h e m ot hera p y d uri n g irra diati o n will i n cl u de de x a met has o ne a n d vi ncristi ne wit h 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
or wit h o ut P E G-as para gi nase. C o nti n uati o n treat me nt will be gi ve n f or at least o ne year 
fr o m ti me of rela ps e (at l east 2 ½ years i ncl u di n g i nitial treat me nt). 
 
1 0. 0 
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C S T U DI E S  
 
1 0. 1 
Hi g h- D ose Met h otre x ate ( H D M T X) 
 
2- 3 ml of bl o o d will be o btai ne d i n E D T A t u bes ( p ur ple t o p) pre- d ose a n d bet wee n 0. 5 a n d 
6 hr, 2 3 hr, a n d 4 2 hr fr o m t he start of t he i nf usi o n. A d diti o nal sa m ples will be o btai ne d i n 
patie nts i n w h o m t here is cli nical s us pici o n of p o or cleara nce, or i n t h ose w h o ha ve hi g h 
plas ma M T X c o nce ntrati o n (e. g., > 0. 5 µ M at 4 2 h o urs), t o a dj ust le uc o v ori n resc ue. ( N ote: 
bl o o d s h o ul d be i n p ur ple t o p t u be t o facilitate d n ucleic aci d rec o v er y fr o m t he b uff y c o at). 
 
1 0. 2 
T hi o p uri nes 
 
B l o o d ( 3 ml) will be o btai ne d at wee k 7 a n d at w ee k 1 7 f or re d bl o o d cell t hi o p uri ne 
c o nce ntr ati o ns a n d T P M T acti vit y, res pecti vel y. A d diti o nal sa m ples ma y be o btai ne d as 
i n dicate d i n Secti o n 8. 2. 
 
1 0. 3 
As para gi nas e, De x a met h as o ne a n d Bi o mar kers 
 
S er u m f or a nti b o dies ( 2 ml bl o o d i n re d-t o p t u be) will be o btai ne d o n Da ys 1, 8, a n d 1 5 
of re missi o n i n d ucti o n t hera p y, da y 1 of c o ns oli dati o n, a n d at Da y 1 of wee ks 7, 8, 9, 1 7, 
a n d 1 9 acc or di n g t o o ur pre vi o usl y esta blis he d met h o ds.  A nti b o dies a gai nst nati ve 
E. C ol i ( Els par), P E G yl ate d E. C oli ( O ncas par), a n d Er wi nia as para gi nase are meas ure d 
b y a n E LI S A i n o ur la b orat or y. T h ose wit h sa gittal si n us t hr o m b osis or a n y dee p vei n 
t hr o m b osis will als o ha ve meas ure me nt of a nti-as para gi nas e a nti b o dies at t he ti me of 
t hr o m b osis. 
 
Plas ma f or as para gi nase ( 3 ml bl o o d) will be o btai ne d o n Da ys 1, 8, a n d 1 5 of re missi o n 
i n d ucti o n t hera p y ( pl us ~ 2- 3 a d diti o nal ti me p oi nts d uri n g t he first 1 4 da ys), da y 1 of 
c o ns oli dati o n, a n d at Da y 1 of wee ks 7, 8, 9, 1 7, a n d 1 9 acc or di n g t o o ur pre vi o usl y 
esta blis he d met h o ds. As para gi nas e will be meas ure d usi n g a s pectr o p h ot o metric assa y 
base d o n c o n v ersi o n of as para gi ne t o as p artic aci d 1 2 2. 
 
I n p atie nts wit h a s us pect e d cli nical aller gi c reacti o n t o a d ose of as p ara gi n ase, bl o o d 
sa m ples f or res earc h p ur p oses ( u p t o 5 sa m ples o ver u p t o 2 wee ks, n or m ore t ha n 2 
sa m ples i n a n y 2 4- h o ur ti me peri o d; eac h t o be n o m ore t ha n 3 ml of bl o o d i n p ur ple-t o p 
E D T A or re d-t o p t u be m a y b e c ollecte d if t he pati e nt has f u ncti o ni n g I V access. 
 
Plas ma f or meas ur e me nt of de x a met has o ne c o n ce ntrati o ns ( 3 ml i n gree n t o p t u be) will be 
o btai ne d o n Da y 8 of Rei n d ucti o ns I a n d II ( Da y 8 of wee ks 7 a n d 1 7). 
 
C S F fr o m t hera p e utic l u m bar p u nct ures will be c ollecte d at SJ C R H a n d place d i nt o 
s ulf osalic ylic aci d- c o ntai ni n g t u bes pri or t o i n d ucti o n t hera p y ( wit h I T M H A) a n d o n Da ys 
8 (if a p plica ble) a n d 1 5 of re missi o n i n d ucti o n t hera p y, a n d o n Da y 1 of c o ns oli dati o n a n d 
da y 1 of wee k 7 of Rei n d ucti o n I.  C S F as para gi ne le vels will be meas ure d acc or di n g t o 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
o ur pre vi o usl y esta blis he d met h o ds. A n a d diti o nal bl o o d sa m ple ( 3 ml gree n t o p t u be) will 
be o btai ne d o n t he da y of dia g n osis of sa gittal si n us t hr o m b osis or a n y d ee p vei n 
t hr o m b osis f or meas ure m e nt of as para gi nase c o nce ntrati o n. 
 
Ser u m ( 3 ml bl o o d i n re d-t o p t u be) will be o btai ne d at da y 1 5 of i n d ucti o n, da y 1 5 of 
c o ns oli dati o n, a n d at wee ks 7, 8, a n d 1 7 of c o nti n u ati o n f or ster oi d/as para gi nase 
bi o mar kers (e. g. ser u m li pi ds, c ortis ol).  
 
1 0. 4 
Plas ma H o m oc ystei n e 
 
A 2 m L sa m ple of bl o o d will be place d i n E D T A ( p ur ple-t o p) t u bes c ollecte d pre- 
i nf usi o n a n d, 6, 2 3 an d 4 2 h o urs p ost t he first a n d sec o n d c o urses of H D M T X d uri n g 
c o ns oli dati o n.  Sa m ples will be se nt t o t he Cli nical P har mac o ki netics La b a n d ke pt at 
4° C u ntil ce ntrif u gati o n.  After ce ntrif u gati o n, sa m ples will be fr oze n a n d assa ye d 
s u bse q ue ntl y f or h o m oc ystei ne. 
 
1 1. 0 
E V A L U A TI O N S, T E S T S, A N D O B S E R V A TI O N S  
 
1 1. 1  
Pretreat me nt E val u ati o n 
 
All partici pa nts s h o ul d be i n vite d t o partici pate i n t he Tiss ue Ba n ki n g Pr ot oc ol 
( TB A N K) at t he ti me of st u d y e ntr y. 
 
 C o m plete hist or y a n d p h ysical e x a m wit h caref ul n otati o n a n d assess me nt of 
cli nical si g ns r ele va nt t o le u ke mia. 
 C o m plete bl o o d c o u nt wit h differe ntial 
 C he mistr y pr ofile: gl uc os e, electr ol ytes, B U N, creati ni ne, L D H, uric aci d, 
bilir u bi n, S G O T, S G P T, calci u m, p h os p h or o us, ma g n esi u m, t otal pr otei n 
an d al b u mi n. 
 L i pi d scree n: T otal c h olester ol, tri gl yceri des, free fatt y aci ds a n d hi g h- 
de nsit y li p o pr otei n c h olester ol 
 Plas ma 1, 2 5- di h y dr o x y vita mi n D, oste ocalci n 
 T h yr oi d f u ncti o n tests (free T 4, T 4, T S H) 
 C hest x-ra y 
 B o ne marr o w e val uati o n: m or p h ol o g y, c yt oc he mistr y, 
i m m u n o p he n ot y pi n g, c yt o ge n etics, D N A i n d e x, m olec ular dia g n osis, 
M R D st u dies 
 L u m bar p u nct ure wit h C S F e x a mi nati o n (cell c o u nt wit h differe ntial of 
c yt os pi n pre parati o n) 
 N K cell rece pt or st u dies, e x ce pt i n patie nts recei vi n g ster oi ds. 
 Ot her st u dies as cli nicall y i n dicat e d, e. g. sic kle cell pre p, he m o gl o bi n 
electr o p h oresis a n d G 6 P D scree n f or blac k c hil dre n; varicella titer; H e patitis B 
a nti ge n; HI V, E B V, T O X O, C M V titers. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 1. 2  
Data t o be O btai n e d Seri all y W hile O nst u d y  
Test/e v al u ati o n  
At di a g n osis  
I n d ucti o n/ C o ns oli d ati o n 
C o nti n u ati o n  
Rei n d ucti o n I & II  
P h ysical E x a m  
At dia g n osis  
q 3 -7 da ys  
q 4 wee k  
q 3 -7 da y  
C B C wit h differe ntial  At dia g n osis  
wee kl y  
wee kl y  
wee kl y  
C oa g ulati o n scree n  
At dia g n osis  
--- 
--- 
--- 
Uric aci d, 
electr ol ytes, calci u m 
p h os p h or o us, 
ma g n esi u m  
At dia g n osis  
Bef ore eac h H D M T X  
 
As i n dicate d  
Da y 1 ( Wee ks 7 & 
1 7)  
Ser u m gl uc os e, 
uri nal ysis  
At dia g n osis  
As i n dicate d  
As i n dicate d  
As i n dicate d  
Bilir u bi n, S G O T, 
S G P T, t otal pr ot ei n, 
al b u mi n,  
L D H, B U N, 
creati ni ne  
At dia g n osis  
Bef ore eac h H D M T X  
As i n dicate d  
Da y 1 of Wee ks 7, 8, 
9, 1 7, a n d 1 9  
M R D *  
( See ta bles bel o w) 
At dia g n osis  
 
Da y 8, Da y 1 5  
( da y 2 2) * , a n d  
E n d of i n d ucti o n  
( Wee k 4 9)*  
Wee k 1 2 0  
( Da y 1 
Wee ks 7 & 1 7) *     
 
T ota l c h olester ol, 
tri gl yceri des, free 
fatt y aci ds, a n d hi g h-
de nsit y li p o pr otei n 
c h olester ol  
At Dia g n osis  
 - - -  
 
After 
c o m pleti o n of 
t hera p y ( Wee k 
1 2 0 or later)  
Da y 1 of eac h Re -
I n d u cti o n ( Da y 1 of 
Wee ks 7 a n d 1 7)  
C S F st u dies  
At dia g n osis 
( wit h first 
i ntrathecal 
treat me nt) 
Wit h eac h i ntrat hecal 
treat me nt 
Wit h eac h 
i ntrat hecal 
treat me nt; t he n  
q 1 6 w k  
 
Wit h eac h  
I ntr at hecal treat me nt 
C hest x -ra y 
At dia g n osis  
E n d of i n d ucti o n i n cases 
wit h me diasti nal mass at 
dia g n osis, t he n as 
i n dicate d.  
Bef ore eac h H D M T X i n 
patie nts o n dasati ni b a n d 
as i n dicate d  
As i n dicate d  
As i n dicate d  
M RI of hi ps a n d 
k nees  
(>  9 year -ol d o nl y)  
- - - 
- - - 
Off t hera p y  
After eac h 
rei n d ucti o n p hase 
( Wee ks 1 2-1 4 a n d 
2 2 -2 4)  
P T/ O T E val uati o n ( >  
9 year -ol d o nl y)  
- - - 
- - - 
Off t hera p y  
After eac h Re -
i n d ucti o n 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Test/e v al u ati o n  
At di a g n osis  
I n d ucti o n/ C o ns oli d ati o n 
C o nti n u ati o n  
Rei n d ucti o n I & II  
Ger mli ne D N A/ R N A  
- - - 
Da y 3 a n d d uri n g 
c o ns oli dati o n ( wit h bl o o d 
f or H D M T X) 
 
- - - 
- - - 
 
 
 
Ps yc h ol o g y * * * *  
 
Wee k 7 C o nti n uati o n 
( Wee k 1 Rei n d ucti o n I) 
Wee k 1 2 0  
T w o years p ost t hera p y  
M RI Brai n * *  
 
Wee k 7 C o nti n uati o n 
( Wee k 1 Rei n d ucti o n I) 
Wee k 1 2 0  
T w o years p ost 
t hera p y * * * 
F u ncti o nal 
M RI * * * * *  
 
 
Wee k 1 2 0  
 
R B C T P M T a n d 
T G N  
- - - 
Da y 3 ( T P M T)  
- - - 
Da y 1 of wee k 7 ( T G N) 
a n d wee k 1 7( T P M T)  
C Y P 2 D 6 g e n ot y pi n g  
 
Da y 1 5  
 
 
 
Plas ma 
H o m oc yst ei ne  
 
Pre a n d 6, 2 3, 4 2 h o urs 
p ost H D M T X # 1 a n d # 2.  
Secti o n 1 0. 4  
 
 
M T X 
P har mac o ki netics  
- - - 
Eac h H D M T X  
- - - 
 
as para gi n ase 
a nti b o dies  
Da y 1  
Da ys 1, 8, 1 5, a n d Da y 1 of 
c o ns oli dati o n  
- - - 
Da y 1 ( wee ks 7, 8, 9,  
1 7,  1 9 )  
C S F as para gi n e  
Wit h first 
i ntrat hecal 
Da ys 8, 1 5 i n d ucti o n a n d  
wee k 1 c o ns oli dati o n  
- - - 
Wee k 7 ( Da y 1)  
Ser u m bi o mar kers  
- - - 
Da y 1 5 of i n d ucti o n a n d 
c o ns oli dati o n  
- - - 
wee ks 7, 8, 1 7  
As para gi nas e acti vit y  
Da y 1  
Da ys 1, 8, a n d 1 5 pl us 2 -3 
time p oi nts o ver t he first 1 4 
da ys  of i n d ucti o n; Da y 1 
c o ns oli dati o n  
- - - 
Da y 1 ( wee ks 7, 8, 9, 
1 7, 1 9  
De x a met has o ne 
acti vit y 
Da y 8  
Da y 8 d uri n g wee ks 7 &  1 7  
- -
  
 
Q C T f or b o ne de nsit y  Wee k 1  
- - - 
Wee ks 1 2 0  
- - - 
Uri nal ysis  
As nee de d  
As nee de d  
As nee de d  
As nee de d  
T h yr oi d f u ncti o n  
At dia g n osis  
- - - 
As cli nicall y 
i n dicate d 
- - - 
A m m o nia l e vel 
- - - 
I n d u cti o n: Da y 1, 5, 8, 1 5, 
a n d 2 2 
C o ns oli dati o n: Da y 1  
S R/ H R 
partici pa nts 
o nl y:  
Da y 1 ( Wee ks 
1, 1 3, 2 3, & 2 9)  
Da y 1: ( Wee ks 7, 8, 9, 
1 7, 1 8, & 1 9)  
N K Cell Rece pt or  
At dia g n osis  
- - -  
- - -  
Wee k 7 ( Da y 1)  
St o ol s a m ples f or 
Micr o bi o me researc h  
 
1) pre -c he m o 
2) wit hi n 2 wee ks 
c o m pleti o n I n d u cti o n.  See 
secti o n 1 6. 7 
 
Da y 1 ( wee ks 7 &  1 7)  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
* See t a bles bel o w f or s a m ples re q uire d f or M R D st u dies  
* * M R  s h o ul d be o bt ai ne d bef ore st arti n g dex a met h as o ne. 
* * * P ati e nts wit h a b n or m al i m a gi n g ev al u ati o ns at week 1 2 0 will h ave a n extr a ex a m 
at  2 ye ars off t her a py t o re assess br ai n str uct ure.  
* * * * Ne ur o psyc h ol o gic al testi n g s h o ul d be perf or me d pri or t o i niti ati o n of  dex a met h as o ne 
o n d ay 1 of Rei n d ucti o n I. Testi n g m a y  be c o m plete d u p t o 4 weeks pri or t o d ay 1 of  
Re i n d ucti o n I t o a cc o m m o d ate a p atie nt’s tr a vel a n d tre at m e nt sc he d ule. If u n a ble t o 
sc he d ule pri or t o dex a met h as o ne, c o nt act Dr. C o n kli n f or sc he d uli n g. 
* * * * * F u ncti o n al M RI will be perf or me d o nly o n p atie nts w h o q u alify f or t his ex a m. F or a 
list of  eli gi bility re q uire me nts, s e e Secti o n 1 2. 0.  
* * * * * * N K Cell Rece pt or st u dies will n ot be d o ne i n p atie nts recei vi n g ster oi ds 
 
S a m ples re q uire d f or M R D st u dies d uri n g re missi o n i n d ucti o n 
Ti me p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
  Da y 8  
P B  
P B  
  Da y 1 5  
B M  
B M a n d P B  
 ( Da y 2 2 if M R D+  o n Da y 1 5)  
B M  
B M a n d P B  
  Da y 4 3  
B M  
B M a n d P B  
P B = peri p her al bl o o d; B M = b o ne m arr o w 
 
S a m ples re q uire d f or M R D st u dies p ost-re missi o n i n d ucti o n 
Ti me  p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
Da y 4 3 M R D +  
Da y 4 3 M R D - 
Da y 4 3 M R D + ( or 
“at y pical” T -A L L)  
Da y 4 3 M R D - 
Da y 1 ( Wee ks 7, 1 7, 4 9)  
B M  
N o ne  u nless 
cli nicall y 
i n dicate d, or 
M L L +  
B M a n d P B  
P B  
Wee k 1 2 0 ( off t hera p y)  
B M  
B M  
B M a n d P B  
B M a n d P B  
P B = peri p her al bl o o d; B M = b o ne m arr o w  
 
1 1. 3 
Off- T h era p y E v al uati o ns 
 
It is rec o m me n de d t hat p atie nts will be f oll o we d e ver y 4 m o nt hs f or 1 year, e ver y 6 
m o nt hs f or 1 year a n d t he n yearl y u ntil t he patie nt is i n re missi o n f or 1 0 years a n d is at 
least 1 8 years ol d.  T h ere after, t he p atie nt will bec o me al u m ni a n d will be f oll o we d 
acc or di n g t o t he i nstit uti o n’s p olic y.  D uri n g t he St. J u de visit, C B C wit h differe ntial a n d 
ot her la b orat or y st u dies as cli nicall y i n dicat e d will be o btai ne d.  It is rec o m me n de d t hat 
Q C T f or b o ne de nsit y be perf or me d at 5 years off-st u d y. 
 
Patie nts will be c o nsi dere d off t hera p y 3 0 da ys after last treat me nt ta k e n.  A d verse e ve nts 
will n ot be re p orte d w hil e patie nt is off-t hera p y u nless t he y are d ee me d rel ate d t o t hera p y 
b y t he site PI.  After attai ni n g c o nti n u o us, c o m plet e re missi o n f or 6 years or m ore, SJ C R H 
patie nts will be i n vite d t o partici pate i n t he l o n g-ter m f oll o w- u p u m brella pr ot oc ol a n d 
ma y  b e referre d t o t he After C o m pleti o n of T hera p y Cli nic ( A C T).  W he n a SJ C R H 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
patie nt has bee n i n r e missi o n f or 1 0 years a n d is at least 1 8 years of a ge, t h e patie nt will 
bec o me SJ C R H al u m ni a n d will be f oll o we d acc or di n g t o t he SJ C R H i nstit uti o nal p olic y. 
 
1 2. 0 
E V A L U A TI O N C RI T E RI A  
 
1 2. 1 
Res p o nse Criteria 
 
1 2. 1. 1  C o m plete re missi o n: M 1 marr o w stat us wit h rest or ati o n of n or mal 
he mat o p oiesis a n d n or mal perf or ma nce stat us. 
 
1 2. 1. 2  In d u cti o n fail ure:  5 % l e u ke mic blasts i n marr o w after 4 2 da ys of 
re missi o n i n d ucti o n treat me nt. 
 
1 2. 1. 3  B o ne marr o w rela pse: 2 5 % le u ke mic blasts i n marr o w 
 
1 2. 1. 4  C N S rela pse: 
pre parati o n. 
 
1 2. 1. 5  Testic ular rela pse: Is olat e d testic ular rela pse m ust be c o nfir me d 
pat h ol o gic all y; i n t he e v e nt of b o ne marr o w rela ps e, c o m bi ne d testic ular 
rela pse ca n be b ase d o n t estic ular e nlar ge me nt ( d o c u me nte d b y s o n o gra m) 
wit h o ut bi o ps y. 
 
1 2. 2  
T o xicit y E val u ati o n Criteria 
 
T his st u d y will utilize t he C T C A E Versi o n 3. 0 f or t o xicit y a n d perf or ma n ce re p orti n g.  A 
c o p y of t he C T C A E versi o n 3. 0 ca n be d o w nl o a de d fr o m t he C T E P h o me pa ge 
(htt p://cte p.i nf o. ni h. g o v) .  A d diti o nall y, t he t o xicities are t o be re p ort e d o n t he a p pr o pri ate 
data c ollecti o n f or ms. 
 
1 2. 3 
F u ncti o nal M RI E val uati o n Criteria 
 
P artici pa nts/ g uar dia ns will be gi ve n t he o pti o n t o a gree t o t his a d diti o nal res earc h t est 
eit her d uri n g t he i nf or m e d c o nse nt pr ocess f or C o ns oli dati o n a n d C o nti n uati o n of 
Treat me nt or b ef ore t he s ca n is perf or me d at e n d of treat me nt f or all t hree ris k ar ms.  O nl y 
t h ose patie nts w h o ha ve a gree d t o t his a d diti o nal test a n d meet t he f oll o wi n g eli gi bilit y 
criteria will be sc h e d ule d f or t his e x a m. 
 
 P atie nt is at least 8 years ol d at Wee k 1 2 0. 
 Patie nt’s pri mar y la n g ua ge is E n glis h. 
 Patie nt d oes n ot ha ve braces or ort h o d o ntic a p plia nces t hat ca us e i ma ge 
dist orti o n or si g nal l oss o utsi de of t he m o ut h a n d si n us area. 
 Patie nt d oes n ot ha ve a n y maj or p h ysic al, ne ur ol o gical, or ps yc hiatric c o n diti o n 
t hat w o ul d precl u de parti ci pati o n i n t he f u ncti o nal M RI. 
 Patie nt d oes n ot ha ve a d oc u me nte d lear ni n g dis a bilit y or atte nti o n dis or der 
t hat pre dates ca ncer dia g n osis. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 3. 0  
S U P P O R TI V E C A R E  
 
1 3 . 1 
Fe ver at Dia g n osis 
 
All patie nts wit h fe ver at dia g n osis will be a d mitte d f or br oa d s p ectr u m pare nteral 
a nti bi otic treat me nt u ntil a n i nfecti o us eti ol o g y ca n be e x cl u de d. 
 
1 3. 2  
Meta b olic Dera n ge me nts 
 
It is i m p orta nt t o pre v e nt or treat h y per urice mia a n d h y per p h os p hate mia wit h sec o n dar y 
h y p ocalce mia res ulti n g fr o m s p o nta ne o us or c he m ot hera p y-i n d uce d le u ke mic cell l ysis, 
es peciall y i n T-cell A L L. 
 
 P atie nts wit h lar ge l e u ke mic cell b ur de n s h o ul d recei ve h y drati o n a n d oral 
p h os p hate bi n der. 
 
 P atie nts wit h l ar ge l e u ke mic cell b ur de n wit h or wit h o ut h y per urice mia (e. g., W B C 
1 0 0 x 1 0 9/ L, uri c aci d 7. 5 m g/ dl or 6. 5 m g/ dl i n patie nts < 1 3 years ol d) ma y b e 
treate d wit h ras b uricas e if t he y h a ve n o hist or y of G 6 P D deficie nc y or o n g oi n g 
pre g na nc y.  F or patie nts n ot at hi g h ris k of h y per urice mia, h y drati o n, all o p uri n ol, 
a n d j u dici o us use of al kali nizati o n ( kee pi n g uri ne p H bet wee n 6. 5 a n d 7. 4) ma y b e 
s ufficie nt. 
 
1 3. 3 
H y p erle u k oc yt osis 
 
F or patie nts wit h e xtre me h y p erle u k o c yt osis (i. e., W B C > 3 0 0 x 1 0 9/ L), le u ka p heresis or 
e x c ha n ge tra nsf usi o n (i n s mall c hil dre n) ma y be c o nsi dere d. T he Direct or of t he Bl o o d 
Ba n k s h o ul d be c o ns ulte d f or t his pr oce d ure. 
 
1 3. 4 
A vasc ular Necr osis of B o ne 
 
Oste o necr osis of t h e b o n e, a k n o w n c o m plicati o n of treat me nt wit h c ortic oster oi ds, c a n be 
e x pecte d t o occ ur i n a p pr o xi matel y 1 0- 1 5 % of patie nts, es peciall y i n t h ose ol der t ha n ni ne 
years of a ge.  T his de v astati n g c o m plicati o n ma y res ult i n c olla pse of t he artic ulati n g 
s urface wit h s u bse q ue nt pai n a n d de vel o p me nt of art hritis. Earl y detecti o n of s mall lesi o ns 
will per mit i nter ve nti o n w hic h ma y pre v e nt pai n a n d irre v ersi ble da ma ge of t he j oi nts.  I n 
t his st u d y, all patie nts 9 years of a ge a n d ol d er will ha ve M RI sca ns of t he p el vis/ hi ps a n d 
k nees aft er eac h rei n d ucti o n p hase, at off t hera p y date, a n d as n ee de d t h ereafter. 
 
Patie nts dia g n ose d wit h oste o necr osis (see secti o n 7. 8) will be referre d t o ort h o pe dics. 
A n y p atie nt w h o de vel o ps s y m pt o ms of j oi nt pai n pri or t o or bet wee n sc he d ule d M RI 
sca ns s h o ul d ha ve a n M RI p erf or me d t o r ule o ut oste o necr osis or pr o gressi o n of t his 
c o m plicati o n. 
 
F or patie nts w h o re q uire s ur gical i nter ve nti o n, treat me nt will var y b ase d o n de gree of 
pr o gressi o n, i.e., o bser vati o n, c ore dec o m pressi o n, b o ne grafti n g a n d res urfaci n g 
he miart hr o plast y. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 3. 5  
Pa nc yt o p e nias 
 
Pa tie nts wit h pr ol o n ge d ( > 3 wee ks) u ne x plai ne d a ne mia ( he m o gl o bi n < 7 g/ dl) or 
ne utr o pe nia ( A N C < 3 0 0/ m m 3) d uri n g re missi o n s h o ul d be e val uate d f or B 1 9 par v o vir us 
i nfecti o n or he m ol ysis or t o xicit y fr o m n o n-c he m ot hera pe utic a ge nts (e. g., T M P/ S M Z). 
 
1 3. 6 
N utriti o nal S u p ple me ntati o n 
 
N utriti o nal or vita mi n t hera pies s h o ul d n ot res ult i n patie nts recei vi n g m or e t ha n t he R D A 
f or f olic aci d wit h dietar y a n d s u p ple me nt i nta ke, t o pre ve nt i nterfere nce wit h t he 
effecti ve ness of met h otr e x ate. 
 
1 3. 7 
Dr u g I nteracti o ns 
 
Be ca use c o nc urre nt use of e nz y me i n d uci n g a ntic o n v ulsa nts (e. g. p he n yt oi n, 
p he n o bar bital, a n d car ba maze pi ne) wit h a nti-le u ke mic t hera p y h as rece ntl y bee n 
ass ociate d wit h i nferi or E F S, e ver y eff ort s h o ul d be ma de t o a v oi d t hese a ge nts, as well as 
rifa m pi n, w hic h als o i n d uces ma n y dr u g met a b olizi n g e nz y mes. 
 
Ga ba pe nti n d oes n ot i n d uce he p atic dr u g meta b olizi n g e nz y mes a n d ma y b e a s uita ble 
alter nati ve a ntic o n v ulsa nt.  
 
Az ole a ntif u n gals (fl uc o n az ole, itrac o naz ole, v oric o naz ole, a n d ket oc o naz ol e) a n d t he 
macr oli de gr o u p of a nti bi otics (e. g. er yt hr o m yci n, rifa m pi n, a n d zit hr o ma x) ma y h a ve 
p ote nt i n hi bit or y effects o n dr u g- meta b olizi n g e n z y m es, a n d t he d oses of s o me a nti-
le u ke mic dr u gs (e. g. vi n cristi ne, a nt hrac ycli n es, ster oi ds, et o p osi de) ma y n ee d t o be 
red uce d i n s o me p atie nts o n c hr o nic az ole a ntif u n gals or a nti bi otics.  C o ns ult 
P har mac o ki netics if l o n g-ter m use of t hes e i nteracti n g dr u gs is u na v oi da ble. 
 
Pe nicilli ns i nterfere wit h t u b ular e x creti o n of met h otre x ate, a n d it is rec o m me n de d t hat a n 
alter nati ve n o n- p e nicilli n a nti bi otic be use d. 
 
1 3. 8 
D o w n S y n dr o m e 
 
P atie nts wit h D o w n’s s y n dr o me s h o ul d be cl osel y m o nit ore d f or t o xicit y, a n d offere d 
a g gressi ve s u p p orti ve care. Met h otre x ate d osa ge will be re d uce d as descri be d i n secti o n 
7. 1. 1.  Hist oricall y, m ost of t hese patie nts will be treate d i n t he l o w-ris k cat e g or y, a n d 
s h o ul d ha ve t heir c h e m ot hera p y d oses a p pr o pri atel y re d u ce d t o a v oi d u n d u e t o xicit y. Oral 
le uc o v ori n ( 5 m g/ m2 q 1 2 hr x 2) s h o ul d be gi ve n 2 4 hrs after eac h I T M H A. All D o w n’s 
patie nt will recei ve t h e c o n ve nti o nal ( 2 5 0 0 u nits/ m 2) d ose of P E G-as para gi nase p ost 
re missi o n i n d ucti o n a n d will n ot be i ncl u de d i n t he ra n d o mizati o n t o t he hi g her d ose of 
P E G-as para gi nase. A 3 0 % d ose re d u cti o n of de x a met has o ne a n d/ or hi g h d ose c yt ara bi ne 
s h o ul d be c o nsi dere d f or D o w n’s s y n dr o me patie nts treate d o n t he sta n dar d/ hi g h-ris k ar m 
w h o e x perie nce hi g her t h a n e x pecte d t o xicit y d uri n g earlier p hases of t hera p y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 3. 9  
R S V P r o p h yl a xis 
 
All i nfa nts s h o ul d recei v e R S V pr o p h yla xis as per c urre nt i nstit uti o nal p olic y. 
 
1 3. 1 0 Pr o p h yla ctic A nti bi otics D uri n g Peri o ds of Pr ol o n ge d Ne utr o pe nia 
 
P atie nts wit h e x pecte d peri o ds of se vere ne utr o p e nia ( A N C < 3 0 0) of 5 da ys or l o n ger (e. g., 
d uri n g  i n d ucti o n, r ei n d ucti o n, a n d i nte nsificati o n) s h o ul d recei ve pr o p h yl actic a nti bi otics 
( va nc o m yci n + ci pr ofl o x aci n or cefe pi me) a n d a ntif u n gals ( micaf u n gi n if patie nt is 
recei vi n g w ee kl y vi ncristi ne, or v oric o naz ole if patie nt has c o m plete d all vi ncristi ne d oses 
i n t he treat me nt p hase). 
 
1 4. 0 
O F F- T R E A T M E N T A N D O F F- S T U D Y C RI T E RI A  
 
1 4. 1  
Off Treat me nt Criteria 
 
A pa tie nt is ta ke n off T O T X VI t hera p y if a n y of t he f oll o wi n g o cc urs: 
 
 F ail ure t o a c hie ve re missi o n after re missi o n i n d ucti o n, c o ns oli dati o n, a n d 
rei nte nsificati o n treat me nt 
 B o ne marr o w or e xtra me d ullar y (e x ce pt C N S) rel a pse  
 S ec o n d mali g n a nc y (e. g., t hera p y-i n d uce d A M L or brai n t u m or) 
 De vel o p me nt of u nacce pta ble t o xicit y d uri n g treat me nt ( wit h c o nc urre nce 
of t he PI or c o- PI) 
 P atie nts wit h se vere c o n ge nital i m m u n o deficie nc y (e. g. ata xia 
tela n gi ectasia) or HI V i nfecti o n will be ta ke n off T O T X VI t hera p y a n d 
will recei ve alter nate t h era p y (t o pre v e nt e xcessi ve t o xicities) wit h 
c urati ve i nte nt. 
 C o m pleti o n of all pr ot oc ol- prescri b e d treat me nt 
 P artici pa nt/fa mil y decisi o n t o wit h dra w fr o m pr ot oc ol treat me nt at a n y 
ti me f or a n y reas o n 
 I n v esti gat or deci d es c o nti n ue d pr ot oc ol treat me nt is n o l o n ger i n patie nt’s 
best i nterest 
 
1 4. 2 
Off St u d y Criteria 
 
A pa tie nt is ta ke n off T O T X VI st u d y if a n y of t h e f oll o wi n g occ urs: 
 
 Deat h 
 L ost t o f oll o w- u p 
 Wit h dra wal of c o nse nt f or c o nti n ue d f oll o w- u p 
 F o u n d t o be i neli gi ble (e. g., i nc orrect dia g n osis) 
 
F oll o w u p will st o p at t he ti me t he patie nt is off st u d y. T he f oll o w u p ti me of a n 
off-st u d y patie nt is ce ns ore d at t his p oi nt, a n d n o o utc o me data be y o n d t h e off- 
st u d y ti me will be use d i n a nal ys es. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 5 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 5. 0 
D A T A S A F E T Y M O NI T O RI N G B O A R D  
 
T he  pr ot oc ol pr o gress will be re vie we d a n d m o nit ore d b y t he St. J u de C hil dre n’s Researc h 
H os pital Data Safet y M o nit ori n g B o ar d ( D S M B).  Data s u m maries will be pr o vi de d t o t he 
D S M B b y t h e De p art me nt of Bi ostatistics after re vie w b y t h e Pri nci pal I n v esti gat or.  T he 
data will i ncl u de patie nt accr ual, de m o gra p hic s u m maries, gra de 3/ 4 t o xicities, maj or 
a d verse e ve nts (i.e. d eat hs, rela pses, sec o n d mali g na ncies) a n d res ults of i nteri m a n d fi nal 
a nal ys es as s pe cifie d i n t he pr ot oc ol.  T he d ata are retri e ve d fr o m t he dat a b ase a n d are 
re vie we d at e ver y T O T X VI meeti n g, w hic h is ge n erall y hel d t wice a m o nt h, a n d are 
reflecte d i n t he mi n utes, w hic h are pr o vi de d t o t he bi ostatisticia n. W he n t he a p pr o priate 
n u m ber of patie nts ha v e faile d or accr ue d, tri g geri n g i nteri m or fi n al a nal ysis, t he 
bi ostatisticia n will be i nf or me d b y t h e PI.  S h o ul d a safet y st o p pi n g r ule b e e x cee de d, t he 
pr ot oc ol will be te m p oraril y cl ose d u ntil t he D S M B ca n re vie w t he sit uati o n. Re p orti n g 
will c o m pl y wit h i nstit uti o nal g ui deli nes f or m o nit ori n g. 
 
1 6. 0 
BI O L O GI C S T U DI E S  
 
1 6. 1 
Mi ni mal Resi d ual Disease 
 
T his s t u d y will a p pl y i m m u n ol o gic a n d m olec ular met h o ds as d o ne i n T O T X V. T he 
le u ke mia mar kers c o m m o nl y use d t o st u d y mi ni mal resi d ual diseas e b y 4- c ol or fl o w 
c yt o metr y are liste d i n t he t a ble bel o w. D uri n g t h e c o urse of T O T X VI, we will gra d u all y 
i ncreas e t he para meters t o be st u die d si m ulta ne o usl y, ta ki n g a d va nt a ge of n o vel 
i nstr u me nts t hat all o w t he detecti o n of 6 or m ore fl u or oc hr o mes. T his s h o ul d all o w a 
better discri mi nati o n of le u ke mi a cells w hile re d u ci n g t he n u m b er of cells re q uire d f or t he 
a nal ysis. 
 
I m m u n o p he n ot y pic mar kers m ost c o m m o nl y use d t o st u d y M R D i n c hil dre n wit h A L L 
A L L  li nea ge 
P he n ot y pe  
Fre q ue nc y  ( %)† 
B -li nea ge 
C D 1 9/ C D 3 4/ C D 1 0/ T d T *  
3 0 -5 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 3 8 *  
3 0 -5 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 4 5 *  
3 0 -5 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 1 3  
1 0 -2 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 1 5  
5 -1 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 3 3  
5 -1 0  
 
C D 1 9/ C D 3 4/ C D 1 0/ 7. 1  
3 -5  
 
C D 1 9/ C D 3 4/ C D 1 0/ C D 6 6c  
1 0 -2 0  
 
C D 1 9/ C D 3 4/ T d T/c yt o plas mic  µ *  
1 0 -2 0  
T -li nea ge 
T d T/ C D 3/ C D 5  
9 0 -9 5  
 
C D 3 4/ C D 3/ C D 5  
3 0 -5 0  
* T he use of t hese i m m u n o p he n oty pes f or M R D st u dies relies m ai nly o n differe nces i n i nte nsities of ex pressi o n  
bet wee n le uke mic ly m p h o bl asts a n d n or m al ly m p h oi d pr o ge nit or cells. T he re m ai ni n g c o m bi n ati o ns rely  m ai nly 
o n t he a berr a nt ex pressi o n of o ne of t he m arker s.  †Pr o p orti o n of c hil d h o o d A L L c ases i n w hic h o ne le uke mic 
cell i n 1 0 4 n or m al b o ne m arr o w cells c a n be  detecte d wit h t he liste d i m m u n o p he n oty pic c o m bi n ati o n. M ost c ases 
ex press m ore t h a n o ne c o m bi n ati o n s uit a ble f or M R D st u dies.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A n y p artici pa nt re gistere d i n T O T X VI w h ose l e u ke mic cells are a me na ble t o o ur assa ys 
will be eli gi ble f or testi n g.  Peri p h eral bl o o d sa m ples ( 5- 1 0 ml) will be ta k e n o n da y 8 i n 
all patie nts. B o ne marr o w sa m ples will be e x a mi ne d i n all patie nts o n da y 1 5 ( +/- 2 2) of 
remissi o n i n d ucti o n t hera p y a n d at c o m pleti o n of i n d ucti o n t hera p y; patie nts wit h T-
linea ge A L L will als o ha ve t heir peri p h eral bl o o d e x a mi ne d at t hese ti me p oi nts. All 
patie nts wit h B-li nea ge A L L wit h resi d ual blasts at e n d of i n d ucti o n will ha ve se q ue ntial 
M R D assa ys d uri n g re missi o n (e. g. d a y 1 of rei n d ucti o n I a n d II), a n d wee k 4 8 of 
c o nti n uati o n treat me nt. All patie nts wit h T-li nea ge A L L a n d resi d ual blasts at t he e n d of 
i n d ucti o n a n d t h ose wit h “at y pical” T- A L L will ha ve se q ue ntial M R D assa ys i n b o ne 
marr o w a n d p eri p heral bl o o d d uri n g re missi o n (e. g. da y 1 of rei n d u cti o n I a n d II), a n d 
wee k 4 8 of c o nti n uati o n treat me nt. Patie nts wit h T-li nea ge A L L a n d n o resi d ual blasts at 
t he en d of i n d ucti o n will ha ve M R D deter mi ne d o nl y i n peri p heral bl o o d at t he sa me ti me 
p oi nts. M R D will be als o deter mi ne d i n all patie nts w he ne ver cli nicall y i n dicate d. 
 
We will use dee p se q ue n ci n g te c h ni q ue t o e v al uate M R D i n C S F wit h t he ai m of 
deter mi ni n g w h et her l e vels of M R D i n t he C S F at dia g n osis a n d d y n a mics of earl y M R D 
re d ucti o n i n C S F c o ul d b e use d t o f urt her refi ne t h e ris k of C N S rela pse. T his mi g ht 
p ote ntiall y lea d t o i m pr o ve d classificati o n f or pati e nts at ris k of C N S rela pse a n d all o w t he 
re d ucti o n of i ntrat he cal t hera p y i n f ut ure st u dies i n c hil dre n wit h rare i de ntifia ble blast b y 
m or p h ol o g y b ut l o w le vels of M R D.  We will als o f oll o w M R D of t he b o ne marr o w a n d 
peri p heral bl o o d b y d ee p se q ue nci n g tec h ni q u e t o deter mi ne if t his m ore se nsiti ve a n d 
s pecific test will s h o w c o nc or da nce u nli ke t he fl o w a n d P C R base d M R D tests.  If 
c o nc or da nt, t he n we ca n m o nit or B- A L L patie nt usi n g a less i n vasi ve t esti n g of t he 
peri p heral bl o o d si milar t o T- A L L patie nts. 
 
1 6. 2  
Ger mli ne D N A/ R N A 
 
Peri p heral bl o o d ( 5 ml) at da y 3 (f or i nitial T P M T ge n ot y pi n g a n d as a bac k- u p f or a n y 
partici pa nts wit h earl y wit h dra wal or d eat h) a n d c o nc urre nt wit h t he bl o o d c ollecte d f or 
M T X plas ma le vels d uri n g c o ns oli dati o n.   Le u k o c yt es will be is olate d, a n d cells will be 
cr y o pres er ve d or D N A a n d R N A will be is olate d usi n g sta n dar d tec h ni q ues. 
 
A n ali q u ot of D N A fr o m e ver y patie nt w h o h as si g ne d T B A N K ( or its s uccee di n g b a n ki n g 
pr ot oc ol) will be a vaila bl e fr o m t he p har mac o ge netics D N A sa m ple t o t he Cell Ba n k 
la b orat or y. 
 
1 6. 3 
De x a met has o ne/ As para gi nase Ser u m P har mac o d y na mic Bi o mar kers 
 
B l o o d sa m ples ( 3 ml eac h) will be dra w n i n a re d t o p t u be at da y 1 5 of i n d ucti o n a n d da y 
1 5 of c o ns oli dati o n a n d at wee ks 7, 8, a n d 1 7 of c o nti n uati o n, a n d a gree n t o p t u be ( 3 ml 
eac h) will be dra w n o n D a y 8 of wee ks 7 a n d 1 7 of c o nti n uati o n. 
 
I n a d diti o n, hei g hts are n o w rec or de d caref ull y m o nt hl y o n a sta di o meter ( usi n g t he 
a vera ge of 3 re plicate m eas ures) a n d t hese d ata are e ntere d i n t he A S 4 0 0 a n d 
MI L LI/ P o w erc h art s yste ms.  B ot h c ortis ol a n d hei g ht c ha n ge ha v e bee n rel ate d t o 
gl uc o c ortic oi d plas ma A U C pre vi o usl y. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 6. 4  
Deter mi nati o n of A L L Blast Se nsiti vit y t o A nti- Le u ke mic A ge nts, i n vitro  
 
We will use a p orti o n of t he dia g n ostic b o ne marr o w fr o m eac h patie nt ha vi n g a n a de q u ate 
n u m ber of cells i n t he sa me e x vi v o dr u g se nsiti vit y assa y we ha v e pre vi o usl y use d t o 
meas ure resista nce t o a nti- leu ke mic a ge nts, as we ha ve pre vi o usl y des cri be d i n detail 1 3.  
W it hi n h o urs of sa m pli n g, m o n o n uclear cells are is olate d fr o m b o ne marr o w as pirates b y 
Fic oll- H y pa q u e gra di e nt; if necessar y, sa m ples are f urt her e nri c he d t o m ore t ha n 9 0 
perce nt le u k e mic blasts b y re m o vi n g n o n- mali g n a nt cells usi n g ma g netic acti vate d cell 
s orti n g.  Le u k e mic cells are t he n re-s us pe n de d i n c ult ure me di u m c o nsisti n g of R P MI 
1 6 4 0 s u p ple me nte d wit h 2 0 perce nt fetal calf ser u m, 2 m M L- gl uta mi ne, 2 0 0 g/ ml 
ge nt a mici n, 1 0 0 I U/ ml pe nicilli n, 1 0 0 g / ml stre pt o m yci n, 0. 1 2 5 g/ ml f u n giz o ne, a n d 5 
g/ ml i ns uli n, 5 g/ ml tra nsferri n a n d 5 n g/ ml s o di u m sele nite.  T hese t u m or cells are 
c ult ure d i n a 9 6- w ell micr o c ult ure plate i n t he prese nce of a ra n g e of dr u g c o nce ntr ati o ns. 
 
After 4 da ys of c ult ure, M T T ( 3- 4, 5- di met h ylt hiaz ol- 2, 5- di p he n yl tetraz oli u m br o mi de) is 
ad de d f or s e veral h o urs, as pre vi o usl y descri be d i n detail 1 3.  T his met h o d is use d t o 
de ter mi ne dr u g se nsiti vit y t o merca pt o p uri ne, t hi o g ua ni n e, pre d nis ol o ne, de x a met has o ne, 
vi ncr isti ne, L-as para gi nase, c yt ara bi ne, a n d d a u n or u bici n.   T hese st u dies re q uire < 2 x 1 05 
cells per well, f or 6 dr u g dil uti o ns i n d u plicate pl us 6 c o ntr ol wells, f or a t otal of 3 x 1 0 6 
cells per dr u g (If fe wer t ha n 2. 4 x 1 0 7 cells are a v aila ble, t he n we will w or k wit h t he 
Pat h ol o g y De p art me nt t o pri oritize w hic h dr u gs ca n be st u die d base d o n t he n u m ber of 
cells a vaila ble.  T his is t he sa me pr o ce d ure we h a v e ha d i n place si nce 2 0 0 0.) T he dr u g 
co nce ntr ati o n let hal t o 5 0 perce nt of t he le u ke mia cells ( L C 5 0- val ue) is use d as t he 
meas ure of cell ular dr u g resista nce. 
 
F or eac h a nti-l e u ke mic a ge nt, w e will treat t he i n vitr o i n di vi d ual dr u g a n d m ulti- dr u g 
cr oss se nsiti vities as c o nti n u o us p he n ot y pes i n dat a a nal yses. I n a d diti o n, we will se parat e 
patie nts i nt o t o p 2 5 %, mi d dle 5 0 % a n d b ott o m 2 5 % gr o u ps base d o n t heir dr u g 
se nsiti vities, ra n gi n g fr o m t he m ost resista nt t o t he m ost se nsiti ve. We will als o e x a mi ne if 
patie nts ca n be s e parate d i nt o gr o u ps bas e d o n a m o del base d cl usteri n g met h o d 
( M C L U S T) b ase d o n t heir dr u g s e nsiti vities. We will e x pl ore w het her i n di vi d ual dr u g 
se nsiti vities or m ulti- dr u g cr oss se nsiti vities differ a m o n g A L L s u bt y pes (e. g. B-li nea ge 
vs. T-cell). 
 
1 6. 5 
N K C ell R ece pt or St u d y 
 
Peri p heral bl o o d ( 3 ml) will be o btai ne d at dia g n osis f or i m m u n o p he n ot y pi n g a n d ( 8. 5 ml) 
bef ore rei n d ucti o n f or i m m u n o p he n ot y pi n g a n d ge n ot y pi n g f or N K cell rece pt ors as 
descri be d pre vi o usl y 8 2; 1 2 3.  Bl o o d sa m ples will be c ollecte d i n A C D ( yell o w-t o p) t u bes.  
We will assess N K cell rece pt ors i ncl u di n g KI Rs, N C Rs, N K G 2 D, D N A M- 1, 2 B 4, a n d 
N T B A.  T h e sa m ple s h o ul d be o btai ne d bef ore t h e a d mi nistrati o n of ster oi ds. 
 
1 6. 6 
I ntesti nal Micr o bi o me Researc h 
 
T o partici pate i n t his researc h, partici pa nts ca n n ot ha ve recei ve d c he m ot hera p y, f or l o n ger 
t ha n 7 2 h o urs, a n d m ust n ot ha ve recei ve d a nti micr o bial a ge nts f or > 7 2 h o urs wit hi n o ne 
wee k pri or t o e nr oll me nt.  Partici pa nts m ust als o n ot ha ve a cli nical or micr o bi ol o gicall y-
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
pr o ve n diarr heal ill ness. 
 
T w o st o ol s peci me ns will be c ollecte d fr o m res earc h partici pa nts, o ne is d uri n g a ti me 
peri o d bef ore starti n g i n d ucti o n c he m ot hera p y ( or u ntil t he first 7 2 h o urs after starti n g 
i n d ucti o n c he m ot hera p y), a n d t he sec o n d s a m ple will be c ollecte d wit hi n 2 wee ks after 
co m pleti o n of A L L re missi o n-i n d ucti o n c he m ot hera p y ( bef ore t he H D M T X d ose # 2 of t he 
c o ns oli dati o n p hase) t o i n vesti gate t h e c ha n ges i n t he g ut micr o bi ota. Pair e d st o ol sa m ples 
will be batc he d t o be a nal yz e d si m ulta ne o usl y. Bacterial ge n o mic D N A will be har veste d 
fr o m t hese sa m ples a n d utilize d f or ri b os o mal D N A se q ue nci n g t o deter mi ne t he o verall 
bacterial micr ofl ora pri or t o a n d f oll o wi n g c h e m ot hera p y. T h ese t w o met h o d ol o gies will 
pr o vi de a preli mi nar y i n v esti gati o n i nt o a n y n ota bl e alterati o ns i n bacterial di versit y 
res ulti n g fr o m t hera p e utic i nter ve nti o ns.  I n ta n de m, we will als o is olate R N A fr o m t hese 
sa m ples f or se q u e nci n g i n or der t o i de ntif y n o vel R N A vir uses. O nce n ot a ble differe nces 
i n t he micr o bi o me bef ore a n d after c he m ot hera p y are det er mi ne d, we will t he n atte m pt t o 
descri be t he gastr oi ntesti nal c o m plicati o ns d uri n g i n d ucti o n a n d o ver t he ne xt si x m o nt hs. 
I n p artic ular, we are i ntereste d i n w het her t h e a b u n da nce or a bse n ce of parti c ular bacteri al 
or viral pat h o ge ns will s h o w ass ociati o n wit h s u bse q ue nt gastr oi ntesti nal ill nesses. O ver 
t he a p pr o xi matel y 6 m o nt h peri o d after t h e c ollecti o n of t he sec o n d st o ol sa m ple, t w o 
f oll o w- u p st o ol sa m ples will be pr os pecti vel y c oll ecte d at ti me p oi nts w here patie nts are 
see n i n Me m p his: wit hi n 4 8 h o urs of Da y 1 of R ei n d ucti o n I a n d Rei n d ucti o n II. T hese 
st o ol sa m ples will be c ollecte d at t he s p ecifie d ti m e p oi nts irres pecti ve of i nta ke of 
a nti micr o bial a ge nts. I n a d diti o n, a 1. 0- 2. 0 m L v ol u me of left o ver st o ol s pe ci me ns 
c ollecte d at SJ C R H f or cli nical p ur p oses will be pr os pecti vel y o bt ai ne d fr o m t he cli nical 
bacteri ol o g y a n d vir ol o g y la b orat ories wit hi n 4 8 h o urs of c ollecti o n. T hes e st o ol sa m ples 
will be use d f or f urt her testi n g of bacterial a n d viral D N A usi n g P C R assa ys t hat will be 
de vel o pe d t o dete ct a n y viral or bact erial pat h o ge n t hat was pr o mi ne nt b y t he ge ne 
se q ue nci n g a n al ysis of t h e c ha n gi n g micr o bi o me.  T he sa me a p pr oac h will be use d t o 
i n vesti gate f u n gal pat h o ge ns.  Me dical r ec or ds will be re vie we d t o c ollect d ata a b o ut 
i nfecti o us diseases, pr o bi otics, a ntaci ds a n d a nti micr o bial use d uri n g t he st u d y peri o d. 
O nl y des cri pti ve statistics s uc h as me dia n, ra n ge a n d perce nt a ges will be us e d as 
a p pr o priate. T he pr o p ose d st u d y is i nte n de d t o be a pil ot i n vesti gati o n t o test feasi bilit y of 
t his a p pr oac h a n d o pti mi ze e x peri me ntal pr oce d ures. T he data a n d i nf or mati o n o btai ne d i n 
t hese i n vesti gati o ns will be utilize d as preli mi nar y data f or a lar ger scal e st u d y a n d f ut ure 
gra nt a p plicati o ns. 
 
1 6. 6. 1  Visi t A:  St o ol sa m ple will be c ollecte d d uri n g a ti me peri o d bef ore starti n g 
i n d ucti o n c he m ot hera p y ( or u ntil first 7 2 h o urs aft er starti n g i n d ucti o n c he m ot hera p y). T his 
s peci me n will be use d t o r u n t he la b orat or y i n v esti gati o n i n Dr. T u o m a ne n’s a n d Dr. 
Sc h ultz- C herr y’s rese arc h la b orat ories as d escri b e d i n secti o n 1 6. 7. 4. Visit A ca n occ ur o n 
t he sa me da y as s cree ni n g/e nr oll me nt. 
 
