Transplantation of Umbilical Cord Blood in Patients With Hematological Malignancies Using a Treosulfan Based Preparative Regimen
Phase: PHASE2
Conditions: Acute Biphenotypic Leukemia, Acute Lymphoblastic Leukemia in Remission, Acute Myeloid Leukemia in Remission, Blasts Under 5 Percent of Bone Marrow Nucleated Cells, Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive, Myelodysplastic Syndrome (MDS)
Sponsor: Fred Hutchinson Cancer Center

Offici al Titl e:  
Tr a ns pl a nt ati o n of U m bilic al C or d Bl o o d i n P ati e nts Wit h 
H e m at ol o gic al M ali g n a nci es Usi n g a Tr e os ulf a n B as e d 
Pr e p ar ati v e R e gi m e n 
N C T N u m b er : 
N C T 0 0 7 9 6 0 6 8  
D oc u m e nt T y p e:  
St u d y Pr ot oc ol a n d St atistic al A n al ysis Pl a n  
D at e of t h e 
D oc u m e nt:  
A pril 1 4, 2 0 2 2  

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F R E D H U T C HI N S O N C A N C E R R E S E A R C H C E N T E R 
U NI V E R SI T Y O F W A S HI N G T O N S C H O O L O F M E DI CI N E 
      
 
Title:      
  
  
Tra ns pla ntati o n of U m bilical C or d Bl o o d i n Patie nts wit h 
He mat ol o gical Mali g na n cies Usi n g a Tre os ulfa n Base d Pre par ati ve 
Re gi me n  
 
Pr ot oc ol N u m ber:      
2 2 7 5 
 
C urre nt V ersi o n:   
  
0 1/ 2 4/ 1 9 
 
Pri or Versi o n(s):    
  
0 1/ 1 4/ 19 
 
 
I N D N u m ber:  
  
7 2 4 7 9 
 
I n vesti g ati o n al A ge nt:  
Tre os ulfa n 
 
St u d y Re gi m e n:   
  
Fl u dara bi n e a n d Tre os ulfa n- base d c o n diti o ni n g re gi me n f oll o we d 
b y t otal b o d y irra diati o n a n d u m bilical c or d bl o o d tra ns pla nt  
 
Pri nci p al I n vesti g at or:   
Fili p p o Mila n o, M D, Assista nt Me m ber, Fre d H ut c h Cli nical 
Researc h Di visi o n 
  
Assista nt Pr ofess or, Me dical O nc ol o g y, U ni versit y of Was hi n gt o n 
Sc h o ol of Me dici ne 
 
I N D S p o ns or:   
  
Fre d H utc hi ns o n Ca ncer Researc h C e nter 
  
  
  
  
1 1 0 0 Fair vie w A ve N, M/ S L M- 2 0 0 
  
  
  
  
Seattle, W A 9 8 1 0 9- 1 0 2 4 
 
 
 
 
( O): 2 0 6- 6 6 7- 2 7 3 1 
 
 
 
 
( F):  2 0 6- 6 6 7- 6 0 6 8 
 
 
 
 
I SI O C @fre d h utc h. or g 
 
Me dic al M o nit or:     
Sc ott Ba ker, M D 
 
 
 
 
Me m ber, Fre d H ut c h Cli nical Researc h Di visi o n 
 
 
 
 
( O): 2 0 6- 6 6 7- 5 5 9 4 
 
 
 
 
ks ba ker @fre d h utc h. or g  
 
A ut h orize d S p o ns or Re prese nt ati ve: 
Na me (t y pe d or pri nte d):  
Sc ott Ba ker, M D  
  
  
  
  
  
  
 
I nstit uti o nal Title:     
Me m ber, I SI O C Me dical M o nit or  
  
  
  
  
  
I nstit uti o n: 
  
 
Fre d  H utc hi ns o n Ca ncer Researc h C e nter        
  
  
  
 
Si g nat ure:  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
I R O r e c ei v e d 0 3/ 1 8/ 2 2
F H C R C I R B A p pr o v al  
0 4/ 1 4/ 2 0 2 2 
D o c u m e nt R el e a s e d D at e

2 2 7 5. 0 0 
 
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Si g n at ure P a ge: 
 
I n v esti gat or State me nt: 
 
I h a ve car ef ull y rea d Pr ot oc ol 2 2 7 5 e ntitle d “ Tra ns pla ntati o n of U m bilical C or d Bl o o d i n 
Patie nts wit h He mat ol o gical Mali g na ncies Usi n g a Tre os ulfa n Bas e d Pre parati ve Re gi me n ” 
versi o n date 0 1/ 2 4/ 2 0 1 9.   
 
I a gree t o carr y o ut m y res p o nsi bilities i n acc or da n ce wit h t he Pr ot oc ol, a p plica ble la ws a n d 
re g ulati o ns (i ncl u di n g 2 1 C F R Part 3 1 2), G o o d Cli nical Practice: C o ns oli date d G ui da nce (I C H-
E 6), a n d a p plica ble p olicies of Fr e d H utc h.   
 
Pri nci pal I n v esti gat or: 
 
Na me (t y pe d or pri nte d):  
Fili p p o Mila n o, M D    
  
  
  
  
  
  
 
I nstit uti o n a n d A d dress:   
Fre d H utc hi ns o n Ca ncer Researc h C e nter  
  
  
  
 
  
  
  
  
1 1 0 0 Fair vie w A ve n u e N, M/ S M D- B 3 0 6    
  
  
 
  
  
  
  
Seattle, W A   9 8 1 0 9    
  
  
  
  
  
 
 
P h o ne N u m ber:  
  
2 0 6- 6 6 7- 5 9 2 5   
  
  
  
  
  
  
 
 
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
  
 

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1.  
I ntr o d ucti o n 
 
C o n ve nti o nal m yel oa blati ve all o ge neic he m at o p oiet ic ste m cell tra ns pla ntati o n ( H C T) is 
li mite d b y lac k of ra pi dl y a vaila ble H L A m atc he d d o n ors a n d e xcess tra ns pla nt relate d m ortalit y 
( T R M). U m bilical c or d bl o o d ( U C B) is a n alter nati ve he mat o p oietic ste m cell s o urce wit h t he 
a d va nta ges of relati ve t ol era nce of H L A dis parit y [ 1- 5] a n d ra pi d a v aila bilit y [ 6]. E mer gi n g data 
s u p p orts t he efficac y U C B tra ns pla ntati o n ( U C B T) t o treat he mat ol o gic mali g na ncies, i ncl u di n g 
ac ute m yel oi d le u ke mia ( A M L), ac ute l y m p h o blastic le u ke mia ( A L L), a n d m yel o d ys plastic 
s y n dr o me ( M D S).  O pti mal c o n diti o ni n g re gi me ns f or U C B T, h o we ver, p artic ularl y i n ol der a n d 
i nfir m patie nts wit h hi g h-ris k disease, h a ve n ot yet bee n defi ne d.  
C o n diti o ni n g re gi me ns pla y a si g nifica nt r ole i n t h e o utc o me of H C T.  W hil e a g gressi ve 
m yel oa blati ve re gi me ns are ge n er all y ass ociate d wit h l o wer rela ps e ris k, t he y are als o ass ociat e d 
wit h i ncrease d