1 6. 6. 2  Visit B:  St o ol sa m ple will be c ollecte d wit hi n 2 w ee ks aft er c o m pleti o n of A L L 
re missi o n- i n d ucti o n c he m ot hera p y ( bef ore t h e H D M T X d ose # 2 of t he c o ns oli dati o n 
p ha se).  T his s peci me n will be use d t o r u n t he la b orat or y i n vesti gati o n i n Dr. T u o ma ne n’s 
a n d Dr. Sc h ultz- C herr y’s researc h la b orat ories as descri be d i n secti o n 1 6. 7. 4. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 6. 6. 3  F oll o w- u p st o ol s peci me ns:  O ver t he a p pr o xi matel y 6 m o nt h peri o d after t he 
c ollecti o n of t he sec o n d st o ol sa m ple ( Visit B), t w o f oll o w- u p st o ol sa m ples will be 
pr os pecti vel y c ollecte d at ti me p oi nts w here patie nts are see n i n M e m p his: wit hi n 4 8 h o urs 
of Da y 1 of Rei n d u cti o n I a n d Rei n d ucti o n II. T h ese st o ol sa m ples will be c ollecte d at t he 
s pecifie d ti me p oi nts irres pecti ve of i nta ke of a nti micr o bial a ge nts. I n a d diti o n t o t hese 
sa m ples, 1. 0- 2. 0 m L of left- o ver st o ol s peci me ns c ollecte d at SJ C R H f or bacterial st o ol 
c ult ure a n d C. difficile t o xi n detecti o n will be pr os pecti vel y o btai ne d fr o m t he cli nical 
bacteri ol o g y a n d vir ol o g y la b orat ories, res pecti vel y, wit hi n 4 8 h o urs of c ollecti o n. T hese 
st o ol sa m ples will be use d f or f urt her testi n g of bacterial a n d vir al D N A usi n g P C R assa ys 
t hat will be de vel o pe d t o detect a n y vir al or bact eri al pat h o ge n t hat was pr o mi ne nt b y t he 
ge n e se q ue n ci n g a nal ysis of t he c ha n gi n g micr o bi o me.  T he sa me a p pr oac h will be use d t o 
i n vesti gate f u n gal pat h o ge ns. 
 
1 6. 6. 4  La b orat or y met h o ds a n d materials 
 
Fecal sa m ples will be c ollecte d a n d i m me diatel y place d i nt o R N A Pr otect, a sta bilizati o n 
rea ge nt. T u b es will be pre pare d i n a d va nce a n d st ore d u ntil sa m ple c ollecti o n. Sa m ples 
will t he n be pr ocesse d wit hi n 6 h o urs of c ollecti o n. Fecal sa m ples will be st ore d at - 8 0˚ C 
u ntil pr ocessi n g at a later ti me i n batc he d r u ns. D N A a n d R N A will be e xtracte d fr o m t he 
sa m ple b y b ea d- b eati n g f oll o we d b y p h e n ol c hl or of or m e xtracti o n or c ol u m n p urificati o n 
met h o ds.  A n y left- o ver st o ol s peci me ns after t h e c o m pleti o n of t he D N A a n d R N A 
e xtracti o n will be discar de d. 
 
T he g ut micr o bi ota will be se q ue nce d usi n g t w o i n de pe n de nt met h o d ol o gies. O ne 
met h o d ol o g y will utilize u ni versal pri mers a n d s u bcl o ni n g t o a m plif y t he ri b os o mal 
se q ue nces fr o m t he is olat e d bacterial D N A. T h ese s u bcl o nes will t he n be utilize d t o 
ge n erat e a n Ill u mi na ge n o mic li brar y. T he ot her a p pr oac h will utilize D N A a n d R N A t hat 
has bee n e nric he d fr o m a n y e u k ar y otic c o nt a mi nati o n wit h o ut a n y s u bcl o ni n g. O ur 
met h o d ol o g y s h o ul d yi el d a p pr o xi matel y 1 0 0 µ gs of D N A a n d 2 0 µ gs of R N A, s ufficie nt 
f or a p pr o xi matel y te n i n d e pe n de nt se q u e nci n g r u ns. T his will all o w f or t he deter mi nati o n 
of bacterial di versit y i n t he g ut as well as t he i de ntificati o n of n o vel, g ut ass ociate d vir uses 
t hat c orrel ate wit h d o w nstrea m cli nical o utc o mes. 
 
F or t he se q u e nci n g, 3 p M of eac h s m all li brar y will be l oa de d o nt o a fl o w cell o n t he 
Ill u mi na Cl uster Stati o n. A 3 p M P hi X D N A sa m ple was use d as a cl uster a n d se q ue nci n g 
c o ntr ol.  T he rea ds o n t he si n gle rea d fl o wcell will t he n be s u bjecte d t o 1 5 2 c ycles of 
se q ue nci n g o n t he Ill u mi na Ge n o me A n al yzer platf or m. T he base calls were a nal yz e d 
usi n g Ill u mi na's Pi peli ne versi o n 1. 4. 0. T his met h o d ol o g y all o ws f or t he ge n erati o n of 
a p pr o xi matel y 1 0 milli o n rea ds of a n a vera ge le n gt h of 1 0 0 base pairs, pr o vi di n g e x celle nt 
ge n etic c o v era ge.   
 
T he rea ds will t he n be a n al yze d b y a n u m b er of rea dil y a v aila ble s oft w are pr o gra ms 
s pecificall y desi g ne d f or meta ge n o mic a nal ysis a n d p h yl o ge n etic rec o nstr ucti o n. T his will 
all o w f or t he det er mi nati o n of c ha n ges i n o v erall bacterial di versit y a n d p o p ulati o n 
d y na mics. T his met h o d ol o g y will als o all o w f or t h e detecti o n of a n y k n o w n or pre vi o usl y 
u nc haracteriz e d vir uses i n t he sa m ple. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 7. 0 
N E U R OI M A GI N G S T U DI E S  
 
T he  ne ur oi ma gi n g ai ms are or ga nize d u n der t he h y p ot hesis t hat t hera p y f or A L L ca n h a ve 
a detri me ntal i m pact o n t he de vel o pi n g brai n res ulti n g i n ne ur oc o g niti ve deficits, w hic h 
will res ult i n decreas e d q ualit y of life i n s ur vi v ors. T hera p y i n d uce d i ma gi n g c h a n ges i n 
t he de vel o pi n g brai n (s u c h as m yeli n a n d c ortical t hic k ness de vel o p me nt) c o ul d partiall y 
be relate d t o ge netic p ol y m or p his ms ass ociate d wit h f olate meta b olis m. 
 
St u d y  
I n d ucti o n 
C o ns oli dati o n  
Wee k  7,  c o nti n uati o n  
( Wee k 1 Re -i n d ucti o n I) 
Wee k  1 2 0,  
c o nti n uati o n 
T w o  year  p ost  
t hera p y 
P sy ch ol o g y   
 
X  
X  
X  
M RI -brai n  
 
 
X *  
X  
X * *  
* M R s h o ul d be o bt ai ne d bef ore st arti n g dex a met h as o ne. 
* * P atie nts wit h a b n or m al i m a gi n g ev al u ati o ns at week 1 2 0 will h ave a n extr a ex a m at 2 
ye ars off t her a py t o re assess br ai n str uct ure.  
 
1 7. 1 
M R I ma gi n g 
 
M R I of t he brai n will be o btai ne d at 2 ti me p oi nts: W ee k 1 of Rei n d ucti o n I ( Wee k 7 
C o nti n uati o n bef ore starti n g de x a met has o ne) a n d wee k 1 2 0 of c o nti n uati o n t hera p y. T hes e 
st u dies were d esi g n e d t o yi el d l o n git u di nal meas ures of w hite matter i nte grit y 
( m yeli nati o n) a n d c ortical t hic k ness d uri n g tr eat m e nt. 
 
T he first M RI e x a mi nati o n at Rei n d ucti o n I will pr o vi de a q ua ntitati ve meas ure of m yeli n 
a n d c ortical t hic k n ess de vel o p me nt relati ve t o a ge n der a n d a ge mat c he d h ealt h y c o ntr ol 
gr o u p, w hic h ma y be disr u pte d b y t hera p y. T h e sec o n d M RI e x a mi nati o n is at wee k 1 2 0 of 
c o nti n uati o n (e n d of t hera p y). B y assessi n g all patie nts at t his ti me p oi nt, we ca n 
deter mi ne if t he n or m al brai n de vel o p me nt has b ee n affecte d b y t hera p y. 
 
T hese a b bre viate d cli nical M RI sca ns will c o nsist of T 1 sa gittal f or l ocalizati o n f oll o we d 
b y hi g h-res ol uti o n T 1, T 2/ P D, a n d F L AI R i ma ges c o veri n g t he e ntire cere br u m ac q uire d 
at 3 Tesla. T hes e are f oll o we d b y D TI a n d m yeli n water i ma gi n g. T he f ull e x a mi nati o n 
ca n be p erf or m e d i n a p pr o xi matel y 4 5 mi n utes f or c hil dre n n ot re q uiri n g se dati o n a n d 7 5 
mi n utes f or c hil dre n re q uiri n g se d ati o n. 
 
M ost  c hil dre n si x years of a ge a n d ol d er ca n t olerate t he pr oce d ure wit h o ut se dati o n. All 
sca ns will be e val u ate d b y a n e ur ora di ol o gist f or cli nicall y rel e va nt fi n di n gs t hat will be 
ca pt ure d i n a d ata re p orti n g f or m. 
 
T he T 1, T 2/ P D, a n d F L AI R i ma ges will be a nal yz e d wit h s oft ware de vel o p e d a n d 
vali date d at o ur ce nter s p ecificall y f or q ua ntificati o n of w hite matter c h a n ges a n d brai n 
tiss ue v ol u mes. T hese hi g h-res ol uti o n i ma ges will als o be use d t o assess c ortical t hic k ness 
base d o n t he se g me nt e d tiss ue ma ps usi n g t he Free S urfer s oft ware. D TI ac q uires a set of 
diff usi o n i ma ges i n si x or m ore directi o ns a n d us es t he m t o f ull y defi n e a diff usi o n te ns or 
f or eac h p oi nt i n t he i ma ge1 2 4; 1 2 5.  O nce t he te ns ors ha ve bee n calc ul ate d, Ei ge n v al ues ca n 
be  deri ve d a n d use d t o c alc ulate a p pare nt diff usi o n c oeffi cie nt ( A D C), per pe n dic ular a n d 
parallel diff usi o n c o effi cie nts ( D , D||), an d fracti o nal a nis otr o p y ( F A) ma ps f or t he w h ole 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
brai n. T hese me as ures are relate d t o t he i nte grit y of t he m yeli n s h eat h w hi c h restricts t he 
diff usi o n of water per pe n dic ular t o t he a x o ns wit hi n t he w hite matter fi ber tracts. M yeli n 
water i ma gi n g will be a n al yze d usi n g s oft ware de vel o pe d a n d vali dat e d at o ur ce nter 
s pecificall y f or q ua ntificati o n of m ulti-e x p o ne ntial T 2 rela xati o n data t o assess t he 
i nte grit y of t he m yeli n s h eat h. Q ua ntitati ve m ulti ple e x p o ne ntial fitti n gs of t he T 2 
rela x ati o n c o m p o ne nts i n w hite matter ca n b e use d t o ge n erate M W F m a ps (fr o m t he T 2 
c o m p o ne nts less t ha n 4 0- 5 0 ms) a n d L W F ma ps ( T 2 c o m p o ne nts 2 0 0- 8 0 0 ms). 
 
I ma gi n g fr o m a ver y lar ge a ge-si milar healt h y c o ntr ol p o p ulati o n has bee n c ollecte d u n der 
t he “ NI H M RI St u d y of N or mal Brai n De v el o p me nt”  
(htt p:// w w w. bic. m ni. m c gill.ca/ ni h p d/i nf o/ ). T he first p hase of t his pr oject e nr olle d 
c hil dre n a ges 4 years, 6 m o nt hs t hr o u g h 1 8 years (t otal N = 4 3 3). T his sa m ple was 
recr uite d acr oss t he si x Pe diatric St u d y Ce nt ers usi n g c o m m u nit y b ase d sa m pli n g t o reflect 
t he de m o gra p hics of t h e U nite d States i n ter ms of i nc o me, race, a n d et h nicit y. T he s u bjects 
are st u die d wit h b ot h i ma gi n g a n d cli nical/ be ha vi oral meas ures at t w o year i nter vals f or 
t hree ti me p oi nts. I m a gi n g c ollecte d i ncl u de d c o n ve nti o nal T 1-/ T 2-/ P D- wei g hte d M R 
i ma gi n g as w ell as diff usi o n te ns or i ma gi n g. T hes e i ma gi n g d ata sets will be a nal yz e d wit h 
t he sa me pr oce d ures us e d f or t he patie nt e xa mi nati o ns. 
 
1 7. 2 
Ge netic P ol y m or p his ms 
 
All patie nts wil l be ge n ot y p e d as descri be d i n secti o n 2. 2. 1. We will f oc us o ur a nal ysis o n 
a t he oreticall y j ustifie d cl ass of p ol y m or p his ms relate d t o t he f olate met a b olis m pat h wa y. 
All rele va nt f olate pat h w a y p ol y m or p his ms will be i ncl u de d, gi ve n t heir relati o ns hi p t o 
M T X treat me nt a n d ele v ate d h o m oc ystei ne. Ge nes of i nterest i ncl u de M T H F R, D H F R, 
T S, R F C, M S, M T R R, a n d C B S. 
 
1 7. 3 
Ps yc h ol o gical T esti n g 
 
A ge  a p pr o priate ps yc h ol o gic al testi n g will be perf or me d i n all partici pa nts at Wee k 1 of 
Rei n d ucti o n I ( Wee k 7 of C o nti n uati o n), at wee k 1 2 0 of C o nti n uati o n, a n d t w o years p ost 
t hera p y. Ps yc h ol o gical m eas ures were caref ull y selecte d base d o n ps yc h ol o g y a n d M RI 
fi n di n gs fr o m t he T O T X V pr ot oc ol, as well as t he a vaila ble researc h literat ure1 2 6 - 1 3 2. B ot h 
li nes of e m pirical s u p p ort c o n ver ge i n i de ntif yi n g atte nti o n/e x ec uti ve f u ncti o ns, me m or y 
( partic ularl y n o n v er bal) a n d pr ocessi n g s pee d as v ul nera ble c o g niti ve f u ncti o ns i n t his 
p o p ulati o n. B y f oc usi n g t he assess me nt batter y o n s pecific c o g niti ve f u n cti o ns, rat her t ha n 
m ore tra diti o nal gl o bal meas ures (i.e., I Q a n d aca d e mic ac hie ve me nt), t he pr o p ose d 
batter y will ha ve i ncreas e d se nsiti vit y t o t h ose deficits m ost li kel y t o be de m o nstrate d b y 
A L L s ur vi v ors. F urt her, a f oc use d assess me nt will facilitate t he i de ntificati o n of s pecific 
c o g niti ve areas f or earl y i nt er ve nti o n a n d assist i n t he i de ntificati o n of u n derl yi n g 
ne ur ol o gi cal mec h a nis ms. I n a d diti o n t o be ha vi oral s pecificit y, m eas ures w ere sel ecte d 
t hat ha ve ne ur oa nat o mic s pecificit y i n kee pi n g wit h T O T X V ne ur oi ma gi n g fi n di n gs. 
T heref ore, me as ures w ere select e d t h at are p ut ati vel y s u b ser ve d b y fr o ntal brai n re gi o ns 
(e. g., atte nti o n, fl ue n c y a n d w or ki n g m e m or y) a n d peri ve ntric ular areas (e. g., ver bal a n d 
n o n ver bal me m or y). M eas ures were als o c h os e n t hat ha ve bee n de m o nstrat e d i n ot her 
cli nical p o p ulati o ns t o be se nsiti ve t o w hite matter c ha n ges (i. e., pr ocessi n g s pee d a n d 
vis ual-s patial a bilities). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
All selecte d meas ures ha ve a ge-s p ecific n or ms fr o m lar ge, re prese nt ati ve sta n dar dizati o n 
sa m ples. Meas ur es als o h a ve a p pr o priatel y de m o nstrate d relia bilit y a n d vali dit y. Gi ve n t he 
l o n git u di nal st u d y desi g n, meas ures w ere c h ose n wit h a p pr o priate test-retest relia bilit y a n d 
ne gli gi ble practice effects f or t he pr o p ose d i nter val bet wee n testi n g ti me p oi nts. A n eff ort 
was ma de t o select meas ures t hat c o ul d assess t he wi dest a ge ra n ge p ossi ble gi v e n t he 
li kel y a ge distri b uti o n at prese ntati o n a n d l o n git u di nal desi g n. N o net heless, n o si n gle 
i ntelli ge nce m eas ur e e xists t hat c o vers t his e ntire a ge s p ectr u m, s uc h t hat a se parat e I Q 
meas ure is ne e de d f or c hil dre n less t ha n t hree years of a ge. C hil dre n less t h a n t hree years 
of a ge will be a d mi nistere d t he M ulle n Scales of Earl y Lear ni n g 1 3 3.  Pare nt q uesti o n naires 
will  be t he sa me f or patie nts t o all o w f or l o n git u di nal a nal yses i ncl u di n g t his y o u n g gr o u p. 
Please see A p p e n di x VI f or a c o m plete listi n g of test meas ures, assesse d a bilities, 
ad mi nistrati o n a ge ra n ge a n d esti mate d testi n g ti m e f or c hil dre n. 
 
A pri mar y assess me nt g o al was t o select a batter y t hat c o ul d be a d mi nistere d i n a 
circ u mscri be d p eri o d of ti me t o re d uce t he ti me b ur de n f or c hil dre n, t heir p are nts a n d t he 
researc h te a m. T he a d mi nistrati o n ti me f or t he test batter y is 1- 3 h o urs, de p e n de nt o n t he 
a ge of t he c hil d a n d t he s pee d wit h w hic h t he y ca n c o m plete tas ks. It is a ntici pate d t hat t he 
a vera ge a d mi nistrati o n ti me will be 2 h o urs. T he ma xi m u m a d mi nistrati o n ti me of 3 h o urs 
is o nl y e x pecte d f or ol d er c hil dre n (i.e., 7- 8 years of a ge) or c hil dre n t h at are n ota bl y sl o w 
(e. g., u n us uall y sl o w s pe e d of c o g niti ve a n d/ or p h ysical pr ocessi n g). T h eref ore, t he 
a d mi nistrati o n le n gt h of t he c urre nt batter y rea dil y lies wit hi n t he sta n dar d le n gt h of 
t y pical cli nical a n d researc h batteri es. It is a ntici pate d t hat pare nts will s pe n d o n a vera ge 
of 4 5 mi n utes c o m pleti n g q uesti o n nair es w hile t h eir c hil d is bei n g assesse d i n a se parate 
r o o m. 
 
1 7. 4 
F u ncti o nal M R I m a gi n g 
 
B l o o d O x y ge n ati o n Le vel De pe n de nt I ma gi n g ( B O L D) is t he 'sta n dar d tec h ni q ue' us e d t o 
ge n erat e i ma ges i n f u ncti o nal M RI st u dies, a n d relies o n re gi o nal differe n ces i n cere bral 
bl o o d fl o w t o deli neate re gi o n al acti vit y d uri n g t h e perf or ma nce of a s p ecific 
ne ur oc o g niti ve tas k. B O L D i ma gi n g is a c q uire d acr oss t he e ntire brai n c o nti n u o usl y 
d uri n g t he p erf or ma nce of t he tas k. T he N- Bac k tas k is a pr ot ot y pical w or ki n g me m or y 
meas ure t hat re q uires a n o n-se date d p artici pa nt t o res p o n d t o a prese nte d sti m ul us (eit her 
letters or o bjects i n o ur i m ple me ntati o n) o nl y w he n it is t he sa me as t he o ne prese nt e d o n a 
trial a pre d eter mi ne d n u m ber ( N) pri or t o t he c urre nt trial. F or eac h letter partici pa nts nee d 
t o hit a res p o nse b utt o n w he n t he letter is i de ntical t o t he letter pres e nte d o ne or t w o bac k 
i n se q ue nce f or t he 1- b ac k a n d 2- bac k trials, res pecti vel y. A c o ntr ol c o n diti o n ( 0- bac k 
trial) will be use d d uri n g w hic h t he sa me c o nti n u o us strea m of si n gle letters or o bj ect is 
prese nte d b ut t he p artici p a nt nee d o nl y deci de w het her eac h letter or o bj ect matc hes a 
si n gle tar get c o m m u nicat e d at t he start of t he t as k. Patie nts w h o meet eli gi bilit y f or t he 
f u ncti o nal M RI (see Secti o n 1 2. 3) will u n der g o t his test at Wee k 1 2 0 of C o nti n uati o n.  I n 
a d diti o n t o t he letter a n d o bject versi o ns of t he N Bac k t as k, t he f u ncti o nal M RI will als o 
i ncl u de a tas k t o i de ntif y t he pri mar y vis ual c ort e x a n d a tas k t o i de ntif y resti n g net w or ks. 
 
F u ncti o nal B O L D i ma ges will be a nal yze d wit h S P M ( S P M 5, U ni versit y C olle ge L o n d o n, 
U K) via 2-le v el a nal ysis. N or malizati o n of f M RI data fr o m c hil dre n a n d a d ults t o t he sa me 
stere otactic brai n s pace h as bee n vali dat e d f or c hil dre n ol der t ha n 7 years 1 3 4; 1 3 5.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
I n d e pe n de nt c o m p o ne nt a nal ysis (I C A) of f M RI d ata will be c o n d uct e d wit h t he GI F T 
T o ol b o x  f or S P M. N- Bac k data will be a nal yze d acc or di n g t o a fi x e d-effect G L M. T as k-
i n d uce d acti vit y will be re prese nt e d b y a b o x car f u ncti o n c o n v ol ve d wit h t he ca n o nical 
he m o d y n a mic res p o nse f u ncti o n. After para meter esti mati o n, t he c o ntrasts reflecti n g t he 
effect of i nterest (e. g., 2- bac k > 1- b ac k) will be set i n t he m o del, a n d t he c orres p o n di n g 
co ntrast i ma ge will be ge nerate d. T h e c o ntr ast i ma ge fr o m eac h s u bject will t he n be use d 
as a vari a ble i n sec o n d-le vel, ra n d o m-effect a nal ysis t o i de ntif y gr o u p patter ns of 
acti vati o n a n d areas i n w hic h brai n acti vit y is ass o ciate d wit h be ha vi or al perf or ma nce.  
V o x els will be c o nsi dere d acti ve f or p < 0. 0 5, c orrecte d f or m ulti ple c o m paris o ns. O ur 
pri mar y a nal ysis will f oc us o n acti vati o n i n t he d ors olateral pr efr o nt al c orte x d uri n g t he N-
bac k tas k. 
 
1 8. 0 
S T A TI S TI C A L C O N SI D E R A TI O N S  
 
T O T X VI h as a si n gle pri mar y o bj ecti ve t o c o m pare t he distri b uti o ns of c o nti n u o us 
c o m plete re missi o n ( C C R) of patie nts ra n d o mize d o n t he first da y of c o nti n uati o n p hase t o 
recei v e hi g h er d ose P E G-as para gi nase or t o recei ve c o n ve nti o nal d osi n g ( 2, 5 0 0 u nits/ m 2). 
T he stratifie d a n al ysis of t he pri mar y o bjecti ve will i ncl u de all eli gi ble patie nts as 
ra n d o mize d a n d will be c o n d ucte d c o nsiste nt wit h t he i nte nt-t o-treat h y p ot h esis. Zel e n’s 
ra n d o mizati o n al g orit h m, as i m ple me nte d i n t he De part me nt of Bi ostatistics si nce 1 9 9 2, 
will be use d wit h a bl oc ki n g fact or of 4 i n eac h strat u m. Details of t he desi g n, sa m ple siz e 
a n d statistical met h o d ol o g y re q uire d f or t he pri mar y o bjecti ve is a d dresse d i n Secti o n 1 7. 2 
a n d will be t he defi ni n g s a m ple siz e f or T O T X VI.  
 
T he ref us al of partici pati o n i n a n y of t he res earc h ai ms will n ot re n der a patie nt i neli gi ble 
f or T O T X VI; patie nts w h o ref use t o c o nse nt t o s o me or all of t he researc h o bjecti ves will 
still be e val ua ble f or ot her st u d y ai ms i ncl u di n g esti mati o n of t he distri b uti o ns of e ve nt-
free s ur vi val a n d s ur vi val. Desi g n p ara m eters f or t he pri mar y o bjecti ve will n ot be 
a dj uste d f or m ulti ple tests. H o we ver, wit hi n a sec o n dar y o bjecti ve it ma y b e a p pr o pri ate t o 
a p pl y met h o ds t o c o ntr ol t he t y pe I err or rate i n ter ms of t he fa mil y- wise t y pe I err or 
pr o ba bilit y or t he false disc o ver y rate, a n d t hes e are s pelle d o ut bel o w. All a nal yses of t he 
ra n d o mize d q uesti o n will be c o nsiste nt wit h t he “i nte nt t o treat” h y p ot hesis; t hat is, all 
eli gi ble ra n d o mize d patie nts will be f oll o we d f or t he pri mar y o utc o me a n d i ncl u de d i n 
a nal ys es as r a n d o mize d. T o t he e xte nt p ossi ble, as i n dicate d i n t he f oll o wi n g secti o ns, all 
eli gi ble patie nts will be i ncl u de d i n all a nal yses.  
 
Met h o d ol o g y f or a nal yzi n g dat a relat e d t o sec o n d ar y o bjecti ves are prese nt e d, b ut i n 
ge n eral p o w er calc ulati o ns are n ot pr o vi de d si nce t he sa m ple siz e f or t he trial is g o ver ne d 
b y t he pri mar y o bjecti ve. M ore o ver, if d uri n g t he c o urse of t his trial m ore a p pr o priate 
statistical met h o ds are i de ntifie d or de v el o pe d, t he n t h ose met h o ds will be use d t o a nal yze 
t he data. 
 
Effect siz e: T he i nte nt- t o-treat h y p ot hesis bei n g teste d i n T O T X VI is t hat d oses of P E G-
as para gi n ase hi g her t h a n c o n ve nti o nal d oses bei n g use d b y ot h er A L L researc h gr o u ps 
will i m pr o ve o utc o me of c hil dre n wit h A L L. T he trial will be gi n b y ra n d o mizi n g patie nts 
t o recei v e eit her 3, 5 0 0 u nits/ m2 or 2, 5 0 0I u nits/ m2 of P E G-as para gi nase d uri n g 
co nti n uati o n t hera p y a n d if 3, 5 0 0 u nits/ m 2 pr o ves t o be t o o t o xic (see 1 7. 1. 2) t he trial will 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c o nti n ue wit h patie nts bei n g ra n d o mize d t o eit her 3, 0 0 0 u nits/ m 2 or 2, 5 0 0 u nits/ m 2.  It 
s h o ul d be n ote d t hat t he i nte nt of T O T X VI is t o test w het her hi g her-t ha n-c o n ve nti o nal 
d oses of P E G-as para gi nase i m pr o ve o utc o me a n d n ot t o deter mi ne t he differe nce i n 
effic ac y or t o xicit y bet w ee n 3, 5 0 0 u nits/ m 2 a n d 3, 0 0 0 u nits/ m2 d osa ges. As disc usse d 
bel o w, s h o ul d t he hi g h er d ose of 3, 5 0 0 u nits/ m 2 pr o ve t o be t o o t o xic, we still will be a ble 
t o ge n erat e ne w i m p orta nt i nf or mati o n a n d i nter preta ble res ults.  
 
T he c o nje ct ure d effect size f or hi g h er d oses of P E G-as para gi nase re prese nts ris k- be nefit 
c o nsi derati o ns of w h at o utc o me is reas o n a ble t o e x pect a n d w o ul d j ustif y acce pti n g 
p ossi bl y sli g htl y hi g h er rates of ma na gea ble as para gi n ase t o xicities. W het her t he 
h y p ot hesize d effect size will be ass ociate d wit h e x p os ure t o 3, 5 0 0 u nits/ m 2 or 3, 0 0 0 
u nit s/ m2 is n ot k n o w n a n d w het her t here will be u nacce pta ble t o xicities ass ociate d wit h 
t he hi gher d ose is als o n ot k n o w n. W hat we d o k n o w is t hat t he trial wit h tra diti o nal 
statistical desi g n para met ers pr o vi des p o wer f or detecti n g a differe n ce i n 5- year 
c o nti n u o us c o m plete re missi o n ( C C R) rates of 8. 5 3 % bet wee n t he c o n v e nti o nal vers us t he 
hi g her d ose a n d fi nal i nter pretati o ns re q uire t hat t h e o verall effect size of 8. 5 3 % is 
mai ntai ne d if t o xicit y re q uires t hat t he d ose of P E G-as para gi nase b e re d uce d f or m 3, 5 0 0 
u nits/ m 2 t o 3, 0 0 0 u nits/ m2. Secti o n 1 7. 2 i ncl u des o ne of ma n y p ossi ble realizati o ns of t he 
trial t hat w o ul d be c o nsiste nt wit h a n o verall 8. 5 3 % i m pr o ve me nt i n t he 5- year C C R rate.  
We d o n ot k n o w w hat deli vera ble d ose of P E G-as para gi nas e is act uall y necessar y t o 
pr o d uce t hes e res ults. We d o belie ve d os es hi g h er t ha n c o n ve nti o nal d oses ca n be s afel y 
gi ve n a n d t hat t hese hi g h er d oses will pr o d uce i m pr o ve d o utc o me, w hi c h re mai ns a n 
i m p orta nt g oal f or c hil d h o o d A L L treat me nt as c urre ntl y n ot all c hil dre n are c ure d. 
 
I nter pret ati o n: We belie ve t hat 3, 5 0 0 u nits/ m
2 of P E G-as para gi nase ca n be deli vere d 
safel y wit hi n t he c o nte xt of T O T X VI ris k- directe d re gi me ns, a n d e x pect t hat t he m ost 
li kel y realizati o n of t he trial is t hat a t o xicit y m o nit ori n g r ule d uri n g c o nti n uati o n t hera p y 
will n ot be tri g gere d a n d we will n ot ha ve t o d ose-re d uce P E G-as para gi nas e. H o we v er, we 
ha ve pla n ne d a c o urse of acti o n if u nacce pta bl e t o xicit y were t o materialize.  
 
T he q uesti o n t hat re mai ns is w hat i nfere n ce will b e dra w n at t he e n d of t h e trial if d ose-
re d ucti o n of P E G- as para gi nas e is re q uire d. If it is necessar y t o d ose-re d uce, a n d if t he 
pla n ne d fi nal a n al ysis of t he trial res ults i n a p- val ue greater t ha n 0. 0 4 5, t he pri mar y 
c o ncl usi o n will be t hat, as i nte n de d t o be deli vere d i n T O T X VI, t he statistical e vi de n ce is 
n ot s ufficie nt t o c o ncl u de t hat t he distri b uti o ns of C C R bet wee n patie nts w h o w o ul d 
recei ve hi g her d os es of P E G-as para gi nas e a n d t h ose patie nts w h o w o ul d recei ve 
c o n ve nti o nal d osi n g differ. F urt her m ore, we w o ul d ha ve e vi de nce t hat, at t he a pri ori  
t hres h ol d set f or t o xicit y, 3, 5 0 0 u nits/ m2 of P E G-as para gi nas e was dee me d t o o t o xic. As 
wit h m ost a m pl y p o were d ne gati ve trials, a d diti o n al a nal yses will li kel y b e atte m pte d t o 
el uci date t he fi n di n gs. T h ese a n al ys es w o ul d pre d o mi na ntl y rel y o n esti mati o n a n d n ot 
testi n g, al beit wit h li mite d p o wer. We s pec ul ate o n o nl y a fe w of t h e ma n y p ossi ble 
reas o ns w h y t he tri al ma y e n d wit h t his res ult. It mi g ht be t hat t he o verall treat me nt res ults 
f or b ot h c o n ve nti o nal a n d hi g her d ose P E G-as p ara gi n ase re gi me ns were s o g o o d t hat n o 
differe nce c o ul d be det ecte d; t hat ha d 3, 5 0 0 u nits/ m 2 bee n t olerate d t he h y p ot hesize d 
diff ere nce m a y ha ve b ee n detecte d; t hat t here was e vi de nce t h at patie nts ra n d o mize d t o 
t he hi g her d ose P E G- as p ara gi nas e treat me nt re gi me n di d e x perie nce a better o utc o me b ut 
n ot as great as n ecessar y f or t he n u m ber of patie nts ra n d o mize d a n d e ve nts o bser ve d t o 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 6 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
s h o w a statistical differe nce; t hat patie nts ra n d o mize d t o c o n ve nti o nal d osi n g ha d a m uc h 
better o utc o me t ha n e x pecte d. P u blicati o n of fi n di n gs fr o m t his a de q uatel y p o were d 
ne gati ve st u d y w o ul d i ncl u de retr os pecti ve a n al ys es e x pl ori n g “ w h y, ” as w o ul d be 
e x pecte d b y j o ur nal re vi e wers a n d rea d ers. We m ust a d d t hat if t he trial were st o p pe d d ue 
t o f utilit y, t hes e a nal ys es w o ul d be c o n d ucte d wit h m uc h less statistical p o wer a n d w o ul d 
be less li kel y t o yiel d usef ul i nf or mati o n o n w hic h f ut ure i n vesti gati o ns c o ul d be b uilt.  
 
If it is necessar y t o d ose-re d uce a n d t he pla n n e d fi nal a nal ysis of t he trial r es ults i n a 
statisticall y si g nifi ca nt p- val ue ( < 0. 0 4 5), t he pri mar y c o ncl usi o n will be t hat, as i nte n de d 
t o be deli vere d i n T O T X VI, t he statistical e vi de n ce is s ufficie nt t o c o ncl u d e t hat t he 
distri b uti o ns of C C R bet wee n patie nts w h o w o ul d recei ve hi g her d oses of P E G-
as para gi n ase a n d t h ose p atie nts w h o w o ul d recei v e c o n ve nti o nal d osi n g are differe nt. 
F urt her m ore, w e w o ul d h a ve e vi de nce t hat, at t he a pri ori  t hres h ol d set f or t o xicit y, 3, 5 0 0 
u nit s/ m2 of P E G-as para gi nase was d ee me d t o o t o xic. A d diti o nal a nal yses will be re q uire d 
t o f ully el uci d ate t he fi n di n gs a n d a gai n we s p ec ul ate o n se veral p ossi ble reas o ns f or t he 
res ults. It mi g ht be t hat t he o utc o me f or p atie nts r a n d o mize d t o 3, 5 0 0 u nits/ m 2 was s o 
s u peri or t hat differe n ces f or t his strat u m d o mi nate d t he o verall res ults; t hat o utc o me f or 
patie nts ra n d o mize d t o b ot h 3, 5 0 0 u nits/ m 2 a n d 3, 0 0 0 u nits/ m2 were si milar a n d s u peri or 
t o the o utc o me f or patie nts w h o were ra n d o mize d t o 2, 5 0 0 u nits/ m 2; or t hat m ost patie nts 
ra n d o mize d t o hi g h d ose P E G-as para gi nase were i n t he 3, 0 0 0 u nits/ m2 re gi me n a n d t he 
o utc o me  was s u peri or t o t he o utc o me f or p atie nt r a n d o mize d t o c o n ve nti o nal d oses of 
P E G-as para gi nase. All t hree p ossi bilities are easil y i nter prete d a n d t he first w o ul d 
sti m ulate researc h as t o h o w 3, 5 0 0 u nits/ m 2 ma y b e safel y gi ve n. 
 
We ha ve p ur p osef ull y n ot s pecifie d a n accr ual n u m ber at w hic h t he tri al w o ul d be 
restarte d usi n g o nl y t he l o wer 3, 0 0 0 u nits/ m2 P E G-as para gi nase, if t h e hi g h er d ose is t o o 
t o xic, n or ha ve we s u g geste d t hat o utc o me at t hat ti me c o ul d hel p ma ki n g a decisi o n 
re gar di n g restarti n g t he trial. T here are si m pl y t o o ma n y s p ec ulati ve sce nari os t hat c o ul d 
occ ur a n d i n all li keli h o o d t here w o ul d be t o o little o utc o me i nf or mati o n t o s he d li g ht o n 
t he sit uati o n. H o we ver, T O T X VI will be m o nit ore d b y t he St. J u de D S M B t hat is 
c o m p ose d of se ni or, e x perie nce d cli nical trial e x perts. We ha ve c h ose n t o d esi g n t he tri al 
as we ha v e, k n o wi n g a n d f ull y e x pecti n g t hat t he D S M B will pr o vi de g ui da nce i n t he 
u nli kel y e v e nt t hat 3, 5 0 0 u nits/ m 2 pr o ves t o be t o o t o xic.   
 
S a m ple size & st u d y d ur ati o n : T he accr ual g oal of t his st u d y is 4 2 0 e val u a ble patie nts f or 
t he c o nti n uati o n p hase ra n d o mizati o n bet wee n hi g her d ose P E G-as para gi nase a n d sta n dar d 
d ose P E G-as para gi nase. T his sa m ple siz e is dictate d b y p o wer c o nsi derati o ns f or t he 
pri mar y o bjecti ve, as disc usse d i n Secti o n 1 7. 2. C urre nt T O T X V e x perie nce s h o ws t hat 
a b o ut 5 % of t he patie nts faile d t o e nter t he c o nti n uati o n p hase of treat me nt. Alt h o u g h e v er y 
eff ort will be ma d e t o c o nse nt patie nts t o t he ra n d o mize d st u d y, we a ntici p ate a p pr o xi matel y 
1 0 % of patie nts will n ot c o nse nt t o partici pate i n t he ra n d o mizati o n; t h us a n attriti o n rate of 
1 4. 5 % is e x pecte d a n d a t otal accr ual of a p pr o xi matel y 5 3 1 eli gi ble p atie nts t o T O T X VI 
will  be necessar y. Hist orical data fr o m T O T XIII A, T O T XIII B, a n d T O T X V (see Secti o n 
1 7. 2) i n dicate t hat t his accr ual g oal ca n be reac he d i n a b o ut 8. 6 years.  
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T his sa m ple siz e pr o vi des a p pr o xi matel y 8 0 % p o wer t o detect t he h y p ot hesiz e d 
i m pr o ve me nt i n t he distri b uti o n of C C R ( α = 0. 0 5; t w o-si de d test) f or patie nts treate d o n 
t he hi g h d ose P E G-as para gi n ase re gi me n. D ue t o t w o pla n ne d i nteri m a nal ys es, t he fi nal 
a nal ysis, if all 4 2 0 patie nts are ra n d o mize d, will be c o n d ucte d at t he 0. 0 4 5 le vel. T his fi nal 
anal ysis will be c o n d ucte d t hree years after t he last patie nt is ra n d o mize d. T h us, t he t otal 
d urati o n of t he st u d y c o ul d be a p pr o xi matel y 1 1. 6 years.  
 
1 8. 1  
Safet y M o nit ori n g  
 
T he  t hres h ol ds f or s afet y m o nit ori n g were c h ose n after caref ul c o nsi derati o n of t he 
p ote ntial ris k/ be nefit rati o f or t he trial. All eli gi ble patie nts w h o recei ve a n y T O T X VI 
i n d ucti o n t hera p y will be i ncl u de d i n safet y m o nit ori n g des cri be d b el o w fr o m t he i nitiati o n 
of i n d ucti o n t hera p y t o t h e be gi n ni n g of c o nti n uati o n t hera p y. All eli gi ble p atie nts w h o are 
ra n d o mize d a n d recei ve a n y c o nti n uati o n t hera p y will be i ncl u de d i n safet y m o nit ori n g 
descri be d b el o w f or t he i nter val fr o m i nitiati o n of c o nti n uati o n t hera p y t o t he e n d of Wee k 
3 5 of c o nti n uati o n. M o nit ore d e ve nts t hat occ ur after wee k 3 5 of c o nti n uati o n t hera p y are 
n ot li kel y t o be rel ate d t o P E G-as para gi nase a n d t h us will n ot be c o nsi dere d i n t he f or mal 
safet y m o nit ori n g pla n. 
 
Critical f or t he ti m el y s afet y m o nit ori n g descri be d i n t his secti o n is u p- t o- date a n d 
acc urate dat a f or a nal ysis. Eac h of t he m o nit ori n g a nal ys es, e x ce pt f or d eat h d uri n g 
i n d ucti o n, will be c o n d ucte d as f oll o ws: 
 
1.  T he  tri g geri n g e v e nt will be c o nfir me d b y t h e atte n di n g p h ysici a n a n d t h e pr ot oc ol 
PI. U p o n c o nfir mati o n, all ass ociate d i nf or mati o n f or t he e v e nt ( dates, gra d e, etc) 
will be l oc ke d (fr oze n) i n t he T O T X VI d ata bas e. 
2.  T he  pr ot oc ol bi ostatisticia n will e xtract data fr o m t he T O T X VI d ata bas e a n d 
c o n d uct t he a n al ysis. 
a. If t he safet y st o p pi n g t hr es h ol d is n ot reac he d, t h e trial c o nti n ues u na bate d 
an d t his will c o ncl u de t he a nal ysis f or t his e ve nt. 
b.  If t he safet y st o p pi n g t hr es h ol d is e x cee de d, t he a nal ysis is re p eate d b y 
ass u mi n g t hat patie nts w h o d o n ot ha ve data i n t h e T O T X VI data bas e 
c urre nt t o t he d ate of t he tri g geri n g e ve nt are “s afe” o n t hat date.  
i. 
If t he a n al ysis of t hes e data still e xcee ds t he st o p pi n g t hres h ol d, 
t he n t he a p pr o pri ate acti o n descri be d b el o w is e x ec ute d. 
ii. 
If t he a n al ysis of t hes e data d oes n ot res ult i n t he st o p pi n g t hres h ol d 
be i n g e x cee de d, t he n t h e rele va nt dat a i n t he T O T X VI data base is 
i m me diatel y ( wit hi n se veral da ys) u p dat e d a n d t he a nal ysis 
re peat e d. T his will c o nstit ute t he fi nal a nal ysis tri g gere d b y t he 
e ve nt a n d a p pr o priate acti o n will be ta ke n pe n di n g o n w het her t he 
st o p pi n g t hres h ol d is or is n ot e x cee de d. 
3.  S afet y m o nit ori n g r ules pr o vi de a statistical fra me w or k i n w hic h t o c o nsi der 
w het her o bser ve d t o xicities are e x cessi ve. U p o n c o m pleti o n of a n i nteri m a nal ysis, 
t he fi n di n gs will be re p orte d t o t he St. J u de D S M B t hat will ma ke 
rec o m me n dati o ns t o t he pr ot oc ol PI a n d a d vise t h e St. J u de lea ders hi p o n 
c o nti n ui n g, st o p pi n g or a me n di n g t he trial.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
F or t he m o nit ore d t o xicities d uri n g T O T X V i n d ucti o n, t he rece nt e x perie n ce (as of 
6/ 5/ 2 0 0 7) s h o ws t hat o ut of 4 5 3 patie nts, t here are 2 ( 0. 4 4 %) deat hs, 5 ( 1. 1 %) seiz ures 
( gra de 2 or m ore), 1 1 ( 2. 4 %) m uc ositis, a n d 1 1 ( 2. 4 %) i nfecti o ns ( gra de 4). As of 
5/ 2 3/ 2 0 0 7, t he c u m ulati ve i nci de nce of disse mi nat e d f u n gal i nfecti o ns till t he e n d of re-
i n d ucti o n II is 4. 6 % ± 1. 0 9 %, a n d is 5. 9 % ± 1. 2 4 % o ver t he e ntire treat me nt d urati o n. As of 
6/ 2 5/ 2 0 0 7 t here are 6 fat al c he m ot hera p y t o xicities o n T O T X V ( 4 at SJ: 2 i n i n d ucti o n, 1 
i n c o ns oli dati o n, a n d 1 i n c o nti n uati o n; 2 at C o o k’s: 1 i n re-i n d ucti o n I a n d 1 i n re-
I n d u cti o n II). All n o n-fat al t o xicities ha ve bee n m a na gea ble.  
 
Pa ncreatitis a n d dee p vei n t hr o m b osis ( D V T) are t w o as para gi nase  relate d t o xicities t hat 
will  be cl osel y m o nit ore d i n T O T X VI d ue t o t he i n creas e d e x p os ure of patie nts t o t his 
a ge nt. O n T O T X V t hera p y, n o patie nt e x perie nce d re peat e d e pis o des of pa ncreatitis or 
D V T i n t he i nter val bet w ee n i nitiati o n of t hera p y a n d t he be gi n ni n g of c o nti n uati o n 
t hera p y. D uri n g c o nti n uati o n t hera p y o n e patie nt di d e x perie nce t w o e pis o d es of D V T b ut 
n o patie nt e x perie nce d m ulti ple e pis o des of pa ncreatitis. 
 
Pa ncreatitis is a t o xicit y t hat is ass ociate d wit h as p ara gi nas e  treat me nt a n d t h us will be 
caref ull y m o nit ore d d uri n g i n d ucti o n a n d c o nti n uati o n t hera p y. T he c u m ulati ve i nci de nce 
of pa ncreatitis fr o m t he i nitiati o n of i n d ucti o n t hera p y t o t he be gi n ni n g of c o nti n uati o n 
t hera p y i n T O T X V was 0. 9 7 % ( S E = 0. 4 8 %) a n d t here was n o e vi de nce t hat t hat t he 
i nci de nce w as rel ate d t o ris k classificati o n wit h 2 e ve nts i n l o w ris k patie nts a n d 2 
e pis o des i n sta n dar d/ hi g h ris k patie nts w h o recei ve d m ore as para gi nase. All f o ur e ve nts 
occ urre d d uri n g t he first f o ur wee ks of i n d ucti o n t hera p y. T h e 9 5 % u p per c o nfi de nce 
b o u n d j ust pri or t o t he i nitiati o n of c o nti n uati o n t hera p y is 1. 7 6 %.  
 
T he c u m ulati ve i nci de n ce of pa ncreatitis fr o m t he i nitiati o n of c o nti n uati o n t hera p y t o t he 
e n d of re-i n d ucti o n II w as 2. 2 3 % ( S E = 0. 7 4 %) wit h t he last e pis o de bei n g o bser ve d 
wit hi n t w o wee ks of t he l ast d ose of as para gi nas e, w hic h was gi ve n i n wee k 2 1 of 
c o nti n uati o n t hera p y. T h e 9 5 % u p per c o nfi de n ce b o u n d at t he e n d of t his p eri o d is 
3. 4 5 % . T w o ot her e pis o des were o bser ve d i n wee ks 1 0 5 a n d 1 1 1 b ut neit her is t h o u g ht t o 
be relate d t o as para gi nas e e x p os ure a n d t hese are n ot use d i n t he esti mati o n. S/ H R patie nts 
recei v e d m ore e x p os ure t o as para gi n ase d uri n g T O T X V c o nti n uati o n t hera p y t h a n di d l o w 
ris k patie nts. H o we ver, as t he f oll o wi n g fi g ure ill ustrates, t here is n o e vi d e n ce of a d os e-
t o xicit y relati o ns hi p ( p = 0. 7 2). T h us, i n T O T X VI, L R a n d S/ H R patie nts will p o ole d t o 
m o nit or f or e x cessi ve e pis o des of pa ncreatitis.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
CI N of gr a d e 3 p a n cr e atiti s i n T ot al X V P ati e nt s
0
0. 0 0 5
0. 0 1
0. 0 1 5
0. 0 2
0. 0 2 5
0. 0 3
0. 0 3 5
0. 0 4
0. 0 4 5
0. 0 5
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0
2 0 0
W e e k s fr o m t h e b e gi n ni n g of c o nti n u ati o n t h er a p y t o off t h er a p y
CI
L R
S H R
CI N of D e e p v ei n t hr o m b o si s i n cl u di n g gr a d e 2 i n T ot al X V P ati et n s
0
0. 0 0 5
0. 0 1
0. 0 1 5
0. 0 2
0. 0 2 5
0. 0 3
0. 0 3 5
0. 0 4
0. 0 4 5
0. 0 5
0
5
1 0
1 5
2 0
2 5
3 0
W e e k s fr o m b e gi n ni n g of st u d y t o t h e b e gi n ni n g of c o nti n u ati o n t h er a p y
CI
L R
S H R
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
D V T, o n t he ot her h a n d, is a t o xicit y t hat d oes see m t o be ass ociate d wit h t he d ose of 
as para gi n ase as e vi de nce d b y t he c u m ulati ve i nci de nces of D V T d uri n g i n d ucti o n a n d 
c o nti n uati o n t hera p y o bs er ve d i n T O T X V. T he e pis o des of D V T ma y be o bser ve d 3- 4 
we e ks after t he last d ose of as para gi nase. We n ote t hat t he i ncreas e d i nci de nce c o ul d als o 
be relate d t o e x p os ure t o as para gi n ase i n t he c o nte xt of t he m ore i nte nse t hera p y t hat S/ H R 
patie nts recei ve d d uri n g t his peri o d. 
 
T he f oll o wi n g fi g ure s h o ws t he c u m ulati ve i nci de nce of D V T f or t he peri o d fr o m t he 
i nitiati o n of i n d ucti o n t hera p y t o t he i nitiati o n of c o nti n uati o n t hera p y o n T O T X V f or l o w 
ris k a n d sta n dar d & hi g h-ris k patie nts. T he c u m ulati ve i nci de nce f or l o w ris k patie nts 
( N = 2 3 8) is 0. 8 4 % ( S E = 0. 5 9 %) a n d f or S/ H R patie nts ( N = 1 7 6) is 4. 5 5 % ( S E = 1. 5 7 %). 
T he 9 5 % u p per c o nfi de n ce b o u n ds at t he e n d of t his peri o d are 1. 8 1 % a n d 7. 1 3 %, 
res pecti vel y. Gra y’s test c o m pari n g t he t w o c u m ulati ve i nci de nce f u ncti o ns is si g nifica nt 
( p = 0. 0 1 5). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
CI N of D e e p v ei n t hr o m b o si s i n cl u di n g gr a d e 2 i n T ot al X V P ati e nt s
0
0. 0 1
0. 0 2
0. 0 3
0. 0 4
0. 0 5
0. 0 6
0. 0 7
0. 0 8
0. 0 9
0. 1
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
1 8 0
2 0 0
W e e k s fr o m b e gi n ni n g of c o nti n u ati o n t h er a p y t o off t h er a p y
CI
L R
S H R
T he f oll o wi n g fi g ure s h o ws t he c u m ulati ve i nci de nce of D V T d uri n g T O T X V 
c o nti n uati o n t hera p y f or l o w ris k a n d sta n dar d & hi g h-ris k p atie nts. T he last d ose of 
as para gi n ase is gi ve n wee k 2 1 of c o nti n uati o n t hera p y a n d e pis o d es of D V T were s ee n i n 
S/ H R patie nts u p t o t hree wee ks later. T he c u m ulati ve i nci de nce f or l o w ris k patie nts 
( N = 2 0 9) is 1. 4 4 % ( S E = 0. 8 3 %) a n d f or S/ H R patie nts ( N = 2 0 5) is 8. 8 7 % ( S E = 2. 0 6 %). 
T he 9 5 % u p per c o nfi de n ce b o u n ds at t he e n d of t his peri o d are 2. 8 1 % a n d 1 2. 5 8 %, 
res pecti vel y. Gra y’s test c o m pari n g t he t w o c u m ulati ve i nci de nce f u ncti o ns is si g nifica nt 
( p = 0. 0 0 0 6). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 8. 1. 1 D u ri n g i n d u cti o n a n d t o t he i nitiati o n of c o nti n uati o n t hera p y 
 
F or m o nit ori n g p ur p oses we will c o u nt t he first e pis o de of a m o nit ore d t o xicit y s h o ul d t he 
sa me t o xicit y occ urs m ulti ple ti mes o n a si n gle patie nt d uri n g i n d ucti o n. T O T X VI has 
m ore i nte nse i n d ucti o n a n d I T t h era p y t ha n T O T X V. T heref ore we will cl osel y m o nit or 
t o xic deat h, pa ncreatitis, D V T a n d seiz ures d uri n g t he i n d ucti o n p hase. 
 
De at h:  Base d o n t h e T O T X V data, t he 9 5 % u p per c o nfi de nce b o u n d o n t he deat h rate 
d uri n g i n d ucti o n is 0. 9 5, w hic h i m plies t hat 9 9 % of patie nts w o ul d be e x pecte d t o s ur vi ve 
i n d ucti o n. Be gi n ni n g wit h t he sec o n d deat h d uri n g i n d ucti o n, we will c o nstr uct t he 9 5 % 
u p per c o nfi d e nce b o u n d of t he tr ue u n k n o w n pr o ba bilit y of s ur vi vi n g i n d ucti o n t hera p y, 
usi n g t he Bl yt h- Still- Cas ella met h o d, w he n a d eat h occ urs. If at a n y a nal ysis t his u p per 
b o u n d dr o ps bel o w 0. 9 9 0, we will cl ose t he trial t o accr ual a n d c o nsi d er c h a n ges t o t he 
i n d ucti o n t hera p y. N ote t hat t he de n o mi nat or i n t hese a nal ys es will be t he n u m ber of 
patie nts t hat ha ve c o m plete d i n d ucti o n t hera p y at t he ti me of t he i n de x deat h.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he f oll o wi n g t a ble ill ustrates t he st o p pi n g c haract eristics. 
 
St o p pi n g R ule f or De at h D uri n g I n d ucti o n 
N  
# Dt h.  
% 
Dt h.  
9 5 % U B  Decisi o n  
1 0 0  
2  
2. 0  
0. 9 9 5  
G o  
1 0 0  
3  
3. 0  
0. 9 8 9  
St o p  
2 0 0  
4  
2. 0  
0. 9 9 1  
G o  
2 0 0  
5  
2. 5  
0. 9 8 7  
St o p  
3 0 0  
6  
2. 0  
0. 9 9 1  
G o  
3 0 0  
7  
2. 3 3  
0. 9 8 8  
St o p  
 
P a ncre atitis ( Gr a de 3 or hi g her):  T he 9 5 % u p per c o nfi de nce b o u n d o n t he c u m ulati ve 
i nci de nce of pa ncreatitis d uri n g t he peri o d fr o m i nitiati o n of i n d ucti o n t o i nitiati o n of 
c o nti n uati o n t hera p y is 1. 7 6 %. P E G-as para gi nase has a l o n ger half-life t hat t he 
f or m ulati o n of as para gi n ase use d i n T O T X V a n d d ue t o t he e x pecte d i ncrease d efficac y of 
Pe g- as para gi nase, w e will t olerate a tr ue c u m ulati ve i nci de nce of 3 % b ef ore 
rec o m me n di n g t hat accr ual t o t he trial be st o p pe d. Be gi n ni n g wit h t he fift h patie nt 
e x perie nci n g a n e pis o de of pa ncreatitis pri or t o i nitiati o n of c o nti n uati o n t hera p y we will 
esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % l o wer c o nfi de n ce b o u n d is 
greater t ha n 3. 0 0 %, w e will rec o m me n d t hat accr ual ceas e. Fe w deat hs or rela pses 
(c o m peti n g e ve nts) are e x pecte d fr o m i nitiati o n of i n d ucti o n t hera p y t o t he be gi n ni n g of 
c o nti n uati o n t hera p y s o t he f oll o wi n g ta bl e base d o n t he bi n o mi nal distri b uti o n pr o vi des 
a p pr o xi mate  st o p pi n g criteria. 
 
N O T E:  We will u p gr a de a ny p a ncre atitis res ulti n g i n disc o nti n u ati o n of P E G-
as p ar a gi n ase t o Gr a de 3 (eve n if Gr a d e 2 by C T C A E v 3 criteri a). 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of 
P a ncre atitis: I n d ucti o n t o C o nti n u ati o n T her a p y  
N  
# E pis o des  
% E pis o des  
9 5 % 
L B  
Decisi o n  
1 0 0  
6  
6. 0 0 %  
2. 6 5 %  
G o  
1 0 0  
7  
7. 0 0 %  
3. 6 8 %  
St o p  
2 0 0  
1 0  
5. 0 0 %  
2. 9 6 %  
G o  
2 0 0  
1 1  
5. 5 0 %  
3. 1 2 %  
St o p  
3 0 0  
1 4  
4. 6 7 %  
2. 8 4 %  
G o  
3 0 0  
1 5  
5. 0 0 %  
3. 2 5 %  
St o p  
 
 
Seiz ures ( Gr a de 3 or hi g her):   T he 9 5 % u p p er c o nfi de nce b o u n d f or seiz ures d uri n g t he 
pe ri o d bet wee n i nitiati o n of i n d ucti o n t hera p y a n d t he be gi n ni n g of c o nti n uati o n t hera p y 
f or T O T X V was 1. 9 1 %. T O T X VI h as m ore i nte nse I T t hera p y t hat is c o nsi dere d 
p ote ntiall y m ore effecti v e t ha n T O T X V I T t hera p y, s o w e will t olerate a tr ue seiz ure 
i nci de nce of 3 %. Be gi n ni n g wit h t he fift h p atie nt e x perie nci n g a s eiz ure pri or t o i nitiati o n 
of c o nti n uati o n t hera p y, we will esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
l o wer c o nfi d e nce b o u n d is greater t h a n 3. 0 0 %, we will rec o m me n d t hat accr ual ceas e. We 
will use t he sa me st o p pi n g criteria as f or pa n creatitis d uri n g i n d ucti o n (see a b o ve ta ble). 
 
D V T ( Gr a de 3 or hi g her): S/ H R patie nts will recei ve a hi g h er c u m ulati ve d ose of P E G-
as para gi n ase d uri n g i n d u cti o n t ha n L R patie nts a n d t h us, will be m o nit ore d se parat el y. 
Base d o n T O T X V, t he 9 5 % u p per b o u n d f or D V T d ue t o i n d ucti o n t hera p y f or L R p atie nts 
is 1. 8 1 % a n d f or S/ H R is 7. 1 3 %.   
 
P E G-as para gi nase h as a l o n ger half-life t hat t he f or m ulati o n of as para gi nas e use d i n 
T O T X V a n d d u e t o t he e x pecte d i ncreas e d efficac y of P E G-as para gi nase, we will t olerate 
a tr ue c u m ulati ve i nci d e n ce of 3 % i n L R patie nts b ef ore rec o m me n di n g t hat accr u al t o t he 
trial be st o p pe d. Be gi n ni n g wit h t he sec o n d patie nt e x perie nci n g a n e pis o de of D V T pri or 
t o i nitiati o n of c o nti n uati o n t hera p y, we will esti mate t he c u m ulati ve i nci de nce f u ncti o n 
a n d if t he 9 5 % l o wer c o nfi de nce b o u n d is greater t ha n 3. 0 0 %, we will rec o m me n d t hat 
accr ual cease.   
 
Fe w d eat hs or rela pses ( c o m peti n g e v e nts) are e x pecte d fr o m i nitiati o n of i n d ucti o n 
t hera p y t o t he be gi n ni n g of c o nti n uati o n t hera p y s o t he f oll o wi n g ta ble b as e d o n t he 
bi n o mi nal distri b uti o n pr o vi des a p pr o xi mate st o p pi n g criteria. 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
L R P atie nts: I n d ucti o n t o C o nti n u ati o n T her a p y  
N  
# E pis o des  % E pis o des  9 5 % L B  Decisi o n  
5 0  
3  
6. 0 0 %  
2. 2 2 %  
G o  
5 0  
4  
8. 0 0 %  
3. 5 4 %  
St o p  
1 0 0  
6  
6. 0 0 %  
2. 6 5 %  
G o  
1 0 0  
7  
7. 0 0 %  
3. 6 8 %  
St o p  
1 5 0  
8  
5. 3 3 %  
2. 8 3 %  
G o  
1 5 0  
9  
6. 0 0 %  
3. 2 6 %  
St o p  
 
F or S/ H R patie nts we will t olerate a tr ue c u m ulati ve i nci de nce of 1 0 % b ef ore 
rec o m me n di n g t hat accr ual t o t he trial be st o p pe d. Be gi n ni n g wit h t he se ve nt h patie nt 
e x perie nci n g a n e pis o de of D V T pri or t o i nitiati o n of c o nti n uati o n t hera p y, we will 
esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % l o wer c o nfi de n ce b o u n d is 
greater t ha n 1 0. 0 %, w e will rec o m me n d t hat accr ual ceas e.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Fe w d eat hs or rela pses ( c o m peti n g e v e nts) are e x pecte d fr o m i nitiati o n of i n d ucti o n 
t hera p y t o t he be gi n ni n g of c o nti n uati o n t hera p y s o t he f oll o wi n g ta ble b as e d o n t he 
bi n o mi nal distri b uti o n pr o vi des a p pr o xi mate st o p pi n g criteria. 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
S/ H R P atie nts: I n d ucti o n t o C o nti n u ati o n T her a p y  
N  
# E pis o des  % E pis o des  9 5 % L B  Decisi o n  
5 0  
8  
1 6. 0 0 %  
8. 2 2 %  
G o  
5 0  
9  
1 8. 0 0 %  
1 0. 4 6 %  
St o p  
1 0 0  
1 5  
1 5. 0 0 %  
9. 7 4 %  
G o  
1 0 0  
1 6  
1 6. 0 0 %  
1 0. 5 %  
St o p  
1 5 0  
2 1  
1 4. 0 0 %  
9. 9 1 %  
G o  
1 5 0  
2 2  
1 4. 6 7 %  
1 0. 1 4 %  
St o p  
 
1 8. 1. 2 D uri n g c o nti n uati o n t hr o u g h t he e n d of Wee k 3 5 a m o n g all ra n d o mize d 
pa rtici pa nts 
 
T he ra n d o mizati o n t o t w o differe nt d osi n g sc h e d ules of P E G-as para gi nas e d uri n g 
c o nti n uati o n t hera p y re q uires t hat we cl osel y m o nit or f or gra d e 3 or m ore p a ncreatitis a n d 
dee p vei n t hr o m b osis. T h e m o nit ori n g peri o d is fr o m da y 1 of c o nti n uati o n t o t he W ee k 
3 5, w hic h is a p pr o xi matel y 4 wee ks aft er t he last P E G-as para gi nase gi ve n t o t he S/ H R 
patie nts. F or m o nit ori n g p ur p oses, we will c o u nt t he first e pis o de of a m o nit ore d t o xicit y 
s h o ul d t he sa me t o xicit y occ urs m ulti ple ti mes i n a n i n di vi d ual patie nt d uri n g t he 
m o nit ori n g peri o d. 
 
M o nit ori n g f or p a ncreatitis a n d D V T will be base d o n t he c o m bi ne d treat me nt re gi me ns. 
H o we ver, if m o nit ori n g s u g gests t hat accr ual s h o ul d be st o p pe d, t he c u m ulati ve i nci de nce 
f u ncti o ns f or t he t w o treat me nt re gi me ns will be c o m pare d t o caref ull y ass ess w het her t h e 
pr o ble m is o nl y wit h t he hi g her d ose P E G-as p ara gi nase re gi me n. 
 
P a ncre atitis ( Gr a de 3 or hi g her):  T he 9 5 % u p per c o nfi de nce b o u n d of t he c u m ulati ve 
i nci de nce of pa ncreatitis o n T O T X V is 3. 4 5 % d uri n g c o nti n uati o n t hera p y. ( See secti o n 1 7. 1 
a b o ve) We e x pect t hat t h e i nci de nce will be greater o n T O T X VI d u e t o t he use of P E G-
as para gi n ase a n d are willi n g t o acce pt a tr u e rat e as hi g h as 7 %. T his i ncrease ris k of a 
ma na gea bl e t o xicit y is cli nicall y acce pt a ble d ue t o t he e x pecte d be nefits of usi n g P E G-
as para gi n ase. Be gi n ni n g wit h t he ni nt h patie nt e x perie nci n g a n e pis o de of pa ncreatitis pri or 
t o wee k 3 5 of c o nti n uati o n t hera p y, we will esti mate t he c u m ulati ve i nci de n ce f u ncti o n a n d 
if t he 9 5 % l o wer c o nfi de nce b o u n d is greater t ha n 7. 0 0 %, we will rec o m me n d t hat accr ual 
cease. Fe w deat hs or rela pses (c o m peti n g e ve nts) are e x pecte d fr o m i nitiati o n of 
c o nti n uati o n t hera p y t o t he e n d of wee k 3 5 s o t he f oll o wi n g ta ble b ase d o n t he bi n o mi nal 
distri b uti o n pr o vi des a p pr o xi mate st o p pi n g criteri a. 
 
N O T E:  We will u p gr a de a ny p a ncre atitis res ulti n g i n disc o nti n u ati o n of P E G-
as p ar a gi n ase t o Gr a de 3 (eve n if Gr a d e 2 by C T C A E v 3 criteri a). 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of 
P a ncre atitis: C o nti n u ati o n T her a p y t hr o u g h Wee k 
3 5  
N  
# E pis o des  
% E pis o des  
9 5 % 
L B  
Decisi o n  
1 0 0  
1 1  
1 1. 0 0 %  
6. 5 6 %  
G o  
1 0 0  
1 2  
1 2. 0 0 %  
7. 0 7 %  
St o p  
2 0 0  
2 0  
1 0. 0 0 %  
6. 8 3 %  
G o  
2 0 0  
2 1  
1 0. 5 0 %  
7. 2 8 %  
St o p  
3 0 0  
2 8  
9. 3 3 %  
6. 7 2 %  
G o  
3 0 0  
2 9  
9. 6 7 %  
7. 0 0 2 %  
St o p  
D V T ( Gr a de 3 or hi g her):   T he dat a fr o m T O T X V clearl y s h o ws t h at t he 
S/ H R patie nts e x perie nce d a hi g h er c u m ulati ve i nci de nce of D V T t ha n di d 
t he L R patie nts.  
 
As s h o w n i n secti o n 1 7. 1 a b o ve, t he 9 5 % u p p er c o nfi de nce b o u n d f or t he c u m ulati ve 
i nci de nce of D V T i n t he L R patie nts d uri n g c o nti n uati o n t hera p y was 2. 8 1 %. Si nce l o w 
ris k patie nts ra n d o mize d t o t he hi g h d ose P E T- A S P re gi me n are pr ojecte d t o e x perie nce 
o nl y a 2- 4 % i m pr o ve me nt i n d urati o n of C C R, we will n ot acce pt a rate of D V T m uc h 
hi g her t h a n t hat o bser ve d f or L R p atie nts i n T O T X V.  Be gi n ni n g wit h t he sec o n d patie nt 
ex perie nci n g a n e pis o de of D V T pri or d uri n g c o nti n uati o n t hera p y we will esti mate t he 
c u m ulati ve i nci de nce f u ncti o n a n d if t he 9 5 % l o w er c o nfi d e nce b o u n d is greater t ha n 
3. 0 0 %, we will rec o m me n d t hat accr ual cease.  
 
Fe w d eat hs or rela pses ( c o m peti n g e v e nts) are e x pecte d fr o m i nitiati o n of c o nti n uati o n 
t hera p y t o wee k 3 5 s o t he f oll o wi n g ta bl e base d o n t he bi n o mi nal distri b uti o n s h o ws 
a p pr o xi mate  st o p pi n g criteria.  
 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
L o w Ris k: C o nti n u ati o n T her a p y t hr o u g h Wee k 3 5  
N  # E pis o des  % E pis o des  9 5 % L B  
Decisi o n  
5 0  
3  
6. 0 0 %  
2. 2 2 %  
G o  
5 0  
4  
8. 0 0 %  
3. 5 4 %  
St o p  
1 0 0  
6  
6. 0 0 %  
2. 6 5 %  
G o  
1 0 0  
7  
7. 0 0 %  
3. 6 8 %  
St o p  
1 5 0  
8  
5. 3 3 %  
2. 8 3 %  
G o  
1 5 0  
9  
6. 0 0 %  
3. 2 6 %  
St o p  
  
As s h o w n i n secti o n 1 7. 1 a b o ve, t he 9 5 % u p p er c o nfi de nce b o u n d o n t he c u m ulati ve 
i nci de nce of D V T i n S/ H R patie nts d uri n g c o nti n u ati o n t hera p y i n T O T X V is 1 2. 5 2 %. We 
w o ul d acce pt a sli g htl y hi g her i n ci de nce, 1 5 %, f or t he S/ H R patie nts t hat recei ve d t he l o w 
d ose P E G-as para gi nase re gi me n of T O T X VI. T he S/ H R patie nts ra n d o mize d t o t he hi g h 
d ose P E G-as para gi nase re gi me n are e x pecte d t o d eri ve c o nsi dera ble be nefit i n ter ms of 
i m pr o ve d distri b uti o n of C C R a n d s o we are willi n g t o acce pt a hi g h er rate of D V T i n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hese patie nts, 2 0 %. Be gi n ni n g wit h t he ele ve nt h p atie nt e x perie nci n g a n e pis o de of D V T 
pri or d uri n g c o nti n uati o n t hera p y we will esti mate t he c u m ulati ve i nci de nce f u ncti o n a n d 
if t he 9 5 % l o wer c o nfi de nce b o u n d is greater t ha n 1 7. 5 0 %, we will rec o m me n d t hat 
accr ual cease. Fe w d eat hs or rela pses (c o m peti n g e ve nts) are e x pecte d fr o m i nitiati o n of 
c o nti n uati o n t hera p y t o wee k 3 5 s o t he f oll o wi n g ta ble base d o n t he bi n o mi nal distri b uti o n 
s h o ws a p pr o xi mate st o p pi n g criteria. 
 
A p pr o xi m ate St o p pi n g R ule f or E pis o des of D V T  
S/ H R Ris k: C o nti n u ati o n T her a p y t hr o u g h Wee k 
3 5  
N  
# E pis o des  % E pis o des  
9 5 % 
U B  
Decisi o n  
5 0  
1 3  
2 6. 0 0 %  
1 6. 2 %  
G o  
5 0  
1 4  
2 8. 0 0 %  
1 8. 6 %  
St o p  
1 0 0  
2 4  
2 4. 0 0 %  
1 7. 1 3 %  
G o  
1 0 0  
2 5  
2 5. 0 0 %  
1 8. 0 4 %  
St o p  
1 5 0  
3 4  
2 2. 6 7 %  
1 7. 1 6 %  
G o  
1 5 0  
3 5  
2 3. 3 3 %  
1 7. 7 6 %  
St o p  
 
1 8. 1. 3 D uri n g e ntire t hera p y: disse mi nate d f u n gal i nfecti o ns 
 
T he  sa me as i n T O T- X V trial, we will m o nit or t he i nci de nce of disse mi nat e d f u n gal 
i nfecti o ns. We will m o nit or a gai nst a bas eli ne rat e of 5 % a n d will s u g gest m o dif yi n g t he 
st u d y if t here is statistical e vi de nce t h at t he disse mi nate d f u n gal i nfecti o n rate e x cee ds 
1 0 %. T he o verall si g nifica nce le vel will be 0. 0 5 6 7 wit h a p o wer of 0. 9 9 6 7 t o detect t he 
u nacce pta ble hi g her l e vel. 
 
O nl y t he first e ve nt i n a gi ve n patie nt will be c o u nte d alt h o u g h we will cl osel y m o nit or f or 
re peat e d i nfecti o ns.  Sa m ple siz e ( de n o mi nat or) is t he n u m ber of p atie nts eit her w h o ha v e 
rec o vere d fr o m t he sec o n d re-i n d ucti o n or de v el o p e d visceral f u n gal i nfecti o n bef ore 
rec o ver y fr o m se c o n d rei n d ucti o n.  T he n u merat or is t he n u m ber of t he first e ve nts a m o n g 
all m o nit ore d patie nts (i.e. t h ose i n de n o mi nat or).  Accr u al will be s us pe n d e d if t he n u m ber 
of e ve nts ( n u merat or) is e q ual t o or e x cee ds t hat c orres p o n di n g t o eac h sa m ple siz e. 
 
I nteri m anal ysis  
Sa m ple s ize 
( patie nts)  
M o dif y if # p atie nts 
wit h disse mi nate d 
f u n gal infecti o ns   
1  
3 0  
6  
2  
6 0  
9  
3  
1 2 0  
1 4  
4  
1 8 0  
1 8  
5  
2 4 0  
2 1  
6  
3 0 0  
2 8  
7  
3 6 0  
3 1  
8  
4 2 0  
3 3  
9  
4 8 0  
3 5  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 7 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 8. 1. 4  Decrease of P E G-as p ara gi nase d os e i n t he Hi g her D ose P E G-as para gi nas e re gi me n.  
 
O nce a n y of t he st o p pi n g c o n diti o ns f or t he m o nit ori n g peri o d i n t he C o nti n uati o n p hase is 
met, we will caref ull y e x a mi ne a n d a n al yze all t he t o xicit y i nci de nces. Treat me nt o utc o me 
( C C R, E F S a n d s ur vi val) will n ot  be a nal yze d si m pl y d ue t o a st o p pi n g criteria ha vi n g 
bee n met. Certai nl y if t here has bee n a rece nt pla n ne d a nal ysis of o utc o me, t he D S M B 
ma y c o nsi der t hat i nf or m ati o n i n f or matti n g t heir rec o m me n dati o n. C u m ulati ve i nci de nce 
f u ncti o ns of t he c o ncer ni n g t o xicit y f or t he t w o treat me nt re gi me ns will be c o m pare d f or 
e vi de nt t hat t he m o nit ore d t o xicities are m ore pre v ale nt i n t he 3 5 0 0 u nits/ m 2 re gi me n. We 
will  als o c o nsi der w het her t he u p per c o nfi de nce b o u n ds f or eac h t he t w o re gi me ns e x cee d 
w hat were p ost ulate d t o be acce pta ble. If st o p pi n g criteria are e x cee de d f or b ot h re gi me ns, 
w hic h is n ot e x pecte d, c o nsi derati o n will be gi v e n t o st o p pi n g t he trial. If o nl y t he hi g her 
d ose re gi me n has e x cessi ve t o xicit y, t he n c o nsi derati o n will be gi ve n t o re d uci n g t he d os e 
of P E G-as para gi nase t o 3 0 0 0 u nits/ m 2 a n d t o c o nti n ue t he ra n d o mizati o n.  
 
Ass u mi n g t hat t he pr ot oc ol is a me n de d t o re d uce t he d ose of P E G-as para gi nase, t he 
ran d o mizati o n w o ul d c o nti n ue a n d t he fi nal a n al ysis a n d a n y s u bse q ue nt i nteri m a nal yses 
of t he pri mar y st u d y q uesti o n w o ul d be stratifie d b y patie nts r a n d o mize d pri or t o a n d p ost 
t he pr ot oc ol a me n d me nt. All patie nts w h o were ra n d o mize d at t he ti me t hat t he hi g h d ose 
of P E G-as para gi nase was 3 5 0 0 u nits/ m 2 will be i ncl u de d i n t he i n t he “ pri or a me n d me nt” 
strat u m; all patie nts ra n d o mize d after t he P E G-as para gi nas e d ose was re d u ce d t o 3 0 0 0 
u nits/ m 2 will be i ncl u de d i n t he “ p ost a me n d me nt” strat u m. N ote t hat t he fi ve ori gi n al 
strata are mai ntai ne d wit hi n t his u m brella stratificati o n wit h n o c ha n ge i n t he ra n d o mize d 
se q ue nce of ra n d o mize d bl oc ks; s o t he ra n d o mizati o n bet wee n hi g her d ose P E G-
as para gi n ase a n d c o n ve nti o nal d osi n g will re mai n bala nce d. Zele n’s ra n d o mizati o n 
sc he me wit h bl oc k sizes of 4 will be use d. T h us, t he a bs ol ute w orst case f or i m bala nce 
bet wee n hi g h d ose P E G- as para gi n ase a n d c o n ve nti o nal d ose P E G-as para gi nase wit hi n 
eit her a me n d me nt d efi ne d strata is 1 0 patie nts. Certai nl y t his i m bala nce is u nli kel y t o 
oc c ur as i n d e pe n de ntl y i n eac h strat u m, ra n d o mizati o n is c o ntr olle d b y ra n d o m se q ue nces 
of ra n d o m bl oc ks of size 4. T h us a n y i m bal a nce t h at ma y o cc ur s h o ul d b e s mall a n d t h us 
will ha ve little effect o n t he statistical p o wer of t h e trial. 
 
T he a b o ve pla n a d mits t he use of all dat a t o a d dress t he pri mar y st u d y q u esti o n a n d a v oi ds 
ha vi n g t o ma d e a d h oc d ecisi o ns as t o w het her t h e trial s h o ul d be a me n de d t o start all o ver 
a gai n. E ve n patie nts w h o e x perie nce t o xicities, w hic h are ma na gea ble, ma y still be nefi t 
fr o m t he treat me nt a n d t o xicities s h o ul d n ot be a reas o n f or e x cl u di n g t he m fr o m t he 
pri mar y a nal ysis. F urt her m ore, t he pr o p ose d f utilit y a n al ysis, disc uss e d bel o w, w o ul d 
li kel y st o p t he trial if, i n fact, 3 0 0 0 m g/ m2 is n ot as effecti ve as has b ee n h y p ot hesiz e d f or 
t he hi gh d ose P E G-as para gi n ase re gi me n. F urt h er m ore, realisticall y if t he 3 5 0 0 u/ m 2 d ose 
is t o o t o xic t he n t he m o nit ori n g b o u n daries will be e x pecte d t o be reac he d relati vel y earl y 
d uri n g t he tri al, at w hic h ti me fe w C C R/ E F S-relat e d e ve nts will ha ve o cc urre d; t h us t he 
t o xicit y-st o p pi n g ti me p oi nt is n ot li kel y t o occ ur at a ti me t hat statisticall y mea ni n gf ul 
c o m paris o ns of o utc o me ca n be c o n d ucte d a n d i nter pret e d. T heref ore, we d o n ot pla n t o 
perf or m a n y a nal ysis of o utc o me d ue t o earl y e x cessi ve t o xicit y. Clearl y if i nteri m 
anal ys es of o utc o me h a v e alrea d y bee n c o n d ucte d, t he n t h ose res ults w o ul d be a vaila ble 
f or t he D S M B w h e n t he y c o nsi der a n d a d vise re gar di n g a n y o bser ve d statistical st o p pi n g 
criteria f or t o xicities.   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T o xicit y m o nit ori n g r ules w o ul d be rei nitialize d wit h t his maj or c ha n ge i n t hera p y a n d if 
3 0 0 0 u nit s/ m2 s u bse q ue ntl y pr o ves t o be t o o t o xic t he n t he trial w o ul d li kel y be cl ose d, as 
t he pri mar y res earc h q uesti o n w o ul d n o l o n ger be via ble. 
 
If t o xicit y is e x cessi ve i n b ot h treat me nt re gi me ns, seri o us c o nsi derati o n as t o w het her t he 
st u d y s h o ul d c o nti n ue usi n g P E G-as para gi nase. T his e ve nt w o ul d li kel y res ult i n per ma ne nt 
cl os ure of t he tri al or at t he ver y least a maj or c h a n ge i n t he tr eat me nt r e gi me ns. 
 
1 8. 2 
Pri mar y O bj ecti ve 
 
T he  pri mar y o bje cti ve of t his st u d y is t o c o m pare t he distri b uti o ns of c o nti n u o us c o m plete 
remissi o n of patie nts ra n d o mize d o n t he first da y of c o nti n uati o n p hase t o r ecei ve hi g h er 
d ose of P E G-as p ara gi nas e or t o recei ve c o n ve nti o nal d ose ( 2, 5 0 0 u nits/ m 2). 
 
Desi g n:  T his st u d y will be c o n d ucte d b y a n o pe n-l a bel, ra n d o mize d trial. Partici pati n g 
pa tie nts will be ra n d o mize d t o recei ve eit her hi g h d ose P E G-as para gi nase or c o n ve nti o nal 
d osi n g of 2, 5 0 0 u nits/ m 2 P E G- As para gi n ase per d ose d uri n g t h e c o nti n uati o n p hase. 
 
T he ra n d o mizati o n will be stratifie d b y se v eral f act ors base d o n t he f oll o wi n g 
c o nsi derati o n: L o w ris k a n d sta n dar d/ hi g h ris k patie nts recei ve differe nt treat me nts i n t he 
c o nti n uati o n p hase; t here ha ve bee n re p orts t hat c hil dre n wit h T-cell A L L be nefit m ore 
fr o m as para gi nase tr eat m e nt t ha n c hil dre n wit h B-li nea ge A L L; a n d Da y- 1 9 M R D 
p ositi vit y ( ≥0. 0 1 %) is a n i m p orta nt pr o g n ostic fact or o n T O T X V.  
 
T he f oll o wi n g t a ble s h o ws t he 5- year C C R rate si nce c o nti n uati o n i n eac h strat u m o n 
T O T X V (as of 4/ 5/ 2 0 0 7). Patie nts wit h n o Da y- 1 9 M R D res ults are e x cl u de d. 
 
Str at a  
n  
5 -ye ars C C R si nce 
c o nti n u ati o n Esti m ate  ±  
S E ( %)  
L R  
1 5 2  
9 6. 1 ± 3. 5  
S R & T -cell & M R D 1 9 +  
2 7  
7 3. 5 ± 2 1. 8  
S R & T -cell & M R D 1 9 - 
1 9  
8 8. 9 ± 1 3. 3  
S R & B -cell & M R D 1 9 +  
6 3  
7 7. 2 ± 1 1. 1  
S R & B -cell & M R D 1 9 - 
2 7  
7 6. 4 ± 1 5. 1  
H R  
1 4  
3 9. 3 ± 2 1. 6  
 
T h us, t he ra n d o mizati o n will be stratifie d first b y t he ris k stat us f or t he c o nti n uati o n p hase 
(L o w, Sta n dar d, Hi g h; se e Secti o n 4. 0), t he n wit hi n Sta n dar d ris k b y li nea ge ( T-li nea ge, 
B-li nea ge) a n d f urt her wit hi n t he T- li nea ge b y Da y- 1 5 M R D le v el ( < 0. 0 1 % vs. ≥0. 0 1 %), 
creati n g 5 strat a. 
 
T he ra n d o mizati o n will occ ur o n t he starti n g d a y of t he c o nti n uati o n p hase, at w hic h ti me 
all i nf or mati o n necess ar y f or perf or mi n g t he ra n d o mizati o n s h o ul d be a vaila ble. I n t he rare 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
case t hat i m m u n o p he n ot y p e a n d/ or Da y- 1 5 M R D is n ot a vaila ble, we will ma ke t he 
f oll o wi n g ass u m pti o ns: If i m m u n o p he n ot y pe is u n k n o w n at t he ti me t he ra n d o mizati o n is 
t o be e x ec ute d, t he n it will be ass u me d B-li nea ge. If Da y- 1 5 M R D is u n k n o w n at t he ti me 
of ra n d o mizati o n, t he n it will be ass u me d ne gati ve ( < 0. 0 1 %). Past e x perie n ce i n dicate t hat 
fe w patie nts will fall i nt o t hese u n k n o w n cate g ories. 
 
N ote o nl y eli gi ble p atie nts w h o c o nse nt a n d are ra n d o mize d are e val ua bl e f or t his o bjecti ve. 
T he st u d y e n d p oi nt is d urati o n of c o nti n u o us c o m plete re missi o n p ost ra n d o mizati o n. 
D urati o n of C C R will be meas ure d fr o m t he ra n d o mizati o n date t o t he date of i nitial fail ure 
f or patie nts w h o f ail. Fail ure i ncl u des t he f oll o wi n g e n d p oi nts: 
 
 rela pse i n a n y site 
 sec o n d mali g n a nc y 
 de at h d uri n g re missi o n 
 
D urati o n of C C R will be meas ure d t o t he d ate of l ast c o ntact f or p atie nts w h o are fail ure 
free at t he ti me of a n al ys es.  
 
Accr u al: T h e distri b uti o n of t he le n gt h of t he ti me i nter val bet wee n t w o c o nsec uti ve 
e nr oll me nts (t he i nter- arri val ti me) o n T O T X V (e x cl u di n g patie nts treate d at C o o k’s) is 
dis pl a ye d i n t he f oll o wi n g fi g ure, i n w hic h t he ti m e u nit is year. T his distri b uti o n will be 
use d i n t he M o nte Carl o esti mati o n of statistical p o wer. T he m ea n i nter-arri val ti me o n 
T O T X V is esti mate d 0. 0 1 8 1 year; t he sta n d ar d de viati o n of i nter-arri val ti me is esti mate d 
0. 0 1 9 5 year. T h us t he esti mate d e nr oll me nt fre q u e nc y is a p pr o xi matel y 5 6 patie nts per 
year. We e x pect t he e nr oll me nt fre q ue nc y i n T O T X VI will be si milar a n d t h us t he accr ual 
g oal will be ac hie v e d i n 8 t o 9 years. T he t otal accr ual ti me will be assesse d b y t he 
si m ulati o n st u d y i n t he p o wer c o nsi derati o n secti o n. 
0. 0
0. 0 5
0. 1 0
0. 1 5
0
1 0
2 0
3 0
4 0
I nt er- arri v al ti m e o n T O T A L- X V
 
Hist oric al d at a:  T he f oll o wi n g ta ble a n d fi g ure s h o w res pecti vel y t h e 5- year K M 
esti mates of d urati o n of C C R fr o m t he be gi n ni n g of c o nti n uati o n t hera p y i n T O T XIII A, 
B, a n d T O T X V (e x cl u di n g C o o k’s patie nts) st u di es. Beca use T O T X V di d n ot i ncl u de 
i nfa nts, o utc o me data of t he i nfa nts o n t he I N F A N T 9 9 pr ot oc ol w h o e nr olle d after 
T O T X V was o p e ne d w ere a d de d t o T O T X V o utc o me t o i m p ute t he sce nari o of i ncl u di n g 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
C C R Si n c e C o nti n u ati o n
0
0. 1
0. 2
0. 3
0. 4
0. 5
0. 6
0. 7
0. 8
0. 9
1
0
2
4
6
8
1 0
1 2
1 4
1 6
y e ar
Pr o b a bilit y
T 1 3 A
T 1 3 B
T 1 3 A B
T 1 5 +i nf n
i nfa nts o n T O T X V.  Pati e nts w h o faile d t o e nter t he c o nti n uati o n p hase were e x cl u de d. 
N ote i n t his ta ble t here are 1 6 i nfa nts a n d 1 1 T O T X V patie nts wit h o ut Da y- 1 9 M R D are 
i ncl u de d f or “ T 1 5 +I nf n.”  
 
S T U D Y  
T ot al  
Ac hie vi n g C R  
# P ati e nts  
E nter e d 
C o nti n u ati o n  
# I nf a nts  
E ntere d  
C o nti n u ati o n  
5 -Ye ar C C R 
R ate  
Fr o m I niti ati o n 
of C o nti n u ati o n  
Esti m ate ± S E 
( %) 
T 1 3 A  
1 6 2  
1 6 0  
4  
7 8. 1 ± 3. 3  
T 1 3 B  
2 4 2  
2 3 7  
1 0  
8 2. 6 ± 2. 5  
T 1 3 A & B 
c o m bi ne d  
4 0 4  
3 9 7  
1 4  
8 0. 8 ± 2. 0  
T 1 5 +I nf n (as of 
4/ 5/ 0 7)  
3 7 5  
3 2 9  
1 6  
8 5. 6 ± 4. 4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he f oll o wi n g t a ble s h o ws t he 5- year d urati o n of C C R rates fr o m t he be gi n ni n g of 
c o nti n uati o n t hera p y of t hese pre vi o us st u dies b y ris k strata, w here i nfa nts descri be d a b o ve 
were a d de d t o t he T O T X V Sta n dar d/ Hi g h ris k strat u m.  
 
RI S K A R M S  
n  
5 -Ye ar C C R R ate  
Fr o m I niti ati o n of 
C o nti n u ati o n  
Esti m ate ± S E ( %)  
T 1 3 A S/ H  
1 5 0  
7 6. 7 ± 3. 4  
T 1 3 B S/ H  
1 2 3  
7 6. 4 ± 3. 8  
T 1 5 S/ H wit h i nfa nts (as of 
4/ 5/ 2 0 0 7)  
1 7 1  
7 6. 1 ± 7. 3  
T 1 3 A L  
1 0  
1 0 0 ± 0. 0  
T 1 3 B L  
1 1 4  
8 9. 3 ± 2. 9  
T 1 5 L (as of 4/ 5/ 2 0 0 7)  
1 5 8  
9 6 . 2 ± 3. 4 
 
T O T XIII A a n d B c o m bi ne d pr o vi de a n a de q uat e descri pti o n of t he C C R distri b uti o n i n 
rece nt st u dies a n d will be use d as preli mi nar y d ata f or p o wer c o nsi derati o n, as descri be d 
bel o w. Beca us e T O T X V has n ot st o p pe d accr ual a n d has relati vel y s h ort f oll o w- u p, it will 
be use d sec o n d aril y f or p o wer c o nsi derati o n. 
 
A n al ysis:  T he fi nal a nal ysis of t he pri mar y o bjecti ve will be t hree years aft er t he last 
pa tie nt is ra n d o mize d. T he pri mar y a n al ysis is a M a ntel- Hae nszel (stratifie d l o g-ra n k) test 
c o m paris o n of t he distri b uti o ns of C C R f or patie nts ra n d o mize d t o t he t w o treat me nt ar ms, 
usi n g t he strata d efi ne d f or ra n d o mizati o n. P o wer c o nsi derati o n f or t his a nal ysis is gi ve n 
bel o w. Ka pla n- Meier ( K M) esti mates of t he distri b uti o n of C C R f or eac h treat me nt ar m 
will be pr o vi de d.  
 
T w o i nteri m a nal yses, o n e at t he e n d of year 3 a n d o ne at year 6. 5 are pla n ne d. T he 
a nal ys es will perf or m t w o-si de d Ma ntel- Hae nszel (stratifie d l o g-ra n k) test c o m paris o n of 
t he distri b uti o ns of C C R f or patie nts ra n d o mize d t o t he t w o treat me nt ar ms, usi n g t he 
strata defi ne d f or ra n d o miz ati o n a n d t he statistical si g nifica n ce le vel α = 0. 0 0 5. A f utilit y 
a nal ysis as detaile d bel o w will be c o n d ucte d as part of t he 6. 5 year i nteri m a nal ysis if t he 
c o m paris o n at t he 0. 0 0 5 l e vel is n ot statisticall y si g nifica nt. D ue t o t he t w o pla n ne d 
i nteri m a nal ys es, t he fi nal a nal ysis will be c o n d u ct e d at α = 0. 0 4 5. 
 
S u bset a nal ys es c o m pari n g t he t w o ar ms wit hi n strata ma y be c o n d ucte d as well, usi n g t he 
l o g-ra n k test. T hese s u bs et a nal yses will ha ve li mite d statistical p o wer t o detect 
differe n ces a n d will be i nter prete d wit h e xtre me ca uti o n as descri pti ve. K M esti mates of 
t he distri b uti o n of C C R b y treat me nt ar m wit hi n eac h strat u m will be pr o vi de d. 
 
P o w er c o nsi der ati o n:  Here p o wer c o nsi derati o n is de vel o pe d bas e d o n t he u nstratifie d 
test. O verall, t he 5- year C C R rate fr o m i nitiati o n of c o nti n uati o n t hera p y i n T O T XIII A & 
B c o m bi ne d a n d T O T X V pl us i nfa nts are 8 0. 8 ± 2. 0 % a n d 8 5. 6 ± 4. 4 %, res pecti vel y; t he 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
5 - year C C R rate fr o m i nitiati o n of c o nti n uati o n t hera p y i n t h e T O T X V l o w ris k strat u m is 
9 6. 2 ± 3. 4 %. We belie ve t hat t he effect size i n eac h ris k- base d strat u m as s h o w n bel o w is 
cli nicall y me a ni n gf ul, base d o n t he c o nsi derati o ns: ( 1) pre vi o us fr o nt-li ne A L L tri als ha ve 
s h o w n t hat a t hera p y a u g me nte d wit h as para gi nas e c o ul d i m pr o ve 5- year e ve nt-free 
s ur vi val b y 2 0 %; 1 a n d patie nts recei vi n g less as para gi nase t hera p y c o ul d h a ve 5- year E F S 
re d uce d b y 1 7 %;2  ( 2) males will n ot be recei vi n g t he a d diti o nal 2 6 wee ks of c o nti n uati o n 
t hera p y o n T O T X VI; ( 3) T O T X VI will i ncl u de a p pr o xi matel y 2 0 i nf a nts a n d ( 4) t he 
f oll o w u p ti me of T O T X V is still s h ort. 
 
P ost ul ate d effect size i n e ac h str at u m b ase d o n T O T X V 
Str at u m  
n ( %)  
5 -Y C C R 
si nce 
c o nti n u ati o n 
Esti m ate ± 
S E ( %)  
P ost ul a
te 5 -y 
C C R 
i n t he 
2 5 0 0 u/
m 2 ar m  
( %) 
P ost ul ate
5 -y C C R 
i n t he 
hi g h -
d ose ar m  
( %) 
Wei g hte d 
effect size  
H R  
1 4 ( 4. 6 4)  
3 9. 3 ± 2 1. 6  
3 2  
6 4  
1. 4 8 4  
S R & T -
cell & M R D 1 9 +  
2 7 ( 8. 9 4)  
7 3. 5 ± 2 1. 8  
6 6  
9 2  
2. 3 2 4  
S R & T -
cell & M R D 1 9 - 
1 9 ( 6. 2 9)  
8 8. 9 ± 1 3. 3  
8 2  
9 2  
0. 6 2 9  
S R & B -cell 
9 0 
( 2 9. 8 0) 
7 7. 3 ± 9. 2  
7 3  
9 2  
5. 6 6 2  
L R  
1 5 2 
( 5 0. 3 3) 
9 6. 1 ± 3. 5  
9 4  
9 8  
2. 0 1 2  
O verall  
3 0 2  
 
8 1. 5 7 9  
9 3. 7 2 2  
1 2. 0 2 1  
 
T he l o w ris k gr o u p n o net heless c o ntri b utes a n a p precia ble a m o u nt of effect ( 2 %, t he t hir d 
hi g hest) t o t he o v erall effect size. Alt h o u g h t he statistical p o wer is m ostl y br o u g ht b y t he 
effects i n t he S/ H ris k gr o u ps, we c h o ose t o r a n d o mize t he l o w ris k patie nts as well i n or der 
t o ha ve a n o p p ort u nit y t o f ull y u n dersta n d P E G-as para gi nas e P K (i n b ot h i nte nsi vel y a n d 
less i nte nsi vel y treate d p atie nts), t o e val uate t heir t olera nce t o hi g her d ose of as para gi nase, 
a n d t o o bser ve t heir l o n g ter m o utc o me i n t he c o nt e xt of t he T O T X VI t hera p y. As is s h o w n 
bel o w, we will ha ve a de q uate statistical p o wer t o d etect t he p ost ulate d effect size i n t he 
e ntire c o h ort. 
 
T h us f or T O T X VI, we p ost ulate o verall t he 5- year C C R rate p ost ra n d o mizati o n will be 
a p pr o xi matel y 8 2 % i n t h e 2 5 0 0 U/ m 2 ar m a n d 9 4 % i n t he hi g h d ose P E G-as para gi n ase 
ar m. T he st u d y will be p o were d t o det ect a 1 2 % differe n ce i n t he fi ve- year C C R rate. 
 
C o nsi deri n g t he pr o b a bilit y distri b uti o n of t he fail ure ti mes, t he f oll o wi n g fi g ure s h o ws a 
n o n para metri c esti mate of its hazar d rate f u n cti o n base d o n t he C C R distri b uti o n fr o m 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T O T XIII A & B c o m bi ne d. T his esti mate is c o nstr ucte d via s pli ne esti mates of t he q ua ntile 
a n d q ua ntile de nsit y f u ncti o ns of t he C C R distri b uti o n a n d is a s pecial case of t he 
esti mat ors i n vesti gate d b y C he n g. 1 3 6 T he e x p o ne ntial distri b uti o n ass u m pti o n of a c o nsta nt 
ha zar d rate is cl earl y vi ol ate d. As t he hazar d rate f u ncti o n is o nl y a p pr o xi matel y c o nsta nt 
d uri n g years o n e a n d t hree, it is n ot reall y feasi ble t o esti mate t his f u ncti o n wit h a se q ue nce 
of piece- wise e x p o ne ntials. W e ca n esti mate t he statistical p o wer f or a n y gi ve n sa m ple a n d 
effect sizes b y si m ulati o n usi n g n o n para metric esti mates o btai ne d fr o m t he hi g h q ualit y 
preli mi nar y data. He re w e esti m ate t he p o w er f or 3 0 0 e v al u a ble p atie nts at t he a b o ve-
s pecifie d effect size. Si m ulati o n als o all o ws f or o btai ni n g esti mates of ot her i m p orta nt trial 
pa ra meters (e. g., t h e pr o b a bilit y distri b uti o n of t he t otal accr ual ti me t o reac h t he tar get of 
3 0 0 e val ua ble p atie nts) t hat are n ot a vaila ble fr o m c o n ve nti o nal met h o ds.  
F ail ur e ti m e ( y e ar)
H a z ar d r at e
0 
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0
0. 0 
0. 0 2 
0. 0 4 
0. 0 6 
0. 0 8 
0. 1 0 
0. 1 2
E sti m at e d H a z ar d R at e F u n cti o n fr o m T- 1 3 A & B
 
T he statistical p o wer of a t w o-si de d l o g-ra n k test at t he 5 % si g nifica nce l e v el f or t he 
sa m ple siz e of 3 0 0 a n d t he p ost ulate d effect size is esti mate d b y 1 0 0 0 si m ul ati o n r u ns. 
T he M o nte C arl o esti m ate of t he p o w er is 0. 8 5, wit h 9 5 % c o nfi de nce i nter v al ( CI) 
[ 0. 8 3, 0. 8 8]. T he esti mate d pr o ba bilit y t hat m or e t ha n 7 years of t otal accr ual ti me will be 
re q uire d is 0. 0 2 ( 9 5 % CI [ 0. 0 1, 0. 0 3]), a n d t he esti mate d pr o ba bilit y of less t ha n 6 years 
t otal accr ual ti me is 0. 2 4 ( 9 5 % CI [ 0. 2 1, 0. 2 6]).  
 
C o nsi deri n g t o i ncl u de t h e rece nt ( 4/ 5/ 2 0 0 7) T O T X V o utc o me data as preli mi nar y d ata f or 
M o nte Carl o p o wer esti mati o n as well, t he f oll o wi n g fi g ures s h o w K M esti mates of t he 
C C R s ur vi val c ur ve wit h p oi nt- wise 9 5 % CI ( d otte d li nes) a n d tic k mar ks i n dicati n g 
ce ns ori n g, f or T O T XIII A a n d T O T XIII B, T O T X V pl us i nfa nts, T O T X V Sta n dar d/ Hi g h 
ris k, a n d T O T X V L o w ris k.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
0 
2 
4 
6 
8
1 0 
1 2 
1 4
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 3 A & B
0 
2 
4 
6 
8
1 0 
1 2 
1 4
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 3 & 1 3 B, T- 1 5 +I nf n
0. 0 
1. 0 
2. 0 
3. 0 
4. 0 
5. 0 
6. 0
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 5 L o w Ri s k
0. 0 
1. 0 
2. 0 
3. 0 
4. 0 
5. 0 
6. 0
0. 0 
0. 2 
0. 4 
0. 6 
0. 8 
1. 0
T- 1 5 S/ H Ri s k
 
E x cessi ve ce ns ori n g wit hi n 6 years i n T O T X V is n oticea ble, e v e n i n t he l o w ris k c o h ort; 
e vi de nt of rel ati vel y s h ort f oll o w u p ti me. T he f oll o wi n g fi g ure s h o ws n o n p ara metri c 
hazar d rate f u ncti o n esti mates fr o m T O T XIII A, T O T XIII B, a n d T O T X V wit h i nfa nts 
c o m bi ne d ( All), T O T X V wit h i nfa nts, a n d T O T XIII A & B. T h e irre g ular s ha pe of t he 
hazar d rate f u ncti o n esti mate f or T O T X V is lar gel y d ue t o hea v y ce ns ori n g ca use d b y lac k 
of f oll o w u p. 
ti m e ( y e ar)
H a z ar d R at e
0 
1 
2 
3 
4 
5 
6 
7 
8 
9
1 0
0. 0 
0. 0 2 
0. 0 4 
0. 0 6 
0. 0 8 
0. 1 0 
0. 1 2
T 1 5 +I nf n
T 1 3 A B
All
H a z ar d R at e F u n cti o n E sti m at e s
 
M o nte Carl o esti mates of t he statistical p o wer of t he l o g ra n k test base d T O T XIII A, 
T O T XIII B, a n d T O T X V pl us i nfa nts is 8 4 %, wit h t he 9 5 % CI [ 0. 8 1, 0. 8 6]. 
 
C o nser vati vel y we ne xt c o nsi der p ost ulati n g t he effect sizes base d o n t he p oi nt esti mates 
fro m t he T O T X V d ata: 8 5. 1 9 9 % vs. 9 3. 7 2 2 % C C R at year 5 si nce c o nti n uati o n; see ta ble 
bel o w. B ase d o n T O T XIII A a n d XIII B preli mi n ar y d at a, t he esti m ate d p o wer at 5 % 
si g nific a nce le vel is 0. 7 9 1 ( 9 5 % CI [ 0. 7 6 6, 0. 8 1 6]) if t he s a m ple size is i ncre ase d t o 
4 2 0.  F o r t his sa m ple siz e t he pr o ba bilit y of m ore t ha n 9. 5 accr ual is 0. 0 5 4 ( 9 5 % CI [ 0. 0 4 0, 
0. 0 6 8]); t he pr o ba bilit y of less t ha n 8. 5 year accr ual is 0. 2 4 7 ( 9 5 % CI [ 0. 2 2 0, 0. 2 7 4]). 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
P ost ul ate d effect size i n e ac h str at u m b ase d o n p oi nt esti m ates fr o m T O T X V 
Str at u m  
n ( %)  
5 -Y C C R 
si nce 
c o nti n u ati o n 
Esti m ate ± 
S E ( %)  
P ost ul ate
5 -y C C R 
i n t he 
2 5 0 0 u/ m
2 ar m  
( %) 
P ost ul ate
5 -y C C R 
i n t he 
hi g h -
d ose ar m  
( %) 
Wei g hte d 
effect size  
H R  
1 4 ( 4. 6 4)  
3 9. 3 ± 2 1. 6  
3 9  
6 4  
1. 1 6 0  
S R & T -
cell & M R D 1 9 +  
2 7 ( 8. 9 4)  
7 3. 5 ± 2 1. 8  
7 3  
9 2  
1. 6 0 1  
S R & T -
cell & M R D 1 9- 
1 9 ( 6. 2 9)  
8 8. 9 ± 1 3. 3  
8 9  
9 2  
0. 1 8 9  
S R & B -cell 
9 0 ( 2 9. 8 0)  
7 7. 3 ± 9. 2  
7 7  
9 2  
4. 4 7 0  
L R  
1 5 2 
( 5 0. 3 3) 
9 6. 1 ± 3. 5  
9 6  
9 8  
1. 0 0 7  
O verall  
3 0 2  
 
8 5. 1 9 9  
9 3. 7 2 2  
8. 5 3 3  
 
F utilit y assess me nt at ye ar 6. 5: If t he i nteri m a n al ysis at year 6. 5 fails t o detect a 
statisticall y si g nifica nt differe nce at t he 0. 0 0 5 le vel (t w o-si de d test) bet wee n t he t w o P E G-
as para gi n ase re gi me ns, a f utilit y a nal ysis, as re q u este d b y t he C T- S R C, will be c o n d ucte d. 
We n ote t hat cli nical trials t hat are desi g ne d wit h statistical p o wer of 8 0 % t o detect a 
h y p ot hesize d effect h a ve a pr o ba bilit y of 0. 2 0 ( 2 0 %) of bei n g “f utile” e v e n if t he 
h y p ot hesize d effect size is tr ue. I n t his c o nte xt “f utilit y” d oes n ot mea n t hat t he researc h 
h y p ot hesis is n ot tr ue b ut rat her t hat at t he fi nal a nal ysis n o statisticall y si g nifica nt 
differe n ce is det ecte d.  
 
T h us, t he g o al of t his f utilit y a nal ysis is t o assess earl y e vi de nce t hat t he c o nject ure d 
8. 5 3 % effect size bet wee n hi g h d ose P E G-as para gi nase a n d c o n v e nti o nal d osi n g of P E G-
as para gi n ase is t o o o pti mistic a n d c o nti n ue d ra n d o mizati o n will wit h hi g h pr o ba bilit y 
res ult i n a f utile fi nal a n al ysis (i.e., fi nal p- val ue > 0. 0 4 5). T he si m ulati o n st u d y i n dicat es 
t hat at year 6. 5 we will h a ve o bser ve d a p pr o xi matel y 3 7 % of t he t otal n u m ber of e v e nts 
e x pecte d at t he pla n ne d fi nal a nal ysis. Gi ve n t he g oal a n d t he li mite d a m o u nt of 
i nf or mati o n e x pecte d t o be a vaila ble 6. 5 year after i nitiati o n of ra n d o mizati o n, we pr o p ose 
t he f oll o wi n g n o n-st a n dar d a p pr oac h. T his pr o p os e d f utilit y a n al ysis is n ot gr o u n de d i n 
peer-re vie we d p u blis he d statistical researc h, b ut w e belie ve t hat t he m et h o d is vali d a n d 
i n dee d at first gla n ce it d oes ha ve s o me n ecess ar y o perati n g c h aracteristics of a f utilit y 
a nal ysis. We f ull y e x pect t o c o m plete researc h o n t he pr o p ose d met h o d wit hi n a year a n d 
at t hat ti me or wit h t he first T O T X VI pr ot o c ol a m e n d me nt i ncl u de t he fi n al f utilit y 
a nal ysis desi g n a n d j ustificati o n f or C P S R M C c o nsi derati o n. If we are u na ble t o j ustif y t he 
statistical vali dit y of o ur met h o d, we will s witc h t o a sta n dar d a p pr oac h.  
 
We will c o n d uct t he f utilit y a nal ysis i n a wa y t hat t he fi nal pla n ne d a n al ysis will n ot be 
affecte d s h o ul d t he trial c o nti n ue t o t hat a nal ysis. F or t his p ur p ose we defi n e “f utilit y” as 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t he (c o n diti o nal) e v e nt t hat t he t w o-si de d test i n t he fi nal a nal ysis is n ot st atisticall y 
si g nifica nt at t he 0. 0 4 5 le vel gi ve n t h at t he n ull h y p ot hesis of n o differe nce is n ot rejecte d 
i n fa v or of t he o n e-si de d alter nati ve h y p ot hesis t hat t he hi g h d ose P E G-as para gi nase 
re gi me n has s u peri or distri b uti o n of C C R, at s o me yet t o be d efi ne d si g nifica nt le vel γ. We 
call t he c o n diti o nal pr o ba bilit y of (faili n g t o reject t he n ull h y p ot hesis b y t he t w o-si de d 
test at t he 0. 0 4 5 le vel i n t he fi nal a nal ysis gi ve n faili n g t o reject t he n ull h y p ot hesis i n 
fa v or of t he o ne-si de d alter nati ve at t he si g nifica n ce le vel γ i n t he f utilit y assess me nt) t he 
pr o b a bility of f utility  ( P o F u(γ)), w hic h we n ote is a f u ncti o n of γ.  
 
Af ter 6. 5 years of ra n d o mizati o n, we will declare t he trial statisticall y f utile, if we fail t o 
reject, at t he γ si g nifi ca n ce le vel, t he n ull h y p ot hesis of n o differe n ce a gai nst t he o ne-si de d 
alter nati ve h y p ot hesis t hat t he hi g h d ose P E G-as para gi nase re gi me n has t he s u peri or 
dist ri b uti o n of C C R.  
 
T he si g nifica nce le vel γ is a para m eter t o be deter mi ne d t o e ns ure t he f utilit y assess me nt h as 
t he foll o wi n g desir a ble o perati n g c haracteristics: ( 1) If t he act ual effect size is at least as 
p ost ulate d (i.e., 8. 5 %), t h e n wit h pr o ba bilit y great er t ha n 0. 8 0 t he trial will c o nti n ue; ( 2) If t h e 
act ual effect size is ver y s mall ( or e ve n if t he hi g h d ose P E G-as para gi nase re gi me n act u all y is 
less effecti ve), wit h hi g h pr o ba bilit y t he trial will be declare d f utile a n d he nce ra n d o mizati o n 
is st o p pe d. T he val ue of γm  t hat ma xi mizes P o F u(γ) has t hese pr o perties. I nt uiti vel y, t h e 
de cisi o n r ule t hat st o ps t he trial f or faili n g t o r eject t he n ull h y p ot hesis at t h e γ m  si g nifica nce 
le vel ma xi mizes t he pr o ba bilit y of i de ntif yi n g w he n c o nti n ue d ra n d o mizati o n a n d f oll o w u p is 
n ot li kel y t o pr o d uce a st atisticall y si g nifica nt r es ult. 
 
T he pr o ba bilit y of f utilit y a n d t h e pr o ba bilit y of declari n g t he trial f utile at vari o us γ 
va l ues a n d effect sizes are esti mate d b y si m ulati o n usi n g t he sa me preli mi nar y data as i n 
t he a b o ve p o w er c o nsi derati o n. At t he 8. 5 % effect size, t he esti mate d pr o ba bilit y of f utilit y 
is ma xi mize d at γ = 0. 3 1 5 a n d P o F u( 0. 3 1 5) = 0. 5 3 9 ( 9 5 % CI [ 0. 5 1 7, 0. 5 6 1]). T his mea ns t hat 
if t he act ual effect size is 8. 5 % a n d if we fail t o rej ect t he n ull h y p ot h esis i n fa v or of t he 
o ne-si de d alter nati ve at t he 3 1. 5 % le vel, t he n wit h 5 3. 9 % pr o ba bilit y we will n ot reje ct t he 
n ull h y p ot hesis at t he 0. 0 4 5 le vel usi n g t he t w o-si de d test i n t he fi nal a nal ysis. T he 
pr o ba bilit y of declari n g f utilit y (st o p pi n g t he trial w he n it s h o ul d ha ve c o nti n ue d) w he n 
t he tr ue effect size is 8. 5 % f or γ = 0. 3 1 5 is esti mate d t o be 0. 1 0 2 ( 9 5 % CI [ 0. 0 8 9, 0. 1 1 5]). 
T he f oll o wi n g t a ble s h o ws t he o perati n g c h aracteristic of t he f utilit y assess me nt usi n g 
γ = 0. 3 1 5 at a fe w effect sizes ( ne gati ve effect size mea ns t hat t he 5- year C C R of t he hi g h 
d ose P E G-as para gi nase re gi me n is a ct uall y l o wer b y t he gi ve n a m o u nt). 
 
  
  
  
Pr o ba bilit y of f utilit y   
Pr o ba bilit y of declari n g 
Tr ue effect size  
P o F u( 0. 3 1 5) ( 9 5 % CI)  
f utilit y/st o p ( 9 5 % CI) 
8. 5 %   
  
0. 5 3 9 ([ 0. 5 1 7, 0. 5 6 1])   
0. 1 0 2 ([ 0. 0 8 9, 0. 1 1 5]) 
4. 0 %   
  
0. 9 6 4 ([ 0. 9 5 6, 0. 9 7 2])   
0. 3 7 8 ([ 0. 3 5 6, 0. 3 9 9]) 
2. 0 %   
  
0. 9 0 8 ([ 0. 8 9 5, 0. 9 2 1])   
0. 7 7 3 ([ 0. 7 5 5, 0. 7 9 1]) 
-4. 0 %   
  
0. 8 2 0 ([ 0. 8 0 3, 0. 8 3 7])   
0. 8 7 9 ([ 0. 8 6 5, 0. 8 9 3]) 
 
S o if t he tr ue effect size is 4. 0 % ( 2. 0 %) i n fa v or of t he hi g h d ose P E G-as para gi n ase 
re gi me n, t he n wit h pr o ba bilit y 0. 3 7 8 ( 0. 7 7 3), t he trial will st o p at 6. 5 years. Wit h 
pr o ba bilit y 0. 6 2 2 ( 0. 2 3 7) t he trial will c o nti n ue a n d t he pr o ba bilit y t hat t he fi nal t w o-si de d 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 8 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
test will be statisticall y si g nifica nt is 0. 0 3 6 ( 0. 0 9 2) gi ve n t he tri al c o nti n ues t o t he p oi nt of 
fi nal a nal ysis. N ote t hat t he 2. 0 % effect size has a hi g her pr o ba bilit y of res ulti n g i n a 
statisticall y si g nifica nt fi n di n g d ue t o t he fi n al test bei n g t w o-si de d; t hat is s o meti mes t he 
c o n ve nti o nal d ose ar m will ha ve a s u peri or distri b uti o n of C C R. 
  
T h us, w e will decl are t he tri al st atistic all y f utile t o c o nti n ue a n d st o p accr u al b ase d 
o n t he 6. 5 ye ar a n al ysis, if t he test of t he n ull a g ai nst t he o ne-si de d alter n ati ve t h at 
t he hi g h d ose P E G- as p a r a gi n ase re gi me n h as t he better distri b uti o n of C C R is n ot 
si g nific a nt at t he 3 1. 5 % le vel. 
 
T he a b o ve pla n f or t he f utilit y a n al ysis will eit her be j ustifie d b y s oli d statistical scie nce 
i ncl u di n g assess me nt of t he o perati n g c h aracteristi cs wit hi n a year of pr ot oc ol i nitiati o n or 
t he desi g n will be re pla ce d wit h a m ore sta n dar d a p pr oac h.  
 
I n s u m mar y, t o ha ve acce pta ble p o wer t o detect a reas o na bl e a n d cli nicall y mea ni n gf ul 
i mpr o ve me nt i n t he distri b uti o n of d urati o n of C C R f or t he hi g h- d ose P E G-as para gi n ase 
re gi me n, we will accr ue 5 3 1 patie nts wit h t he e x pectati o n t hat 4 2 0 will be ra n d o mize d. 
T his n u m ber of patie nts will pr o vi de a p pr o xi matel y 8 0 % statistical p o wer ( α = 0. 0 5; t w o-
si de d test) t o detect a n i m pr o ve me nt of 8. 5 3 % i n t he 5- year C C R f or t he hi g h- d ose 
re gi me n as c o m p are d t o t he sta n dar d- d ose re gi me n. Zel e n’s ra n d o mizati o n al g orit h m, as 
i mple me nte d i n t he De part me nt of Bi ostatistics si nce 1 9 9 2, will be use d wit h a bl oc ki n g 
fact or of 4 i n eac h strat u m.   T w o i nteri m a nal ys es f or efficac y are pla n ne d after 3 a n d 6. 5 
y ears after i nitiati o n of ra n d o mizati o n a n d a f utilit y a n al ysis will als o be c o n d ucte d at t he 
6. 5 year mar k. T he st u d y d urati o n is esti mate d t o re q uire a p pr o xi matel y 8. 6 years of 
accr ual a n d t he fi nal a nal ysis of t he pri mar y o bjecti ve will be 3 years after t he last patie nt 
is ra n d o mize d. T h us t he t otal st u d y d urati o n will b e 1 1- 1 2 years.  
 
1 8. 3 
T hera p e utic O bjecti ves 
 
T o esti m ate t he eve nt-fre e s urviv al a n d over all s urviv al of c hil dre n wit h A L L w h o are 
tre ate d wit h risk- directe d t her a py a n d t o c o m p are t he E F S res ults of T O T X VI wit h t h at 
of T O T X V. 
 
T hese a n al ys es will o nl y be c o n d ucte d at t he ti me t he pla n ne d i nteri m a nal yses c o m pari n g 
t he t w o c o nti n uati o n re gi me ns are c o m plete d. T hat is after 3 a n d 6. 5 years of accr ual. 
 
E F S will be meas ure d fr o m t he date of c o m plete res p o nse t o t he date of i nitial fail ure f or 
patie nts w h o fail. Fail ure i ncl u des t he tra diti o nal e n d p oi nts of fail ure t o ac hie ve a 
c o m plete re missi o n, rela pse i n a n y site, sec o n dar y mali g na n c y, a n d deat h d uri n g i n d ucti o n 
or re missi o n. E F S ti me will be meas ure d t o t he dat e of last c o ntact f or patie nts w h o are 
fail ure free at t he ti me of a nal ysis. T h e E F S ti me is defi ne d t o be zer o ( 0) f or patie nts w h o 
die d ur i n g i n d ucti o n t hera p y or fail t o ac hie ve a c o m plete re missi o n. 
 
T he f oll o wi n g t a ble a n d fi g ure s h o w res p ecti vel y t he 5- year a n d E F S distri b uti o n 
esti mates of T O T XIII A, T O T XIII B, a n d T O T X V pl us i nfa nts.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 0  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
E F S di stri b uti o n
0
0. 1
0. 2
0. 3
0. 4
0. 5
0. 6
0. 7
0. 8
0. 9
1
0
2
4
6
8
1 0
1 2
1 4
1 6
y e ar
Pr o b a bilit y
T 1 3 A
T 1 3 B
T 1 3 A B
T 1 5 +i nf n
S T U D Y  
n  
T ot al  
 
n  
I nf a nts  
5 -Ye ar E F S  
Esti m ate ± S E ( %)  
T 1 3 A  
1 6 5  
5  
7 7. 0 ± 3. 3  
T 1 3 B  
2 4 7  
1 0  
8 0. 9 ± 2. 5  
T 1 3 A & B c o m bi ne d  
4 1 2  
1 5  
7 9. 3 ± 2. 0  
T 1 5 +I nf n (as of 4/ 5/ 0 7)  
3 8 1  
1 6  
8 3. 7 ± 4. 2  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T he f oll o wi n g t a ble s h o ws t he 5- year E F S of t h ese pre vi o us st u dies b y ris k strata, w here 
i nfa nts descri be d a b o ve were a d de d t o t he T O T X V Sta n dar d/ Hi g h ris k strat u m.  
 
RI S K A R M S  
n  
5 -Ye ar E F S Esti m ate ± S E 
( %) 
T 1 3 A S/ H  
1 5 1  
7 6. 8 ± 3. 4  
T 1 3 B S/ H  
1 2 6  
7 6. 1 ± 3. 8  
T 1 5 S/ H wit h i nfa nts  
1 9 4  
7 5. 8 ± 6. 6  
T 1 3 A L  
1 1  
1 0 0 ± 0. 0  
T 1 3 B L  
1 1 6  
8 9. 5 ± 2. 9  
T 1 5 L  
1 8 1  
9 5. 7 ± 3. 4  
 
Ka pla n- Mei er esti mates of E F S a n d s ur vi val will be pr o vi de d a n d c o m pare d hist oricall y 
wit h t h ose of T O T X V, T O T XIII A a n d T O T XIII B. All eli gi ble patie nts e nt ere d o n 
T O T X VI will be i ncl u de d i n t hese a nal yses, as a p pr o priate. I nfa nts will be e x cl u de d fr o m 
t he T otal X VI f or c o m paris o ns wit h T O T X V as o nl y c hil dre n at least o ne year of a ge at 
dia g n osis were tr eate d o n T otal X V. C o m paris o ns will be ma de b ot h u nstratifie d a n d 
stratifie d b y T O T X VI defi ne d ris k gr o u ps.  S o me ass u m pti o ns will be necessar y as n ot all 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 1  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
fact ors defi ni n g ris k o n T O T X VI will be a v aila ble f or all patie nts treate d o n T O T XIII A 
a n d B. T h e c o m paris o ns wit h T O T X V defi n e t he sta n dar ds wit h w hic h t he fi nal res ults of 
t his st u d y s h o ul d be c o m pare d t o ass ure c o nti n ue d pr o gress t o war ds t he St. J u de g oal of 
i m pr o vi n g t he c ure rate of c hil d h o o d A L L. T he f oll o wi n g ta ble s h o ws t he rece nt E F S i n 
T O T X V ( D ata fr oze n o n 4/ 5/ 2 0 0 7). 
 
E F S i n T O T A L - X V  
Year  
Ris k  
Fail  
Ce ns  
Pr o b  
S E  
0  
3 6 5  
6  
0  
0. 9 8 4  
0. 0 0 7  
1  
3 5 9  
1 1  
5 2  
0. 9 5 0  
0. 0 1 2  
2  
2 9 6  
7  
6 7  
0. 9 2 5  
0. 0 1 7  
3  
2 2 2  
3  
6 1  
0. 9 1 0  
0. 0 2 2  
4  
1 5 8  
3  
5 3  
0. 8 8 7  
0. 0 2 9  
5  
1 0 2  
4  
3 6  
0. 8 4 6  
0. 0 4 2  
6  
6 2  
0  
5 0  
0. 8 4 6  
0. 0 9 2  
7  
1 2  
0  
1 2  
0. 8 4 6  
0. 3 3 2  
 
T hese c o m paris o ns are n ecessar y t o assess t he i m pr o ve me nt i n o utc o me t h at t he ris k- base d 
T O T X VI t hera p y f or A L L has o v er t he T O T X V t hera p y.  
 
Si nce male patie nts will recei ve s h orter d urati o ns of t hera p y o n T O T X VI t ha n o n T O T X V, 
we will s pecificall y c o m pare t he distri b uti o ns of E F S f or male p atie nts bet wee n t hese t w o 
trials. Als o we will c o m pare t he distri b uti o ns of C C R fr o m t he p oi nt t hat T O T X VI t hera p y 
f or male patie nts c eases. 
 
T o st u dy w het her i nte nsifyi n g i n d ucti o n, i ncl u di n g fr acti o n ate d cycl o p h os p h a mi de a n d 
t hi o g u a ni ne, i n p atie nts wit h d ay 1 5 M R D > 5 %, will res ult i n i m pr ove d le uke mi a 
cyt ore d ucti o n i n t his s u b gr o u p c o m p are d t o T X V. 
  
 
T hese a n al ys es will o nl y be c o n d ucte d at t he ti me t he pla n ne d i nteri m a nal yses c o m pari n g 
t he t w o c o nti n uati o n re gi me ns are c o m plete d. T hat is after 3 a n d 6 years of accr ual. 
  
 
As of 3/ 2 1/ 0 7, T O T X V d ata i n dicate t hat 4 5/ 4 3 9 = 1 0. 5 % of patie nts ha d Da y- 1 9 M R D of 
at least 5 %. A m o n g t his s u b gr o u p, 9/ 4 5 = 2 0 % ac hie ves ne gati ve M R D ( < 0. 0 1 %) at Da y 
4 6, a n d 8 0 % re m ai ns M R D p ositi ve at t he e n d of re missi o n i n d ucti o n ( 9 5 % CI [ 0. 6 8 3, 
0. 9 1 6 8]). T he a nal ysis will first c o m pare t he pr o p orti o n of T O T X V patie nts w h o ha d Da y-
1 9 M R D ≥5 % wit h t he pr o p orti o n of patie nts o n T O T X VI wit h Da y- 1 5 M R D ≥5 %. Ne xt 
we will c o m pare t h e pr o p orti o n of patie nts wit h Da y- 1 5 M R D ≥5 % o n T O T X VI w h o are 
Da y- 4 2 M R D p ositi ve wit h t he pr o p orti o n of Da y- 4 6 M R D p ositi ves i n t he c orres p o n di n g 
s u b gr o u p i n T O T X V b y Fis her’s e x act test. Wit h t he accr ual of a p pr o xi matel y 3 5 0 
patie nts, we c o nser vati vel y a ntici pate t h ere will be at least 3 4 patie nts w h o ha ve Da y- 1 5 
M R D ≥5 %. T he f oll o wi n g ta ble s h o ws t he p o wer of t w o-si de d e x act test at t he 0. 0 5 
si g nifica n ce le v el f or se v eral p ost ulate d pr o p orti o ns of Da y- 4 2 M R D p ositi ve patie nts a n d 
sa m ple siz es fr o m eac h trial. 
  
  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 2  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
CI N of i s ol at e d C N S r el a p s e s i n St. J u d e p ati e nt s fr o m T ot al X V
0
0. 1
0. 2
0. 3
0. 4
0. 5
0. 6
0. 7
0. 8
0. 9
1
0
1
2
3
4
5
6
7
Y e ar s fr o m C R d at e
CI
C N S- 2 or C N S- 3 or tr a u m ati c bl a st + or T- c ell wit h W B C > = 1 0 0
N. T 1 5 Pr o p. T 1 5  
N. T 1 6 Pr o p. T 1 6  
P o wer  
  
  
  
4 5  
0. 6 8 
  
3 4  
0. 5 0 
  
0. 3 4 
  
  
  
4 5  
0. 8 0 
  
3 4  
0. 5 0 
  
0. 7 7 
 
  
  
4 5  
0. 9 2 
  
3 4  
0. 5 0 
  
0. 9 9 
 
  
  
4 5  
0. 8 0 
  
3 4  
0. 5 5 
  
0. 6 2 
 
  
  
4 5  
0. 9 2 
  
3 4  
0. 5 5 
  
0. 9 7 
 
  
  
4 5  
0. 8 0 
  
3 4  
0. 6 0 
  
0. 4 4 
 
  
  
4 5  
0. 9 2 
  
3 4  
0. 6 0 
  
0. 9 2 
 
T o assess w het her i nte nsific ati o n of C N S directe d i ntr at hec al a n d syste mic c he m ot her a py 
will i m pr ove o utc o me i n p atie nts at hi g h risk of C N S rel a pse . 
 
T he se a n al ys es will o nl y be c o n d ucte d at t he ti me t he pla n ne d i nteri m a nal yses c o m pari n g 
t he t w o c o nti n uati o n re gi me ns are c o m plete d. T hat is after 3 a n d 6 years of accr ual. 
 
T he T O T X V e x perie nce has c o nfir me d t hat C N S- 2 a n d C N S- 3 stat us, tra u matic l u m ber 
p u nct ure wit h blast, a n d T-li nea ge wit h W B C m ore t ha n 1 0 0, 0 0 0 re mai n hi g hl y ass ociat e d 
wit h C N S rela pse. O n T otal X V, 9 8 of 3 5 9 ( 2 3. 3 %) patie nts fell i nt o t his cate g or y of bei n g 
hi g h ris k f or C N S r ela pse. Of partic ular i nterest here is is olate d C N S rela ps e. O n T O T X V, 
as of 4/ 5/ 2 0 0 7 all C N S rela pses i n t his s u b gr o u p are is olate d, t he c u m ulati ve i nci de nce of 
w hic h is gi ve n b el o w. T h e 5- year c u m ulati ve i nci d e nce of is olat e d C N S rela pse is 
1 0. 4 % ± 4 %. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
F or T O T X VI, c u m ulati v e i nci de nces of is olate d C N S rela pse as w ell as c o m bi ne d C N S 
rela pse a m o n g all patie nts, a n d a m o n g t he hi g h-ris k C N S patie nts ( defi ne d as ha vi n g a n y 
of C N S- 2 or 3, tra u matic L P wit h blast, or T-li nea ge wit h W B C > 1 0 0, 0 0 0) will be 
esti mate d b y t he Kal bflis c h- Pre ntice esti mat or. 1 3 7 T he c u m ulati ve i nci de n ce f u ncti o ns of 
is olate d a n d c o m bi ne d C N S rela pse a m o n g t hes e hi g h-ris k C N S patie nts o n T O T X VI will 
be c o m pare d t o t he c orres p o n di n g gr o u p o n T O T X V usi n g Gra y’s test. 1 3 8  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 3  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
1 8. 4  
E x pl orat or y P har mac ol o gic O bj ecti ves 
 
T o i de ntify p h ar m ac o ge netic, p h ar m ac oki netic a n d p h ar m ac o dy n a mic pr e dict ors f or 
tre at me nt-rel ate d o utc o mes i n t he c o ntext of t he syste mic t her a py use d i n t h e pr ot oc ol. 
 
T his e x pl orat or y o bjecti v e is i n c o ncert wit h t he bi ol o gical o bjecti ve “ T o i d e ntif y n e w 
pr o g n ostic fact ors b y a p pl yi n g de vel o pi n g tec h n ol o gies t o st u d y patie nt material (e. g., 
st ore d plas ma, ser u m, cere br os pi nal fl ui d, a n d n or mal a n d le u ke mic cells.” Statistical 
c o nsi derati o ns f or t his ai m will be gi ve n i n Secti o n 1 7. 5. 
  
 
T o c o m p are t he p h ar m ac oki netics a n d p h ar m ac o d y n a mics of P E G- as p ar a gi n ase give n i n 
hi g her d ose of ( 3, 5 0 0 u nits/ m 2 or 3, 0 0 0 u nits/ m2) vers us t h ose of P E G- as p ar a gi n ase give n 
i n c o nve nti o n al d ose ( 2, 5 0 0 u nits/ m 2) i n t he c o nti n u ati o n p h ase.  
  
 
C o m paris o n of a P K/ P D meas ure me nt at a fi x e d ti me p oi nt bet w ee n t he t w o P E G-
as para gi n ase ar ms will be d o ne b y t he Wilc o x o n ra n k-s u m test. C o m paris o n of a 
l o n git u di nal P K/ P D meas ure me nt will be d o ne b y ge n eral li near m o dels ( G L M) f or 
re peat e d meas ur es t o acc o u nt f or i ntra- patie nt c orrelati o n; s uc h a m o del will i ncl u de t he 
treat me nt ar m, a p atie nt r a n d o m effect, a n d p ossi bl y ot her c o vari ates as mai n effects as 
well as i nteracti o n effects b y t hese fact ors w he n d ee me d as a p pr o priat e. F or c o m paris o n 
p ur p oses s y m metrizi n g a n d varia nce sta bilizi n g tra nsf or mati o ns ma y be a p plie d t o t he 
P K/ P D meas ure me nts if necessar y, t o ma ke t he data better a d here t o t he m o del ass u m pti o n 
of n or mal distri b uti o n f or t he res p o nse varia ble. 
 
1 8. 5 
E x pl orat or y Bi ol o gic al O bjecti ves 
 
T o deter mi ne t he pr o g n ostic v al ue of d ay 8 levels of mi ni m al resi d u al dise ase i n 
peri p her al bl o o d. 
 
C u m ulati ve i nci de nce hazar d re gressi o n m o deli n g 1 3 9 will be use d t o m o del t he ca use-
s pecific fail ures of h e mat ol o gical or c o m bi ne d he mat ol o gical r ela pses (i ncl u di n g fail ures 
t o ac hie ve re missi o n, f or w hic h ti me t o e ve nt is set t o zer o) as a f u ncti o n of Da y- 8 M R D 
le vel, al o n g wit h ot her k n o w n pr o g n ostic fact ors as c o vari ates. T he Da y- 8 peri p heral 
bl o o d M R D le vels will be treate d i n t w o wa ys: as a c o nti n u o us varia ble, a n d cate g orize d 
i nt o t w o or t hree cate g ori es; f or e x a m ple 0 % t o < 1 % vs. 1 % t o < 1 0 % vs. 1 0 % a n d m ore.  
 
T o ge n oty pe n at ur al killer ( N K) cell rece pt ors a n d me as ure t heir e x pressi o ns at di a g n osis 
a n d bef ore rei n d ucti o n, a n d t o ass oci ate t hese fe at ures wit h tre at me nt o utc o me. 
 
F or t his e x pl orati ve o bjecti ve, ass ociati o ns of ge n ot y pes ( or ge n e e x pressi o ns) wit h l o n g-
ter m treat me nt o utc o mes will be e x pl ore d b y fail ure ti me m o dels1 3 9; ass ociati o ns of t he 
ge n ot y p es wit h cate g orical cli nical o utc o mes (e. g., M R D stat us at t he e n d of i n d ucti o n) 
will be a nal yze d b y c o nti n ge n c y ta bles a n d C hi-s q uare tests; ass ociati o ns of ge n e 
e x pressi o ns wit h cate g orical cli nical o utc o mes will be a nal yz e d b y ra n k- bas e d pr oce d ures 
s uch as t he Wilc o x o n test. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 4  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T o i de ntify ne w pr o g n ostic f act ors by a p plyi n g devel o pi n g tec h n ol o gies t o st u dy p atie nt 
m ateri al (e. g., st ore d pl as m a, ser u m, cer e br o-s pi n al fl ui d, a n d n or m al a n d le uke mic cells). 
 
T his is a n e x pl orat or y o bjecti ve. Bi o mar kers t o be c o nsi dere d ma y c o me fr o m se veral 
s o urces i ncl u di n g ( b ut n ot li mite d t o) ca n di date ge nes a n d de vel o pi n g tec h n ol o gies s uc h as 
m R N A e x pressi o n arra ys, e x o n e x pressi o n arra ys, S N P arra ys, arra y C G H, a n d 
pr ote o mics. T he basic a p pr oac h t o t his o bjecti ve will be ge n ot y p e- p he n ot y pe ass ociati o n 
st u dies a n d ge n o me- wi de ass ociati o n a nal ysis ( G W A). Us uall y, t he ge n ot y p e will reflect 
ger mli ne D N A v ariati o n, R N A tra nscri pt variati o n (“f u ncti o nal ge n o mic varia bilit y), or 
ac q uire d ge n o mic vari ati o n (fr o m c o m paris o ns of blast a n d ger mli ne D N A variati o n). Of 
c o urse, b ot h R N A variati o n a n d ac q uir e d ge n o mic variati o n ca n als o be c o nsi dere d 
p he n ot y p es t hat are partl y a pr o d uct of ger mli ne v ariati o n t he msel ves. We ha ve a m ple 
e x perie nce i n e x peri me nt ati o n a n d a nal yses f or ge n o me- wi de a n d ca n di dat e ge ne 
a p pr oac h es 2; 1 0; 1 2; 5 2- 5 7; 5 9; 6 1- 6 5; 1 4 0 
 
Statistical met h o d ol o gies f or G W A a n d ge n ot y pe- p he n ot y p e ass ociati o n a n al yses b ase d o n 
ca n di date ge nes r ece ntl y de vel o pe d i n t his i nstit uti o n a n d else w h ere will be a p plie d t o t he 
da ta a nal yses f or t his ai m.1 4 1- 1 4 3 Alt h o u g h o ur a nal ys es caref ull y e val u ate false disc o ver y 
rate1 4 4 a n d w he n necessar y, us e per m utati o n tec h ni q ues f or assi g ni n g “ p val ues” t o 
ass ociati o ns, t he pri mar y “ vali dati o n” of ge n ot y p e/ p he n ot y p e ass ociati o ns is de pe n de nt 
u p o n re plicati o n i n m ulti ple cli nical st u dies, bi ol o gical pla usi bilit y a n d/ or l a b orat or y 
m o del verificati o n. T heref ore, statistical tests are o nl y a p art of t he e val uati o n of 
ge n ot y p e/ p he n ot y pe ass o ciati o ns. We ne xt ill ustrate t he ma g nit u de of false p ositi ve a n d 
false ne gati ve err ors t hat we a ntici pate f or t hese st u dies b y t w o t y pes of st u di es: 
ha pl ot y pe- p he n ot y pe ass ociati o n a n d micr oarra y ge n e e x pressi o n pr ofili n g, after a 
c o nsi derati o n f or p o wer of testi n g ca n di date ge ne p ol y m or p his ms. 
 
P o w er of testi n g c a n di d ate ge ne p ol y m or p his ms. A n e x a m ple f or t he p o wer t o e val u ate 
a ca n di dat e ge n ot y pe a n d a dic h ot o m o us p he n ot y p e (e. g. M R D vs. n o M R D) is gi ve n here. 
A n I L 1 5 S N P (rs I D # A- 4 2 6 4 5 1 9) o bser ve d i n o n e of o ur ge n o m e- wi de a n al yses of 
g er mli ne p ol y m or p his ms relate d t o e n d- of-i n d ucti o n M R D stat us has a mi n or allele 
fre q ue n c y of ~ 1 0 %. O n t he SJ c o h ort i n t he T T ge n ot y pe 1 8. 9 8 % ( 0. 1 8 9 8) were M R D 
p ositi ve w hereas i n t he T C/ C C ge n ot y pe 3 7. 2 5 % ( 0. 3 7 2 5) were M R D p ositi ve. We will 
test w het her t his p ol y m or p his m is si milarl y ass oci ate d wit h M R D stat us (e n d of i n d ucti o n) 
i n T O T X VI. Wit h a sa m ple siz e of 4 0 0, at t he 0. 0 5 si g nifica n ce le vel t here will be 8 2. 7 8 % 
p o wer t o dete ct t he differe nce of 0. 1 8 2 7 ( 1 8. 9 8 % vs. 3 7. 2 5 %) o bs er ve d i n t he ge n o me-
wi de st u d y. 
 
H a pl ot y pes a n d a c o nti n u o us v ari a ble p he n ot y pe. T his is ill ustrate d f or a mi ni m u m 
sa m ple siz e of 3 0 0,  a t otal of 4- 1 0 maj or ha pl ot y p es, a n d t he ass u m pti o n t hat t he s mallest 
n u m ber  of i n di vi d uals i n t he m ost rare ge n ot y p e/ ha pl ot y pe b e 1 0 % or n = 3 0. F or 
statistical p o wer we c o ns er vati vel y c o nsi der t w o less fa v ora ble sa m ple siz e a n d effect 
c o nfi g urati o ns. If t here are te n gr o u ps wit h res p ecti ve sa m ple siz es 1 0, 1 0, 2 0, 2 0, 4 0, 4 0, 
6 0, 6 0, 2 0, 2 0, a n d t he mea ns (f or e x a m ple, f or a c o nti n u o us varia ble reflecti n g t o xicit y, 
s uc h as h o m oc ystei ne le v el) i n t he first fi ve ha pl ot y p e gr o u ps differ fr o m t h e o verall me a n 
b y 2, 2, 2, 2, a n d 1 ti mes wit hi n- gr o u p sta n d ar d de viati o n, res pecti vel y, t here will be 8 1 % 
p o wer t o dete ct t his differe nce at t he 5 % si g nifica nce ( o ne- wa y A N O V A).  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 5  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A ntici p ate d f alse disc o ver y r ate. T o ill ustrate t he ma g nit u de of false p ositi ve a n d fals e 
ne gati ve err ors w e ma y e nc o u nter i n a ge n o m e- wi de ass ociati o n a n al ysis ( G W A) s uc h as 
ge n e e x pressi o n pr ofili n g, we s h o w t he a v era ge p o wer ( A P) a n d a ntici pate d false disc o ver y 
rate (a F D R) 1 4 5 base d o n a data set use d i n a rece nt st u d y of ge n e e x pressi o n, M R D a n d 
rela pse of A L L.1 2 T his data set c o nsists of l o g-tra nsf or me d si g n al i nte nsities fr o m 9 9 
Aff y metri x U 1 3 3 A Ge ne C hi ps r u n o n t he dia g n ostic b o ne marr o w bl asts of 9 9 T O T XIII B 
patie nts a n d t heir ti me t o A L L rela ps e (fail ure) or l ast f oll o w u p. Ass ociati o n bet wee n t he 
e x pressi o n of eac h pr o beset a n d fail ure ti me is test e d b y c u m ulati ve i nci de nce hazar d rate 
re gressi o n,1 3 9 creati n g 2 2 2 7 6 P val ues, o ne f or eac h pr o beset. T he f oll o wi n g fi g ure s h o ws 
t he pr ofile i nf or mati o n criteri o n1 4 1 (I p) c o m p ute d f or t his set of P val ues.  
al p h a
I p
0. 0
0. 0 2
0. 0 4
0. 0 6
0. 0 8
0. 1 0
0
2 0 0 0 
4 0 0 0 
6 0 0 0 
8 0 0 0
1 0 0 0 0 
1 2 0 0 0
pi 0 = 0. 9 3 0 4 al p h. o pt = 0. 0 0 3 5 0 4 F D R = 0. 2 2 6 4  mi n I p = 1 2 8. 8 4 5 7 
 
T he pr o p orti o n of pr o b es ets ( ge ne e x pressi o ns) n ot ass ociate d wit h rela ps e is esti mate d 
pi 0 = 9 3 %, t he “ o pti mal” P- val ue c ut off (al p ha. o pt) b y I p t hat bala nces t he l e vels of fals e 
p ositi ve a n d false ne gati ve err ors is 0. 0 0 3 5, a n d at t his al p ha le vel t he F D R is esti mate d 
2 2. 6 4 %.  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 6  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T he f oll o wi n g t a ble s h o ws, base d o n t he a b o v e s et of  P val ues, t he a ntici pate d n u m ber of 
false p ositi ves (a N F P), tr ue p ositi ves (a N T P), a n d a F D R i n o ne ge ne e x pressi o n pr ofili n g 
a nal ysis f or se v eral c o m bi nati o ns of t he pr o p orti o n of n o n-ass ociati ve ge nes ( π), n u m ber of 
n o n-ass ociati ve ge n es ( m 0), n u m ber of ass ociati ve ge n es ( m 1), a n d al p ha le vels. T he t otal 
n u m ber  of pr o b esets is m 0 + m 1 = 2 2 2 7 6. 
 
 
 
α = 0. 0 0 1  
α = 0. 0 0 3  
α = 0. 0 0 5  
π = 9 0 %  
m 0 = 2 0 0 4 8  
m 1 = 2 2 2 8  
a N T P  
aN F P  
a F D R ( %)  
1 4 6  
2 0  
1 2. 0 8  
2 2 7  
6 0  
2 0. 9 2  
2 9 2  
1 0 0  
2 5. 5 7  
π = 9 3 %  
m 0 = 2 0 7 1 7  
m 1 = 1 5 5 9  
a N T P  
a N F P  
a F D R ( %)  
1 4 5  
2 1  
1 2. 4 8  
2 2 5  
6 2  
2 1. 6 2  
2 8 8  
1 0 4  
2 6. 4 3  
π = 9 9 %  
m 0 = 2 2 0 5 3  
m 1 = 2 2 3  
a N T P  
a N F P  
a F D R ( %)  
1 4 4  
2 2  
1 3. 2 8  
2 2 2  
6 6  
2 3. 0 2  
2 2 3  
1 1 0  
2 8. 1 3  
 
V ali d ati o n i nfere nce f or ge ne e x pressi o n. We pla n t o vali date o n T O T X VI a n u m ber of 
ca n di date ge nes i de ntifie d fr o m t he pre vi o us ge n e e x pressi o n pr ofili n g a nal ys es of 
T O T X V a n d T O T XIII data. T o vali date t hese ge ne e x pressi o ns f or t heir ass ociati o n wit h 
t he p he n ot y p es of i nterest (e. g. ge ne e x pressi o ns relate d t o M R D a n d rel a pse; see Secti o n 
2), t w o met h o ds will be a p plie d. First a ge n e- b y - ge ne e x a mi nati o n will be perf or me d: T h e 
sa me a nal yses i n t he pre vi o us p u blicati o ns will be a p plie d t o t he vali dati o n data ( data 
c ollecte d o n T O T X VI), a n d t h e ge nes of i nterest will be e x a mi ne d f or t heir ass ociati o n 
wit h t he p he n ot y p es acc or di n g t o t he test P val ues a n d w het her t h e sa me directi o ns of 
ass ociati o n are o bs er ve d i n t he vali dati o n data a n d t he pre vi o us a nal yses. It is i m p orta nt t o 
realize t hat d ue t o u nc o ntr olla ble ra n d o m variati o ns t he o bser ve d  statistical si g nifica n ce 
( P val ues) of t hes e ge nes i n t he pre vi o us st u dies is u nsta ble a n d is u nli kel y t o re plicate – 
t he test P val ue of eac h ge ne c o m p ute d o n t he vali dati o n data ca n b e eit her greater or 
s maller t ha n t hat i n t he pre vi o us a nal yses. F or t his reas o n, w e d o n ot i nsist t hat t he tests of 
t hese ge nes o n t he v ali dati o n data ha ve t o reac h e q ual or hi g h er si g nifica n ce le vels t ha n i n 
t he pre vi o us a nal yses. I nstea d, we will test t he n ull h y p ot hesis t hat t he P val ues of t hese 
g e n es fr o m t he v ali dati o n data are c o m pletel y ra n d o ml y ( u nif or ml y) distri b ute d bet wee n 0 
a n d 1 a gai nst t he alter nati ve t hat t he y t e n d t o cl uster t o war d 0. T his will be acc o m plis he d 
b y a p er m utati o n test. Sec o n d, a rece ntl y de v el o pe d met h o d 1 4 6 will be a p plie d t o vali date 
g e n e c o- e x pressi o n cl usters ge nerate d fr o m t hese ca n di date ge nes. A c o-e x pressi o n cl uster 
f or a ca n di date ge ne is a set of ge nes w h os e e x pressi o n is hi g hl y c orrelat e d wit h t he 
ca n di date ge ne. T his met h o d will als o hel p t o disc o ver i nteresti n g ge n es t hat p ote ntiall y 
carr y si milar bi ol o gical f u ncti o ns or are i n t he s a me pat h wa y wit h t he ca n di date ge nes b ut 
di d n ot meet t he p urel y statistical si g nifica n ce criteria use d i n t he pre vi o us a nal yses. 
 
1 8. 6 
E x pl orat or y ne ur oi ma gi n g o bjecti ves 
 
T he se e x pl orat or y o bjecti ves i n v ol ve case-c o ntr ol c o m paris o ns, a nal yses of t he 
ass ociati o ns bet wee n a n u m ber of ne ur oi ma gi n g meas ure me nts ge n erate d at t w o ti me 
p oi nts ( wee k 1 of re-i n d u cti o n I a n d wee k 1 2 0 of c o nti n uati o n) a n d ne ur oc o g niti ve tests 
d o ne at t he sa me ti me p oi nts, a n d  a nal ys es of t he ass ociati o ns bet wee n t h e 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 7  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
ne ur oi ma gi n g m eas ur e me nts a n d t he f olate p at h w a y ge netic p ol y m or p his ms. T hera p y 
differe n ces as i n dicate d b y ris k ( S/ H vs. L) a n d t he i nte nsit y of I T t hera p y (e. g., n u m b er 
of I Ts recei ve d b ef ore t he M RI) will be ta ke n as c o variates (a dj usti n g fact ors) i n t he 
m o dels. S u bset a nal yses wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) ma y b e 
pe rf or me d as well. T he a nal yses f or a si milar st u d y o n T O T X V res ulte d i n a b o ut 4, 0 0 0 
statistical tests. We a ntici pate t hat a lar ge n u m ber of statistical tests will be pr o d uce d f or 
t his ai m o n T O T X VI as well. A dj ust me nts f or m ulti ple tests will be perf or me d usi n g 
rece nt met h o ds f or esti mati o n a n d c o ntr ol of t he false disc o ver y rate.1 4 2, 1 4 3 
 
T o use q u a ntit ative M R me as ures ( Diff usi o n Te ns or I m a gi n g a n d hi g h res ol uti o n 
v ol u metric i m a gi n g) t o assess differe nces i n myeli n a n d c ortic al t hick ness dev el o p m e nt i n 
p atie nts tre ate d f or A L L rel ative t o he alt hy c o ntr ols m atc he d f or a ge a n d g e n der. 
 
T he c o m paris o n will be p erf or me d f or eac h M R ti me p oi nt ( Wee k 1 of re-i n d ucti o n I a n d 
wee k 1 2 0 of c o nti n uati o n) se paratel y. P ossi ble l o n git u di nal c ha n ge will be vis ualize d b y 
statistical gra p hi cs. Ne ur oi ma gi n g meas ure me nts of m yeli n a n d c ortical t hic k ness bet wee n 
patie nts a n d a ge a n d ge n der matc he d n or mal healt h y c o ntr ols will be c o m pare d b y t w o-
sa m ple t tests. S u bset a nal yses wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) m a y be 
perf or me d as well.  
 
T o assess t he i m p act of f ol ate p at h w ay ge netic p oly m or p his ms o n myeli n a n d c ortic al 
t hick ness devel o p me nt a n d ne ur oc o g nitive perf or m a nce.  
 
Ass ociati o ns bet wee n t he ge n etic p ol y m or p his ms a n d t he i ma gi n g m eas ure me nts a n d t he 
ne ur oc o g niti ve meas ure me nts will be a nal yze d b y a n u m b er of ge neral li near m o dels. T he 
i ma gi n g a n d n e ur oc o g niti ve varia bles will be ta k e n as de pe n de nt v aria bles; t he 
p ol y m or p his ms a n d cli nical fact ors (s uc h as ris k a n d I T i nte nsit y) will be ta k e n as 
c o variates. S u bset a n al ys es wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) ma y b e 
perf or me d as well.  
 
T o assess i m p act of fr o nt al- p ariet al l o be myeli n a n d c ortic al t hick ness devel o p me nt o n 
ne ur oc o g nitive perf or m a nce i n atte nti o n, w orki n g me m or y, fl ue n cy, vis u al-s p ati al 
re as o ni n g a n d pr ocessi n g s pee d. 
 
Descri pti ve statistics of t he i ma gi n g a n d t he ne ur o ps yc h ol o gical test res ults will be 
pr o vi de d. Cr oss-secti o nal a nal ys es will be d o ne usi n g ra n k- base d pr oce d ures a n d ge neral 
linear m o dels. Ge n eral li near m o dels a cc o u nti n g f or re peate d meas ures ( b y a patie nt 
ran d o m effect f or e x a m ple) will be a p plie d t o a nal yz e t he l o n git u di nal data (t w o ti me 
p oi nts). T hera p y differe n ces as i n dicat e d b y ris k ( S/ H vs. L) a n d t h e i nte nsit y of I T t h era p y 
(e. g., n u m ber of I Ts recei ve d bef ore t he M RI) will be ta ke n as c o vari ates (a dj usti n g 
fact ors) i n t he m o d els. S u bset a nal yses wit hi n certai n patie nt gr o u ps (e. g., S/ H a n d L ris k) 
ma y b e perf or me d as well.  
 
T o i n vesti gate t h e relati o ns hi p bet wee n t he c h a n ge i n i ma gi n g me as ure me nts a n d t he 
a m plit u de of B O L D si g n al c ha n ge a n d t he v ol u me of acti vate d c orte x will use a si m ple 
li near re gressi o n m o del.  We will test t o assess w het her t here is a si g nifica nt li near 
relati o ns hi p bet wee n t h e m yeli n disr u pti o n a n d B O L D acti vati o n i n s pecifi c c ortical 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 8  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
re gi o ns. Si milar a nal ysis will be carri e d o ut wit h c ha n ge of c ortical t hic k ness as c o variat es 
a n d eit her t he B O L D si g nal a m plit u de or t he acti v ate d v ol u me as de p e n de nt varia ble.  
 
1 8. 7 
E x pl orat or y I ntesti nal Mi cr o bi o me O bjecti ve 
 
T his i s a pr os pecti ve st o ol ba n ki n g st u d y.  St o ol sa m ples will be c ollecte d fr o m all eli gi ble 
patie nts a n d st ore d f or f urt her testi n g.  Descri pti ve statistics s uc h as me dia n, ra n ge a n d 
perce nt a ges will be use d as a p pr o priat e t o meas ure t he o verall alterati o n i n c o m p ositi o n 
a n d p o p ulati o n d y n a mics of g ut micr ofl ora a n d t o descri be t he fre q u e nc y a n d se verit y of 
gastr oi ntesti nal ill nesses d uri n g i n d ucti o n p has e of c he m ot hera p y a n d t he s u bse q ue nt 6 
m o nt hs. T o ta ke i nt o acc o u nt t he differe n ces i n t h e i n d ucti o n, c o ns oli d ati o n a n d 
c o nti n uati o n p hases of c h e m ot hera p y, a n al ysis of t he data will be stratifie d base d o n t he 
A L L ris k classificati o n ( L o w ris k, Sta n dar d ris k, a n d Hi g h-ris k). 
 
1 9. 0  
S A F E T Y A N D A D V E R S E E V E N T R E P O R TI N G R E Q UI R E M E N T S 
 
1 9. 1 
Re p orti n g A d vers e E x perie nces ( A Es) a n d Deat hs 
 
O nl y “ u n a ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nts or ot hers” referre d t o 
hereafter as “ u na ntici pat e d pr o ble ms” are re q uir e d t o be re p orte d t o t he St. J u de I R B 
pr o m ptl y, b ut i n n o e ve nt later t ha n 1 0 w or ki n g d a ys after t he i n ves ti gat or first lear ns of 
t he u na ntici pate d pr o ble m. Re gar dless of w h et her t he e ve nt is i nter nal or e xter nal (f or 
e x a m ple, a n I N D safet y re p ort b y t h e s p o ns or p urs ua nt t o 2 1 C F R 3 1 2. 3 2), o nl y a d v erse 
e ve nts t hat c o nstit ute u na ntici pate d pr o ble ms are re p orta ble t o t he St. J u de I R B.  As 
f urt her des cri be d i n t he d efi niti o n of u na ntici pate d pr o ble m, t his i ncl u des a n y e v e nt t hat i n 
t he PI’s o pi ni o n w as: 
 
 U ne x pecte d (i n ter ms of nat ure, se v erit y, or fre q u e nc y) gi ve n ( 1) t he researc h 
pr oce d ures t hat are descri be d i n t he pr ot oc ol-rel ate d d oc u me nts, s uc h as t h e I R B-
ap pr o ve d researc h pr ot o c ol a n d i nf or me d c o nse nt d oc u me nt, as well as ot h er 
rele va nt i nf or m ati o n a vaila ble a b o ut t he res earc h; ( 2) t he o bser ve d rate of 
occ urre nce (c o m pare d t o a cre di ble b aseli ne f or c o m paris o n); a n d ( 3) t he 
c haracteristics of t he s u bj ect p o p ulati o n bei n g st u die d; a n d 
 R elate d or p ossi bl y relate d t o partici pati o n i n t he researc h; a n d 
 Seri o us; or if n ot seri o us s u g gests t hat t he researc h places s u bjects or ot h ers at a 
greater ris k of har m (i ncl u di n g p h ysical, ps yc h ol o gical, ec o n o mic, or s ocial har m) 
t ha n was pre vi o usl y k n o w n or rec o g nize d.  
 
U nrelate d, e x pecte d deat hs d o n ot re q uire re p orti n g t o t he I R B.  T h o u g h deat h is “seri o us”, 
t he e ve nt m ust meet t he ot her t w o re q uir e me nts of “rel ate d or p ossi bl y relate d” a n d 
“ u ne x pecte d/ u na ntici pate d” t o be c o nsi dere d re p orta ble. 
 
Deat hs meeti n g re p orti n g re q uire me nts are t o be re p orte d i m me diatel y t o t h e St. J u de I R B, 
b ut i n n o e ve nt later t ha n 4 8 h o urs after t h e i n vesti gat or first lear ns of t he d eat h.  
 
T h e f oll o wi n g d efi niti o ns a p pl y wit h r es pect t o re p orti n g a d v erse e x perie nces:  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 9 9  of 1 1 1 
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Seri o us A d verse E ve nt:  A n y a d verse e ve nt te m p orall y ass ociate d wit h t he s u bject’s 
pa rtici pati o n i n researc h t hat meets a n y of t he f oll o wi n g criteria: 
 
 res ults i n deat h; 
 is life-t hreate ni n g ( pl aces t he s u bject at i m me diate ris k of deat h fr o m t he e v e nt as it 
occ urre d); 
 req uires i n patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n; 
 res ults i n a persiste nt or si g nifica nt disa bilit y/i nca pacit y; 
 res ults i n a c o n ge nital a n o mal y/ birt h defect; or 
 an y ot h er a d v erse e ve nt t hat, base d u p o n a p pr o pri ate me dical j u d g me nt, m a y 
je o par dize t he s u bject’s h ealt h a n d ma y re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t his defi niti o n (e x a m ples of s uc h e ve nts 
i ncl u de:  a n y s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life f u ncti o ns, 
aller gic br o n c h os pas m re q uiri n g i nte nsi ve treat me nt i n t he e mer ge nc y r o o m or at 
h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitalizati o n, or t he de vel o p me nt of dr u g de p e n de nc y or dr u g a b use), a 
c o n ge nital a n o mal y/ birt h defect, s ec o n dar y or c o n c urre nt ca ncer, me dicati o n 
o ver d ose, or is a n y m e dical e ve nt w hi c h re q uir es treat me nt t o pre ve nt a n y of t he 
me dical o utc o mes pre vi o usl y list e d.   
 
U ne x pec te d A d ve rse E v e nt:  
 
 A n y a d vers e e ve nt f or w hic h t he s pecificit y or se verit y is n ot c o nsiste nt wit h t he 
pr ot oc ol-relat e d d oc u me nts, i ncl u di n g t he a p plica ble i n vesti gat or br oc h ure, I R B 
a p pr o ve d c o ns e nt f or m, I n vesti gati o nal N e w Dr u g (I N D) or I n vesti gati o nal De vice 
E x e m pti o n (I D E) a p plicati o n, or ot her rele va nt s o urces of i nf or mati o n, s uc h as 
pr o d uct la beli n g a n d pac ka ge i nserts; or if it d oes a p pear i n s u c h d oc u me nts, a n 
e ve nt i n w hic h t he s pecificit y, se verit y or d urati o n is n ot c o nsiste nt wit h t he ris k 
i nf or mati o n i ncl u de d t herei n; or  
 T he  o bser ve d rate of occ urre nce is a cli nicall y si g nifica nt i ncrease i n t he e x pecte d 
rate ( b ase d o n a cre di ble baseli ne rat e f or c o m paris o n); or  
 T he occ urre n ce is n ot c o nsiste nt wit h t he e x pecte d nat ural pr o gressi o n of a n y 
u n derl yi n g dise ase, dis or der, or c o n diti o n of t he s u bject(s) e x perie n ci n g t h e 
a d verse e ve nt a n d t h e s u bject’s pre dis p osi n g ris k fact or pr ofile f or t h e a d v erse 
e ve nt.  
 
I nter n al E ve nts: E ve nts e x perie nce d b y a researc h partici pa nt e nr olle d at a site u n der t he 
j uris dicti o n of St. J u de I R B f or eit her m ultice nter or si n gle-ce nter res earc h pr ojects. 
 
E xter n al E ve nts:  E ve nts e x perie nce d b y partici pa nts e nr olle d at a site e xter nal t o t he 
j uris dicti o n of t he St. J u de I nstit uti o nal Re vie w B oar d (I R B) or i n a st u d y f or w hic h St. 
Ju de is n ot t he c o or di nati n g ce nter or t he I R B of rec or d. 
 
U n a ntici p ate d Pr o ble m I n v ol vi n g Ris ks t o S u bjects or Ot hers: A n u n a ntici pate d 
pr o ble m i n v ol vi n g ris ks t o s u bjects or ot hers is a n e ve nt w hic h was n ot e x pecte d t o occ ur 
a n d w hic h i ncreases t he de gree of ris k p ose d t o r esearc h p artici pa nts.   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 0  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S uc h e ve nts, i n ge neral, meet all of t he f oll o wi n g criteria:  
 
 u ne x pecte d;  
 relate d or p ossi bl y rel ate d t o partici pati o n i n t he researc h; a n d  
 s u g gests t hat t he researc h places s u bjects or ot h ers at a greater ris k of h ar m 
(i ncl u di n g p h ysic al, ps yc h ol o gical, ec o n o mic, or s ocial har m) t ha n was pre vi o usl y 
k n o w n or rec o g niz e d.  A n u na ntici pate d pr o ble m i n v ol vi n g ris k t o s u bjects or 
ot hers ma y e xist e ve n w he n act ual h ar m d oes n ot occ ur t o a n y p artici pa nt.  
 
C o nsiste nt wit h F D A a n d O H R P g ui da nce o n re p orti n g u na ntici pat e d pr o bl e ms a n d 
a d verse e ve nts t o I R Bs, t he St. J u de I R B d oes n ot re q uire t he s u b missi o n of e xter nal 
e ve nts, f or e x a m ple I N D safet y re p orts, n or is a s u m mar y of s uc h e v e nts/re p orts re q uire d; 
h o we ver, if a n e v e nt gi vi n g rise t o a n I N D s afet y or ot her e xter nal e ve nt re p ort c o nstit utes 
a n “ u na ntici pate d pr o ble m i n v ol vi n g ris ks t o s u bjects or ot hers ” it m ust be re p orte d i n 
acc or da nce wit h t his p olic y.  I n ge neral, t o be re p orta ble e xter nal e ve nts n ee d t o ha ve 
i m plicati o ns f or t he c o n d uct of t he st u d y (f or e x a m ple, re q uiri n g a si g nifica nt a n d us uall y 
safet y-relate d c ha n ge i n t he pr ot oc ol a n d/ or i nf or me d c o nse nt f or m). 
 
Alt h o u g h s o me a d v erse e ve nts will q ualif y as u n a ntici pate d pr o ble ms i n v ol vi n g ris ks t o 
s u bjects or ot hers, s o me will n ot; a n d t here ma y b e ot her u na ntici pat e d pr o ble ms t hat g o 
be y o n d t h e defi niti o ns of seri o us a n d/ or u ne x pecte d a d verse e ve nts.  E x a m ples of 
u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o s u bjects or ot hers i ncl u de: 
 
 Im pr o p erl y sta gi n g a p artici pa nt’s t u m or res ulti n g i n t he partici pa nt bei n g assi g ne d 
t o a n i nc orrect ar m of t h e researc h st u d y; 
 T he  t heft of a researc h c o m p uter c o ntai ni n g c o nfi d e ntial s u bject i nf or mati o n 
( breac h of c o nfi de ntialit y); a n d  
 T he c o nta mi nati o n of a st u d y dr u g.  U na ntici pate d pr o ble ms ge nerall y will warra nt 
c o nsi derati o n of s u bsta nti ve c ha n ges i n t he researc h pr ot oc ol or i nf or m e d c o nse nt 
pr ocess/ d oc u me nt or ot h er c orrecti ve acti o ns i n or der t o pr otect t he s afet y, welfare, 
or ri g hts of s u bj ects or ot hers.  
 
2 0. 0 
I N F O R M E D C O N S E N T P R O C E S S  
 
2 0. 1 
C o nse nt/asse nt at Re missi o n I n d ucti o n a n d P ost Re missi o n T hera pies 
 
T he pr ocess of i nf or me d c o nse nt f or T O T X VI will f oll o w i nstit uti o nal p olic y. T h e 
i nfor me d  c o nse nt pr ocess is a n o n g oi n g o ne t hat be gi ns at t he ti me of dia g n osis a n d e n ds 
after t he c o m pleti o n of t hera p y.  I nf or me d c o nse nt s h o ul d be o btai ne d b y  t h e atte n di n g 
p h ysicia n or his/ her desi g nee, i n t he prese nce of at least o ne n o n- p h ysicia n wit ness.  
I nitiall y, i nf or me d c o nse nt will be s o u g ht f or t he T B A N K pr ot oc ol (researc h st u d y), 
bl o o d tra nsf usi o n (if nee de d), t he first i ntrat hecal t hera p y (if t he dia g n osis of le u ke mia is 
certai n eit her b y  referral b o ne marr o w s mears or bl o o d s mears at SJ C R H), a n d treat me nt 
wit h rec o m bi na nt urate o xi dase, if nee de d.   After t he dia g n osis of A L L is esta blis he d, we  
will  i n vite t he patie nt t o partici pate i n t he T O T X VI pr ot oc ol, as well as o btai n sta n dar d 
me d ical c o nse nt f or HI V testi n g.  After t he patie nt attai ns c o m plete re missi o n, we  will 
see k i nf or me d c o nse nt f or t heir partici pati o n i n ris k- directe d i nte nsificati o n/c o nti n uati o n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 1  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hera p y (l o w-, sta n dar d- or hi g h-ris k acc or di n g t o prese nti n g feat ures, treat me nt res p o nse 
an d t he le vel of mi ni mal resi d ual le u ke mia).  Rare patie nts wit h l o w- or sta n dar d- ris k 
le u ke mia ma y b e  reassi g ne d t o hi g h-ris k t hera p y d ue t o persiste ntl y hi g h mi ni mal 
resi d ual le u ke mia (see Secti o n 5. 3). T hese patie nts will be as ke d t o re- c o nse nt wit h t he 
hi g h-ris k t hera p y c o ns e nt. T he ti meli ne f or vari o us i nf or me d c o nse nts is i n dicate d i n t he 
fi gure bel o w. 
 
At prese ntati o n:  
T B A N K  (researc h st u d y) 
Bl o o d  tra nsf usi o n 
Tri ple i ntrat hecal  treat me nt 
 
 
Dia g n osis  of  A L L  esta blis he d:  
T O T X VI  i n d ucti o n t hera p y (researc h st u d y) 
 
 
U p o n ac hie vi n g c o m plete re missi o n: 
L o w- * , sta n dar d-* , or hi g h-ris k 
i nte nsificati o n/c o nti n uati o n t hera p y (researc h st u d y) 
* R are  p atie nts will s u bse q ue ntly be tre ate d wit h hi g h-risk t her a py d ue t o t he 
pe rsiste nce of mi ni m al resi d u al dise ase, per pr ot oc ol. 
 
T hr o u g h o ut t he e ntire treat me nt peri o d,  partici pa nts a n d t heir pare nts recei ve c o nsta nt 
e d ucati o n fr o m healt h pr ofessi o nals at SJ C R H a n d are e nc o ura ge d t o as k q uesti o ns 
regar di n g alter nati ves a n d t hera p y. All fa milies ha ve rea d y access t o c ha plai ns, 
ps yc h ol o gists, s ocial w or kers, a n d t he St. J u de o m b u ds pers o n f or s u p p ort, i n a d diti o n t o 
t hat pr o vi de d b y  t he pri m ar y p h ysicia n a n d ot her cli nicia ns i n v ol ve d i n t heir care.  We  
will als o o btai n ver bal asse nt fr o m c hil dre n 7 t o 1 4 years ol d a n d writte n asse nt f or all 
pa tie nts > 1 4 years of a ge. 
 
2 0. 2 
C o nse nt at A ge of Maj orit y 
 
T he  a ge of  maj orit y i n t he state of Te n nessee is 1 8 years ol d. Researc h partici pa nts o n 
acti ve t hera p y m ust be c o nse nte d at t he ne xt cli nic visit after t heir 1 8 t h birt h da y. 
Partici pa nts, w h o ha ve reac he d a ge of  maj orit y a n d ha ve c o m plete d all pr ot oc ol- directe d  
t hera p y, wi ll be re-c o nse nte d wit h a se parate c o nse nt s pecificall y f or t his p ur p ose 
( AO M c o nse nt). Partici pa nts, w h o reac h a ge of maj orit y after t he 5 year pr ot oc ol 
req uire d f oll o w- u p, will be f oll o we d f or s ur vi val a n d late effects as per t he SJ L T F U. A 
wa i ver f or A O M c o nse nt will be re q ueste d f or t hese partici pa nts at St. J u de. 
 
If a n affiliate site is l ocate d i n a state w here a differe nt a ge of maj orit y a p plies, t hat 
l ocati o n m ust c o nse nt t he partici pa nts acc or di n g t o t heir l ocal la ws. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 2  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2 0. 3 
C o nse nt W he n  E n glis h  is N ot t he Pri mar y La n g ua ge 
 
W he n E n glis h is n ot t he patie nt, pare nt, or le gall y a ut h orize d re prese ntati ve’s pri mar y 
la n gua ge, t he S ocial W or k de part me nt will deter mi ne t he nee d f or a n i nter preter. T his 
i nf ormati o n will be d oc u me nte d i n t he partici pa nt’s me di cal rec or d. Eit her a certifie d 
i nter preter or t he tele p h o ne i nter preter’s ser vice will be use d t o tra nslate t he c o nse nt 
i nfor mati o n. T he pr ocess f or o btai ni n g a n i nter preter a n d f or t he a p pr o priate use of a n 
i nter preter is o utli ne d o n t he I nter preter Ser vices, O H S P, a n d C P D M O we bsites. 
 
2 1. 0 
D A T A C O L L E C TI O N, M O NI T O RI N G A N D  C O N FI D E N TI A LI T Y 
 
2 1. 1 
Data C ollecti o n 
 
Ele ctr o nic case re p ort f or ms (e-C R Fs) will be c o m plete d b y  t he SJ C R H 
Le u ke mia/ L y m p h o ma C R As. Data will be e ntere d fr o m rec or d directl y i nt o a sec ure 
C RI S data base, de vel o pe d a n d mai ntai ne d b y  St. J u de Cli nical Researc h I nf or matics. 
 
Data ma na ge me nt will be s u per vise d b y  t he Direct or of Cli nical Trials 
Ma na ge me nt, 
a n d Ma na ger of Cli nical Researc h O perati o ns f or t he Le u ke mia/ L y m p h o ma Di visi o n, 
w or ki n g wit h Dr. J e ha a n d her desi g nees.  All pr ot oc ol-s pecific data a n d all gra de 3- 5 
ad verse e ve nts will be rec or de d b y  t he cli nical researc h ass ociates i nt o t he C RI S 
da ta base, i deall y wit hi n 2- 4 wee ks of c o m pleti o n of  st u d y p hase. All q uesti o ns will be 
dire cte d t o t he atte n di n g p h ysicia n a n d/ or PI  a n d re vie we d at re g ularl y-sc he d ule d 
w or ki n g meeti n gs. T he atte n di n g p h ysi cia ns ( or t heir desi g nees) are res p o nsi ble f or 
ke e pi n g u p-t o-date r oa d ma ps i n t he patie nt’s pri mar y SJ C R H me dical c hart. 
 
R e g ular ( bi- m o nt hl y) s u m maries of t o xicit y a n d pr ot oc ol e ve nts will be ge nerate d f or t he 
PI  a n d t he de part me nt of Bi ostatistics t o re vie w. 
 
It is u n d erst o o d t hat de viati o ns fr o m t he pr ot oc ol s h o ul d be a v oi de d, e x ce pt w he n 
ne cessar y t o eli mi nate a n i m me diate hazar d t o a researc h partici pa nt. I n s uc h case, t he 
de viati o n m ust be re p orte d t o t he I R B.   H o we v er, it is e x pecte d t hat patie nts will 
oc casi o nall y miss s o me d oses or recei ve t he wr o n g d ose of oral c he m ot hera p y.  
C o m plia nce wit h oral me dicati o n will be ca pt ure d i n t he C RI S data base a n d 
ap pr o priatel y d oc u me nt e d i n t he partici pa nts’ me dical rec or ds.  A p pr o priatel y 
d oc u me nte d d oses of misse d or wr o n g d oses of c h e m ot hera p y will n ot c o nstit ute a 
de vi ati o n u nless t he a m o u nt i n q uesti o n is o ver 1 0 %  of t he e x pecte d t otal d ose d ue i n t he 
res pecti ve pr ot oc ol c ycles (t hese are s pecifie d i n t he C RI S T O T X VI data base).   Misse d 
d ose s d o n ot i ncl u de d oses hel d or re d uce d f or me dical reas o ns (t o xicit y, ill ness) a n d will 
n ot be c o nsi dere d pr ot oc ol de viati o ns or vi olati o ns. 
 
2 1. 2 
St u d y M o nit ori n g 
 
S o urce d oc u me nt verificati o n of eli gi bilit y f or all SJ C R H cases will be perf or me d wit hi n 
t w o wee ks of c o m pleti o n of e nr oll me nt. T his will i ncl u de verificati o n of a p pr o priate 
d oc u me nta ti o n of c o nse nt. M o nit ori n g of ti meli ness of seri o us a d verse e ve nt re p orti n g 
will  be d o ne as e ve nts are re p ort e d i n T R A C K S. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 3  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
M o nit ori n g of t his pr ot oc ol is c o nsi dere d  t o be i n t he “ m o derate” ris k cate g or y. T he 
M o nit ori n g Pla n is o utli ne d i n a se parate d oc u me nt fr o m t his pr ot oc ol, b ut has bee n 
s u b mitte d f or re vie w a n d a p pr o val b y  t he Cli nical Trials Scie ntific Re vie w C o m mittee a n d 
t he I nstit uti o nal Re vie w B oar d. 
 
St. J u de affiliates a n d d o mestic c olla b orati n g st u d y sites will be m o nit ore d o n-site b y  a 
re prese ntati ve of St. J u de at i nter vals s pecifie d i n t he Data a n d Safet y 
M o nit ori n g Pla n.  
Inter nati o nal c olla b orat ors will be m o nit ore d acc or di n g t o t he st u d y-s pecific m o nit ori n g 
pla n.  
 
2 1. 3 
C o nfi de ntialit y 
 
S t u d y n u m bers will be use d i n place of a n i de ntifier s uc h as a me dical rec or d n u m ber. N o 
researc h partici pa nt na mes will be rec or de d o n t he data c ollecti o n f or ms. T he list 
co ntai ni n g t he st u d y n u m ber a n d t he me dical rec or d n u m ber will be mai ntai ne d i n a 
l oc ked file a n d will be destr o ye d after all data ha ve bee n a nal yze d.   T he me dical rec or ds 
of st u d y partici pa nts ma y be re vie we d b y  t he St. J u de I R B, F D A, a n d St. J u de cli nical 
researc h m o nit ors.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 4  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2 2. 0  R E F E R E N C E S  
Refere n ce List 
 
  
1.  Nac h ma n J B, Sat her H N, Se nsel M G et al. A u g me nte d p ost-i n d ucti o n t hera p y f or c hil dre n 
wit h hi g h-ris k ac ute l y m p h o blastic le u ke mia a n d a sl o w res p o nse t o i nitial t hera p y. 
N. E n gl.J Me d. 1 9 9 8; 3 3 8: 1 6 6 3- 1 6 7 1. 
 
2.  Sil ver ma n L B, Gel b er, R. D., a n d Dalt o n, V. K. I m pr o ve d o utc o me f or c hil dre n wit h ac ute 
l y m p h o blastic le u ke mia: Res ults of Da na Far ber C o ns orti u m Pr ot oc ol 9 1- 0 1. Bl o o d 9 7, 
1 2 1 1- 1 2 1 8. 2 0 0 1. 
 
3.  V ora, A., Mitc hell, C. D., Le n n ar d L, a n d et.al. T o xicit y a n d efficac y of 6-t hi o g na ni ne 
vers us 6- merca pt o p uri ne i n c hil d h o o d l y m p h o bl astic le u ke mia: a ra n d o mize d trial. La ncet 
3 6 8, 1 3 3 9- 1 3 4 8. 2 0 0 6. 
 
4.  
Mitc hell C D, Ric har ds S M, Ki nse y S E et al. Be n efit of de x a met has o ne c o m pare d wit h 
pre d nis o l o ne f or c hil d h o o d ac ute l y m p h o blastic le u kae mia: r es ults of t he U K Me dical 
Researc h C o u n cil A L L 9 7 ra n d o mize d trial. Br.J Hae mat ol. 2 0 0 5; 1 2 9: 7 3 4- 7 4 5. 
 
5.  B ostr o m B C, Se nsel M R, Sat her H N et al. De x a met has o ne vers us pre d nis o ne a n d dail y 
oral vers us w ee kl y i ntra v e n o us merca pt o p uri ne f or patie nts wit h sta n dar d-ris k ac ute 
l y m p h o blastic le u ke mia: a re p ort fr o m t he C hil dre n's Ca ncer Gr o u p. Bl o o d 
2 0 0 3; 1 0 1: 3 8 0 9- 3 8 1 7. 
  
6.  
Matl o u b Y, Li n de m ul der S, Ga y n o n P S, a n d et.al. I ntr at hecal tri ple t hera p y decreases 
ce ntral ner v o us s yste m rela pse b ut fails t o i m pr o ve e ve nt-free s ur vi v al w he n c o m paire d 
wit h itrat hecal met h otre x ate: res ults of t he C hil dre n's Ca ncer Gr o u p ( C C G) 1 9 5 2 st u d y f or 
sta n dar d-ris k ac ute l y m p h o blasti c le u ke mia, re p orte d b y t he C hil dre n's O nc ol o g y Gr o u p. 
Bl o o d 1 0 8, 1 1 6 5- 1 1 7 3. 2 0 0 6. 
  
7.  Pi n heir o J P, B o os J. T he best wa y t o use as p ara gi n ase i n c hil d h o o d ac ute l y m p hatic 
le u kae mia--still t o be defi ne d? Br.J Hae mat ol. 2 0 0 4; 1 2 5: 1 1 7- 1 2 7. 
 
8.  
Wetzler M, Sa nf or d B L, K urtz ber g J et al. Effecti ve as para gi ne de pl eti o n wit h pe g ylat e d 
as para gi n ase res ults i n i m pr o ve d o utc o mes i n a d ult ac ute l y m p h o blastic l e u ke mia: Ca ncer 
a n d Le u ke mia Gr o u p B St u d y 9 5 1 1. Bl o o d 2 0 0 7; 1 0 9: 4 1 6 4- 4 1 6 7. 
 
9.  Hiji ya N, Fra n kli n J, R ytti n g M. A p has e I st u d y of cl ofara bi ne i n c o m bi nati o n wit h 
c ycl o p h os p ha mi de a n d et o p osi de: a ne w re gi me n i n pe diatric patie nts wit h r efract or y or 
rela pse d ac ute le u k e ma [a bstract]. A S H A n n ual Meeti n g A bstracts 2 0 0 7; 2 5: 
 
1 0.  Fl ot h o C, C o usta n- S mit h E, Pei D et al. Ge nes c o ntri b uti n g t o mi ni mal resi d ual disease i n 
c hil d h o o d ac ute l y m p h o blastic le u ke mia: pr o g n ostic si g nifica nce of C A S P 8 A P 2. Bl o o d 
2 0 0 6; 1 0 8: 1 0 5 0- 1 0 5 7. 
 
1 1.  Fl ot h o C, C o usta n- S mit h E, Pei D et al. A set of ge nes t hat re g ul ate cell pr oliferati o n 
pre dicts treat me nt o utc o me i n c hil d h o o d ac ute l y m p h o blastic le u ke mia. Bl o o d 
2 0 0 7; 1 1 0: 1 2 7 1- 1 2 7 7. 
 
1 2.  H olle ma n, A., C he o k, M. H., de n B o er, M. L., a n d et.al. Ge ne-e x pressi o n patter ns i n dr u g-
resista nt ac ute l y m p h o blastic le u ke mia cells a n d res p o nse t o treat me nt. N. E n gl.J Me d. 
3 5 1, 5 3 3- 5 4 2. 2 0 0 4. 
 1 3.  L u gt hart S, C he o k M H, de n B oer M L et al. I d e ntificati o n of ge nes ass ociate d wit h 
c he m ot hera p y cr ossresista nce a n d treat me nt r es p o nse i n c hil d h o o d ac ute l y m p h o blastic 
le u ke mia. Ca ncer Cell 2 0 0 5; 7: 3 7 5- 3 8 6. 
 1 4.  P ui C H, E va ns W E. Treat me nt of ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 
2 0 0 6; 3 5 4: 1 6 6- 1 7 8. 
 
1 5.  P ui C H, Relli n g M V, D o w ni n g J R. Ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 5  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
2 0 0 4; 3 5 0: 1 5 3 5- 1 5 4 8. 
 
1 6.  Hil de n, J. M., Di n n d orf P A, Meer ba u m S O, a n d et.al. A nal ysis of pr o g n ostic fact ors of 
acute l y m p h o blastic le u k e mia i n i nfa nts: re p ort o n C C G 1 9 5 3 fr o m t he C hil dre n's 
O nc ol o g y Gr o u p. Bl o o d 1 0 8, 4 4 1- 4 5 1. 2 0 0 6. 
 1 7.  Pieters R, Sc hra p pe M, D e L P et al. A treat me nt pr ot oc ol f or i nfa nts y o u n ger t ha n 1 year 
wit h ac ute l y m p h o bl astic le u kae mia (I nterfa nt- 9 9): a n o bser vati o nal st u d y a n d a 
m ultice ntre ra n d o mise d trial. La ncet 2 0 0 7; 3 7 0: 2 4 0- 2 5 0. 
 1 8.  P ui C H, Ca m pa na D, E va ns W E. C hil d h o o d ac ute l y m p h o blastic le u kae mia --c urre nt stat us 
a n d f ut ure p ers pecti ves. La n cet O n c ol. 2 0 0 1; 2: 5 9 7- 6 0 7. 
 1 9.  P ui C H, E va ns W E. Ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 1 9 9 8; 3 3 9: 6 0 5- 6 1 5. 
 2 0.  C o usta n- S mit h E, Sa nc h o J, Be h m F G et al. Pr o g n ostic i m p orta nce of meas uri n g earl y 
cleara nce of le u ke mic cells b y fl o w c yt o metr y i n c hil d h o o d ac ute l y m p h o bl astic le u ke mia. 
Bl o o d 2 0 0 2; 1 0 0: 5 2- 5 8. 
 2 1.  P ui C H. Ce ntral ner v o us s yste m diseas e i n ac ute l y m p h o blastic le u ke mia: pr o p h yla xis a n d 
treat me nt. He mat ol o g y. A m. S oc. He mat ol. E d uc. Pr o gra m. 2 0 0 6 1 4 2- 1 4 6. 
 
2 2.  P ui C H, Sa n dl u n d J T, Pei D et al. I m pr o ve d o utc o me f or c hil dre n wit h ac ut e 
l ym p h o blastic le u ke mia: res ults of T otal T hera p y St u d y XIII B at St J u de C hil dre n's 
Researc h H os pital. Bl o o d 2 0 0 4; 1 0 4: 2 6 9 0- 2 6 9 6. 
 
2 3.  P ui C H, Ga y n o n P S, B o yett J M et al. O utc o me of treat me nt i n c hil d h o o d ac ute 
l y m p h o blastic le u kae mia wit h rearra n ge me nts of t he 1 1 q 2 3 c hr o m os o mal re gi o n. La ncet 
2 0 0 2; 3 5 9: 1 9 0 9- 1 9 1 5. 
 
2 4.  Aric o M, Valse cc hi M G, Ca mitta B et al. O utc o me of treat me nt i n c hil dre n wit h 
P hila del p hia c hr o m os o me- p ositi ve ac ute l y m p h o blastic le u ke mia. N. E n gl.J Me d. 
2 0 0 0; 3 4 2: 9 9 8- 1 0 0 6. 
 
2 5.  Tal paz M, S ha h N P, Ka ntarjia n H et al. Dasati ni b i n i mati ni b-resista nt P hila del p hia 
c hr o m os o me- p ositi ve le u ke mias. N. E n gl.J. Me d. 2 0 0 6; 3 5 4: 2 5 3 1- 2 5 4 1. 
 2 6.  Ott ma n n O, D o m bret H, Marti nelli G et al. Dasati ni b i n d uces ra pi d he mat ol o gic a n d 
c yt o ge netic res p o nses i n a d ult patie nts wit h P hila del p hia c hr o m os o me p ositi ve ac ute 
l y m p h o blastic le u ke mia wit h resista nce or i nt olera nce t o i mati ni b: i nteri m res ults of a 
p hase 2 st u d y. Bl o o d 2 0 0 7; 1 1 0: 2 3 0 9- 2 3 1 5. 
 2 7.  Ka ntarjia n H, Pas q ui ni R, Ha mersc hl a k N et al. D asati ni b or hi g h- d os e i mati ni b f or 
c hr o nic- p h ase c hr o nic m yel oi d le u ke mia after fail ure of first-li ne i mati ni b: a ra n d o mize d 
p hase 2 trial. Bl o o d 2 0 0 7; 1 0 9: 5 1 4 3- 5 1 5 0. 
 2 8.  C o usta n- S mit h E, M ulli g ha n C G, O nci u M et al. E arl y T-cell prec urs or le u kae mia: a 
s u bt ype of ver y hi g h-ris k ac ute l y m p h o blastic le u kae mia. La n cet O nc ol 2 0 0 9; 1 0: 1 4 7- 1 5 6. 
 2 9.  Sc hra p pe M, Zi m mer ma n n M, M oric ke A et al. D e x a met has o ne i n I n d ucti o n Ca n 
Eli mi nate O ne T hir d of All Rela pses i n C hil d h o o d Ac ute L y m p h o blastic Le u k e mia 
( A L L): Res ults of A n I nt er nati o nal Ra n d o mize d Trial i n 3 6 5 5 Patie nts ( Trial AI E O P- B F M 
A L L 2 0 0 0). A S H A n n ual Meeti n g A bstracts 2 0 0 8; 1 1 2: 7. 
 
3 0.  Reiter A, Sc hra p p e M, L u d wi g W D et al. C he m ot hera p y i n 9 9 8 u nselecte d c hil d h o o d 
ac ute l y m p h o blastic le u k e mia patie nts. R es ults a n d c o ncl usi o ns of t he m ultice nter trial 
A L L- B F M 8 6. Bl o o d 1 9 9 4; 8 4: 3 1 2 2- 3 1 3 3. 
 3 1.  C o nter V, Aric o M, V alsecc hi M G et al. I nte nsi ve B F M c he m ot hera p y f or c hil d h o o d 
A L L: i nteri m a n al ysis of t he AI E O P- A L L 9 1 st u d y. Ass oci azi o ne It alia na E mat ol o gia 
O nc ol o gi a Pe diatrica. Hae mat ol o gica 1 9 9 8; 8 3: 7 9 1- 7 9 9. 
 3 2.  Gal pi n AJ, Sc h uetz J D, Mass o n E et al. Differe n ces i n f ol yl p ol y gl uta mate s y nt hetas e a n d 
di h y dr of ol ate re d u ctase e x pressi o n i n h u ma n B-li nea ge v ers us T-li nea ge le u ke mic 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 6  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
l y m p h o blasts: mec ha nis ms f or li n ea ge differe nces i n met h otre x ate p ol y gl uta m ylati o n a n d 
c yt ot o xicit y. M ol. P har m ac ol. 1 9 9 7; 5 2: 1 5 5- 1 6 3. 
 
3 3.  S y n ol d T W, Relli n g, M. V., B o yett, J. M., a n d et.al. Blast cell met h otre x ate- p ol y gl uta m ate 
acc u m ulati o n i n vi v o defers b y li nea ge, pl oi d y, a n d met h otre x ate d ose i n ac ute 
l y m p h o blastic le u ke mia. J Cli n I n vest 9 4, 1 9 9 6- 2 0 0 1. 1 9 9 4. 
 
3 4.  Nie me yer C M, G el ber R D, Tar bell NJ et al. L o w- d ose vers us hi g h- d ose m et h otre x ate 
d uri n g re missi o n i n d ucti o n i n c hil d h o o d ac ute l y m p h o blastic le u ke mia ( Pr ot oc ol 8 1- 0 1 
u p date). Bl o o d 1 9 9 1; 7 8: 2 5 1 4- 2 5 1 9.  
 3 5.  E va ns W E, Sc hell MJ, P ui C H. M T X cleara nce is m ore i m p orta nt f or i nter me diate-ris k 
A L L. J. Cli n. O nc ol. 1 9 9 0; 8: 1 1 1 5- 1 1 1 6. 
 3 6.  
Wall A M, Gajjar A, Li n k A et al. I n di vi d ualize d met h otre x ate d osi n g i n c hil dre n wit h 
rela pse d ac ute l y m p h o blastic le u ke mia. Le u ke mia 2 0 0 0; 1 4: 2 2 1- 2 2 5. 
 3 7.  E va ns W E, Relli n g M V, R o d ma n J H et al. C o n ve nti o nal c o m pare d wit h i n di vi d ualize d 
c he m ot hera p y f or c hil d h o o d ac ute l y m p h o blastic le u ke mia. N. E n gl.J. Me d. 1 9 9 8; 3 3 8: 4 9 9-
5 0 5. 
 3 8.  B ostr o m B, G a y n o n P S, Sat her H N. De x a met has o ne ( D E X) decreas es ce ntral ner v o us 
s yste m ( C N S) rela pse a n d i m pr o ves e ve nt-free s ur vi val ( E F S) i n l o wer ris k ac ute 
l y m p h o blastic le u ke mia ( A L L) [a bstract]. A m S oc of Cli nical O nc ol o g y 1 9 9 8; 1 7: 5 2 7 9. 
 
3 9.  Relli n g, M. V., Ha n c oc k, M. L., B o yett, J. M., a n d et.al. Pr o g n ostic i m p orta nce of 6-
merca pt o p uri n e d ose i nte nsit y i n ac ute l y m p h o blastic le u ke mia. Bl o o d 9 3, 2 8 1 7- 2 8 2 3. 
1 9 9 9. 
 4 0.  A m yl o n M D, S h uster J, P ulle n J et al. I nte nsi ve hi g h- d ose as para gi nase c o ns oli dati o n 
i m pr o ves s ur vi val f or pe diatric patie nts wit h T cell ac ute l y m p h o bl astic le u ke mia a n d 
a d va nce d sta ge l y m p h o blastic l y m p h o ma: a Pe diatric O nc ol o g y Gr o u p st u d y. Le u k e mia 
1 9 9 9; 1 3: 3 3 5- 3 4 2. 
 4 1.  P ui C H, Relli n g M V, Be h m F G et al. L-as para gi n ase ma y p ote ntiate t he l e u ke m o ge nic 
effect of t he e pi p o d o p h yll ot o xi ns. Le u ke mia 1 9 9 5; 9: 1 6 8 0- 1 6 8 4. 
 4 2.  N ys o m K, H ol m K, Li psitz S R et al. Relati o ns hi p bet wee n c u m ulati ve a nt hrac ycli ne d os e 
a n d late car di ot o xicit y i n c hil d h o o d ac ute l y m p h o blastic le u ke mia. J. Cli n. O nc ol. 
1 9 9 8; 1 6: 5 4 5- 5 5 0. 
 4 3.  L u d wi g W D, Rie der H, Bartra m C R et al. I m m u n o p he n ot y pic a n d ge n ot y pic feat ur es, 
cli nical c haracteristics, a n d treat me nt o utc o me of a d ult pr o- B ac ute l y m p h o blastic 
le u ke mia: res ults of t he Ger ma n m ultice nter trials G M A L L 0 3/ 8 7 a n d 0 4/ 8 9. Bl o o d 
1 9 9 8; 9 2: 1 8 9 8- 1 9 0 9. 
 4 4.  J e ha S, Pei D, Rai m o n di S C et al. I ncreas e d ris k f or C N S rela pse i n pr e- B cell le u ke mia 
wit h t he t( 1; 1 9)/ T C F 3- P B X 1. Le u k e mia 2 0 0 9; 2 3: 1 4 0 6- 1 4 0 9. 
 4 5.  B urt o n N K, A h er ne G W. T he effect of c otri m o x az ole o n t he a bs or pti o n of orall y 
a d mi nistere d 6- merca pt o p uri ne i n t he rat. Ca ncer C he m ot her. P har mac ol. 1 9 8 6; 1 6: 8 3- 8 4. 
 4 6.  Laf olie P, Bj or k O, Ha y d er S, A hstr o m L, Pet ers o n C. Varia bilit y of 6- merca pt o p uri ne 
p har mac o ki netics d uri n g oral mai nte na nce t hera p y of c hil dre n wit h ac ute le u ke mia. 
Me d. O nc ol. T u m or P har mac ot her. 1 9 8 9; 6: 2 5 9- 2 6 5. 
 
4 7.  L o n ner h ol m G, Kre u ger A, Li n dstr o m B, M yr dal U. Oral merca pt o p uri ne i n c hil d h o o d 
le u ke mia: i nfl ue nce of f o o d i nta ke o n bi oa vaila bilit y. Pe diatr. He mat ol. O nc ol. 1 9 8 9; 6: 1 0 5-
1 1 2. 
 4 8.  Riccar di R, Balis F M, Ferrara P et al. I nfl ue n ce of f o o d i nta ke o n bi oa vaila bilit y of oral 6-
merc a pt o p uri n e i n c hil dr e n wit h ac ute l y m p h o blastic le u ke mia. Pe diatr. He mat ol. O nc ol. 
1 9 8 6; 3: 3 1 9- 3 2 4.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 7  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
4 9.  Ri var d G E, H o y o u x C, I nfa nte C, a n d et. al. Mai nte na nce c he m ot hera p y f or c hil d h o o d 
ac ute l y m p h o blastic le u k ae mia: better i n t he e ve ni n g. La n cet 3 2 6, 1 2 6 4- 1 2 6 6. 1 9 8 5. 
 
5 0.  Sc h mie gel o w K, Gl o mstei n A, Kristi nss o n J et al. I m pact of m or ni n g vers us e ve ni n g 
sc he d ule f or oral met h otre x ate a n d 6- merca pt o p uri ne o n rela ps e ris k f or c hil dre n wit h 
ac ute l y m p h o blastic le u k e mia. N or dic S ociet y f or Pe diatric He mat ol o g y a n d O nc ol o g y 
( N O P H O). J. Pe diatr. He mat ol. O nc ol. 1 9 9 7; 1 9: 1 0 2- 1 0 9. 
 5 1.  Li n ds y Ha ge ma n W, Y. C. Hee y o u n g Ki m, K or n e ga y N et al. 3 6 9 I m pact of 6 
Meca pt o p uri ne ( 6 M P) Pill- Ta ki n g Ha bits o n A d here nce, T hi o g ua ni ne N ucle oti de ( T G N) 
Le v els a n d Rela ps e Ris k i n C hil dre n wit h Ac ute L y m p h o blastic Le u k e mia ( A L L):  R es ults 
fr o m a C hil dre n's O nc ol o g y Gr o u p ( C O G) St u d y ( A A L L 0 3 N 1) [a bstract]. A S H 
2 0 1 4; 2 0 1 4: 
 
5 2.  Ye o h EJ, R oss M E, S h urtleff S A et al. Classificati o n, s u bt y pe disc o v er y, a n d pre dicti o n of 
o utc o me i n pe diatric ac ut e l y m p h o blastic le u ke mia b y ge ne e x pressi o n pr ofili n g.  Ca ncer 
C ell 2 0 0 2; 1: 1 3 3- 1 4 3. 
 
5 3.  R oc ha J C, C he n g C, Li u W et al. P har mac o ge neti cs of o utc o me i n c hil dre n wit h ac ute 
l y m p h o blastic le u kemia . Bl o o d 2 0 0 5; 1 0 5: 4 7 5 2- 4 7 5 8. 
 5 4.  C he o k, M. H. a n d E va ns, W. E. Ac ute l y m p h o blastic le u ke mia: a m o del f or t he 
p har mac o ge n o mics of ca ncer t hera p y. Nat. Re v. Ca ncer 6, 1 1 7- 1 2 9. 2 0 0 6. 
 
5 5.  E va ns W E, Relli n g M V. M o vi n g t o war ds i n di vi d u alize d me dici ne wit h 
p har mac o ge n o mics.  Nat ure 2 0 0 4; 4 2 9: 4 6 4- 4 6 8. 
 5 6.  Relli n g M V, P ui C H, C he n g C, E v a ns W E. T hi o p uri ne met h yltra nsferase i n ac ute 
l y m p h o blastic le u ke mia. Bl o o d 2 0 0 6; 1 0 7: 8 4 3- 8 4 4. 
 5 7.  B o g ni A, C he n g C, Li u W et al. Ge n o me- wi de a p pr oac h t o i de ntif y ris k fact ors f or 
t hera p y-relate d m yel oi d l e u ke mia. Le u k e mia 2 0 0 6; 2 0: 2 3 9- 2 4 6. 
 5 8.  Ya n g JJ, C he n g C, Ya n g W et al. Ge n o me- wi de I nterr o gati o n of Ger mli ne Ge netic 
Variati o n Ass ociate d Wit h Treat me nt Res p o nse i n C hil d h o o d Ac ute L y m p h o blastic 
Le u k e mia. J A M A: T he J o ur nal of t he A merica n Me dical Ass ociati o n 2 0 0 9; 3 0 1: 3 9 3- 4 0 3. 
 5 9.  Relli n g M V, Ya n g W, D as S et al. P har mac o ge netic ris k fact ors f or oste o n ecr osis of t he 
hi p a m o n g c hil dre n wit h le u ke mia. J. Cli n. O nc ol. 2 0 0 4; 2 2: 3 9 3 0- 3 9 3 6. 
 6 0.  Ya n g J, C he n g C, Ya n g W et al. Ge n o me- wi de ger mli ne variati o n a n d tr eat me nt res p o nse 
i n ac ule l y m p h o bl astic le u ke mia ( A L L) [a bstract]. A m J H u m Ge net 2 0 0 7; Meeti n g 
A bstract: 
 
6 1.  Kis hi S, C he n g C, Fre n c h D et al. A ncestr y a n d p har mac o ge netics of a ntile u ke mic dr u g 
t o xicit y. Bl o o d 2 0 0 7; 1 0 9: 4 1 5 1- 4 1 5 7. 
 6 2.  Kis hi S, Ya n g W, B o urea u B et al. Effects of pre d nis o ne a n d ge netic p ol y m or p his ms o n 
et o p osi de dis p ositi o n i n c hil dre n wit h ac ute l y m p h o blastic le u ke mia. Bl o o d 2 0 0 4; 1 0 3: 6 7-
7 2. 
 6 3.  Kis hi S, Grie ner J, C he n g C et al. H o m oc yst ei ne, p har mac o ge netics, a n d n e ur ot o xicit y i n 
c hil dre n wit h le u ke mia. J Cli n O nc ol 2 0 0 3; 2 1: 3 0 8 4- 3 0 9 1. 
 6 4.  Bla nc o J G, E dic k MJ, Ha nc oc k M L et al. Ge netic p ol y m or p his ms i n C Y P 3 A 5, C Y P 3 A 4 
a n d N Q O 1 i n c hil dre n w h o de vel o pe d t hera p y-rel ate d m yel oi d mali g na n ci es. 
P har mac o ge n etics 2 0 0 2; 1 2: 6 0 5- 6 1 1. 
 6 5.  
M ulli g ha n C G, G o or ha S, Ra dt ke I et al. Ge n o me- wi de a nal ysis of ge n etic alterati o ns i n 
ac ute l y m p h o blastic le u k ae mia. Nat ur e 2 0 0 7; 4 4 6: 7 5 8- 7 6 4. 
 6 6.  
Wei ns hil b o u m R M, Sla de k S L. Merca pt o p uri ne p har mac o ge netics: m o n o ge nic i n herita nce 
of er yt hr oc yt e t hi o p uri ne met h yltra nsferase acti vit y. A m J. H u m. Ge net. 1 9 8 0; 3 2: 6 5 1- 6 6 2. 
 6 7.  A vra mis VI, Se ncer S, Pericl o u A P et al. A ra n d o mize d c o m paris o n of nati ve Esc heri c hia 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 8  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c oli as para gi n ase a n d p ol yet h yle ne gl yc ol c o nj u gate d as para gi nase f or treat m e nt of 
c hil dre n wit h ne wl y dia g n ose d sta n dar d-ris k ac ute l y m p h o blastic le u ke mia: a C hil dre n's 
Ca ncer Gr o u p st u d y. Bl o o d 2 0 0 2; 9 9: 1 9 8 6- 1 9 9 4. 
 
6 8.  Vieira Pi n heir o J P, We n ner K, Esc h eric h G et al. Ser u m as para gi nase acti vities a n d 
as para gi n e c o nce ntrati o ns i n t he cere br os pi nal fl ui d after a si n gle i nf usi o n of 2, 5 0 0 
IU/ m( 2) P E G as para gi nase i n c hil dre n wit h A L L treate d acc or di n g t o pr ot oc ol C O A L L-
0 6- 9 7. Pe diatr. Bl o o d Ca n cer 2 0 0 6; 4 6: 1 8- 2 5. 
 6 9.  Ya n g L, Pa netta J C, Cai X et al. As para gi nase ma y i nfl ue n ce de x a met has o ne 
p har mac o ki netics i n ac ut e l y m p h o blastic le u ke mia. J Cli n O nc ol 2 0 0 8; 2 6: 1 9 3 2- 1 9 3 9. 
 7 0.  
Wei G, T w o me y D, La m b J et al. Ge ne e x pressi o n- base d c h e mical ge n o mics i de ntifies 
ra pa m yci n as a m o d ulat or of M C L 1 a n d gl uc oc ortic oi d resista nce. Ca n cer Cell 
2 0 0 6; 1 0: 3 3 1- 3 4 2. 
 7 1.  C he o k M H, Ya n g W, P ui C H et al. Treat me nt-s pecific c ha n ges i n ge ne e x pressi o n 
discri mi nate i n vi v o dr u g res p o nse i n h u ma n le u ke mia cells. Nat. Ge n et. 2 0 0 3; 3 4: 8 5- 9 0. 
 7 2.  Q ui n n C T, Grie ner J C, B otti glieri T et al. Ele v ati o n of h o m oc yst ei ne a n d e x citat or y a mi n o 
aci d ne ur otr a ns mitters i n t he C S F of c hil dre n w h o recei v e met h otre x ate f or t he treat me nt 
of ca ncer. J Cli n O nc ol 1 9 9 7; 1 5: 2 8 0 0- 2 8 0 6. 
 7 3.  Drac ht ma n R A, C ole P D, G ol de n C B et al. De xtr o met h or p ha n is effecti ve i n t he treat me nt 
of s u bac ute met h otre x ate ne ur ot o xicit y. Pe diatr. He mat ol O nc ol 2 0 0 2; 1 9: 3 1 9- 3 2 7. 
 7 4.  Brattstr o m L, Wilc ke n D E, O hr vi k J, Br u di n L. C o m m o n met h yl e netetra h y dr of olate 
re d uctas e ge ne m utati o n lea ds t o h y p er h o m oc ystei ne mia b ut n ot t o vasc ular disease: t he 
res ult of a meta-a nal ysis. Circ ulati o n 1 9 9 8; 9 8: 2 5 2 0- 2 5 2 6. 
 7 5.  C ha n g o A, E m er y- Fill o n N, de C o urc y G P et al. A p ol y m or p his m ( 8 0 G- > A) i n t he 
re d uce d f olate carrier ge ne a n d its ass ociati o ns wit h f olate stat us a n d h o m oc ystei n e mia. 
M ol Ge net Meta b 2 0 0 0; 7 0: 3 1 0- 3 1 5. 
 7 6.  Ca m pa na D. Deter mi nati o n of mi ni mal resi d ual disease i n le u kae mia patie nts. 
Br.J. Hae mat ol. 2 0 0 3; 1 2 1: 8 2 3- 8 3 8. 
 7 7.  Fa ha m M, Z h e n g J, M o or hea d M et al. Dee p-se q u e nci n g a p pr oac h f or mi ni mal resi d ual 
disease dete cti o n i n ac ute l y m p h o blastic le u ke mia. Bl o o d 2 0 1 2; 1 2 0: 5 1 7 3- 5 1 8 0. 
 7 8.  I mai K, M ats u ya ma S, Mi ya k e S, S u ga K, Na kac hi K. Nat ural c yt ot o xic acti vit y of 
peri p heral- bl o o d l y m p h o c yt es a n d ca ncer i nci de nce: a n 1 1- year f oll o w- u p st u d y of a 
ge n eral p o p ulati o n. La ncet 2 0 0 0; 3 5 6: 1 7 9 5- 1 7 9 9. 
 
7 9.  C ostell o R T, Si v ori S, Marce n ar o E et al. Defecti v e e x pressi o n a n d f u ncti o n of nat ural 
killer cell-tri g geri n g rece pt ors i n patie nts wit h ac ute m yel oi d le u ke mia. Bl o o d 
2 0 0 2; 9 9: 3 6 6 1- 3 6 6 7. 
 
8 0.  Fa uriat C, J ust- La n di S, Mallet F et al. Deficie nt e x pressi o n of N C R i n N K cells fr o m 
ac ute m yel oi d le u ke mia: E v ol uti o n d uri n g le u ke mia treat me nt a n d i m pact of le u ke mia 
cells i n N C R d ull p he n ot y pe i n d ucti o n. Bl o o d 2 0 0 7; 1 0 9: 3 2 3- 3 3 0. 
 8 1.  Pe n de D, S pa g giari G M, Marce n ar o S et al. A n al ysis of t he rece pt or-li ga n d i nteracti o ns i n 
t he nat ural killer- me di ate d l ysis of fres hl y is olate d m yel oi d or l y m p h o blastic le u ke mias: 
e vi de nce f or t he i n v ol ve me nt of t he P oli o vir us rece pt or ( C D 1 5 5) a n d Necti n- 2 ( C D 1 1 2). 
Bl o o d 2 0 0 5; 1 0 5: 2 0 6 6- 2 0 7 3. 
 8 2.  Le u n g W, I ye n gar R, T ur ner V et al. Deter mi na nts of a ntile u ke mia effects of all o ge neic 
N K cells. J.I m m u n ol. 2 0 0 4; 1 7 2: 6 4 4- 6 5 0. 
 8 3.  Re d dic k W E, Glass J O, Helt o n KJ et al. Pre vale nce of le u k o e nce p h al o pat h y i n c hil dre n 
treate d f or ac ut e l y m p h o blastic le u ke mia wit h hi g h- d ose met h otre x ate. AJ N R A m 
J. Ne ur ora di ol. 2 0 0 5; 2 6: 1 2 6 3- 1 2 6 9. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 0 9  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
8 4.  Re d dic k W E, Glass J O, Helt o n KJ et al. A q ua ntitati ve M R i ma gi n g assess me nt of 
le u k oe nce p h al o pat h y i n c hil dre n treate d f or ac ute l y m p h o blastic le u ke mia wit h o ut 
irra diati o n. AJ N R A m J. Ne ur ora di ol. 2 0 0 5; 2 6: 2 3 7 1- 2 3 7 7. 
 8 5.  T o ga A W, T h o m ps o n P M, S o well E R. Ma p pi n g brai n mat urati o n. Tre n ds Ne ur osci. 
2 0 0 6; 2 9: 1 4 8- 1 5 9. 
 8 6.  S o well E R, T h o m ps o n P M, Le o n ar d C M et al. L o n git u di nal ma p pi n g of c ortical t hic k ness 
a n d brai n gr o wt h i n n or m al c hil dre n. J. Ne ur osci. 2 0 0 4; 2 4: 8 2 2 3- 8 2 3 1. 
 8 7.  K h o n g P L, Le u n g L H, F u n g A S et al. W hite matter a nis otr o p y i n p ost-treat me nt c hil d h o o d 
ca ncer s ur vi v ors: pr eli mi nar y e vi de nce of ass ociati o n wit h ne ur oc o g niti ve f u ncti o n. 
J. Cli n. O nc ol. 2 0 0 6; 2 4: 8 8 4- 8 9 0. 
 8 8.  La ul e C, K ozl o ws ki P, Le u n g E et al. M yeli n wat er i ma gi n g of m ulti ple scler osis at 7 T: 
c orrel ati o ns wit h hist o pat h ol o g y. Ne ur oi ma ge. 2 0 0 8; 4 0: 1 5 7 5- 1 5 8 0. 
 8 9.  
Ma dler B, Dra b ycz S A, K oli n d S H, W hittall K P, Mac ka y A L. Is diff usi o n a nis otr o p y a n 
acc urate m o nit or of m yeli nati o n? C orrelati o n of m ultic o m p o ne nt T 2 rela x ati o n a n d 
diff usi o n te ns or a nis otr o p y i n h u ma n brai n. Ma g n Res o n.I m a gi n g 2 0 0 8; 2 6: 8 7 4- 8 8 8. 
 9 0.  La ul e C, Va vas o ur I M, Ma dler B et al. M R e vi de nce of l o n g T 2 water i n p at h ol o gical 
w hite matter. J Ma g n Res o n.I ma gi n g 2 0 0 7; 2 6: 1 1 1 7- 1 1 2 1. 
 9 1.  
M o nt o ur- Pr o ul x I, K ue h n S M, Kee ne D L et al. C o g niti ve c h a n ges i n c hil dre n treate d f or 
ac ute l y m p h o blastic le u k e mia wit h c he m ot hera p y o nl y acc or di n g t o t he Pe diatric 
O nc ol o g y Gr o u p 9 6 0 5 pr ot oc ol. J. C hil d Ne ur ol. 2 0 0 5; 2 0: 1 2 9- 1 3 3. 
 9 2.  Es p y K A, M o ore I M, Ka uf ma n n P M et al. C he m ot hera pe utic C N S pr o p h yl a xis a n d 
ne ur o ps yc h ol o gic c h a n ge i n c hil dre n wit h ac ute l y m p h o blastic le u ke mia: a pr os pecti ve 
st u d y. J. Pe diatr. Ps yc h ol. 2 0 0 1; 2 6: 1- 9. 
 9 3.  Kae mi n g k K L, Care y M E, M o ore I M, H erzer M, H utter JJ. Mat h wea k nesses i n s ur vi v ors 
of ac ute l y m p h o blastic le u ke mia c o m pare d t o healt h y c hil dre n. C hil d Ne ur o ps yc h ol. 
2 0 0 4; 1 0: 1 4- 2 3. 
 9 4.  Care y M E, H oc k e n berr y MJ, M o ore I M et al. Brief re p ort: effect of i ntra ve n o us 
met h otre x ate d ose a n d i nf usi o n rate o n ne ur o ps yc h ol o gical f u n cti o n o ne year aft er 
dia g n osis of ac ute l y m p h o blastic le u ke mia. J. Pe diatr. Ps yc h ol. 2 0 0 7; 3 2: 1 8 9- 1 9 3. 
 9 5.  Br o w n R T, Ma d a n- S wai n A, Pais R et al. C he m ot hera p y f or ac ut e l y m p h o c ytic l e u ke mia: 
c o g niti ve a n d aca de mic s e q uelae. J. Pe diatr. 1 9 9 2; 1 2 1: 8 8 5- 8 8 9. 
 9 6.  Paa k k o E, Harila- Sa ari A, Va ni o n paa L et al. W hite matter c h a n ges o n M RI d uri n g 
treat me nt i n c hil dre n wit h ac ute l y m p h o blastic le u ke mia: c orrelati o n wit h 
ne ur o ps yc h ol o gical fi n di n gs. Me d. Pe diatr. O nc ol. 2 0 0 0; 3 5: 4 5 6- 4 6 1. 
 9 7.  G ol d ma n I D, Mat herl y L H. T he cell ular p har mac ol o g y of met h otre x ate. P har mac ol. T h er. 
1 9 8 5; 2 8: 7 7 - 1 0 2. 
 9 8.  Ulric h C M, R o bie n K, S par ks R. P har mac o ge neti cs a n d f olate m eta b olis m -- a pr o misi n g 
directi o n. P har mac o ge n o mics. 2 0 0 2; 3: 2 9 9- 3 1 3. 
 
9 9.  Kra us J P, Oli veri us o va J, S o k ol o va J et al. T he h u ma n c yst at hi o ni ne beta-s y nt hase ( C B S) 
ge n e: c o m plete se q u e nce, alter nati ve s plici n g, a n d p ol y m or p his ms. Ge n o mi cs 
1 9 9 8; 5 2: 3 1 2- 3 2 4.  
 1 0 0.  Kr ull K R, Br o u wers P, Jai n N et al. F ol ate pat h w a y ge netic p ol y m or p his ms are relate d t o 
atte nti o n dis or ders i n c hil d h o o d le u ke mia s ur vi v ors. J. Pe diatr. 2 0 0 8; 1 5 2: 1 0 1- 1 0 5. 
 1 0 1.  Re d dic k W E, S ha n Z Y, Glass J O et al. S maller w hite- matter v ol u mes are ass ociate d wit h 
lar ger deficits i n atte nti o n a n d lear ni n g a m o n g l o n g-ter m s ur vi v ors of ac ute l y m p h o blastic 
le u ke mia. Ca ncer 2 0 0 6; 1 0 6: 9 4 1- 9 4 9. 
 1 0 2.  O we n A M, Mc Milla n K M, Lair d A R, B ull m ore E. N- bac k w or ki n g me m or y p ara di g m: a 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 1 0  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
meta-a nal ysis of n or m ati ve f u ncti o nal ne ur oi ma gi n g st u dies. H u m Brai n M a p p. 
2 0 0 5; 2 5: 4 6- 5 9.  
 1 0 3.  S or g C, Rie dl V, M u hla u M et al. Selecti ve c h a n ges of resti n g-state n et w or ks i n 
i n di vi d uals at ris k f or Alz hei mer's diseas e. Pr oc. Natl. Aca d. Sci. U. S. A 2 0 0 7; 1 0 4: 1 8 7 6 0-
1 8 7 6 5. 
 1 0 4.  Dr u ker BJ, Sa w yers C L, Ka ntarjia n H et al. Acti vit y of a s p ecific i n hi bit or of t he B C R-
A B L t yr osi ne ki nas e i n t he blast crisis of c hr o ni c m yel oi d le u k e mia a n d ac ute 
l y m p h o blastic le u ke mia wit h t he P hila del p hia c hr o m os o me. N. E n gl.J. Me d. 
2 0 0 1; 3 4 4: 1 0 3 8- 1 0 4 2. 
 1 0 5.  Ott ma n n O G, Dr u ker BJ, Sa w yers C L et al. A p hase 2 st u d y of i mati ni b i n patie nts wit h 
rela pse d or refract or y P hila del p hia c hr o m os o me- p ositi ve ac ute l y m p h oi d le u ke mias. 
Bl o o d 2 0 0 2; 1 0 0: 1 9 6 5- 1 9 7 1. 
 1 0 6.  
Wass ma n n B, Pfeifer H, Sta dler M et al. Earl y m olec ular res p o nse t o p osttr a ns pla ntati o n 
i mati ni b deter mi nes o utc o me i n M R D + P hila del p hia- p ositi ve ac ute l y m p h o blastic 
le u ke mia ( P h + A L L).  Bl o o d 2 0 0 5; 1 0 6: 4 5 8- 4 6 3. 
 1 0 7.  Lee S, Ki m D W, Ki m YJ et al. Mi ni mal resi d ual disease- bas e d r ole of i mati ni b as a first-
li ne i nteri m t hera p y pri or t o all o ge n eic ste m cell tr a ns pla ntati o n i n P hila del p hia 
c hr o m os o me- p ositi ve ac ute l y m p h o blastic le u ke mia. Bl o o d 2 0 0 3; 1 0 2: 3 0 6 8- 3 0 7 0. 
 1 0 8.  T h o mas D A, Fa derl S, C ortes J et al. Treat me nt of P hila del p hia c hr o m os o me- p ositi ve 
ac ute l y m p h oc ytic le u ke mia wit h h y per- C V A D a n d i mati ni b mes yl ate. Bl o o d 
2 0 0 4; 1 0 3: 4 3 9 6- 4 4 0 7. 
 1 0 9.  Carter T A, W o dic ka L M, S ha h N P et al. I n hi biti o n of dr u g-resista nt m uta nts of A B L, KI T, 
a n d E G F rece pt or ki nases. Pr oc. Natl. Aca d. Sci. U. S. A 2 0 0 5; 1 0 2: 1 1 0 1 1- 1 1 0 1 6. 
 1 1 0.  S ha h N P, Tra n C, Lee F Y et al. O verri di n g i mati ni b resista nce wit h a n o vel A B L ki nas e 
i n hi bit or. Scie nce 2 0 0 4; 3 0 5: 3 9 9- 4 0 1. 
 1 1 1.  Ka ntarjia n H, Ott ma n n O, Pas q ui ni R. Dasati ni b ( S P R Y C E L) 5 0 m g or 7 0 m g BI D vs. 
1 0 0 m g or 1 4 0 Q D i n patie nts wit h c hr o nic m yel oi d le u ke mia i n c hr o nic p hase ( C M L- C P) 
resista nt or i nt olera nt t o i mati ni b:  res ults of t he C A 1 8 0- 0 3 4 st u d y [a bstract]. A S H A n n ual 
Meeti n g A bstracts 2 0 0 6; 7 4 6. 
 1 1 2.  J e ha S, Ga n d hi V, C ha n K W et al. Cl ofara bi ne, a n o vel n ucle osi de a n al o g, is acti ve i n 
pe diatric patie nts wit h a d va nce d le u ke mia. Bl o o d 2 0 0 4; 1 0 3: 7 8 4- 7 8 9. 
 1 1 3.  J e ha, S., Ga y n o n P S, Razz o u k, B., a n d et.al. P hase II st u d y of cl of ara bi ne i n pe diatric 
pati e nts wit h refract or y or rela pse d ac ute l y m p h o blastic le u ke mia. J Cli n O nc ol 2 4, 1 9 1 7-
1 9 2 3. 2 0 0 6. 
 1 1 4.  Hiji ya N, Ga y n o n P, Barr y E et al. A m ulti-ce nter p hase I st u d y of cl ofara bi ne, et o p osi de 
a n d c ycl o p h os p ha mi de i n c o m bi nati o n i n pe diatri c patie nts wit h refract or y or rela pse d 
ac ute le u k e mia. Le u ke mi a 2 0 0 9; 2 3: 2 2 5 9- 2 2 6 4. 
 1 1 5.  Baile y L C, Reill y A F, R hei n g ol d S R. I nfecti o ns i n pe diatric patie nts wit h he mat ol o gic 
mali g na n cies. Se mi n. He mat ol 2 0 0 9; 4 6: 3 1 3- 3 2 4. 
 1 1 6.  S u n g L, Ga mis A, Al o nz o T A et al. I nfecti o ns a n d ass ociati o n wit h differe nt i nte nsit y of 
c he m ot hera p y i n c hil dre n wit h ac ute m yel oi d le u ke mia. Ca ncer 2 0 0 9; 1 1 5: 1 1 0 0- 1 1 0 8. 
 1 1 7.  Pac ke y C D, Ci or ba M A. Micr o bial i nfl ue nces o n t he s mall i ntesti nal res p o nse t o ra diati o n 
i nj ur y. C urr. O pi n. G astr o e nter ol. 2 0 1 0; 2 6: 8 8- 9 4. 
 1 1 8.  Se kir o v I, Fi nla y B B. T h e r ole of t he i ntesti nal mi cr o bi ota i n e nteric i nfecti o n. J P h ysi ol 
2 0 0 9; 5 8 7: 4 1 5 9- 4 1 6 7. 
 1 1 9.  Clar ke T B, Da vis K M, L ys e n k o E S et al. Rec o g niti o n of pe pti d o gl yca n fr o m t he 
micr o bi ota b y N o d 1 e n ha nces s yste mic i n nate i m m u nit y. Nat Me d 2 0 1 0; 1 6: 2 2 8- 2 3 1. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 1 1  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 1 2 0.  de la C oc hetiere M F, M o ntassier E, Har d o ui n J B et al. H u ma n i ntesti nal micr o bi ota ge ne 
ris k fact ors f or a nti bi otic-ass ociate d diarr hea: pers pecti ves f or pre ve nti o n. Ris k fact ors f or 
a nti bi otic-ass ociate d diarr hea. Micr o b. Ec ol. 2 0 1 0; 5 9: 8 3 0- 8 3 7. 
 1 2 1.  H oc h ha us A, Ka ntarjia n H M, Baccara ni M et al. Dasati ni b i n d uces n ota bl e he mat ol o gic 
a n d c yt o ge netic res p o nses i n c hr o nic- p has e c hr o ni c m yel oi d le u ke mia aft er fail ure of 
i mati ni b t hera p y. Bl o o d 2 0 0 7; 1 0 9: 2 3 0 3- 2 3 0 9. 
 1 2 2.  Ha k LJ, Relli n g M V, C h e n g C et al. As para gi nase p har mac o d y n a mics differ b y 
f or m ulati o n a m o n g c hil dre n wit h ne wl y dia g n ose d ac ute l y m p h o blastic le u ke mia. 
Le u k e mia 2 0 0 4; 1 8: 1 0 7 2- 1 0 7 7. 
 1 2 3.  Le u n g W, I ye n gar R, Tri plett B et al. C o m paris o n of killer I g-li ke rece pt or ge n ot y pi n g a n d 
p he n ot y pi n g f or selecti o n of all o ge neic bl o o d ste m cell d o n ors. J.I m m u n ol. 
2 0 0 5; 1 7 4: 6 5 4 0- 6 5 4 5. 
 1 2 4.  Basser PJ, J o nes D K. Diff usi o n-te ns or M RI: t h e or y, e x peri me ntal desi g n a n d data a nal ysis 
- a tec h nic al re vie w. N M R Bi o me d. 2 0 0 2; 1 5: 4 5 6- 4 6 7. 
 1 2 5.  Le B D, M a n gi n J F, P o u p o n C et al. Diff usi o n te ns or i ma gi n g: c o nce pts a n d a p plicati o ns. 
J. Ma g n Res o n.I m a gi n g 2 0 0 1; 1 3: 5 3 4- 5 4 6. 
 1 2 6.  Ca m p bell L K, Sc a d ut o M, S har p W et al. A meta-a nal ysis of t he n e ur oc o g niti ve se q uel ae 
of treat me nt f or c hil d h o o d ac ute l y m p h oc ytic le u ke mia. Pe diatr. Bl o o d Ca n cer 2 0 0 7; 4 9: 6 5-
7 3. 
 1 2 7.  
M oles ki M. Ne ur o ps yc h ol o gical, n e ur oa n at o mical, a n d ne ur o p h ysi ol o gi cal c o nse q ue nces 
of C N S c he m ot hera p y f or ac ute l y m p h o blastic le u ke mia. Arc h. Cli n. Ne ur o ps yc h ol. 
2 0 0 0; 1 5: 6 0 3- 6 3 0. 
 1 2 8.  Be dell BJ, Nara ya n a P A. A ut o matic re m o val of e xtra me ni n geal tiss ues fr o m M R i ma ges 
of h u ma n brai n. J. Ma g n Res o n.I m a gi n g 1 9 9 6; 6: 9 3 9- 9 4 3. 
 1 2 9.  
M ul her n R K, Wasser ma n A L, Fair cl o u g h D, Oc hs J. Me m or y f u ncti o n i n disease-free 
s ur vi v ors of c hil d h o o d ac ute l y m p h oc ytic le u ke mia gi v e n C N S pr o p h yl a xis wit h or 
wit h o ut  1, 8 0 0 c G y cra nial irra diati o n. J. Cli n. O nc ol. 1 9 8 8; 6: 3 1 5- 3 2 0. 
 1 3 0.  
M ul her n R K, Ar mstr o n g F D, T h o m ps o n SJ. F u ncti o n-s pecific ne ur o ps yc h ol o gical 
assess me nt. Me d. Pe diatr. O nc ol. 1 9 9 8; S u p pl 1: 3 4- 4 0. 
 1 3 1.  Nat ha n P C, Patel S K, Dille y K et al. G ui deli nes f or i de ntificati o n of, a d v o cac y f or, a n d 
i nter ve nti o n i n ne ur oc o g niti ve pr o ble ms i n s ur vi v ors of c hil d h o o d ca n cer: a re p ort fr o m 
t he C hil dre n's O n c ol o g y Gr o u p. Arc h. Pe di atr. A d oles c. Me d. 2 0 0 7; 1 6 1: 7 9 8- 8 0 6. 
 1 3 2.  H oc ke n berr y M, Kr ull K, M o ore K et al. L o n git u di nal e val uati o n of fi ne m ot or s kills i n 
c hil dre n wit h le u ke mia. J. Pe diatr. He mat ol. O nc ol. 2 0 0 7; 2 9: 5 3 5- 5 3 9. 
 1 3 3.  
M ulle n E M. M ulle n Scales of Earl y Lear ni n g. Cir cle Pi nes, M N: A m erica n G ui da nce 
Ser vice; 1 9 9 2. 
 1 3 4.  B ur g u n d E D, Ka n g H C, Kell y J E et al. T he feasi bilit y of a c o m m o n stere otactic s pace f or 
c hil dre n a n d a d ults i n f M RI st u dies of de vel o p me nt. Ne ur oi ma ge. 2 0 0 2; 1 7: 1 8 4- 2 0 0. 
 1 3 5.  Ka n g H C, B ur g u n d E D, L u gar H M, Peters e n S E, Sc hla g gar B L. C o m paris o n of f u ncti o nal 
acti vati o n f oci i n c hil dre n a n d a d ults usi n g a c o m m o n stere otactic s pace. Ne ur oi ma ge. 
2 0 0 3; 1 9: 1 6- 2 8. 
 1 3 6.  C he n g C. Al m ost-s ure u nif or m err or b o u n ds of ge neral s m o ot h esti mat ors of q ua ntile 
de nsit y f u ncti o ns. Statistics & Pr o ba bilit y Letters 2 0 0 2; 5 9: 1 8 3- 1 9 4. 
 1 3 7.  Kal bfleisc h J D, Pre ntice R L. T he Statistical A nal ysis of Fail ure Ti me Data. H o b o ke n, NJ: 
J o h n Wile y & S o ns, I nc.; 2 0 0 2. 
 1 3 8.  Gra y, R. J. A class of K-sa m ple tests f or c o m pari n g t he c u m ulati ve i nci de nce of a 
c o m peti n g ris k. A n n Stat 1 6( 3), 1 1 4 1- 1 1 5 4. 1 9 8 8. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
P a ge 1 1 2  of 1 1 1  
 
 
R e visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 1 3 9.  Fi ne, J. P. a n d Gra y, R. J. A Pr o p orti o nal Hazar ds M o del f or t he S u b distri b uti o n of a 
C o m peti n g Ris k. J. A mer. Statistical Ass oc. 9 4( 4 4 6), 4 9 6- 5 0 9. 1 9 9 9. 
 1 4 0.  C he n g Q, Ya n g W, Rai m o n di S C et al. Kar y ot y pic a b n or malities create disc or da nce of 
ger mli ne ge n ot y pe a n d ca ncer cell p he n ot y pes. Nat. Ge net. 2 0 0 5; 3 7: 8 7 8- 8 8 2. 
 1 4 1.  C he n g C, P o u n ds S B, B o yett J M et al. Statistical si g nifica n ce t hr es h ol d crit eria f or 
a nal ysis of micr oarra y ge ne e x pressi o n data. Stat A p pl. Ge net. M ol. Bi ol. 2 0 0 4; 3: Article 3 6. 
 1 4 2.  P o u n ds S, C he n g C. R o b ust esti mati o n of t he false disc o ver y rate. Bi oi nf or matics. 
2 0 0 6; 2 2: 1 9 7 9- 1 9 8 7. 
 1 4 3.  Be nja mi ni Y, Kri e ger A M, Ye k utieli D. A da pti ve li near ste p- u p pr oce d ures t hat c o ntr ol 
t he false disc o ver y rat e. Bi o metri ka 2 0 0 6; 9 3: 4 9 1- 5 0 7. 
 1 4 4.  P o u n ds S, C he n g C. R o b ust esti mati o n of t he false disc o ver y rate. Bi oi nf or matics 
2 0 0 6; 2 2: 1 9 7 9- 1 9 8 7. 
 1 4 5.  P o u n ds S, C he n g C. Sa m ple siz e deter mi nati o n f or t he false disc o ver y rate. Bi oi nf or matics 
2 0 0 5; 2 1: 4 2 6 3- 4 2 7 1. 
 1 4 6.  C he n g C. Micr o arra y ge n e c o-e x pressi o n a n al ysis a n d vali dati o n b y a se q ue ntial cl usteri n g 
al g orit h m [a bstract]. J oi nt Statistical Meeti n gs of t he A merica n Statistical Ass ociati o n 
2 0 0 7; Salt La ke Cit y, U T: 
 1 4 7.  De Pa u w B, Wals h T, D o n nell y J et al. Re vise d Defi niti o ns of I n vasi ve F u n gal Dise ase 
fr o m t he E ur o pea n Or ga niz ati o n f or Researc h a n d Treat me nt of Ca ncer/I n vasi ve F u n gal 
I nfecti o ns C o o perati ve Gr o u p a n d t he Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseases 
M yc os es St u d y Gr o u p ( E O R T C/ M S G) C o nse ns us Gr o u p. Cli nical I nfecti o us Diseases 
2 0 0 8; 4 6: 1 8 1 3- 1 8 2 1. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
A P P E N DI X I:  T R E A T M E N T/ E V A L U A TI O N C A L E N D A R S  
 
Re missi o n I n d ucti o n Pretreat me nt - See Pre- Pri nte d Or der s heets.  Offer e nr oll me nt f or i nstit uti o nal 
tiss ue ba n ki n g pr ot oc ol ( T B A N K). 
 
1  
L P , I T M H A, L V 
resc ue  
P R E D ( D E X f or 
E T P π ) 
V C R  
D A U N O §  
P E, C B C diff, Uric 
Aci d,  U A, C he m. 
1 8[ 1, 2, 3, 4, 8 ]  
2  
P R E D ( D E X 
f or E T Pπ ) 
P E, C B C diff, 
Uric Aci d, 
l ytes, Ca, P, 
M g,  
 
3  
P R E D ( D E X 
f or E T Pπ ) 
P E G -A S P  
P E, C B C diff, 
Uric Aci d, 
l ytes, Ca, P, 
M g,  
[ 6, 7]  
4  
L P, I T M H A( *), 
L V resc ue  
P R E D ( D E X f or 
E T P π ) 
P E, C B C diff, 
Uric Aci d, l ytes, 
Ca, P, M g  
C S F St u dies *  
5  
P R E D ( D E X f or 
E T P π ) 
P E, C B C diff, 
U R A, l ytes, Ca, P, 
M g  
bili, S G P T  
 
6  
P R E D ( D E X 
f or E T Pπ ) 
P E, C B C diff, 
U R A, l ytes, Ca, 
P, M g,  
 
 
7  
P R E D ( D E X 
f or E TP π ) 
C B C, diff, 
U R A, l ytes, 
Ca, P, M g  
 
 
 
 
8  
P R E D ( D E X f or 
E T P π ) 
V C R  
D A U N O §  
( *)I T M H A, L V 
resc ue 
M R D  
C S F St u dies *[ 3, 4]  
9  
P R E D ( D E X 
f or E T Pπ ) 
 
1 0  
P R E D ( D E X 
f or E T Pπ ) 
 
1 1  
P R E D ( D E X f or 
E T P π ) 
( *)I T M H A, L V 
resc ue 
C S F St u dies *  
1 2  
P R E D ( D E X f or 
E T P π ) 
C B C diff  
 
 
1 3  
P R E D ( D E X 
f or E T Pπ ) 
 
 
 
1 4  
P R E D ( D E X 
f or E T Pπ ) 
 
 
 
1 5  
L P, I T M H A, L V 
resc ue  
† B M  
P R E D ( D E X f or 
E T P π ) 
V C R  
() P E G-A S P  
T M P -S M Z  
M R D  
C S F St u dies * [ 3, 4, 
5]  
1 6  
P R E D ( D E X 
f or E T Pπ ) 
T M P -S M Z  
1 7  
P R E D ( D E X 
f or E T Pπ ) 
T M P -S M Z  
 
1 8  
P R E D ( D E X f or 
E T P π ) 
 
1 9  
P R E D ( D E X f or 
E T P π ) 
C B C diff  
 
2 0  
P R E D ( D E X 
f or E T Pπ ) 
 
2 1  
P R E D ( D E X 
f or E T Pπ ) 
 
 
2 2  
† B M  
( *)I T M H A, L V 
resc ue  
P R E D ( D E X f or 
E T P π ) 
V C R  
C Y C L O ( ) 
T G ( 6 M P f or 
H E T/ deficie nc y) ∞ 
Cl o/ C y/ V P ( ) 
‡ D as ati ni b  
T M P -S M Z  
C S F St u dies *  
M R D  
2 3  
P R E D ( D E X 
f or E T Pπ ) 
A R A -C  
T G ( 6 M P f or 
H E T/ defici e n
c y)  
C Y C L O ( ) 
Cl o/ C y/ V P 
() 
‡ D as ati ni b  
T M P -S M Z  
 
 
2 4  
P R E D ( D E X 
f or E T Pπ ) 
A R A -C  
T G ( 6 M P f or 
H E T/ deficie n
c y)  
Cl o/ C y/ V P 
() 
‡ D as ati ni b  
T M P -S M Z  
 
 
2 5  
P R E D ( D E X f or 
E T P π ) 
A R A -C  
T G ( 6 M P f or 
H E T/ deficie nc y)  
Cl o/ C y/ V P ( ) 
‡ D as ati ni b  
 
 
 
2 6  
P R E D ( D E X f or 
E T P π ) 
A R A -C   
T G ( 6 M P f or 
H E T/ deficie nc y)  
Cl o/ C y/ V P ( ) 
‡ D as ati ni b  
C B C diff  
2 7  
P R E D ( D E X 
f or E T Pπ ) 
T G ( 6 M P f or 
H E T/ deficie nc
y)  
‡ D as ati ni b  
2 8  
P R E D ( D E X 
f or E T Pπ ) 
T G ( 6 M P f or 
H E T/ deficie
nc y)  
‡ D as ati ni b  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
2 9  
St o p Pre d nis o ne 
(st o p De x f or 
E T P)  
T G ( 6 M P f or 
H E T/ deficie nc y)  
‡ D as ati ni b  
T M P -S M Z  
3 0  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie n
c y)  
‡ D as ati ni b  
T M P -S M Z  
 
3 1  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie n
c y  
‡ D as ati ni b  
T M P -S M Z  
 
3 2  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie nc y)  
‡ D as ati ni b  
3 3  
A R A -C  
T G ( 6 M P f or 
H E T/ deficie nc y)  
‡ D as ati ni b  
C B C diff, bili, 2 4 -
h o ur uri ne, S p ot 
uri ne  
3 4  
T G ( 6 M P f or 
H E T/ deficie nc
y)  
‡ D as ati ni b  
3 5  
T G ( 6 M P f or 
H E T/ deficie
nc y)  
‡ D as ati ni b  
3 6  
‡ D as ati ni b  
T M P -S M Z  
 
 
3 7  
‡ D as ati ni b  
T M P -S M Z  
 
3 8  
‡ D as ati ni b  
T M P -S M Z  
 
3 9  
‡ D as ati ni b  
4 0  
‡ D as ati ni b  
C B C diff  
 
4 1  
‡ D as ati ni b  
 
4 2  
‡ D as ati ni b  
† B M (see 
c o ns oli dati o n 
cale n dar)  
M R D  
 
N otes: 
* I T met h otre xate + h y dr oc ortis o ne + c ytara bi ne (I T M H A) all partici pa nts Da y 1 a n d 1 5; ( *) P artici pa nts wit h t he 
f oll o wi n g feat ures will recei ve d a d diti o nal tri ple i ntrat hecal treat me nt o n da ys 8 a n d 2 2: W B C > 1 0 0 x 1 0 9/ L at 
prese ntati o n, Prese nce of P hil a d el p hia c hr o m os o me, M L L  re arra n ge me nt or h y p o di pl oi d y.  P artici pa nts wit h t he 
f oll o wi n g feat ures will recei ve a d diti o nal tri ple i ntrat hecal tr eat me nt o n da ys 4, 8, 1 1, a n d 2 2:  T-cell A L L, t 
( 1; 1 9)/E 2 A- P B X 1,  C N S- 3 stat us (i.e., > 5 W B C/L of C S F wit h blasts or cra nial ner ve pals y, C N S- 2 stat us ( < 
5 W B C/ L C S F wit h blasts, or tra u matic stat us ( > 1 0 R B C/ L of C S F wit h blasts.  Le uc o v ori n resc ue ( 5 m g/ m 2/ d ose) 
P O will be gi ve n at 2 4 a n d 3 0 h o urs after eac h tri ple i ntrat he cal treat me nt d uri n g i n d ucti o n.  F oll o w plas ma 
met h otre xate le vels (starti n g 2 4 h o urs after I T t hera p y a n d u ntil le vels bec o me u n detecta ble) i n patie nts wit h re nal 
d ysf u ncti o n or e xtra fl ui d i n t hir d s pace, a n d resc ue wit h le uc o v ori n acc or di n g t o P har m D r ec o m me n dati o n.  C S F 
St u dies t o be d o ne wit h eac h I T M H A treat me nt. 
§    First d ose of Da u n or u bici n ma y be dela ye d t o da y 2 i n patie nts wit h or at hi g h ris k of t u m or l ysis s y n dr o me.  Sec o n d 
d ose of da u n or u bici n c o ul d be dela ye d u p t o o ne wee k if cli nicall y i n dicate d. 
 Sec o n d d ose of P E G-as para gi nase t o be gi ve n as s o o n as M R D >/ = 1 % is c o nfir me d a n d n o later t ha n da y 2 1. 
 P artici pa nts wit h Da y 1 5 M R D < 5 %, will recei ve c ycl o p h os p ha mi de 1 0 0 0 m g/ m2 I V Da y 2 2 f or 1 d ose; P artici pa nts 
wit h Da y 1 5 M R D > 5 % (e xcl u di n g M L L + I nfa nts) will rec ei ve c ycl o p h os p ha mi de 3 0 0 m g/ m 2 e ver y 1 2 h o urs o n Da ys 
2 2 - 2 3 f or a t otal of 4 d oses. 
 
Cl ofara bi ne/c ycl o p h os p ha mi de/et o p osi de i n M L L + I nfa nts o nl y. M L L + I nfa nts will c o nti n ue pre d nis o ne b ut will n ot 
recei ve da y 2 2 vi ncristi ne, t hi o g ua ni ne, or c ytara bi ne i n i n d ucti o n. 
† 
All b o ne marr o w sa m ples f or M R D; B M E val uati o ns re q uir e d o n Da y 1 5, 2 2, a n d E n d of I n d ucti o n ( Da y 3 8- 4 2)  
‡ 
P hila del p hia p ositi ve ( P h +) partici pa nts o nl y 
π 
De xa met has o ne f or E T P i m m u n o p he n ot y pe o nl y.  See Secti o n 5. 2. 1, 1 0 m g/ m 2 P O da ys 1- 2 1, 4 m g/ m2 da ys 2 2- 2 4, a n d 
2 m g/ m 2 P O da ys 2 5-2 8  
∞ T P M T H E T/ deficie nt p atie nts will recei ve merca pt o p uri ne as per T O T X V d uri n g i n d ucti o n i nstea d of t hi o g ua ni ne.  
W T patie nts will recei ve T G, b ut will be cl osel y m o nit ore d f or si g ns or s y m pt o ms of V O D. 
 
S pecial st u dies: 
 
( 1) C B C wit h diff re q uire d dail y f or first 7 da ys, a n d t he n at least wee kl y ( 2) bl o o d c he mistries ( C h e m 
1 8 pr ofile) ( 3) bl o o d f or as para gi nase ( o btai n pre- aspara gi nase, d a y 8, da y 1 5, a n d 2- 3 a d diti o nal 
sa m ples after first d ose b ut bef ore a n y 2 n d d ose  ( 4) C S F As para gi n e – Secti o n 1 0. 3 c ollecte d pri or t o 
IT M H A treat me nts o n D a y 1 a n d 1 5 (a n d 8 if a p plica ble). A d diti o nal sa m ple re q uire d o n d a y of 
dia g n osis of sa gital si n us t hr o m b osis or D V T ( 5) Ser u m bi o mar kers, (e. g.., ser u m li pi ds a n d c ortis ol) 
( 6) bl o o d f or D N A ( % _ D N A sa m ple) ( 7) Re d Bl o o d cell T hi o p uri ne c o n ce ntrati o n – Secti o ns 8. 0 a n d 
1 0. 2.  ( 8) Q C T f or b o n e de nsit y   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
M R D st u dies: 
 
S a m ples re q uire d f or M R D st u dies d uri n g re missi o n i n d ucti o n  
Ti me p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
  Da y 8  
P B  
P B  
  Da y 1 5  
B M  
B M a n d P B  
 ( Da y 2 2 if M R D+  o n Da y 1 5)  
B M  
B M a n d P B  
  Da y 4 3  
B M  
B M a n d P B  
P B; peri p heral bl o o d; B M: b o ne marr o w 
 
C o ns oli dati o n 
 
E n d of I n d ucti o n- M R D res p o nse: B M as pir ate will be perf or m e d ar o u n d d a y 3 8- 4 2 of re missi o n 
i n d ucti o n w he n A N C has rec o vere d t o > 3 0 0/ m m3 a n d platelet c o u nt t o > 5 0 x 1 09/ L.  If t he dat e falls 
o n a wee k-e n d or h oli da y, t he pr oce d ure ma y b e p erf or me d o n t h e cl osest w or ki n g d a y.  M R D le vel 
will be deter mi ne d i n t his b o ne marr o w s a m ple.  P o or res p o nse will be defi ne d as M R D le vel  0. 0 1 % 
ly m p h o blasts b y eit her i m m u n ol o gic or m olec ular assa y.  If b ot h assa ys are u ns uccessf ul or t he 
sa m ple is i na de q uate, t he M R D will be ass u me d t o be ne gati ve.  If t he res ult s h o ul d bec o me a vaila ble 
later a n d discl ose a le vel  0. 0 1 %, t he pr o visi o nal l o w-ris k case will t he n be classifie d as sta n d ar d-ris k 
or hi g h-ris k acc or di n gl y, a n d will recei v e s u bse q ue nt H D M T X at a hi g h er d osa ge (i.e., 5 g m/ m 2). 
 
1  
* I T M H A, L V resc ue 
H D M T X # 1  
6 M P  
‡ D as ati ni b  
C B C diff, [ 1, 2, 3, 4, 5, 6] 
2  
6 M P,  
‡ D as ati ni b  
3  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
4  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
5  
6 M P  
‡ D as ati ni b  
6  
6 M P  
‡ D as ati ni b  
7  
6 M P  
‡ D as ati ni b  
8  
6 M P  
‡ D as ati ni b  
C B C diff  
9  
6 M P  
‡ D as ati ni b  
1 0  
6 M P  
‡ D as ati ni b  
1 1  
6 M P  
‡ D as ati ni b  
1 2  
6 M P  
‡ D as ati ni b  
1 3  
6 M P  
‡ D as ati ni b  
1 4  
6 M P  
‡ D as ati ni b  
1 5  
*I T M H A, L V  
H D M T X # 2  
6 M P  
‡ D as ati ni b  
C B C, diff,  [ 2, 3, 7] 
1 6  
6 M P  
‡ D as ati ni b  
1 7  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
1 8  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
1 9  
6 M P  
‡ D as ati ni b  
2 0  
6 M P  
‡ D as ati ni b  
2 1  
6 M P  
‡ D as at i ni b  
2 2  
6 M P  
‡ D as ati ni b  
C B C, diff  
2 3  
6 M P  
‡ D as ati ni b  
2 4  
6 M P  
‡ D as ati ni b  
2 5  
6 M P  
‡ D as ati ni b  
2 6  
6 M P  
‡ D as ati ni b  
2 7  
6 M P  
‡ D as ati ni b  
2 8  
6 M P  
‡ D as ati ni b  
2 9  
*I T M H A, L V resc ue  
H D M T X # 3  
6 M P  
‡ D as ati ni b  
C B C, diff,[ 1, 2, 3]  
3 0  
6 M P  
‡ D as ati ni b  
3 1  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
3 2  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
3 3  
6 M P  
‡ D as ati ni b  
3 4  
6 M P  
‡ D as ati ni b  
3 5  
6 M P  
‡ D as ati ni b  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
3 6  
6 M P  
‡ D as ati ni b  
C B C, diff,  
3 7  
6 M P  
‡ D as ati ni b  
3 8  
6 M P  
‡ D as ati ni b  
3 9  
6 M P  
‡ D as ati ni b  
4 0  
6 M P  
‡ D as ati ni b  
4 1  
6 M P  
‡ D as ati ni b  
4 2  
6 M P  
‡ D as ati ni b  
4 3  
*I T M H A, L V resc ue  
H D M T X # 4  
6 M P  
‡ D as ati ni b  
C B C, diff [ 1, 2, 3]  
4 4  
6 M P  
‡ D as ati ni b  
4 5  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
4 6  
6 M P  
L V _ _ _ m g  
‡ D as ati ni b  
4 7  
6 M P  
‡ D as ati ni b  
4 8  
6 M P  
‡ D as ati ni b  
4 9  
6 M P  
‡ D as ati ni b  
5 0  
6 M P  
‡ D as ati ni b  
C B C, diff  
5 1  
6 M P  
‡ D as ati ni b  
5 2  
6 M P  
‡ D as ati ni b  
5 3  
6 M P  
‡ D as ati ni b  
5 4  
6 M P  
‡ D as a ti ni b 
5 5  
6 M P  
‡ D as ati ni b  
5 6  
6 M P  
‡ D as ati ni b  
 
N otes: 
*I T met h otrex ate + hy dr oc ortis o ne + cyt ar a bi ne, t o be give n o n d ays 1, 1 5, 2 9, a n d 4 3; I T t her a py s h o ul d be 
give n o n s a me d ay as H D M T X a d mi nistr ati o n (c o ns ult PI or P K if t he I T a n d H D M T X bec o me se p ar ate d by 
m ore t h a n 1 2 h o urs. 
‡  O nly P h + p atie nts 
P hysic al Ex a m every 3- 7 d ays d uri n g C o ns oli d ati o n.  C B C wit h differe nti al nee de d weekly.   
 
S pecial st u dies:  
 
( 1) bl o o d c he mistries ( C he m 1 8 pr ofile); ( 2) C S F St u dies wit h eac h I T M H A ( 3) H D M T X 
P har mac o ki netics – Secti o n 1 0. 1 ( 4) ger mli ne D N A/ R N A ( o btai n sa m ple at re missi o n, bef ore first a n d 
t hir d H D M T X); ( 5) As p ara gi nase A nti b o dies/ Acti vit y – Secti o n 1 0. 3, ser u m a n d plas ma o btai ne d o n 
da ys 1 c o ns oli dati o n ( 6) C S F As para gi ne – d a y 1 c o ns oli dati o n ( 7) Ser u m bi o mar k ers (e. g. li pi ds, 
cortis ol) – Da y 1 5 c o ns oli dati o n  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T R E A T M E N T S C H E M A a n d s pecial la b orat or y tests d uri n g c o nti n uati o n t hera p y 
 
Sta n dar d/ Hi g h Ris k  
L o w Ris k  
 
W ee k  
 
S pecial 
St u dies  
 
S pecial 
St u dies  
 1  
D E X + D O X O + V C R + 6 M P + 
P E G -A S P + ‡ Dasati ni b  
 
6 M P + D E X  + V C R  
 
 2  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
 3  
( *) 6 M P + P E G-A S P + 
‡ Dasati ni b  
 
( *) 6 M P + M T X 
 
 4  
D E X + D O X + V C R + 6 M P + 
‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
 5  
 6 M P + P E G - A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
 6  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
 7  
*( †) Rei n d ucti o n I  
( D E X + D O XO + V C R + P E G -
A S P + ‡ Dasati ni b)  
[ 1, 2, 4, 5, 
6, 7, 8, 9, 
1 0, 1 1]  
*( †) Rei n d ucti o n I  
( D E X + V C R + D O X O + P E G-As p)  
[ 1, 2, 4, 5, 6, 9, 
1 0, 1 1]  
 8  
Rei n d ucti o n I  
( D O X O + V C R ‡ Dasati ni b) 
[ 1, 4, 6, 
1 3, 1 4, 
1 5]  
Rei n d ucti o n I  
( V C R) 
[ 1, 4, 6, ] 
 9  
Rei n d ucti o n I  
(D E X + V C R + P E G -
A S P + ‡ Dasati ni b)  
[ 1, 4] 
Rei n d ucti o n I  
( D E X + V C R + P E G-A S P)  
[ 1, 4] 
1 0  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1  
D O X + V C R + 6 M P + P E G -
A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 2  
* 6 M P + ‡ Dasati ni b  
[ 8] 
* 6 M P + M T X  
[ 8] 
1 3  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 4  
D E X + D O X + V C R + 6 M P + 
‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
1 5  
 6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 6  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 7  
*( †) Rei n d ucti o n II  
 ( D E X + V C R + P E G-
A S P + ‡ Dasati ni b)  
[ 1, 3, 4, 6, 
1 1 ] 
*( †) Rei n d ucti o n II  
( D E X + V C R + P E G-A S P)  
[ 1, 3, 4, 6, 1 1 ] 
1 8  
Rei n d ucti o n II  
 ( V C R + ‡ Dasati ni b) 
 
Rei n d ucti o n II  
( V C R) 
 
1 9  
Rei n d ucti o n II  
( D E X + V C R + H D Ara-C + 
P E G -A S P + ‡ Dasati ni b)  
[ 1, 4] 
Rei n d ucti o n II  
( D E X + V C R + P E G-A S P)  
[ 1, 4] 
2 0  
‡ Dasati ni b  
 
6 M P + M T X  
 
2 1  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 2  
6 M P + ‡ Dasati ni b  
[ 8] 
6 M P + M T X  
[ 8] 
2 3  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 4  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 5  
* D E X + V C R + P E G -A S P + 
Dasati ni b  
 
* 6 M P + D E X + V C R  
 
2 6  
6 M P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 7  
6 M P + P E G -A S P + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 8  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
2 9  
* D E X + V C R + P E G -
A S P + ‡ Dasati ni b  
 
( *) 6 M P + D E X + V C R 
 
3 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 2  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
Sta n dar d/ Hi g h Ris k  
L o w Ris k  
 
W ee k  
 
S pecial 
St u dies  
 
S pecial 
St u dies  
3 3  
* D E X + V C R + ‡ Dasati ni b  
 
* 6 M P + D E X + V C R  
 
3 4  
6 M P + M T X + ‡ D asati ni b  
 
6 M P + M T X  
 
3 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 6  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 7  
* D E X + V C R + ‡ Dasati ni b  
 
( *) 6 M P + D E X + V C R 
 
3 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
3 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 0  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 1  
* D E X + V C R + ‡ Dasati ni b  
 
* 6 M P + D E X + V C R  
 
4 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 4  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 5  
* D E X + V C R + ‡ Dasati ni b  
 
( *) 6 M P + D E X + V C R 
 
4 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 8  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
4 9  
*( †) D E X + V C R + ‡ Dasati ni b  
 
* 6 M P + D E X + V C R  
 
5 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 2  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 3  
D E X + V C R + ‡ Dasa ti ni b 
 
6 M P + D E X + V C R  
 
5 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 6  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 7  
( *) D E X + V C R + ‡ Dasati ni b 
 
6 M P + D E X + V C R  
 
5 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
5 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 0  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 1  
D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
6 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 4  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 5  
( *)D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
6 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 8  
C Y C L O + A R A -C + ‡ Dasati ni b  
 
6 M P + M T X  
 
6 9  
D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
7 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 3  
( *) 6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
7 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 7  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
7 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
7 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 1  
( *)6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
Sta n dar d/ Hi g h Ris k  
L o w Ris k  
 
W ee k  
 
S pecial 
St u dies  
 
S pecial 
St u dies  
8 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 5  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
8 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
8 9  
( *) 6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
9 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 3  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
9 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 7  
( *)6 M P + D E X + 
V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
9 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
9 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 1  
6 M P + D E X + V C R + ‡ Dasati ni b  
 
6 M P + D E X + V C R  
 
1 0 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 5  
6 M P + M T X ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 7  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 0 9  
6 M P + M T X ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 0  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 1  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 2  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 3  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 4  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 5  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 6  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 7  
6 M P + M T X ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 8  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 1 9  
6 M P + M T X + ‡ Dasati ni b  
 
6 M P + M T X  
 
1 2 0  
† 6 M P + M T X + ‡ Dasati ni b  
[ 7, 8, 9, 
1 0 ] 
6 M P + M T X  
[ 7, 8, 9, 1 0 ] 
N otes:  
*I T met h otrex ate + h y dr oc ortis o ne + cyt ar a bi ne: 
 ( *) Tri ple i ntr at hec al tre at me nt will be give n t o l o w-risk c ases wit h C N S- 1 st at us ( n o i de ntifi a ble bl asts i n C S F) o n 
weeks 7, 1 2, 1 7, 2 5, 3 3, 4 1, a n d 4 9. 
 Tri ple i ntr at hec al tre at me nt will be give n t o l o w-risk c ases wit h C N S- 2, tr a u m atic C S F wit h bl asts st at us, or W B C  
1 0 0 x 1 0 9/ L o n weeks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tri ple i ntr at hec al tre at me nt will be give n t o st a n d ar d/ hi g h-risk c ases o n weeks 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5 a n d 4 9. 
 Tri ple i ntr at hec al tre at me nt will be give n t o ot her st a n d ar d/ hi g h-risk c ases wit h W B C 1 0 0 x 1 0 9/ L, T-cell A L L, , t 
( 1; 1 9)/ E 2 A- P B X 1, prese nce of P hil a del p hi a c hr o m os o me, M L L re arr a n ge me nt, hy p o di pl oi dy < 4 4, C N S- 2 or C N S-3 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
st at us, or tr a u m atic l u m b ar p u nct ure wit h bl asts o n weeks 3, 7, 1 2, 1 7, 2 5, 2 9, 3 3, 3 7, 4 1, 4 5, 4 9, 5 7, 6 5, 7 3, 8 1, 8 9 a n d 
9 7.  
 S urveill a nce cere br os pi n al fl ui d ex a mi n ati o n wit h e ac h I T M H A a n d t he n a p pr oxi m ately every 1 6 weeks. 
 
† B o ne m arr o w ex a mi n ati o n; s a m ple f or M R D ( See Secti o n 1 1. 2) 
C B C wit h differe nti al is nee de d weekly, p hysic a n ex a m every 4 weeks, a n d c he mistries as cli nic ally i n dic ate d.  
D uri n g Re-I n d ucti o ns I a n d II: P E re q uire d every 3- 7 d ays, C B C weekly, c he m 1 8 o n D ay 1 Weeks 7, 8, 9, 
1 7. 1 9 
‡ O nly P h + p atie nts 
S urveill a nce cere br os pi n al fl ui d ex a mi n ati o n 
 
S pecial st u dies:   
 
1) Bl o o d c he mistries ( C he m 1 8) ( 2) R B C T G N – Da y 1 Wee k 7 ( 3) R B C T P M T – Da y 1 wee k 1 7 ( 4) 
As para gi nase A nti b o dies/ Acti vit y – Da y 1 Wee k 7, 8, 9, 1 7, a n d 1 9.  ( 5) C S F As para gi ne – Da y 1 Wee k 7 ( 6) 
Ser u m bi o mar kers (e. g. li pi ds, c ortis ol) – Wee k 7, 8, a n d 1 7.  ( 7) Q C T f or b o ne de nsit y – Wee k 1 2 0.  ( 8) M RI 
hi ps/ k nees a n d P T/ O T e val uati o n ( partici pa nts > 9 years of a ge) –  After eac h Re-I n d ucti o n ( wee ks 1 2- 1 4 a n d 
2 2- 2 4, a n d Wee k 1 2 0 or later), ( 9) Ps yc h ol o gical Testi n g, ( 1 0) M RI Brai n.   M R s h o ul d be ac q uire d bef ore 
D E X.  Partici pa nts wit h a b n or mal i ma gi n g e val uati o ns at wee k 1 2 0 will ha ve a n e xtra e xa m at 2 years off 
t hera p y t o reassess brai n str uct ure. ( 1 1) Plas ma f or meas ure me nt of de xa met has o ne c o nce ntrati o ns t o be 
o btai ne d wit h Da y 8 la bs d uri n g Rei n d ucti o ns I a n d II ( wee ks 7 a n d 1 7).  
 
Sa m ples re q uire d f or M R D st u dies p ost-re missi o n i n d ucti o n 
Ti me p oi nt  
B -li nea ge A L L 
T -li nea ge A L L 
Da y 4 3 
M R D +  
Da y 4 3 
M R D - 
Da y 4 3 
M R D + ( or 
“at y pical” T -
A L L)  
Da y 4 3 
M R D - 
Da y 1 ( Wee ks 7, 1 7, 4 9)  
B M  
N o ne  u nless 
cli nicall y 
i n dicate d or 
M L L +  
B M a n d P B  
P B  
Wee k 1 2 0 ( off t hera p y)  
B M  
B M  
B M  a n d P B 
B M a n d P B  
P B; peri p heral bl o o d; B M: b o ne marr o w   
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X II: D R U G I N F O R M A TI O N 
 
1.  
P R E D NI S O N E, P R E D NI S O L O N E 
 
S o urce a n d p h ar mac ol o g y: Pre d nis o ne is a s y nt hetic c o n ge ner of h y dr oc ortis o ne, t he nat ural a dre n al 
h or m o ne.  Pre d nis o ne is a w hite or yell o wis h cr ystalli ne p o w der.  It bi n ds wit h ster oi d rece pt ors o n 
n uclear me m bra nes, i m p airs cell ular mit osis a n d i n hi bits pr otei n s y nt h esis.  Pre d nis o ne als o has p ote nt 
anti-i nfla m mat or y effects a n d s u p presses t he i m m u ne s yste m. Pre d nis o ne is well a bs or be d orall y.  It is 
c o n verte d t o pr e d nis ol o ne, t he p har mac ol o gicall y acti ve meta b olite, i n t he li ver.  Pre d nis ol o ne is 
f urt her meta b olize d t o i nacti ve c o m p o u n ds i n t he li ver. T he meta b olites are e x crete d mai nl y i n t he 
uri ne. 
 
F or m ulati o n a n d sta bilit y: Pre d nis o ne is a vaila ble as vari o us stre n gt h ta blets a n d oral s ol uti o n fr o m 
m ulti ple ma n ufact urers. All d osa ge f or ms c a n be st ore d at r o o m te m perat ure. At St. J u de C hil dre n’ s 
Researc h H os pital, pre d nis ol o ne oral s ol uti o n ma y be s u bstit ute d f or pre d nis o ne li q ui d at e q ual d oses 
d ue t o its s u peri or palata bilit y. 
 
S u p plier: c o m merciall y a vaila ble 
 
T o xicit y: Si de effects of pre d nis o ne var y de pe n di n g o n t he d urati o n of its use. Si de effects t hat ca n 
occ ur wit h s h ort ter m use i ncl u de s o di u m a n d water rete nti o n wit h ass ociat e d h y perte nsi o n, pe ptic 
ulcer wit h p ossi ble perf orati o n a n d he m orr h a ge, i ncreas e d s usce pti bilit y t o i nfecti o ns, e m oti o nal 
i nsta bilit y, i ns o m nia, i ncrease d a p p etite, wei g ht gai n, ac ne a n d h y p er gl yce mia. Si de effects m ore 
c o m m o nl y ass oci ate d wit h pr ol o n ge d use i ncl u de cataracts, i ncrease d i ntra oc ular press ure a n d 
ass ociate d gla u c o ma, de v el o p me nt of a “c us hi n g oi d” state, c o m pr essi o n fract ures, me nstr ual 
irre g ularities, s u p pressi o n of gr o wt h i n c hil dre n, s ec o n dar y a dre n oc ortical a n d pit uitar y 
u nres p o nsi ve ness partic ularl y i n ti mes of stress as i n tra u ma, s ur ger y or ill ness, oste o p or osis a n d 
m uscle wasti n g. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
2.  
V I N C RI S TI N E ( O n c o vi n) 
 
S o urce a n d p h ar mac ol o g y:  Vi ncristi ne is a n al kal oi d o btai ne d fr o m t he peri wi n kle ( Vi n c a r ose a) 
pla nt.  It r e versi bl y bi n ds t o micr ot u b ule a n d s pi n dle pr otei ns ca usi n g meta p hase arrest. Vi ncristi ne 
has p o or pe netrati o n i nt o t he C S F.  It is a p pr o xi matel y 7 5 % pr otei n b o u n d. E xte nsi ve meta b olis m 
occ u rs i n t he li ver. E x creti o n is pri maril y i n t he bile. A d osa ge d ecrease is r ec o m me n de d i n patie nts 
wit h ele vate d bilir u bi n (s ee secti o n 7. 3) 
 
F or m ulati o n a n d sta bilit y: Vi ncristi ne is s u p plie d i n m ulti ple- d ose 1 m g/ ml vials c o ntai ni n g 1 ml, 2 ml 
a n d 5 ml. T he i ntact vials s h o ul d be st ore d u n der refri gerati o n a n d pr otecte d fr o m li g ht. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: D ose li miti n g t o xicit y is ne ur ot o xicit y.  T his ca n be c h aracterize d b y c o nsti pati o n a n d/ or 
paral ytic ile us, pt osis, v ocal c or d paral ysis, wea k n ess, ja w pai n, a b d o mi nal pai n, peri p heral 
ne ur o pat hies, l oss of dee p te n d o n refle x es a n d “f o ot dr o p”. Peri p heral ne ur o pat h y is ofte n t h e first 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
si g n of ne ur ot o xicit y a n d is i nitiall y re versi ble.  Ot her t o xicities re p orte d i ncl u de al o pecia, mil d 
na usea a n d v o miti n g, SI A D H, m yel os u p pressi o n, ort h ostatic h y p ote nsi o n, o ptic atr o p h y, tra nsie nt 
c ortical bli n d ness, a n d a u dit or y da ma ge.  Ac ut e s h ort ness of breat h a n d se v ere br o nc h os pas ms has 
be e n re p orte d f oll o wi n g t he a d mi nistrati o n of vi nca al kal oi ds.  M yel os u p pressi o n is rare at us ual 
d ose s.  Vi ncristi ne is a vesica nt a n d ma y ca use se v ere tiss ue da ma ge if e xtra vasati o n occ urs. N O T E:  
d ose re d ucti o n ma y b e necessar y i n patie nts < 1 year of a ge, or < 1 0 k g wei g ht. D osi n g o n a p er k g 
(rat her t h a n per m2) basis has bee n a d v ocate d f or i nfa nts i n or der t o decreas e t o xicit y. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
3.  
D A U N O R U BI CI N ( Da u n o m yci n, Cer u bi di ne ) 
 
S o urce a n d p h ar mac ol o g y:  Da u n or u bici n is a n a nt hrac ycli ne a nti bi otic deri ve d fr o m Stre pt o myces 
c oer ule or u bi d us . Da u n or u bici n i ntercalates b et wee n base pairs of D N A ca usi n g steric o bstr ucti o n, 
disr u pti o n of D N A f u ncti o n a n d i n hi biti o n of R N A s y nt hesis.  I n a d diti o n, da u n or u bici n i n hi bits 
t o p ois o merase II, a n e nz y m e res p o nsi ble f or all o wi n g stra n ds of D N A t o pass t hr o u g h o n e a n ot her as 
t hey u n wi n d.  E v e n t h o u g h da u n or u bici n e xerts its maj or effects i n t he S p hase, it is c o nsi dere d t o b e 
cell c ycle p h ase n o n-s p ecific.  Da u n or u bici n is wi del y distri b ute d i n tiss ues b ut d oes n ot cr oss t he 
bl o o d brai n barrier.  It is meta b olize d t o da u n or u bici n ol, w hic h is t he maj or acti ve meta b olite a n d 
agl yc o nes (i nacti ve). T h e maj or r o ute of eli mi nati o n is t hr o u g h t he bile ( 4 0 %) wit h a d diti o nal 
eli mi nati o n t hr o u g h t he uri ne.  D osa ges s h o ul d be re d uce d i n p atie nts wit h li ver d ysf u ncti o n (as i n 
secti o n 7. 3) or re nal d ysf u ncti o n (creati ni ne > 3 m g/ d L). 
 
F or m ulati o n a n d sta bilit y:  Da u n or u bici n is s u p plie d i n vials c o ntai ni n g 2 0 m g of re d dis h c ol ore d 
l y o p hiliz e d p o w der a n d 1 0 0 m g of ma n nit ol.  T he i ntact vials s h o ul d be st ore d at r o o m te m perat ure. 
Eac h vial ca n be rec o nstit ute d wit h 4 ml of sterile water f or i njecti o n t o gi v e a fi nal c o nce ntr ati o n of 5 
m g/ ml.  Rec o nstit ute d s ol uti o ns are sta ble f or 2 4 h o urs at r o o m te m perat ure a n d 4 8 h o urs if 
refri gerate d. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: D ose-li miti n g t o xicities of da u n or u bici n i ncl u de m yel os u p pressi o n a n d car di ot o xicit y. T w o 
f or ms of car diac t o xicit y ca n occ ur. Ac ut e t o xicit y ma y ta ke t he f or m of arr h yt h mias, heart bl oc k or 
pe ricar ditis a n d ma y b e fatal. T he c hr o nic f or m of   car di ot o xicit y is r elate d t o t otal c u m ulati ve d ose 
a n d is c haracteriz e d b y h eart fail ure. Me diasti nal ra di ot hera p y a n d/ or ot her car di ot o xic dr u gs ma y 
i ncreas e t he ris k of car di ot o xicit y.  I n ge n eral, t ot al lifeti me d osa ges of 4 5 0- 5 5 0 m g/ m2 s h o uld n ot be 
e x cee de d. Ot her t o xicities i ncl u de na usea a n d v o miti n g, m uc ositis, al o pecia, diarr hea a n d re d 
disc ol orati o n of t he uri ne a n d ot her b o d y fl ui ds. Se vere tiss ue da ma ge a n d necr osis ca n o cc ur u p o n 
e xtra vasati o n.  Ra diati o n recall reacti o ns ca n occ ur a n d ca n b e se vere.  Rarel y, aller gi c reacti o ns ha v e 
occ urre d.  T y p hlitis ca n occ ur w h e n c o m bi ne d wit h c ytara bi ne. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
4.  
P E G - L- A S P A R A GI N A S E ( Pe gas par gase, O ncas p ar) 
 
S o urce a n d p h ar mac ol o g y:  P E G-as p ara gi n ase is a m o difie d versi o n of t he e nz y me, L- as para gi nase.  
L- as para gi nase is m o difi e d b y c o vale ntl y c o nj u gati n g u nits of p ol yet h yl e n e gl yc ol ( P E G) t o t he 
e nz y me.   T he as par a gi nase use d i n t he ma n ufact uri n g of P E G-as para gi nase is deri ve d fr o m 
Esc heric hi a c oli.  As para gi nase h y dr ol yzes s er u m as para gi n e (a n a mi n o aci d re q uire d t o s y nt hesize 
pr otei ns a n d D N A) t o as partic aci d a n d a m m o nia, a n d is t heref ore let hal t o cells t hat ca n n ot s y nt hesi ze 
as para gi n e.  As para gi nas e is acti ve d uri n g all p has es of t he cell c ycle. As p ara gi nase is n ot a bs or b e d 
fr o m t he GI tr act a n d m ust be gi ve n p are nt erall y.  P E G- as para gi nase h as a plas ma half-life of 
ap pr o xi matel y 6 da ys, b ut is meas ura ble f or at least 1 5 da ys f oll o wi n g t he i nitial treat me nt.  It ca n n ot 
be detect e d i n t he uri ne. 
 
F or m ulati o n a n d sta bilit y:  P E G-as para gi n ase is a v aila ble i n si n gle- use vials c o ntai ni n g 5 ml of P E G-
as para gi n ase as a cle ar s ol uti o n.  Eac h vial c o ntai ns 3 7 5 0 u nits of dr u g at a c o nce ntr ati o n of 7 5 0 
u nits/ ml.  T he i ntact vials s h o ul d be st ore d u n der refri gerati o n. Freezi n g d estr o ys its acti vit y, w hic h 
ca n n ot be det ecte d vis uall y.  It s h o ul d n ot be use d if it is cl o u d y or a preci pitate is prese nt. 
 
S u p plier:   C o m mercia ll y a vaila ble 
 
T o xicit y: Ac ute t o xicit y i ncl u des a na p h ylactic reacti o ns w hic h occ ur m ost c o m m o nl y w he n t h e dr u g 
is gi ve n I V. T hese ca n be c haracteriz e d b y lar y n geal c o nstricti o n, h y p ot e nsi o n, dia p h oresis, fe v er, 
c hills, e de ma a n d l oss of c o nsci o us ness.  Aller gic reacti o ns at t he site of I M i njecti o n i ncl u de pai n, 
s welli n g a n d er yt he ma. T he i nci de nce of h y perse nsiti vit y reacti o ns t o P E G- as para gi n ase ma y be l ess 
t ha n wit h c o n ve nti o nal E. c oli deri ve d as p ara gi nas e alt h o u g h cr oss- s e nsiti vit y ca n o cc ur.  Ot her 
ad verse effects i ncl u de n e utr o pe nia a n d ass ociate d i m m u n os u p pressi o n, mil d na usea a n d v o miti n g, 
malaise, a n ore xia, ele vate d L F T’s, p a ncreatitis a n d h y per gl yce mia.  A decrease i n pr otei n s y nt hesis 
i ncl u di n g al b u mi n, fi bri n o ge n a n d ot her c oa g ulati o n fact ors ma y o cc ur w hic h ca n res ult i n t hr o m b osis 
or p u l m o nar y e m b olis m.  Less c o m m o n si de effects i ncl u de re nal d ysf u ncti o n a n d C N S c o m plicati o ns 
i ncl u di n g s o m n ole nce, w ea k ness, let har g y, c o ma a n d seiz ures. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
5.  
E R W I NI A L- A S P A R A GI N A S E ( Er wi n aze) 
 
S o urce a n d p h ar mac ol o g y: Er wi nia as para gi nase is a n e nz y me.  It is deri ve d fr o m Er wi ni a 
c hrys a nt he mi a n d ma y b e usef ul i n patie nts wit h a n aller g y t o t he E. c oli deri ve d pr o d u ct. 
As para gi nas e h y dr ol yz es ser u m as para gi ne (a n a mi n o aci d re q uir e d t o s y nt h esiz e pr otei ns) t o as partic 
aci d a n d a m m o nia, a n d is t heref ore let hal t o cells t hat ca n n ot s y nt hesize as p ara gi ne. As p ara gi n ase is 
acti ve d uri n g all p has es of t he cell c ycl e. As para gi nas e is n ot a bs or be d fr o m t he GI tract a n d m ust be 
gi ve n p are nterall y.  As para gi nase d o es n ot cr oss i nt o t he C S F. T he plas ma half-life of er wi nia 
as para gi n ase w he n gi ve n I M is a p pr o xi matel y 1 6 h o urs. O nl y mi ni mal uri n ar y a n d biliar y e x creti o n 
occ urs. Cleara nc e is u naffecte d b y a ge, re nal f u n cti o n or he patic f u ncti o n. 
 
F or m ulati o n a n d sta bilit y: Er wi nia as para gi nase is a vaila ble i n vials c o ntai ni n g 1 0, 0 0 0 u nits of 
l y o p hiliz e d dr u g.  U n us e d vials s h o ul d be refri gerate d. T he c o nt e nts of eac h vial s h o ul d be dil ute d 
wit h 1 ml of preser vati ve-free n or mal sali ne, gi vi n g a res ulta nt s ol uti o n of 1 0, 0 0 0 u nits/ ml. O nce i n 
s ol uti o n, it is rec o m me n de d t hat it be use d wit hi n 8 h o urs as n o pres er vati v e is a d de d.  Occasi o nall y a 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
s mall n u m ber of gelati n o us-li ke fi bers ma y de v el o p u p o n sta n di n g.  If t his occ urs, t he s ol uti o n ca n b e 
filtere d t hr o u g h a 5 micr o n filter t o re m o ve t he p articles wit h n o c ha n ge i n p ote nc y. 
 
S u p plier:   c o m merciall y a vaila ble. 
 
T o xicit y: Ac ute t o xicit y i ncl u des a na p h ylactic reacti o ns t hat occ ur m ost c o m m o nl y w he n t he dr u g is 
gi ve n I V.  T hes e ca n b e c haract erize d b y lar y n geal c o nstricti o n, h y p ote nsi o n, dia p h oresis, fe v er, 
c hills, e de ma a n d l oss of c o nsci o us ness.  Aller gic reacti o ns at t he site of I M i njecti o n i ncl u de pai n, 
s welli n g a n d er yt he ma.  Ot her a d verse effects i ncl u de ne utr o pe nia a n d ass ociate d i m m u n os u p pressi o n, 
mil d na usea a n d v o miti n g, malaise, a n ore xia, ele vate d L F Ts, p a ncreatitis a n d h y per gl yce mia.  A 
decrease i n pr otei n s y nt h esis i ncl u di n g al b u mi n, fi bri n o ge n a n d ot her c oa g ulati o n fact ors ma y occ ur 
w hic h ca n res ult i n he m orr ha ge. T hr o m b osis a n d/ or p ul m o nar y e m b olis m ca n als o oc c ur.   Less 
c o m m o n si de effects i ncl u de re nal d ysf u ncti o n a n d C N S c o m plicati o ns i ncl u di n g s o m n ole nce, 
wea k ness, let h ar g y, c o m a a n d seiz ures. 
 
G ui deli nes f or a d mi nistrati o n : See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
F or a d diti o nal i nf or mati o n a b o ut t his dr u g, please see pac k a ge i nsert. 
 
6.  
D O X O R U BI CI N ( A dria m yci n ) 
 
S o urce a n d p h ar mac ol o g y:  D o x or u bici n is a n a nt hrac ycli ne a nti bi otic pr o d uce d b y Stre pt o myces 
pe uceti us .  D o x or u bici n e x erts its a nti-t u m or effects i n se veral differe nt w a ys. D o x or u bici n 
i ntercalates b et wee n b ase pairs of D N A ca usi n g st eric o bstr ucti o n, disr u pti o n of D N A f u ncti o n a n d 
i n hi biti o n of R N A s y nt h esis.  I n a d diti o n, d o x or u bici n i n hi bits t o p ois o merase II, a n e nz y me 
res p o nsi ble f or all o wi n g stra n ds of D N A t o pass t hr o u g h o n e a n ot her as t h e y u n wi n d.  Lastl y, 
d o x or u bici n u n der g oes e nz y m atic electr o n re d u cti o n t o ge n erate hi g hl y reacti ve s pecies, i ncl u di n g t he 
h y dr o x yl free ra dic al, w hic h is t h o u g ht t o be res p o nsi ble f or t he dr u g’s car diac t o xicit y, b ut ma y pla y 
a r ole i n its a nti-t u m or acti vit y as well.   D o x or u bici n is cell-c ycle, p hase n o n-s pecific.  D o x or u bici n is 
wi del y distri b ute d i n t he tiss ues a n d plas ma, b ut d oes n ot cr oss t he bl o o d brai n barri er t o a n 
a p preci a ble e xte nt. It is meta b olize d t o d o x or u bici n ol, w hic h is t h o u g ht t o be t he maj or acti ve 
meta b olite, a n d a gl yc o nes. D o x or u bici n a n d its meta b olites are e x crete d m ai nl y i n t he bile a n d feces 
(a p pr o xi matel y 8 0 %).  T he re mai n der is e x crete d i n t he uri ne.  D osa ge s h o ul d be re d uce d i n patie nts 
wit h li ver d ysf u n cti o n (secti o n 7. 3) or re nal d ysf u ncti o n (creati ni ne > 3 m g/ dl). 
 
F or m ulati o n a n d sta bilit y: D o x or u bici n is a vaila ble i n vials c o ntai ni n g 1 0 m g, 2 0 m g, 5 0 m g a n d 2 0 0 
m g as a 2 m g/ ml re d- ora n ge s ol uti o n.  It is als o a vaila ble i n vials c o ntai ni n g 1 0 m g, 2 0 m g, 5 0 m g, 1 0 0 
m g a n d 1 5 0 m g of d o x or u bici n as a re d- ora n ge l y o p hilize d p o w der.  I nt act vials of d o x or u bici n 
s ol uti o n s h o ul d be st ore d u n der refri gerati o n w hile t he l y o p hilize d pr o d uct s h o ul d be st ore d at r o o m 
te m perat ur e.  B ot h pr o d u cts s h o ul d be pr otecte d fr o m li g ht. L y o p hilize d d o x or u bici n ca n be 
rec o nstit ute d b y a d di n g 5, 1 0, 2 5, 5 0 or 7 5 ml of 0. 9 % Na Cl res pecti vel y t o t he 1 0, 2 0, 5 0, 1 0 0 a n d 
1 5 0 m g vials t o pr o d uce a fi nal c o nc e ntrati o n of 2 m g/ ml.  Bacteri ostatic dil ue nts are n ot 
rec o m me n de d.  After rec o nstit uti o n, t he res ulta nt s ol uti o n s h o ul d be pr otecte d fr o m li g ht a n d is sta ble 
f or 7 da ys at r o o m te m p erat ure a n d 1 5 da ys if refri gerate d. 
 
S u p plier:  C o m merciall y a vaila ble 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
T o xicit y: D ose-li miti n g t o xicities i ncl u de m yel os u p pressi o n a n d car di ot o xicit y. T w o f or ms of car diac 
t o xicit y ca n o cc ur.  Ac ut e t o xicit y ma y ta ke t he f or m of arr h yt h mias, heart bl oc k or pericar ditis a n d 
ma y b e fatal.  T h e c hr o ni c f or m of   car di ot o xicit y is relate d t o t otal c u m ulati ve d ose a n d is 
c haracteriz e d b y heart fail ure. Me diasti nal ra di ot h era p y a n d/ or ot her car di ot o xic dr u gs ma y i n crease 
t he ris k of car di ot o xicit y.  I n ge neral, t otal lifeti me d osa ges of 4 5 0- 5 5 0 m g/ m 2 s h o ul d n ot be e x cee de d.  
Ot he r t o xicities i ncl u de na usea a n d v o miti n g, m uc ositis, al o pecia, diarr h ea a n d re d disc ol orati o n of 
t he uri ne a n d ot her b o d y fl ui ds. Se vere tiss ue da m a ge a n d n ecr osis ca n occ ur u p o n e xtra vasati o n. 
Ra diati o n recall reacti o ns ca n occ ur a n d ca n be s e v ere. Rarel y, all er gic reacti o ns ha ve occ urre d. 
T y p hlitis ca n occ ur w h e n c o m bi ne d wit h c yt ara bi n e. 
 
7.  
C Y C L O P H O S P H A MI D E ( C yt o x a n ) 
 
S o urce a n d p h ar mac ol o g y:  C ycl o p h os p ha mi de is a nitr o ge n m ustar d deri vati ve.  It acts as a n 
al k ylati n g a ge nt t hat ca us es cr oss-li n ki n g of D N A stra n ds b y bi n di n g wit h n ucleic aci ds a n d ot her 
i ntracell ular str uct ures, t h us i nterferi n g wit h t he n or mal f u ncti o n of D N A. C ycl o p h os p ha mi de is c ell-
c ycle, p has e n o n-s pecific. C ycl o p h os p ha mi de is w ell a bs or be d fr o m t he GI tract wit h a bi oa vaila bilit y 
of > 7 5 %.  C ycl o p h os p ha mi de is a pr o dr u g t hat re q uires acti vati o n.  It is meta b olize d b y mi x e d-
f u ncti o n o xi dases i n t he li ver t o 4- h y dr o x yc ycl o p h os p ha mi de, w hic h is i n e q uili bri u m wit h 
al d of osfa mi de.  Al d of osfa mi de s p o nta ne o usl y s plits i nt o c ycl o p h os p ha mi de m ustar d, w hic h is 
c o nsi dere d t o be t h e maj or acti ve meta b olite, a n d acr olei n.  I n a d diti o n, 4- h y dr o x yc ycl o p h os p ha mi d e 
ma y b e e nz y m aticall y m eta b oliz e d t o 4- ket oc ycl o p h os p ha mi de a n d al d of osfa mi de ma y be 
e nz y maticall y meta b olize d t o car b o x y p h os p h a mi de, w hic h are ge n erall y c o nsi dere d t o be i nacti ve.  
C ycl o p h os p ha mi de a n d its meta b olites are e x cret e d mai nl y i n t he uri ne.  D osa ge a dj ust me nts s h o ul d be 
ma de i n patie nts wit h a creati ni ne cle ara n ce of < 5 0 ml/ mi n. 
 
F or m ulati o n a n d sta bilit y:  C ycl o p h os p ha mi de is a vaila bl e i n 2 5 a n d 5 0 m g ta blets. 
C ycl o p h os p ha mi de is als o a vaila ble i n vials c o ntai ni n g 1 0 0, 2 0 0, 5 0 0, 1 0 0 0 a n d 2 0 0 0 m g of 
l y o p hiliz e d dr u g a n d 7 5 m g ma n nit ol per 1 0 0 m g of c ycl o p h os p ha mi de.  B ot h f or ms of t he dr u g ca n 
be st ore d at r o o m te m perat ure.  T he vi als are rec o nstit ute d wit h 5, 1 0, 2 5, 5 0 or 1 0 0 ml of sterile wat er 
f or i njecti o n res p ecti vel y t o yiel d a fi n al c o nce ntrati o n of 2 0 m g/ ml.  Rec o nstit ute d s ol uti o ns ma y be 
f urt her dil ute d i n eit her 5 % de xtr ose or 0. 9 % Na Cl c o ntai ni n g s ol uti o ns.  Dil ute d s ol uti o ns are 
p h ysicall y sta ble f or 2 4 h o urs at r o o m te m perat ure a n d 6 da ys if refri gerate d, b ut c o ntai n n o 
preser vati ve, s o it is rec o m me n de d t hat t he y be us e d wit hi n 2 4 h o urs of pre parati o n. 
 
S u p plier:  C o m merciall y a vaila ble  
 
T o xicit y:  D ose li miti n g t o xicities of c ycl o p h os p ha mi de are b o ne m arr o w s u p pressi o n a n d car diac 
t o xicit y.  Car diac t o xicit y is t y picall y ma nifeste d as c o n gesti ve heart fail ure, car diac necr osis or 
he m orr ha gic m y o car ditis a n d ca n b e fatal.  He m orr ha gic c ystitis ma y o cc ur a n d necessitates 
wit h h ol di n g t hera p y.  T h e i nci de nce of he m orr ha gic c ystitis is relate d t o c ycl o p h os p ha mi de d ose a n d 
d urati o n of t hera p y.  F orce d fl ui d i nta ke a n d/ or t he a d mi nistrati o n of mes n a decreas e t he i nci de nce 
a n d se verit y of he m orr ha gic c ystitis.  Ot her t o xicities re p orte d c o m m o nl y i ncl u de na usea a n d 
v o miti n g ( ma y be mil d t o se vere d e pe n di n g o n d os a ge), diarr hea, a n ore xia, al o pecia, 
i m m u n os u p pressi o n a n d sterilit y.  P ul m o nar y fi br osis, SI A D H, a na p h yla xis a n d sec o n dar y ne o plas ms 
ha ve bee n re p orte d rarel y. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
8.  
C Y T A R A BI N E ( Ara- C) ( C yt osar- U ) 
 
S o urce a n d p h ar mac ol o g y:  C yt ara bi n e is a de o x yc yti di ne a nal o g ue.  It m ust be tri- p h os p h or yl ate d t o 
its acti ve f or m, A R A- C T P, b y de o x yc yti di ne ki nase a n d ot her n u cle oti de ki nases. Ara- C T P i n hi bits 
D N A p ol y m eras e. I n a d diti o n, ara- C T P is i nc or p orate d i nt o D N A as a false base, ca usi n g i n hi biti o n of 
D N A s y nt hesis.  It is cell c ycle, S p hase s p ecific. C yt ara bi ne d oes pe n etrat e t he bl o o d brai n barrier.  It 
is c o n verte d t o its i nacti ve f or m, uracil ara bi n osi de, b y p yri mi di ne n ucle osi de dea mi nase.  
A p pr o xi matel y 8 0 % of t he d ose is rec o vere d i n t he uri ne, m ostl y as uracil ara bi n osi de (ara- U). 
 
F or m ulati o n a n d sta bilit y: C yt ara bi n e is a vaila ble i n m ulti- d ose vials c o ntai ni n g 1 0 0, 5 0 0, 1 0 0 0 a n d 
2 0 0 0 m g of l y o p hiliz e d dr u g.  I nta ct vials ca n b e st ore d at r o o m te m perat ur e.  F or I V us e, eit her st erile 
water f or i njecti o n or bacteri ostatic water f or i njecti o n ca n be use d t o r ec o nstit ute t he l y o p hilize d 
dr u g.  F or i ntr at hecal us e, o nl y sterile water f or i njecti o n s h o ul d be use d f or rec o nstit uti o n.  T he 1 0 0 
a n d 5 0 0 m g vials are rec o nstit ute d wit h 2 a n d 1 0 ml res pecti vel y res ulti n g i n a fi nal c o nce ntrati o n of 
5 0 m g/ ml.  T he 1 0 0 0 a n d 2 0 0 0 m g vials are rec o nstit ute d wit h 2 0 ml a n d 4 0 ml res pecti vel y res ulti n g i n 
a fi nal c o nce ntrati o n of 5 0 m g/ ml.  After rec o nstit uti o n, t he dr u g is sta ble f or 8 da ys at r o o m 
te m perat ur e. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  M yel os u p pressi o n is t he d ose li miti n g a d verse effect, wit h le u k o pe nia a n d 
t hr o m b oc yt o pe ni a bei n g pre d o mi na nt.  Ot her a d verse effects r e p orte d c o m m o nl y i ncl u de na us ea a n d 
v o miti n g ( ma y be se v ere at hi g h d oses), diarr h ea, m uc ositis, a n ore xia, al o pecia, s ki n ras h a n d li ver 
d ysf u n cti o n.  A fl u-li ke s y n dr o me c haract erize d b y fe ver, m uscl e a n d b o ne ac hes is c o m m o n. Less 
c o m m o n si de effects i ncl u de aller gic reacti o ns a n d cell ulitis at t he i njecti o n site. Hi g h d oses of 
c yt ara bi ne ca n ca use c o nj u ncti vitis, he patitis, a n d a gr o u p of C N S s y m pt o ms i ncl u di n g s o m n ole nce, 
peri p heral ne ur o pat h y, ata xia, a n d pers o nalit y c ha n ges. C N S s y m pt o ms are us uall y re versi ble a n d are 
m ore c o m m o n i n patie nts w h o ha ve recei v e d pre vi o us cra nial irra diati o n.  I n a d diti o n, a s y n dr o m e of 
s u d de n res pirat or y distress pr o gressi n g t o p ul m o n ar y e de m a has occ urre d. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol.  
 
9.  
C Y T A R A BI N E ( Hi g h D ose A R A- C)  
 
S o urce a n d p h ar mac ol o g y:  C yt ara bi n e is a de o x yc yti di ne a nal o g ue.  It m ust be tri- p h os p h or yl ate d t o 
its acti ve f or m, AR A - C T P, b y de o x yc yti di ne ki nase a n d ot her n u cle oti de ki nases. Ara- C T P i n hi bits 
D N A p ol y m eras e. I n a d diti o n, ara- C T P is i nc or p orate d i nt o D N A as a false base, ca usi n g i n hi biti o n of 
D N A s y nt hesis.  It is cell c ycle, S p hase s p ecific. C yt ara bi ne d oes pe n etrat e t he bl o o d brai n barrier.  It 
is c o n verte d t o its i nacti ve f or m, uracil ara bi n osi de, b y p yri mi di ne n ucle osi de dea mi nase.  
A p pr o xi matel y 8 0 % of t he d ose is rec o vere d i n t he uri ne, m ostl y as uracil ara bi n osi de (ara- U). 
 
F or m ulati o n a n d sta bilit y: C yt ara bi n e is a vaila ble i n m ulti- d ose vials c o ntai ni n g 1 0 0, 5 0 0, 1 0 0 0 a n d 
2 0 0 0 m g of l y o p hiliz e d dr u g.  I nta ct vials ca n b e st ore d at r o o m te m perat ur e.  F or I V us e, eit her st erile 
water f or i njecti o n or bacteri ostatic water f or i njecti o n ca n be use d t o r ec o nstit ute t he l y o p hilize d 
dr u g.  F or i ntr at hecal us e, o nl y sterile water f or i njecti o n s h o ul d be use d f or rec o nstit uti o n.  T he 1 0 0 
a n d 5 0 0 m g vials are rec o nstit ute d wit h 2 a n d 1 0 ml res pecti vel y res ulti n g i n a fi nal c o nce ntrati o n of 
5 0 m g/ ml. T he 1 0 0 0 a n d 2 0 0 0 m g vials are rec o nstit ute d wit h 2 0 ml a n d 4 0 ml res pecti vel y res ulti n g i n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
a fi nal c o nce ntrati o n of 5 0 m g/ ml.  After rec o nstit uti o n, t he dr u g is sta ble f or 8 da ys at r o o m 
te m perat ur e. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  M yel os u p pressi o n is t he d ose li miti n g a d verse effect, wit h le u k o pe nia a n d 
t hr o m b oc yt o pe ni a bei n g pre d o mi na nt.  Ot her a d verse effects r e p orte d c o m m o nl y i ncl u de na us ea a n d 
v o miti n g ( ma y be se v ere at hi g h d oses), diarr h ea, m uc ositis, a n ore xia, al o pecia, s ki n ras h a n d li ver 
d ysf u n cti o n.  A fl u-li ke s y n dr o me c haract erize d b y fe ver, m uscl e a n d b o ne ac hes is c o m m o n. Less 
c o m m o n si de effects i ncl u de aller gic reacti o ns a n d cell ulitis at t he i njecti o n site. Hi g h d oses of 
c yt ara bi ne ca n ca use c o nj u ncti vitis, he patitis, a n d a gr o u p of C N S s y m pt o ms i ncl u di n g s o m n ole nce, 
peri p heral ne ur o pat h y, ata xia a n d pers o nalit y c ha n ges.  C N S s y m pt o ms are us uall y re versi ble a n d are 
m ore c o m m o n i n patie nts w h o ha ve recei v e d pre vi o us cra nial irra diati o n.  I n a d diti o n, a s y n dr o m e of 
s u d de n res pirat or y distress pr o gressi n g t o p ul m o n ar y e de m a has occ urre d. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 0.  
T H I O G U A NI N E ( 6- T G) 
 
S o urce a n d p h ar mac ol o g y:  T hi o g ua ni ne is a p uri ne a nti meta b olite.  It is i ntracell ularl y c o n v erte d t o 
ri b o n ucle oti des w hic h are i nc or p orate d i nt o D N A a n d R N A.  A bs or pti o n of t hi o g ua ni ne is varia ble 
a n d p o or a n d is decrease d b y f o o d. T hi o g u a ni ne u n der g oes e xte nsi ve meta b olis m i n t he li ver a n d 
ot her tiss ues t o t he i nacti ve, met h yl ate d deri v ati ve a n d t o 6-t hi o uracil b y x a nt hi ne o xi dase.  
T hi o g ua ni ne is e x crete d i n t he uri ne al m ost c o m pletel y as meta b olites. 
 
F or m ulati o n a n d sta bilit y: T hi o g ua ni ne is a v aila ble as a 4 0 m g sc ore d ta blet.  It ma y be st or e d at r o o m 
te m perat ur e. 
 
S u p plier:  Ta blets are c o m merciall y a vail a ble.  
 
T o xicit y:  T he maj or d os e-li miti n g t o xicit y is m yel os u p pressi o n. Na usea a n d v o miti n g are us u all y 
mil d. Ot her t o xicities re p orte d i ncl u de diarr hea, ras h, a n ore xia, st o matitis, a n d h y per urice mia.  
J a u n dice a n d ele vate d li v er f u ncti o n tests ha ve bee n re p orte d rarel y 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 1.  
C L O F A R A BI N E ( Cl- F- Ara- A, C A F d A, 2- C hl or o- 9- ( 2-d e o x y- 2-fl u or o- beta- D- 
ara bi n of ura n os yl)- 9 H- p uri n- 6-a mi ne, Cl ofare x, Cl olar) 
 
S o urce a n d p h ar mac ol o g y: Cl ofara bi ne is se q ue ntiall y meta b olize d i ntracell ularl y t o t he 5’- 
m o n o p h os p hate meta b olite b y d e o x yc yti di ne ki nase a n d m o n o- a n d di- p h os p h o ki nases t o t he acti ve 
5’-tri p h os p hate meta b olit e. Cl ofara bi ne has hi g h affi nit y f or t he acti vati n g p h os p h or ylati n g e nz y me, 
de o x yc yti di ne ki nase, e q ual t o or great er t ha n t hat of t he nat ural s u bstrat e, de o x yc yti di ne. Cl ofara bi ne 
i n hi bits D N A s y nt hesis b y decreasi n g cell ular d e o x y n ucl e oti de tri p h os p hat e p o ols t hr o u g h a n 
i n hi bit or y acti o n o n ri b o n ucle oti de re d u ctase, a n d b y ter mi nati n g D N A c hai n el o n gati o n a n d 
i n hi biti n g re pair t hr o u g h i nc or p orati o n i nt o t he D N A c hai n b y c o m p etiti ve i n hi biti o n of D N A 
p ol y merases. T he affi nit y of cl ofara bi ne tri p h os p hate f or t hes e e nz y m es is si milar t o or greater t h a n 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
t hat of de o x ya de n osi n e tri p h os p hate. I n precli nical m o dels, cl ofara bi n e has de m o nstrate d t he a bilit y t o 
i n hi bit D N A re pair b y i n c or p orati o n i nt o t he D N A c hai n d uri n g t he re pair pr ocess. Cl ofara bi ne 5’- 
tri p h os p hate als o disr u pts t he i nte grit y of mit oc h o n drial me m bra ne, l ea di n g t o t he releas e of t he pr o-
a p o pt otic mit oc h o n drial pr otei ns, c yt o c hr o me C a n d a p o pt osis-i n d uci n g fact or, lea di n g t o 
pr o gra m me d cell deat h. Cl ofara bi ne is c yt ot o xic t o ra pi dl y pr oliferati n g a n d q uiesce nt ca n cer cell 
t y pes i n vitr o. 
 
T he p o p ulati o n p har ma c o ki netics of cl ofara bi ne was st u die d i n 4 0 pe diatric patie nts a ge d 2 t o 1 9 years 
( 2 1 males/ 1 9 fe males) wit h rela pse d or refract or y A L L or A M L. At t he gi v e n 5 2 m g/ m 2 d ose, si milar 
c o nce ntr ati o ns were o bt ai ne d o ver a wi d e ra n ge of B S As. Cl ofara bi n e was 4 7 % b o u n d t o plas ma 
pr otei ns, pre d o mi na ntl y t o al b u mi n. Base d o n n o n-c o m part me ntal a nal ysis, s yste mic cl eara nce a n d 
v ol u me of half-life was esti mate d t o be 5. 2 h o urs. N o a p pare nt differe nce i n p har mac o ki netics was 
o bser ve d bet w ee n p atie nts wit h A L L a n d A M L or bet wee n mal es a n d fe mal es. Bas e d o n 2 4- h o ur 
uri ne c ollecti o ns i n t he p e diatric st u dies, 4 9- 6 0 % of t he d ose is e x crete d i n t he uri ne u nc ha n ge d. I n 
vitr o st u dies usi n g is olate d h u ma n he pat oc ytes i n dicate ver y li mite d meta b olis m ( 0. 2 %), t heref ore t h e 
pat h wa ys of n o n-re nal eli mi nati o n re mai n u n k n o w n. 
 
Alt h o u g h n o cli nical dr u g- dr u g i nteracti o n st u dies ha ve bee n c o n d uct e d t o date, o n t he basis of t he i n 
vitr o st u dies, c yt oc hr o me p 4 5 0 i n hi bit ors a n d i n d ucers are u nli kel y t o affect t he meta b olis m of 
cl ofara bi ne. T he effect of cl ofara bi ne o n t he meta b olis m of c yt oc hr o m e p 4 5 0 s u bstrates has n ot bee n 
st u die d. T he p har mac o ki netics of cl ofara bi ne has n ot bee n e val u ate d i n patie nts wit h re nal or he p atic 
d ysf u n cti o n. 
 
F or m ulati o n a n d sta bilit y: Cl ofara bi ne ( 1 m g/ m L) is s u p plie d i n a 2 0 m L, si n gle- us e vial. T h e 2 0 m L 
vial c o ntai ns 2 0 m g cl of ara bi ne f or m ulate d i n 2 0 m L u n b uffere d n or m al sali ne (c o m prise d of Water 
f or I njecti o n, U S P, a n d S o di u m C hl ori de U S P). T he p H ra n ge of t he s ol uti o n is 4. 5 t o 7. 5. St ore at 
2 5° C ( 7 7° F); e x c ursi o ns per mitte d t o 1 5- 3 0° C ( 5 9- 8 6° F). 
 
T o xicit y:  T he m ost c o m m o n t o xicities of cl ofara bi ne are v o miti n g, n a usea, diarr hea, a n e mia, 
le u k o pe nia, t hr o m b oc yt o pe nia, ne utr o pe ni a, fe brile ne utr o pe nia, a n d i nfecti o n.  Greater t ha n 1 0 % of 
pa tie nts recei vi n g cl ofara bi ne ha ve t he f oll o wi n g a d verse e v e nts: tac h ycar di a, a b d o mi nal pai n, 
c o nsti pati o n, gi n gi val ble e di n g, s or e t hr oat, e de ma, fati g u e, i njecti o n site pai n, let har g y, m u c osal 
i nfla m mati o n, pai n, p yre xia, ri g ors, he pat o me gal y, ja u n dice, wei g ht l oss, a n ore xia, art hral gia, 
m yal gia, b ac k pai n, li m b pai n, dizzi ness, hea dac he, s o m n ole nce, tre m or, a n xiet y, de pressi o n, 
irrita bilit y, he mat uria, c o u g h, d ys p nea, e pista xis, ple ural eff usi o n. Res pirat or y distress, c o nf usi o n, 
der matitis, dr y s ki n, er yt he ma, pal mar- pla ntar er yt hr o d ysest h esia s y n dr o m e, petec hi ae, pr urit us, 
fl us hi n g, h y perte nsi o n, h y p ote nsi o n, i ncreases i n A L T, A S T, a n d bilir u bi n, tra nsie nt left ve ntric ular 
s yst olic d ysf u ncti o n, a n d i ncreas e d ser u m creati ni n e. F o ur of 1 1 3 pe diatric patie nts e x perie nce d 
ca pillar y lea k s y n dr o me or SI R S lea di n g t o m ulti- or ga n fail ure. 
 
Fetal a n d t erat o ge ni c effects ha ve bee n n ote d i n a ni mals.  It is n ot k n o w n w het her cl of ara bi n e or its 
meta b olites are e x crete d i n h u ma n mil k. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. Filter 
cl ofara bi ne t hr o u g h a sterile 0. 2 μ m s yri n ge filter a n d t he n f urt her dil ute wit h 5 % de xtr ose i njecti o n 
U S P or 0. 9 % s o di u m c hl ori de i njecti o n U S P t o a c o n ve nie nt v ol u me a n d i nf use o ver 2 h o urs. T he 
res ulti n g a d mi xt ure ma y be st ore d at r o o m te m perat ure, b ut m ust be use d wit hi n 2 4 h o urs of 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
pre parati o n. 
 
T o re d uce t he effects of t u m or l ysis a n d ot her a d v erse e v e nts it is rec o m me n de d t hat c o nti n u o us I V 
fl ui ds be gi ve n t hr o u g h o ut t he 5 da ys of cl ofara bi ne a d mi nistrati o n. See A p pe n di x II f or S u p p orti ve 
Care G ui deli nes. 
 
Si nce cl ofara bi ne is pri m aril y e x crete d t hr o u g h t h e ki d ne ys, dr u gs wit h k n o w n re nal t o xicit y s h o ul d be 
a v oi de d d uri n g t he 5 da ys of cl ofara bi ne a d mi nistrati o n. I n a d diti o n, si nce t he li ver is a k n o w n t ar get 
or ga n f or cl ofara bi ne t o xicit y, c o n c o mita nt use of me dicati o ns k n o w n t o i n d uce he p atic t o xicit y 
s h o ul d be a v oi de d. 
 
S u p plier:  C o m merciall y a vaila ble 
 
1 2.  
M E T H O T R E X A T E 
 
S o urce a n d p h ar mac ol o g y:  Met h otre x ate is a f ol ate a nal o g ue t hat acts b y i n hi biti n g di h y dr of olate 
re d uctas e.  Di h y dr of olat e re d uctas e is a n e nz y m e i m p orta nt i n t he c o n versi o n of f olic aci d t o 
tetra h y dr of olic aci d, w hi c h is necessar y i n t he s y nt hesis of p uri ne n ucle oti d es a n d t h y mi d ylate.  B y 
i n hi biti n g t he pr o d ucti o n of tetra h y dr of olic aci d, m et h otre x ate i nterferes wit h D N A, R N A a n d pr otei n 
s y nt hesis.  Met h otre x ate is p o orl y a n d v aria bl y a bs or be d orall y, wit h a n a v era ge of > 4 0 % f or d oses of 
< 3 0 m g/ m 2.  At hi g her d osa ges, t he e xte nt of a bs or pti o n decreases. Met h otre x ate is a p pr o xi matel y 
5 0 % pr otei n b o u n d.  It distri b utes wi del y i nt o b o d y tiss ues a n d fl ui ds wit h s ustai ne d c o nce ntr ati o ns i n 
t he ki d ney a n d t he li ver.  Met h otre x ate u n der g oes meta b olis m b y c yt os olic al de h y de o xi dase t o 
h y dr o x y m et h otre x ate.  It is e x crete d mai nl y i n t he uri ne as u nc h a n ge d dr u g wit h s mall a m o u nts bei n g 
e x crete d i n t he bile a n d feces. T h e perce nt r ec o vere d as u nc ha n ge d dr u g i n t he uri ne is hi g h er wit h 
s h ort i nf usi o ns t ha n wit h pr ol o n ge d i nf usi o ns.  Met h otre x ate has a bi p hasic eli mi nati o n wit h a n i nitial 
half-life of a p pr o xi matel y 2 - 3 h o urs a n d a t er mi nal half-life of 1 0- 1 2 h o urs. Met h otre x ate ma y b e 
“se q uestere d” i n b o d y fl ui d c ollecti o ns a n d eli mi nate d sl o wl y fr o m t hese areas. Patie nts wit h eff usi o ns 
or GI o bstr ucti o n s h o ul d ha ve plas ma le vels m o nit ore d cl osel y f or dela ye d e x creti o n f oll o wi n g hi g h-
d ose met h otre x ate. 
 
F or m ulati o n a n d sta bilit y: Met h otre x ate is s u p plie d i n si n gle- d ose vials c o ntai ni n g 5 0 m g, 1 0 0 m g, 
2 0 0 m g, a n d 2 5 0 m g of m et h otre x ate as a 2 5 m g/ ml preser vati ve-free s ol uti o n a n d i n vials c o ntai ni n g 
2 0 m g, 5 0 m g, 1 0 0 m g, 2 5 0 m g a n d 1 0 0 0 m g of l y o p hilize d dr u g.  It is als o a vaila ble i n 2. 5 m g ta blets. 
Met h ot re x ate preser vati ve-free s ol uti o n a n d l y o p hilize d dr u g s h o ul d be st or e d at r o o m te m perat ure 
a n d pr otecte d fr o m li g ht.  Met h otre x ate ta blets ca n als o be st ore d at r o o m te m perat ure. T h e vials 
c o ntai ni n g 2 0, 5 0, 1 0 0 a n d 2 5 0 m g of l y o p hilize d pr o d uct ca n b e rec o nstit ute d b y a d di n g sterile wat er, 
0. 9 % Na Cl or D 5 W t o a fi nal c o nce ntrati o n n ot e x cee di n g 2 5 m g/ ml.  T he 1 0 0 0 m g vials c o ntai ni n g 
l y o p hiliz e d pr o d uct are rec o nstit ute d t o a fi nal c o nce ntrati o n of 5 0 m g/ ml. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: 
T he d ose li miti n g t o xicities of met h otre x ate are ge nerall y b o ne marr o w s u p pressi o n, 
ulcerati ve st o matitis, se vere diarr hea or ac ute ne p hr ot o xicit y. T o xicities re p orte d fre q u e ntl y i n cl u de 
na usea a n d v o miti n g, diarr hea, a n ore xia, al o pecia, he patic t o xicit y a n d al o p ecia.  Less c o m m o n si de 
effects i ncl u de bl urre d visi o n, p h ot ose nsiti vit y, a n a p h yl a xis, hea dac he, p n e u m o nitis, s ki n 
de pi g me nt ati o n or h y p er pi g me ntati o n, ras h, v asc ulitis a n d e nce p hal o pat h y. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
D uri n g hi g h- d os e met h otre x ate t hera p y, m ost pati e nts e x perie nce a tra nsie nt decrease i n G F R, b ut 
re nal f ail ure ca n occ ur, partic ularl y if t he p atie nt d oes n ot recei ve uri nar y al kali nizati o n a n d 
a g gressi ve h y drati o n bef ore, d uri n g a n d after recei vi n g hi g h d os e met h otre x ate.  Le uc o v ori n res c ue 
s h o uld be i nitiate d wit hi n 4 8 h o urs of starti n g hi g h- d ose met h otre x ate a n d a dj uste d base d o n M T X 
le vels t o pre ve nt b o ne m arr o w t o xicit y a n d m uc ositis.  Le uc o v ori n ma y als o be necessar y after I T 
a d mi nistrati o n, es peciall y if I T m et h otre x ate t hera p y is gi ve n t o patie nts wit h re nal d ysf u ncti o n.  
Patie nts wit h D o w n s y n dr o me ha ve a te n de n c y t o ha ve dela ye d met h otre x ate cleara nce a n d a great er 
ris k of t o xicit y, des pite i ncreas e d le uc o v ori n res c ue. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 3.  
L E U C O V O RI N (f oli nic aci d) 
 
S o urce a n d p h ar mac ol o g y:  Le u c o v ori n is a race mic mi xt ure of tetra h y dr of olic aci d, w hic h is i n v ol ve d 
as a c ofact or f or 1- car b o n tra nsfer reacti o ns i n t he s y nt hesis of p uri n e a n d p yri mi di nes. Le u c o v ori n is 
a p ote nt a nti d ote f or b ot h t he he mat o p oietic a n d retic ul oe n d ot helial t o xic effects of f olic aci d 
a nta g o nists b y re ple nis hi n g re d uce d f olate p o ols.  It is p ost ulate d t hat i n s o me ca ncers, le u c o v ori n 
e nters a n d “res c ues” n or mal cells fr o m t he t o xic effects of f olic aci d a nta g o nists, i n prefere n ce t o 
t u m or cells, beca us e of differe n ces i n me m br a ne tra ns p ort a n d affi nit y f or p ol y gl uta m yl ati o n. 
Le u c o v ori n is c o n verte d i n t he i ntesti nal m uc osa a n d t he li ver t o 5- met h yl- tetra h y dr of olat e, w hic h is 
als o acti ve as a re d u ce d f olate.  It is e x crete d pri m aril y i n t he uri ne wit h mi n or e x creti o n occ urri n g i n 
t he feces. 
 
F or m ulati o n a n d sta bilit y:  Le u c o v ori n is s u p plie d i n 5, 1 5 a n d 2 5 m g ta blets a n d vials c o ntai ni n g 5 0, 
1 0 0 or 3 5 0 m g of l e uc o v ori n as a l y o p hilize d p o w der.   T he ta bl ets a n d t he l y o p hilize d p o w der ca n b e 
st ore d at r o o m te m perat ure.  T he 5 0 m g a n d 1 0 0 vials ca n be rec o nstit ute d b y a d di n g 5 or 1 0 ml of 
sterile water or bacteri ost atic water f or i njecti o n res pecti vel y t o yiel d a fi nal c o nce ntr ati o n of 1 0 
m g/ ml.  T he 3 5 0 m g vi als ca n be rec o nstit ute d wit h 1 7 ml of sterile water or bacteri ostatic water f or 
i njecti o n t o yiel d a fi n al c o nce ntr ati o n of 2 0 m g/ ml.   T he rec o nstit ute d s ol uti o n is sta ble f or at least 7 
da ys at r o o m te m perat ure.  Le u c o v ori n ma y b e f urt her dil ute d i n 5 % de xtr ose or 0. 9 % Na Cl 
c o ntai ni n g s ol uti o ns. Le u c o v ori n is als o a vaila ble as a 1 m g/ ml or al s ol uti o n. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  Le u c o v ori n is ge n erall y w ell t olerate d.  T o xicities t hat ha ve bee n re p orte d u n c o m m o nl y 
i ncl u de ras h, mil d na usea, hea dac he, a n d w heezi n g ( p ossi ble aller gic reacti o n). I ntrat hecal le uc o v ori n 
is c o ntrai n dicate d a n d has ca use d ne ur ot o xic deat hs.  T here ha v e bee n rare re p orts of le u c o v ori n 
pr o m oti n g seiz ures. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 4.  
M E R C A P T O P U RI N E ( 6- M P) ( P uri net h ol ) 
 
S o urce a n d p h ar mac ol o g y:  Merca pt o p uri ne is a p uri ne a nti meta b olite.  It m ust be c o n verte d 
i ntracell ularl y t o 6-t hi o g ua ni ne n ucle oti des ( 6- T G Ns), t he acti ve f or ms of t he dr u g. T he 6- T G Ns are 
t he n i nc or p orat e d i nt o D N A a n d R N A a n d ca use i n hi biti o n of D N A a n d R N A s y nt h esis. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Merca pt o p uri n e is cell c ycle, S p hase s pecific. A bs or pti o n is varia ble a n d i n c o m plete ( 5- 3 7 %) a n d is 
decrease d b y t he prese n ce of f o o d i n t he g ut.  Merca pt o p uri ne d oes distri b ute i nt o t he C S F, wit h C S F 
c o nce ntr ati o ns of a p pr o xi matel y 2 7 % of plas ma c o nce ntrati o ns w he n gi v e n b y c o nti n u o us i nf usi o n.  
Merca pt o p uri n e u n der g o es first pass meta b olis m i n t he GI m uc osa a n d t he li ver.   It is meta b olize d i n 
he mat o p oeitic tiss ues b y H P R T t o t he acti ve n ucle oti de f or ms.  It is i na cti vate d t o met h yl ate d 
meta b olites b y T P M T (t hi o p uri ne met h yl tra nsferase) a n d t o 6-t hi o uric aci d b y x a nt hi ne o xi dase.  
T P M T is a ge n eticall y re g ulate d, p ol y m or p hicall y distri b ute d e nz y m e a n d is deficie nt i n a b o ut 1 i n 
3 0 0 pers o ns w h o ca n n ot t olerate us ual d oses of 6- M P.  Merca pt o p uri ne is eli mi nate d t hr o u g h t he uri ne 
as b ot h u nc ha n ge d dr u g a n d meta b olites. 
 
F or m ulati o n a n d sta bilit y: Merca pt o p uri ne is c o m merciall y a vaila bl e as a 5 0 m g ta blet a n d a 2 0 
m g/ m L oral s us pe nsi o n. T he ta blets s h o ul d be st ore d at r o o m te m perat ur e a n d pr otecte d fr o m li g ht. 
 
S u p plier:  C o m merciall y a vaila ble. 
 
T o xicit y:  T he d ose-li miti n g t o xi cit y of merca pt o p uri ne is m yel os u p pressi o n. Merca pt o p uri ne ca n 
ca use i ntra h e patic c h ol estasis a n d f ocal ce ntral o b ular necr osis a n d is us uall y ma nifeste d b y 
h y per bilir u bi ne mia a n d i ncreas e d li ver f u n cti o n tests.  Ot her t o xicities i ncl u de mil d na usea a n d 
v o miti n g, s ki n ras h, h y per urice mia, a n d mil d diarr hea. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 5.  
D E X A M E T H A S O N E ( Deca dr o n ) 
 
S o urce a n d p h ar mac ol o g y: De x a met has o ne is a s y nt hetic c o n ge ner of h y dr oc ortis o ne, t he nat ur al 
a dre nal h or m o ne.  De x a met has o ne is a w hite or yell o wis h cr ystalli ne p o w der.  It bi n ds wit h ster oi d 
rece pt ors o n n uclear me m bra nes, i m pairs cell ular mit osis a n d i n hi bits pr otei n s y nt hesis. 
De x a met has o ne als o has p ote nt a nti-i nfla m mat or y effects a n d s u p presses t he i m m u ne s yste m. 
De x a met has o ne is well a bs or be d orall y.  It is meta b olize d i n t he li ver a n d t he meta b olites are e x cret e d 
mai nl y i n t he uri ne. 
 
F or m ulati o n a n d sta bilit y:  De x a met has o ne is a vaila ble as vari o us stre n gt h t a blets a n d as a n eli xir. It is 
als o a vaila ble as a s ol uti o n f or pare nteral use.  All f or m ulati o ns of t he dr u g ca n be st or e d at r o o m 
te m perat ur e.  T he i nject a ble f or m ma y be f urt her dil ute d i n 5 % de xtr ose or 0. 9 % Na Cl c o ntai ni n g 
s ol uti o ns a n d is sta ble f or at least 2 4 h o urs at r o o m te m perat ur e. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y: Si de effects of de x a met has o ne var y d e p e n di n g o n t he d urati o n of its use. Si de effects t hat 
ca n occ ur wit h s h ort ter m use i ncl u de pe ptic ulcer wit h p ossi ble perf orati o n a n d he m orr h a ge, 
i ncreas e d s usce pti bilit y t o i nfecti o ns, e m oti o nal i nsta bilit y, i ns o m nia, i ncrease d a p petite, wei g ht gai n, 
ac ne, a n d h y per gl yce mia. Si de effects m ore c o m m o nl y ass oci ate d wit h pr ol o n ge d us e i ncl u de 
cataracts, i ncrease d i ntra oc ular press ure a n d ass ociate d gl a uc o ma, d e vel o p me nt of a “c us hi n g oi d” 
state, c o m pressi o n fract ures, me nstr ual irre g ulariti es, s u p pressi o n of gr o wt h i n c hil dre n, sec o n d ar y 
a dre n oc ortical a n d pit uitar y u nres p o nsi ve ness p arti c ularl y i n ti mes of stress as i n tra u ma, s ur ger y or 
ill ness, oste o p or osis a n d m uscle wasti n g. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 6.  
H Y D R O C O R TI S O N E, s yste mic ( C ort ef, S ol u- C ortef ) 
 
S o urce a n d p h ar mac ol o g y: H y dr oc ortis o ne is a s y nt hetic ster oi d a ki n t o t he nat ural a dre nal h or m o ne 
c ortis ol.  H y dr oc ortis o ne decreases i nfla m mati o n b y s u p pressi o n of mi grati o n of p ol y m or p h o n u clear 
le u k oc yt es a n d re vers al of i ncrease d ca pillar y per mea bilit y.  It is e x crete d i n t he uri ne a n d cata b olize d 
i n t he li ver. 
 
F or m ulati o n a n d sta bilit y:  S ol u- C ortef sterile p o w der is s u p plie d i n t he f oll o wi n g pac ka ges:  1 0 0 m g 
plai n, a n d 1 0 0 m g, 2 5 0 m g, 5 0 0 m g, a n d 1 0 0 0 m g A C T- O- VI A L ( MI X- O- VI A L). St ore l y o p hilize d 
pr o d uct at c o ntr olle d r o o m te m perat ure 1 5- 3 0° C ( 5 9- 8 6° F). St ore rec o nstit ute d s ol uti o n i n t he 
refri gerat or a n d pr ote ct fr o m li g ht.  U n use d s ol uti o n s h o ul d be discar de d aft er 3 da ys. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  H y per p ha gia, o besit y, striae, ac n e, cat aracts, i m m u n os u p pressi o n, electr ol yte dist ur ba n ces, 
e de ma, h y perte nsi o n, oste o p or osis, pers o nalit y c h a n ges, i ns o m nia, hea d ac h es, dia betes a n d 
C us hi n g oi d S y n dr o me.  Pa ncreatitis, pe ptic ulcer a n d/ or GI blee di n g h a ve als o bee n n ote d.  
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 7.  
E T O P O SI D E ( V P- 1 6) ( Ve pesi d ) 
 
S o urce a n d p h ar mac ol o g y:  Et o p osi de is a n e pi p o d o p h yll ot o xi n deri ve d fr o m P o d o p hyll u m pel at at u m. 
It is t h o u g ht t o act mai nl y b y i n hi biti n g t o p ois o merase II, ca usi n g d o u ble a n d si n gle stra n d D N A 
brea ks.  Et o p osi de is cell c ycle, p has e-s pecific, wit h acti vit y i n t he G 2 a n d S p hases. A bs or pti o n of 
et o p osi de is a p pr o xi matel y 3 0- 4 0 % a n d is hi g hl y varia ble a n d s o m e w hat d ose- de pe n d e nt.  It is 
exte nsi vel y b o u n d t o s er u m pr otei ns a n d is meta b olize d i n t he li ver, i ncl u di n g c yt oc hr o me P 4 5 0 3 A 
me ta b olis m t o se veral m oieties t hat i ncl u de a reacti ve o xi dize d s pecies.  Et o p osi de a n d its meta b olites 
are e x crete d mai nl y i n t h e uri ne wit h a s maller a m o u nt e xcrete d i n t he feces.  D osa ge a dj ust me nts 
s h o ul d be c o nsi dere d i n p atie nts wit h li ver d ysf u ncti o n, ki d ne y d ysf u ncti o n or h y p o al b u mi ne mia. 
 
F or m ulati o n a n d sta bilit y:  Et o p osi de is a vaila ble i n m ulti- d ose vials c o ntai ni n g 1 0 0 m g, 1 5 0 m g, 
5 0 0 m g a n d 1 0 0 0 m g of et o p osi de as a 2 0 m g/ ml s ol uti o n a n d 3 0 % alc o h ol.   Et o p osi de is als o a vaila ble 
as a 5 0 m g ca ps ule. T h e i ntact vials of et o p osi de s ol uti o n s h o ul d be st ore d at r o o m te m perat ur e. T he 
ca ps ules s h o ul d be st ore d u n der refri gerati o n.  Et o p osi de s ol uti o n s h o ul d be dil ute d i n D 5 W or 0. 9 % 
Na Cl pri or t o a d mi nistrati o n.  S ol uti o ns wit h a fi nal c o nce ntr ati o n of 0. 2 a n d 0. 4 m g/ ml are sta bl e at 
r o o m te m perat ur e f or 9 6 h o urs a n d 2 4 h o urs res pecti vel y. 
 
S u p plier:  C o m merciall y a vaila ble 
 
T o xicit y:  D ose li miti n g t o xicit y is m yel os u p pressi o n. Na usea a n d v o miti n g ( us uall y of l o w t o 
m o derate se v erit y), diarr hea, m uc ositis ( partic ularl y wit h hi g h d os es), al o p ecia a n d a n ore xia are fairl y 
c o m m o n.  H y p ote nsi o n ca n occ ur wit h ra pi d i nf usi o ns. Ot her si de effects r e p orte d less c o m m o nl y 
i ncl u de he patitis, fe ver a n d c hills, a na p h yl a xis a n d peri p heral ne ur o pat h y. Sec o n dar y le u ke mia has 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
bee n re p orte d. 
 
G ui deli nes f or a d mi nistrati o n: See treat me nt a n d d ose m o dificati o n secti o ns of t he pr ot oc ol. 
 
1 8.  
D A S A TI NI B ( S P R Y C E L ®) 
 
F O R P H + A L L P A TI E N T S O N L Y  
 
S o urce a n d p h ar mac ol o g y: Das ati ni b (a n a mi n ot hiaz ole a nal o g ue) is a n i n hi bit or of m ulti ple t yr osi ne 
ki nases. It is a p pr o ve d f or t he treat me nt of c hr o nic m yel o ge n o us le u k e mia ( C M L) a n d f or t he 
treat me nt of a d ults wit h P hila del p hia c hr o m os o me- p ositi ve A L L wit h resista nce or i nt olera nce t o 
pri or t hera p y. It is bei n g i n vesti gate d as a br oa d-s p ectr u m a ntit u m or a ge nt a gai nst s oli d t u m ors. 
Dasati ni b is a p ote nt, br o a d s pectr u m A T P-c o m petiti ve i n hi bit or of 5 critical o nc o ge nic t yr osi ne 
ki nase fa milies: B C R- A B L, S R C fa mil y ki nases, c- KI T, e p hri n ( E P) rece pt or ki nases, a n d P D G F β 
rece pt or. Eac h of t hese pr otei n ki nases has bee n str o n gl y li n ke d t o m ulti ple f or ms of h u ma n 
mali g na n cies. I n a d ults, t he ma xi m u m plas ma c o nce ntrati o n of d asati ni b after oral a d mi nistrati o n is 
o bser ve d bet w ee n 0. 5 a n d 6 h o urs. T he o bser ve d effects fr o m f o o d were n ot cli nicall y rele va nt.  T h e 
o ve rall ter mi nal half-life is 3- 5 h o urs. T he dr u g e x hi bits d ose pr o p orti o nal i ncreas es i n A U C a n d 
li near eli mi nati o n c haract eristics o ver t he d ose ra n ge of 1 5 m g t o 2 4 0 m g/ d a y i n a d ults.  Dasati ni b is 
pri maril y met a b olize d i n t he li ver b y t h e h u ma n C Y P 3 A 4 e nz y me, is a si g nifica nt i n hi bit or of 
C Y P 3 A 4. Dasati ni b ma y decrease t he m eta b olic cl eara n ce of dr u gs t hat are si g nifica ntl y meta b olize d 
b y t he C Y P 3 A 4 e nz y me. D ue t o t he p ote ntial of d asati ni b t o pr ol o n g t he Q T/ Q Tc, ca uti o n m ust be 
use d w he n a d mi nisteri n g it wit h ot her p ote ntial Q Tc pr ol o n gi n g m e dicati o ns. D ue t o t he p ossi bilit y of 
gastr oi ntesti nal, c ar diac, a n d c uta ne o us h e m orr ha ge, a v oi d usi n g me di cati o ns t hat i n hi bit platelet 
f u ncti o n or a ntic oa g ul a nts i n c o nj u ncti o n wit h Dasati ni b. Dasati ni b is n ot a p - gl yc o pr otei n i n hi bit or. 
 
F or m ulati o n a n d sta bilit y: Dasati ni b is a vaila ble as ta blets of 2 0 m g, 5 0 m g, or 7 0 m g. T h e c ore ta blet 
is s urr o u n de d b y a fil m c oati n g t o pre v e nt e x p os ure t o t he acti ve dr u g s u bst a nce d uri n g h a n dli n g. If 
ta blets are c ut or cr us h e d, pr oce d ures t o pre v e nt e x p os ure t o t he acti ve dr u g s u bsta nce s h o ul d be 
f oll o we d. Pre g na nt w o m e n or breastfee di n g m ot h ers s h o ul d n ot ha n dle cr us he d a n d/ or br o k e n 
dasati ni b ta blets. 
 
T he i ntact dasati ni b ta blets ca n be place d (a n d all o we d t o diss ol ve) i n 1 o u nce of le m o na de (a d o u ble 
stre n gt h j uic e is rec o m m e n de d t o o bsc ure t he bitter taste), or 1 o u nce of preser vati ve-free a p pl e j uice, 
or 1 o u nce of preser vati v e-free ora n ge j uice. 
 
T he f oll o wi n g (i.e., ste ps 1 t hr o u g h 7) is t he pr oce d ure f or t he pre p arati o n of t he le m o na de d osi n g 
s ol uti o n. F or preser vati ve-free a p pl e j uice or pres er vati ve-free ora n ge j uice, ste ps 2 t hr o u g h 7 s h o ul d 
be f oll o we d. 
 
Mi x t he c o nte nts of o ne 1 2 o u nce ca n of Mi n ute Mai d Pre mi u m Fr oze n C o nce ntrate wit h 2 ca ns (i. e. 
t he e m ptie d le m o na de c o ntai ner) of water. T his will pr o d uce le m o na de t h at is a little m ore t ha n t wice 
as c o nce ntrate d as t he i nstr ucti o ns o n t he ca n wit h a s weeter taste. Pleas e kee p t he le m o na de s ol uti o n 
refri gerate d w he n n ot i n use. 
 
Place 1 o u nce ( 3 0 m L) of t his le m o na de s ol uti o n i nt o a dri n ki n g glass. 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Place t he pr o per d ose of i ntact ta blets i nt o t he le m o na de. Please b e s ure t o al wa ys wear pr otecti ve 
gl o ves w h e n ha n dli n g t he me dicati o n. A mas k is n ot re q uire d w he n ha n dli n g t he me di cati o n.  
 
Al wa ys use t he 1 oz of le m o na de. D o n ot i n creas e t he le m o na de v ol u me. Start ti mi n g f or 2 0 mi n utes. 
At a p pr o xi matel y t he 5 mi n ute mar k, s wirl t he c o nte nts of t he gl ass well f or a b o ut 3 sec o n ds. 
 
At a p pr o xi matel y t he 1 5 mi n ute mar k, s wirl t he c o nte nts of t he gl ass a sec o n d ti me. At t he 2 0 mi n ute 
mar k, s wirl t he c o nte nts of t he gl ass o ne last ti me. I m me diat el y a d mi nister t he e ntire c o nte nts of t h e 
glass. 
 
I n or der t o e ns ure a d mi nistrati o n of t he e ntire me dicati o n d ose, a ri nsi n g ste p is necessar y. A d d 0. 5 
o u nce ( 1 5 m L) of le m o na de i nt o t he sa me glass t hat has j ust bee n e m ptie d. S wirl t he c o nte nts t o 
re m o ve a n y re mai ni n g si g ns of ta bl ets fr o m t he si des or b ott o m of t he gl ass. 
 
A d mi nister t he was hi n g l e m o na de t o t he patie nt. T he i ntact b ottles s h o ul d be st ore d at c o ntr olle d r o o m 
te m perat ur e ( 1 5°- 2 5° C or 5 9°- 7 7 °F) a n d pr otecte d fr o m li g ht. 
 
S u p plier: C o m merciall y a vaila ble  
 
T o xicit y: T he m ost fre q u e ntl y re p orte d a d verse e v e nts i ncl u de fl ui d rete nti o n ( ple ural eff usi o n), 
diarr hea, na usea, a b d o mi nal pai n, ras h, hea dac he, fati g u e, v o miti n g, blee di n g e v e nts a n d 
m yel os u p pressi o n. T he m ost fre q ue ntl y re p ort e d seri o us a d verse e v e nts i ncl u de p yre xia, fe brile 
ne utr o pe nia, gastr oi ntesti nal blee di n g, p ne u m o nia, t hr o m b oc yt o pe ni a, d ys p nea, a n e mia a n d car diac 
fail ure ( 3 %).  Less c o m m o nl y re p orte d are a n ore xia, de h y drati o n, a b d o mi nal diste nsi o n a n d 
flat ule nce, fl us hi n g, pr uritis, ele vate d creati ni ne, a n d ne ur o pat h y. Ele v ati o ns i n tra nsa mi nases a n d 
bilir u bi n ca n us uall y b e ma na ge d wit h d ose re d ucti o ns or d ose i nterr u pti o n. H y p o calce mia d uri n g 
dasati ni b t hera p y ca n be ma na ge d wit h oral calci u m s u p ple me ntati o n. 
 
1 9.  
IM A TI NI B ( Glee v ec ®, i mati ni b mes yl ate, f or merl y k n o w n as S TI 5 7 1) F or P h + A L L p atie nts 
o nl y.  See p ac ka ge i nsert f or a d diti o nal i nf or mati o n 
 
S o urce a n d p h ar mac ol o g y:  i mati ni b mes ylat e is a p he n yl a mi n o p yri mi di ne deri vati ve a n d is a 4- [( 4-
Met h yl- 1- pi perazi n yl) met h yl- N- [ 4- met h yl- 3-[[ 4-( 3-p yri di n yl)- 2- p yri mi d-i n yl] a mi n o]- 
p he n yl] be nza mi de met ha nes ulf o nate.  It is a pr ot ei n-t yr osi n e ki nase i n hi bit or t hat i n hi bits t he Bcr- A bl 
t yr osi ne ki nas e, t he c o nstit uti ve a b n or mal t yr osi ne ki nase create d b y t he P hila del p hia c hr o m os o me 
a b n or malit y. 
 
F or m ulati o n a n d sta bilit y:  Eac h fil m-c oat e d ta blet c o ntai ns 1 0 0 m g or 4 0 0 m g of i mati ni b free bas e.  
T he dr u g s h o ul d be st ore d at 2 5° C ( 7 7° F); e x c ursi o ns per mitte d t o 1 5° C- 3 0° C ( 5 9° F- 8 6° F).  T he 
ta blets s h o ul d be dis pe nse d i n a ti g ht c o nt ai ner, U S P, a n d pr otecte d fr o m m oist ure. 
 
T he prescri be d d ose s h o ul d be a d mi nistere d orall y, wit h a meal a n d a l ar ge glass of water.  I n 
c hil dre n, t he dail y d ose ma y b e s plit i nt o t w o – o nce i n t he m or ni n g a n d o nce i n t he e v e ni n g.  F or 
pa tie nts u na ble t o s wall o w t he fil m-c oate d t a blets, t he ta blets ma y b e dis perse d i n a gl ass of wat er or 
a p ple j uice.  T he re q uir e d n u m ber of ta blets s h o ul d be place d i n t he a p pr o priate v ol u me of be v era ge 
(a p pr o xi matel y 5 0 m L f or a 1 0 0- m g ta blet, a n d 2 0 0 m L f or a 4 0 0- m g ta blet) a n d stirre d wit h a s p o o n.  
T he  s us pe nsi o n s h o ul d be a d mi nistere d i m me diat el y after c o m plete disi nte grati o n of t he ta blet. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
S u p plier: C o m merciall y a vaila ble 
 
T o xicit y:  C o m m o n t o xicities i ncl u de d ys pe psia/ h eart b ur n, n a usea/ v o miti n g, hea dac he, 
m yel os u p pressi o n, a n d fati g ue.  O ccasi o nal t o xicities i ncl u de fe v er, e d e ma i n li m bs, face, peri or bital 
area, wei g ht gai n, i ncreas e d S G O T/ S G P T, al kali ne p h os p hatase, bilir u bi n, a b d o mi nal pai n a n d 
cra m pi n g, m yal gia, art hral gia, d ecreas e d b o ne marr o w cell ularit y, l y m p h o pe nia, ecze ma der matitis, 
ras h, m uscle pai n a n d cra m pi n g, a n ore xia, a n d pi g me ntati o n c ha n ges ( h y p o- vitili g o).  Rare t o xicities 
i ncl u de cere bral e de ma, mele na/ GI blee di n g, a ne mia, diarr hea, d ys p h a gia, es o p ha gitis, o d y n o p ha gi a, 
he m orr ha ge/ blee di n g wit h o ut gra d e 3 or 4 t hr o m b oc yt o p e nia, p ne u m o nitis/ p ul m o nar y i nfiltrat es, late 
he pat ot o xicit y a n d decrease i n t he heart’s a bilit y t o p u m p bl o o d.  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X III: D E FI NI TI O N S R E L A T E D T O I N F E C TI O U S DI S E A S E S 
 
I. 
A S S E S S M E N T S 
 
A.  Fe ver: A si n gl e te m perat ure of > 3 8. 3° C ( 1 0 1° F) or > 3 8. 0° C ( 1 0 0. 4° F) o n t w o 
occasi o ns wit hi n 1 2 h o urs.  T he meas ure me nt m ust be oral wit h gl ass or I V A C  
t her m o meters or at t he t y m pa nic me m bra ne b y i nfrare d i nstr u me nts ( T h er m osca n). 
T he sa me met h o d s h o ul d be use d t hr o u g h o ut t he fe brile e pis o de f or eac h p atie nt. 
B.  Ne utr o pe nia: N e utr o p hil c o u nt < 5 0 0/ m m 3 or < 1, 0 0 0/ m m3 wit h pre dicte d decli ne 
t o < 5 0 0/ m m 3. 
C.  D urati o n of fe ver ( f or e pis o des of fe ver wit h ne utr o pe nia): T he i nitial te m perat ur e 
is t he o ne i m me diatel y b ef ore t h e first d ose of a nti bi otics a n d G C S F.  T his is 
desi g nat e d as zer o h o ur.  T he e n d of a fe brile peri o d is at t he ti me of t he first 
te m perat ur e of 3 8. 0°C or less w hic h is s ustai ne d at t his le vel o ver a peri o d of 2 4 
h o urs or l o n ger wit h o ut a nti p yretic i nter ve nti o n.  T he d urati o n of fe ver is t he 
n u m ber of h o urs fr o m zer o h o ur t o t he e n d of t he fe brile peri o d. 
D.  A nti bi otic t hera p y:  A n y s yste mic a nti bacterial dr u g will be c o nsi dere d as a nti bi otic 
t hera p y w het h er gi ve n orall y or pare nt erall y.  T o pical a nti bi otics will n ot be 
i ncl u de d. 
E.  A ntif u n gal t hera p y:  A n y a ntif u n gal dr u g a d mi nistere d orall y or pare nterall y will 
be c o nsi dere d a ntif u n gal t hera p y.  A ntif u n gal t hera p y will be cate g orize d f or 
a nal ysis as: 
1.  Treat me nt f or oral ca n di diasis 
N ystati n 
Cl otri maz ole tr oc hes 
Micaf u n gi n Fl uc o n az ole 
V oric o naz ole 
 
2.  Treat me nt f or s yst e mic m yc oses (i ncl u des e m piri cal use) 
S yste mic a m p h oteri ci n B (sta n dar d a n d li p os o mal) 
Fl uc o naz ole 
V oric o naz ole 
P osac o naz ole  
Itr ac o n az ole  
Micaf u n gi n 
 
II. 
B A C T E RI A L 
 
1.  Bact ere mia o nl y: D efi ne d as a gr o wt h of a n or ga nis m t hat is j u d ge d n ot t o be a c o nta mi na nt 
i n a bl o o d c ult ure dra w n d uri n g a fe brile e pis o de. Or ga nis ms are c o nsi dere d c o nta mi na nts if 
t he y are p art of s ki n fl ora (e. g., di p ht her oi ds ot her t ha n C ory ne b acteri u m jei kei u m , B acill us 
s p p. n ot B. cere us, Pr o pi o ni b acteri u m s p p., c o a g ul ase- ne g ative st a p hyl oc occ us ( C N S) or 
Micr oc occ us s p p. ) a n d if t he y are is olate d fr o m o nl y o ne c ult ure rece ptacle. All ot her 
or ga nis ms are re gar de d as pat h o ge ns.  ( S pecif y cat heter-relate d or n ot.) 
2.  Bact erial se psis:  p ositi ve bl o o d c ult ure f or a n y b acteri u m pl us cli nical e vi d e nce of 
i nfecti o n (fe v er, c hills, h y p ote nsi o n, etc.).  ( S pecif y cat heter-relate d or n ot.) 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
3.  Uri nar y tract i nfecti o n: uri ne c ol o n y c o u nt of 1 0 0, 0 0 0 or great er of a si n gle or ga nis m 
pl us s y m pt o ms, d ys uria, fla n k pai n, etc.  As y m pt o matic bacti uria is t he sa m e c ol o n y 
c o u nt wit h o ut s y m pt o ms. 
4.  P ne u m o nia ( bacterial):  ra di o gra p hic discer ni ble i nfiltrate pl us is olati o n of p ote ntiall y 
ca usati ve bacteria fr o m br o nc h oal ve olar la va ge, bl o o d or bi o ps y s peci me n.  If p ositi ve 
bl o o d c ult ure, c o de as bacterial se psis wit h p ne u m o nia. 
5.  Me ni n gitis:  p ositi ve c ult ure of ca usati ve bacteria fr o m C S F pl us s y m pt o ms c o m pati ble 
wit h me ni n gitis. 
6.  Oste o m yelitis:  ra di o gra p hic lesi o ns pl us p ositi ve bl o o d or b o ne as pirate/ bi o ps y c ult ures. 
7.  Ac ute Otitis Me dia:  p h ysicia n dia g n osis pl us a nti bi otic treat me nt. 
8.  P har y n gitis:  o nl y if gr o u p A beta he m ol ytic stre pt oc occ us is is olate d fr o m t hr oat c ult ure i n 
patie nt wit h s y m pt o ms. A p ositi ve ra pi d stre pt oc occal test is acce pta bl e i n place of c ult ure.  
Ot her t y p es of p h ar y n gitis will n ot be c o nsi dere d. 
9.  Cell ulitis:  er yt he m a a n d i n d urati o n pl us is olati o n of bacteria fr o m as pirate or drai na ge. 
 
III. 
F U N G A L I N F E C TI O N S 
 
A.  Ca n di diasis 
 
1.  Oral: prese n ce of t y pi cal w hitis h lesi o ns o n t he m uc osal s urface wit h yeast or 
pse u d o m ycelia o n gra m stai n or K O H pre parati o n or is olati o n of C a n di d a s pecies i n 
c ult ure fr o m t he m o ut h. 
2.  Es o p ha geal or uri nar y bl a d der: e vi de n ce of tiss ue i n v ol ve me nt pr o ve n b y e n d osc o p y 
a n d bi o ps y pl us is olati o n of f u n g us i n c ult ure.   
 
B.   
I n v asi ve F u n gal I nfecti o ns1 4 7 
 
1.  
P r o ve n i n vasi ve f u n gal i nfecti o n ( n ot e n de mic m yc osis) 
 
A nal ysis a n d s p eci me n  
M ol ds
a 
Yeasts a 
Micr osc o pic a n al ysis: 
sterile material 
Hist o pat h ol o gic, 
c yt o p at h ol o gic, or dire ct 
micr osc o pic e x a mi nati o n b 
of a s peci me n o bt ai ne d b y 
nee dle as pir ati o n or bi o ps y 
i n w hic h h y p h ae or 
mela nize d yeast -li ke f or ms 
are see n acc o m pa nie d b y 
e vi de nce of ass ociat e d 
tiss ue da ma ge 
Hist o pat h ol o gic, 
c yt o p at h ol o gic, or direct 
micr osc o pic e x a mi nati o n b 
of a s peci me n o bt ai ne d b y 
nee dle as pir ati o n or bi o ps y 
fr o m a n or mall y sterile site 
( ot her t ha n m uc o us 
me m bra nes) s h o wi n g yeast 
cells –  f or e x a m ple, 
Cry pt oc occ us s pecies 
i n dicate d b y e nca ps ulate d 
b u d di n g yeasts or C a n di d a 
s pecies s h o wi n g 
pse u d o h y p h ae or tr ue 
h y p hae c 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
C ult ure  
Sterile material  
Rec o ver y of a m ol d or 
“ blac k yeast” b y c ult ure of 
a s peci me n o btai ne d b y a 
sterile pr oce d ure fr o m a 
n or mall y sterile a n d 
cli nicall y or 
ra di o gra p hicall y a b n or m al 
site c o nsiste nt wit h a n 
i nfecti o us disease pr ocess, 
e x cl u di n g br o nc h oal v e olar 
la va ge fl ui d, a cra nial si n us 
ca vit y s p eci me n, a n d uri ne  
 
 
Rec o ver y of a yeast b y 
c ult ure of a s a m ple 
o btai ne d b y a sterile 
pr oce d ure (i ncl u di n g a 
fres hl y place d [ < 2 4 h a g o] 
drai n) fr o m a n or mall y 
sterile site s h o wi n g a 
cli nical or ra di o gra p hical 
a b n or malit y c o nsiste nt wit h 
a n i nfecti o us diseas e 
pr ocess  
Bl o o d  
Bl o o d c ult ure t hat yiel ds a 
m ol d d (e. g. F us ari u m 
s pecies) i n t he c o nt e xt of a 
c o m pati ble i nfecti o us 
disease pr ocess  
Bl o o d c ult ure t hat yiel ds 
yeast (e. g. Cry pt oc occ us  or 
C a n di d a  s pecies) or yeast-
li ke f u n gi ( e. g. 
Tric h os p or o n s pecies) 
Ser ol o gic al a nal ysis:  C S F  
N ot a p plica ble  
Cr y pt oc occal a nti ge n i n 
C S F i n dicates disse mi nate d 
c yr o pt oc occ osis  
a  If c ult ure is av ail a ble, a p pe n d t he i de ntific ati o n at t he ge n us or s pecies level fr om t he c ult ure res ults.  
b Tiss ue a n d cells s u b mitte d f or hist o p at h ol o gic or cyt o p at h ol o gic st u dies s h o ul d be st ai ne d by 
Gr oc ott ‐G o m orri met he n a mi ne silver st ai n or by peri o dic aci d Sc hiff st ai n, t o f acilit ate i ns pecti o n of f u n g al 
str uct ures. W he never p ossi ble, wet m o u nts of s peci me ns fr o m f oci rel ate d t o i nv asive f u n g al dise ase s h o ul d 
be st ai ne d wit h a fl u oresce nt dye (e. g., c alc ofl u or or bl a nk o p h or).  
c C a n di d a, Tric h os p or o n,  a n d ye ast ‐like Ge otric h u m  s pecies a n d Bl ast osc hiz o myces c a pit at us  m ay als o f or m 
pse u d o hy p h ae or tr ue hy p h ae.  
e Rec overy of As per gill us  s pecies fr o m bl o o d c ult ures i nv ari a bly re prese nts c o nt a mi n ati o n  
 
2.  Pr o ba ble i n vasi ve f u n gal i nfecti o n ( n ot e n de mic m yc osis)  
 
H ost fact ors a 
 R ece nt hist or y of ne utr o p e nia ( < 0. 5 x 1 0 9 ne utr o pils/ m m 3) f or > 1 0 da ys) 
te m p orall y relate d t o t he o nset of f u n gal diseas e 
 R ecei pt of a n all o ge neic ste m cell tra ns pla nt 
 P r ol o n ge d use of c ortic oster oi ds (e x cl u di n g a m o n g patie nts wit h aller gic 
br o nc h o p ul m o nar y as p er gill osis) at a mea n mi ni m u m d ose of 0. 3 m g/ k g/ da y of 
pre d nis o ne e q ui val e nt f or > 3 wee ks. 
 Tr eat me nt wit h ot her rec o g nize d T cell i m m u n us u p pressa nts, s uc h as c ycl os p ori ne, 
T N F- α bl oc kers, s pecific m o n ocl o nal a nti b o dies (s uc h as ale mt uz u ma b), or 
ne ucle osi de a n al o g ues d uri n g t he past 9 0 da ys. 
 I n h erite d se v ere i m m u n o deficie nc y (s uc h as c hr o nic gra n ul o mat o us disease or se vere 
c o m bi ne d i m m u n o deficie nc y) 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Cli nical criteria b 
 L o w er res pirat or y tr act f u n gal disease c 
o  T he  prese n ce of 1 of t he f oll o wi n g 3 si g ns o n C T: 
 De nse, w ell-circ u mscri be d lesi o n(s) wit h o ur wit h o ut a hal o si g n 
 Air -cresce nt si g n 
 C a vit y 
 Tr ac h e o br o nc hitis 
o  Tr ac h e o br o nc hial ulcerati o n, n o d ule, pse u d o me m bra ne, pla q ue, or es c har see n o n 
br o nc h osc o pic a nal ysis 
 S i n o nasal i nfecti o n 
o  Ima gi n g s h o wi n g si n usitis pl us at leas 1 of t he f oll o wi n g 3 si g ns: 
 Ac ute l ocalize d pai n (i ncl u di n g pai n ra di ati n g t o t he e ye) 
 Na sal ulcer wit h blac k es c har 
 E x te nsi o n fr o m t he para n asal si n us acr oss b o n y barriers, i ncl u di n g i nt o t he or bit 
 C N S i nfecti o n 
o  1 of t he  f oll o wi n g 2 si g ns: 
 F ocal lesi o ns o n i ma gi n g 
 Me ni n geal e n ha n ce me nt o n M RI or C T 
 D isse mi nate d ca n di diasisd 
o  At lea st 2 of t he f oll o wi n g 2 e ntities after a n e pis o de of ca n di d e mia wit hi n t he 
pre vi o us 2 wee ks: 
 S mall, tar get-li ke a bscess es ( b ull’s e ye lesi o ns) i n li ver or s plee n 
 Pr o gressi ve reti nal e x u dates o n o p ht hal m ol o gic e x a mi nati o n 
 
M yc ol o gic al criteri a 
 Dire ct test (c yt ol o g y, dir ect micr osc o p y, or c ult ure) 
o  M ol d  i n s p ut u m, br o nc h oal ve olar la v a ge fl ui d, br o nc hial br us h, or si n us as pirate 
sa m ples, i n dicate d b y 1 of t he f oll o wi n g 
 Prese nce of f u n gal ele me nts i n dicati n g a m ol d 
 Rec o ver y b y c ult ure of a m ol d (e. g. As p er gill us, F us ari u m, Zy g o mycetes, or 
Sce d os p ori u m  s peci es) 
 In dir ect tests ( det ecti o n of a nti ge n or cell- wall c o nstit ue nts) e 
o  As pe r gill osis 
 Galact o ma n n a n a nti ge n d etecte d i n plas ma, ser u m, br o nc h oal ve olar la va ge, or 
C S F 
o  In v asi ve f u n gal disease ot her t ha n cr y pt o c occ osis a n d z y g o m yc oses 
 β- D - gl uca n d etecte d i n ser u m 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
N O T E:  Pr o b a ble I F D re q uires t he prese nce of a h ost f act or, a cli nic al criteri a o n, a n d a myc ol o gic al criteri o n.  
C ases t h at meet t he criteri a f or a h ost f act or a n d a cli nic al criteri o n b ut f or w hic h myc ol o gic al criteri a are a bse nt 
are c o nsi dere d p ossi ble I F D. 
a H ost f act ors are n ot sy n o ny m o us wit h risk f act ors a n d are c h ar acteristics by w hic h i n divi d u als pre dis p ose d t o 
I F Ds c a n be rec o g nize d.  T hey are i nte n de d pri m arily t o a p ply t o p atie nts give n tre at me nt f or m ali g n a nt dise ase 
a n d t o reci pie nts of all o ge n eic he m at o p oietic ste m m cell a n d s oli d- or g a n tr a ns pl a nts.  T hese f act ors are als o 
a p plic a ble t o p atie nts w h o receive c ortic oster oi ds a n d ot her T-cell s u p press a nts as well as t o p atie nts wit h 
pri m ary i m m u n o deficie n cies. 
b M ust be c o nsiste nt wit h t he myc ol o gic al fi n di n gs, if a ny, a n d m ust be te m p or ally rel ate d t o c urre nt e pis o de 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
c Every re as o n a ble atte m pt s h o ul d be m a de t o excl u de a n alter n ative eti ol o gy 
d T he prese nce of si g ns a n d sy m pt o ms c o nsiste nt wit h se psis sy n dr o me i n dic ates ac ute disse mi n ate d dise ase, 
w here as t heir a bse n ce de n otes c hr o mic disse mi n ate d dise ase 
e T hese tests are pri m arily a p plic a ble t o as per gill osis a n d c a n di di asis a n d are n ot usef ul i n di a g n osi n g i nfecti o ns 
d ue t o Cry pt oc o cc us s pecies or Zy g o mycetes (e. g. R hiz o p us, M uc or, or A bsi di a s pecies).  Detecti o n of n ucleic 
aci d is n ot i ncl u de d, bec a use t here are as yet n o v ali d ate d or st a n d ar dize d met h o ds. 
 
3.  
P o ssible i n vasi ve f u n gal i nfecti o n ( n ot e n de mic m yc osis) 
 
I n t he t a ble a b o v e, cas es t hat meet t he criteri a f or a h ost fact or a n d a cli nical criteri o n 
b ut f or w hic h m yc ol o gical criteria are a bse nt are c o nsi dere d p ossi ble I F D. 
 
C.   
Hist o plas m osis:  a dia g n osis of disse mi nate d disease ma y be esta blis he d b y a p ositi ve 
Hist o pl as m a  a nti ge n test o n C S F, uri ne or ser u m b y EI A, or t he prese n ce of 
c haracteristic i ntracell ular yeast f or ms i n a p eri p heral bl o o d s mear or i n b o n e marr o w. 
 
Criteria f or t he dia g n osis of e n de mic m yc os es  
Dia g n osis a n d criteri a  
Pr o ve n e n de mic m yc osis  
I n a h ost wit h a n ill ness c o nsiste nt wit h a n e n de mic m yc osis, 1 of t he f oll o wi n g 
 Re oc o ver y i n c ult ur e fr o ma  s peci me n o btai ne d fr o m t he affecte d 
site or fr o m bl o o d 
 Hist o pat h ol o gi c or direct micr osc o pic de m o nstrati o n of a p pr o pri ate 
m or p h ol o gic f or ms wit h a tr ul y disti ncti ve a p p eara nce 
c haracteristic of di m p or p hic f u n gi, s u c h as C occi di o des  s pecies 
s p her ules, Bl ast o myces d er m atitis  t hic k-walle d br oa d -base d 
b u d di n g yeasts, P ar acci di o i des br asile nsis m ulti ple b u d di n g yeast 
cells, a n d, i n t he cas e of hist o plas m osis, t he prese nce of 
c haracteristic i ntracell ular yeast f or ms i n a p h a g oc yt e i n a 
peri p heral bl o o d s mear or i n tiss ue macr o p ha ges  
 F or c o cci di oi d o m yc osis, de m o nstrati o n of c occi di oi dal a nti b o d y i n 
C S F, or a 2 -dil uti o n rise meas ure d i n 2 c o ns ec uti v e bl o o d sa m ples 
teste d c o nc urre ntl y i n t he setti n g of a n o n g oi n g i nf ecti o us disease 
pr ocess.  
 F or parac o cci di oi d o m yc osis, de m o nstrati o n i n 2 c o nsec uti ve ser u m 
sa m ples of a preci piti n ba n d to parac occi di oi di n c o nc urre ntl y i n 
t he setti n g of a n o n g oi n g i nfecti o us disease pr ocess 
Pr o ba ble e n de mic m yc osis  
 Prese nce of a h ost fact or, i ncl u di n g b ut n ot li mite d t o t h ose 
s pecifie d i n # 2 Ta ble a b o ve, pl us a cli nical pict ure c o nsiste nt wit h 
e n de mic m yc osis a n d m yc ol o gical e vi de nce, s uc h as p ositi ve 
Hist o plas ma a nti ge n t est res ult fr o m uri ne, bl o o d, or C S F  
 
N ote:  E n de mic myc osies i ncl u des hist o pl as m osis, bl ast o myc osis, c occi di oi d o myc osis, 
p ar ac o cci di oi d o myc osis, s p or otric h osis, a n d i nfecti o n d ue t o Pe nicilli u m m ar neffei.  O nset wit hi n 3 
m o nt hs after prese nt ati o n defi nes a pri m ary p ul m o n ary i nfecti o n.  T here is n o c ate g ory of p ossi ble 
e n de mic myc osis, as s uc h, bec a use neit her h ost f act ors n or cli nic al fe at ures are s ufficie ntly s pecific; 
s uc h c ases are c o nsi dere d t o be of v al ue t o o li mite d t o i ncl u de i n cli ncic al tri als, e pi de mi ol o gic al 
st u dies, or ev al u ati o ns of di a g n ostic tests. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
D.   
Ot hers:  t he i n vesti gat or ma y i ncl u d e certai n ot her i nfecti o us diseases of u ni q ue nat ure.  
Acce pt a nce re q uir es decisi o n bef ore dec o di n g occ urs a n d wit h t he a gree me nt of t he 
pri nci pal i n vesti gat or a n d a n atte n di n g fr o m t he I nfecti o us Diseas e De p art me nt. 
 
I V.  
P R O T O Z O A N 
 
A.  
P ne u m ocystis c ari nii  P ne u m o nia:  discer ni ble ra di o gra p hic lesi o n pl us i de ntificati o n of P. 
cari nii  i n br o nc h oal ve olar la va ge fl ui d, bi o ps y or i n d uce d s p ut u m. 
B.  
C ry pt os p ori di osis:  C. p ar u m  i de ntifie d i n st o ol pl us diarr hea. 
C.  
T ox o pl as m osis:   see A C T G pr ot oc ol 2 5 4.  
 
V.  
T O P O G R A P HI C A L 
 
A.   
T he f oll o wi n g di a g n oses are acce pta ble f or o bjecti vel y i de ntifie d i nfecti o ns wit h o ut 
c o nfir mati o n of eti ol o g y. 
1.   
P ne u m o nia:  lesi o n o n ra di o gra p h 
2.   
Oste o m yelitis:  ra di ol o gical dia g n osis 
3.   
Si n usitis:  ra di ol o gical di a g n osis ( x-ra y, C T, M RI) 
4.   
Cell ulitis:  p h ysicia n dia g n osis 
 
VI.  
F E V E R O F U N D E T E R MI N E D E TI O L O G Y 
 
B.   
Fe ver wit h o ut a n y f oc us or eti ol o g y i de ntifie d b y cli nical hist or y, p h ysic al 
e x a mi nati o n, ra di ol o gical or micr o bi ol o gic fi n di n g.  I d e ntif y as: 
1.  
ne utr o pe nic = A N C < 5 0 0/ m m 3  
2.   
n o n ne utr o pe nic =  A N C > 5 0 0/ m m3 
 
VII. 
C U L T U R E N E G A TI V E S E P SI S 
 
I n t he I n t he a bs e nce of a p ositi ve c ult ure, a s yste mic res p o nse t o a p ossi ble i nfecti o n b y 
he m o d y n a mic i nsta bilit y, f ocal or m ulti ple or ga n i n v ol ve me nt s uc h as p o or s ki n perf usi o n, 
oli g uria, h y p o x e mia, a n d/ or altere d me ntal stat us or let har g y. 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X I V: C O M M O N S U B S T R A T E S, I N HI BI T O R S A N D I N D U C E R S O F 
C Y P 3 A 4/ 3 A 5 
 
T he f oll o wi n g lists descri be me dicati o ns w hic h are c o m m o n C Y P 3 A 4 s u bstrates, i n hi bit ors a n d 
i n ducers. T his list s h o ul d n ot be c o nsi dere d all i ncl usi ve. C o ns ult P har mace utical Ser vices f or 
s pecific i nf or mati o n o n meta b olis m b y  C Y P 3 A 4/ C Y P 3 A 5. 
S u bstr ates  
Macr oli de a nti bi otics  
clarit hr o m yci n  
er yt hr o m yci n  
N O T  azit hr o m yci n  
A nti -arr h yt h mics 
q ui ni di ne  
Be nz o diaze pi nes  
al praz ola m  
diaze pa m  
mi daz ola m 
triaz ola m 
I m m u ne m o d ulat ors 
c ycl os p ori ne  
tacr oli m us ( F K 5 0 6) 
sir oli m us 
HI V  a ntivirals  
i n di na vir 
nelfi na vir  
rit o na vir 
sa q ui na vir 
A nti hista mi nes  
aste miz ole 
c hl or p he nira mi ne 
terfe ni di ne 
Calci u m  c ha n nel  bl oc kers  
a ml o di pi ne 
diltiaze m  
fel o di pi ne 
lerca ni di pi ne 
nife di pi ne  
nis ol di pi ne 
nitre n di pi ne  
vera pa mil  
H M G  C o A re d uctase i n hi bit ors at or vastati n 
ceri vastati n  
l o vastati n 
N O T  pra vastati n  
Si m vastati n  
 
 
 
 
 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
S u bstrates  - c o nti n ue d 
Ster oi d  6 beta -O H  
estra di ol  
h y dr oc ortis o ne  
pr o gester o ne  
test oster o ne 
Ot her  
alfe nta n yl  
b us pir o ne 
cafer g ot  
caffei ne = > T M U  
c ocai ne 
da ps o ne  
c o dei ne-N -de met h yl  
de xtr o met h or p ha n  
e plere n o ne 
fe nta n yl 
fi nasteri de 
i mati ni b 
hal o peri d ol  (i n part)  
iri n oteca n 
Li d ocai ne  met ha d o ne  
o n da nsetr o n  
pi m ozi de pr o pra n ol ol  
q ui ni ne 
sal metrer ol 
sil de nafil 
ta m o xife n 
paclita xel  
traz o d o ne 
vi ncristi ne  
zale pl o n 
z ol pi de m 
I n hi bit ors 
HI V  a nti virals 
dela viri di ne  
i n di na vir 
nelfi na vir  
rit o na vir 
sa q ui na vir 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Ot her  
a mi o dar o ne N O T azit hr o m yci n  
ci meti di ne 
ci pr ofl o x aci n  
clarit hr o m yci n  
diet h yl -dit hi ocar ba mate  
diltiaze m  
er yt hr o m yci n  
fl uc o naz ole 
fl u v o x a mi ne 
gest o de ne  
gra pefr uit  j uice 
itrac o naz ole 
ket oc o naz ole  
mife prist o ne  
nefaz o d o ne  
n orfl o xaci n  
n orfl u o x eti ne  
mi befra dil  
vera pa mil  
v oric o naz ole  
I n d ucers 
 
HI V  a nti virals 
efa vire nz  
ne vira pi ne  
Ot her  
bar bit urates  
car ba maze pi ne  
gl uc oc ortic oi ds  
m o dafi nil  
p he n o bar bital  
p he n yt oi n  
rifa m pi n 
St.  J o h n’s w ort  
tr o glitaz o ne 
p i o glitaz o ne 
rifa b uti n 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
 
A P P E N DI X V - T O T X VI R A N D O MI Z A TI O N F O R M 
T O T X VI  R A N D O MI Z A TI O N  F O R M  
 
Please fa x t he c o m plete d f or m t o t he St. J u de Ce ntral P har mac y at 
.  
Please call t he St. J u de p har mac y at 
 t o let t he m k n o w y o u’ ve faxe d a re q uest f or T O T X VI 
ra n d o mizati o n.  If y o u are u na ble t o se n d t his f or m b y F A X , t he i nf or mati o n ma y be gi ve n b y p h o ne a n d se nt b y 
F A X  later. 
 
M R N:                                                           I nitials:                               Date:                                    
                                                                                                                                M M          D D          Y Y                              
Na me:                                                                                                                                
 
Has partici pa nt/ L A R si g ne d i nf or me d c o nse nt, a greei n g t o partici pate i n P E G -as para gi nase r a n d o mizati o n? 
 
 
  
Y es 
 
 
N o ( Partici pa nt will n ot be ra n d o mize d -d o N O T fa x t he f or m t o p har mac y)  
 
N ote:  P artici p a nts wit h D o w n sy n dr o me will N O T be r a n d o mize d - D O N O T f ax t he f or m t o p h ar m acy . 
 
Stratificati o n fact ors ( p lease c hec k o nl y o ne i n eac h cate g or y) 
 
1.  Ris k stat us at start of co nti n uati o n p hase ( see secti o n 4. 0): 
 
 
 L o w  
 Sta n dar d  
 
 Hi g h  
 
2.  F or  st a n d ar d ris k partici pa nts o nl y:  
 
 
 T -Li nea ge  
 B -Li nea ge  
 U n k n o w n  
 
3.  F or St a n d ar d r is k, T-Cell li ne a ge partici pa nts o nl y:  
 
 
 Da y 1 5 M R D ne gati ve   
 Da y 1 5 M R D p ositi ve  
 U n k n o w n  
P h ysicia n:  
 
 
( pri nt na me) 
 
C o ntact na me if n ot t he p h ysicia n:   
 
Tele p h o ne c o n t act n u m b er f or q uesti o ns: 
 
P har macist :  Please  e mail d ose assi g n me nt t o e mail gr o u p T O T X VI R a n d o miz ati o n Res ults  
I n cl u de patie nt’s n a me, me dical rec or d n u m ber a n d P E G-as para gi nase d os e assi g n m e nt.   
P ri nt a c o p y of y o ur e mail messa ge a n d place it i n t he n ote b o o k wit h t his f or m 
 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X VI: P S Y C H O L O GI C A L T E S T B A T T E R Y F O R C HI L D R E N O V E R T H R E E 
Y E A R S O F A G E 
D o m ai n  
Me as ure  
Br o a d skill  
T as k c h ar acteristics  
A ge  
ra n ge  
Ti me  
I ntelli ge n ce 
S B -V 1  
R o uti n g S u btests  
Gl o bal C o g niti ve 
F u ncti o n  
O bject Series/ Matrices a n d  
V oca b ular y s u bt ests  
3 +  
2 0  
Atte nti o n & 
E x ec uti ve 
F u ncti o n  
Di git S pa n 2, 3 
A u dit or y Atte nti o n  
& W or ki n g M e m or y  
F or war d - re peat ra n d o m di git 
stra n ds of i ncreasi n g le n gt h 
Bac k war d - re p eat r a n d o m 
di git stra n ds i n re v erse or der  
6 +  
 
5  
 
S patial S pa n 2, 3 
S patial At te nti o n 
& W or ki n g M e m or y  
F or war d - re peat ra n d o m bl oc k 
ta ps of i ncreasi n g l e n gt h  
Bac k war d - re p eat r a n d o m 
bl oc k ta ps i n re verse or der  
6 +  
5  
 
A u dit or y 
Atte nti o n 4  
A u dit or y Selecti ve 
Atte nti o n  
P oi nt t o a pict ure i n dicate d b y  
a s p o ke n w or d; bac k gr o u n d 
n oise is  i ncrease d o v er ti me 
3 +  
5  
 
C P T 5, 6  
S ustai ne d Vis ual 
Atte nti o n  
Selecti vel y res p o n d t o tar gets 
o n a c o m p uter scree n, W hile 
i n hi biti n g res p o nse t o n o n-
tar gets 
4 +  
2 0  
 
A u dit or y W or ki n g 4   
Me m or y  
A u dit or y W or ki n g 
Me m or y  
Re peat w or ds a n d n u m bers 
after or ga nizi n g bas e d o n r ule  
4 +  
5  
 
Retrie val Fl ue n c y 4  
Ver bal Fl ue nc y  
Ge nerate na me of f o o ds, 
pe o ple & a ni mals  
3 +  
5  
( Pare nt 
Meas ures)  
B RI E F 6  
E x ec uti ve F u ncti o n  
Q uesti o n naire ass essi n g 
e x ec uti ve d ysf u ncti o n  
2 +  
1 5  
Me m or y  
C V L T 8, 9  
Ver bal List Lear ni n g  
Lear n ver bal list o ver wit h 
m ulti ple prese ntati o ns, 
i nterfere nce, d ela y & 
rec o g niti o n 
5 +  
1 5  
 
St or y Me m or y 1 0  
St or y Recall  
Recall st ories after si n gl e 
prese ntati o n a n d f oll o wi n g  a 
dela y; rec o g niti o n c uei n g 
pr o vi de d after free recall  
5 +  
1 5  
 
Bea d M e m or y 1 1  
Vis ual Me m or y  
Recrea te bea d patter ns of 
i ncreasi n g le n gt h  
3 +  
5  
 
Re y Fi g ure 1 2  
Vis ual Me m or y  
& Or ga nizati o n  
C o p y a c o m ple x fi g ure 
f oll o we d b y dra wi n g fr o m 
me m or y after s h ort a n d l o n g 
dela ys  
6 +  
2 0  
Pr ocessi n g 
S pee d  
 
 
Vis ual Matc hi n g 4  
Pr ocessi n g S pee d  
Fi n d matc hi n g pairs  
3 +  
3  
 
Decisi o n S pee d 4  
Pr ocessi n g S pee d  
Fi n di n g t w o c o nce pt u all y 
si milar pairs 
3 +  
3  
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
Vis ual S patial/ 
Vis ual M ot or  
S patial Relati o ns 4  
Me ntal R otati o n  
& S patial I nte grati o n  
Pic k o bject t hat matc hes 
p uzzle pieces p ut t o get her  
3 +  
5  
 
V MI 1 3  
 
Vis ual Perce pti o n &  
V is ual-M ot or I nte grati o n  
Matc h s ha pes of decreasi n g 
siz e; Dra w s ha pes of 
i ncreasi n g c o m ple xit y 
3 -2 1  
1 5  
M ot or  
P ur d ue Pe g b o ar d 1 4  
Fi ne M ot or S pee d & 
De xterit y  
Place pe gs usi n g d o mi na nt, 
n o n d o mi na nt & b ot h ha n ds  
3 +  
3  
A da pti ve  
A B A S -II1 5  
A da pti ve F u n cti o ni n g  
Pa re nt q uesti o n naire of 
a da pti ve s kills  
Birt h +  
1 5  
S ocial -
E m oti o nal  
B A S C -II1 6  
Ps yc h o -s o cial 
A dj ust me nt  
Pare nt q uesti o n naire of 
be ha vi oral d o mai ns.  
2 -2 1  
1 5  
(1 ) St a nf or d- Bi net, Fift h E diti o n; (2 ) Wec hsler I ntelli ge nce Sc ale f or C hil dre n, F o urt h E diti o n; (3 ) Wec hsler A d ult 
I ntelli ge n ce Sc ale, T hir d E diti o n; (4 ) W o o dc o ck J o h ns o n, T hir d E diti o n; (5 ) C o n ners’ C o nti n u o us Perf or m a nce Test, 
Sec o n d E diti o n; ( 6 ) C o n ners’ Ki d die Perf or m a nce Test; (7 ) Brief R ati n g I nve nt ory of Exec utive F u ncti o n; (8 ) C alif or ni a 
Ver b al Le ar ni n g Test- C hil dre n’s Versi o n; ( 9 ) C alif or ni a Ver b al Le ar ni n g Test, Sec o n d E diti o n; (1 0 ) C hil dre n’s Me m ory 
Sc ale; ( 1 1 ) St a nf or d- Bi net, F o urt h E diti o n; (1 2 ) Rey- Osterriet h C o m plex Fi g ure; (1 3 ) Beery- B ukte nic a Test of Vis u al-
M ot or I nte gr ati o n; ( 1 4 ) P ur d ue Pe g b o ar d Test; (1 5 ) A d a ptive Be h avi or Assess me nt Syste m-II; (1 6 )Be h avi or Assess me nt 
Syste m f or C hil dre n- II. 
 
Refere nces: 
 
1.  R oi d G. Sta nf or d- Bi net I ntelli ge nce Scales, Fift h E diti o n ( S B- V). R olli n g Mea d o ws, I L: T he Ri versi de P u blis hi n g 
C o m pa n y 2 0 0 3. 
2.  W ec hsler D. W ec hsler I nt elli ge nce Scale f or C hil dre n, F o urt h E diti o n, I nte grate d ( WI S C- I V-I). Sa n A nt o ni o, T X: 
Harc ort Assess me nt, I nc or p orate d 2 0 0 4. 
3.  W ec hsler D. W ec hsler A d ult I ntelli ge nce Scale, T hir d E diti o n 
4.  W o o dc oc k R, Mc Gre w K, Mat her N. W o o dc oc k-J o h ns o n III ( WJIII). Itasca, I L: Ri versi de P u blis hi n g 2 0 0 1.  
5.  C o n ners C K. C o n ners’ C o nti n u o us P erf or ma nce T est II. N ort h T o na wa n da, N Y: M ulti- He alt h S yste ms, I nc.; 2 0 0 1. 
6.  C o n ners C K. C o n ners’ C o nti n u o us P erf or ma nce T est; Ki d die Versi o n V. 5. N ort h T o na wa n da, N Y: M ulti- Healt h 
S yste ms, I nc.; 2 0 0 5. 
7.  Gi oia G A, Is q uit h P K, G u y S G, Ke n w ort h y L. T he Be ha vi or Rati n g I n ve nt or y of E xec uti ve F u ncti o n ( B RI E F).  L utz, 
F L: Ps yc h ol o gical Assess me nt Res o urces, I nc or p orate d 2 0 0 1. 
8.  Delis D C, Kra mer J H, Ka pla n E, O ber B A. Calif or nia Ver bal Lear ni n g T est -  C hi l dre n’s E diti o n ( C V L T-C ). Sa n 
A nt o ni o, T X: Harc o urt Assess me nts, I nc or p orate d 1 9 9 4.  
9.  Delis D C, Kra mer J H, Ka pla n E, O ber B A. Calif or nia Ver bal Lear ni n g T est, Sec o n d E diti o n.. Sa n A nt o ni o, T X: 
Harc o urt Assess me nts, I nc or p orate d 2 0 0 0.  
1 0.  C o he n M. C hil dre n’s Me m or y Scale ( C M S). Sa n A nt o ni o, T X: Harc o urt Assess me nts, I nc or p orate d 1 9 9 7. 
1 1.  T h or n di ke R L, Ha ge n E P, Sattler J S. Sta nf or d- Bi net I ntelli ge nce Scale, F o urt h E diti o n ( S B-I V). Itasca, I L: Ri versi de 
P u blis hi n g 1 9 8 6.  
1 2.  Me yers S E, Me yers K R. Re y- Osterreit h C o m ple x Fi g ure ( Re y- O). L utz, F L: Ps yc h ol o gical Assess me nt Res o urces, 
I nc or p orate d 1 9 9 5. 
1 3.  B eer y K E. T he B eer y- B u kte ni ca De vel o p me ntal T est of Vis ual- M ot or I nte grati o n: A d mi nistrati o n, Sc ori n g a n d 
T eac hi n g Ma n ual ( 4 t h e d.; B eer y V MI). P arsi p pa n y, NJ: M o der n C urric ul u m Press 1 9 9 7.  
1 4.  Tiffi n J, As her EJ. T he P ur d ue P e g b oar d: N or ms a n d st u dies of relia bilit y a n d vali dit y. J o ur nal of A p plie d Ps yc h ol o g y 
1 9 4 8; 3 2: 2 3 4- 2 4 7.  
1 5.  Harris o n P, Oa k T. A da pti ve B e ha vi or Assess me nt S yste m, Sec o n d E diti o n ( A B A S- II) 
1 6.  Re y n ol ds C R, Ka m p ha us R W. B e ha vi or Assess me nt S yste m f or C hil dre n, Sec o n d E diti o n ( B A S C-II). Bl o o mi n gt o n, 
M N: P ears o n Assess me nts Res o urces, I nc or p orate d 2 0 0 4. 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X VII: S C H E M A 
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9

T O T X VI 
 
Re visi o n 5. 6, date d:  0 7- 1 7 -1 5  
  
  
  
  
I R B a p pr o ve d: 0 7 -1 7 -2 0 1 5  
D o c u me nt d ate d:  0 7-1 7 -2 0 1 5  
A P P E N DI X VII I: T E S T S P E R F O R M E D F O R G O O D C LI NI C A L C A R E A N D F O R 
R E S E A R C H 
 
T he sta n dar d of care ser vices i n t his st u d y are as f oll o ws: 
 
 Hist or y & p h ysical e x a ms  
 He mat ol o g y:  C B C wit h diff, c oa g ulati o n scree n  
 All bl o o d a n d uri ne c he mistries, li pi d scree n, plas ma 1, 2 5- di h y dr o x y vita mi n D, oste ocalci n, 
t h yr oi d f u n cti o n tests 
 C hest x-ra ys  
 B o ne marr o w f or m or p h ol o g y, c yt oc he mistr y, i m m u n o p he n ot y pi n g, c yt o ge netics, D N A i n d e x, 
m olec ular st u dies, a n d M R D st u dies  
 Peri p heral bl o o d f or M R D  
 L u m bar p u nct ures wit h C S F e x a mi nati o n a n d a d mi nistrati o n of i ntrat hecal c he m ot hera p y  
 Ot he r st u dies as cli nicall y i n dicat e d (e. g. sic kl e cell pre p, he m o gl o bi n el ectr o p h oresis a n d 
G 6 P D scree n f or bla c k c hil dre n, varicella titer, he patitis B a nti ge n, HI V, E B V, T O X O, C M V 
titers) 
 M R I of hi ps a n d k n ees a n d P T/ O T e val uati o ns 
 Me t h otre x ate p har mac o ki netics 
 Q C T f or b o ne de nsit y  
 Ur i nal ysis 
 A m m o ni a le vels  
 T P M T D N A ( T P M T ge n ot y pi n g)  
 T P M T R B C acti vit y a n d 6 T G N R B C testi n g  
 
 
T he rese arc h ser vices are as f oll o ws: 
 
 B o ne marr o w sa m ple f or bi ol o g y st u dies (ta ke n at sa me ti me b o ne marr o w pr oce d ure is d o ne 
f or r o uti ne care at dia g n osis – pre-trial b o ne marr o w) 
 Ge r mli ne D N A/ R N A  
 Ne ur o ps yc h ol o gic al testi n g 
 M R I brai n (i ncl u des se d ati o n) a n d f u ncti o nal M RI brai n 
 P las ma h o m oc ystei ne 
 S er u m a n d C S F f or as p ara gi n ase a n d a nti-as para gi nase a nti b o dies  
 M R D – ali q u ot of C S F sa m ples se nt t o T B A N K 
 S er u m bi o mar kers 
 As para gi nas e a n d d e x a met has o ne acti vit y 
 N K cell rece pt or st u dies 
 I ntesti nal micr o bi o me res earc h – st o ol s peci me ns 
 
  
 
St. J u d e
I R B N U M B E R: Pr o 0 0 0 0 0 5 8 9
I R B A P P R O V A L D A T E: 0 7 / 0 1 / 2 0 1 9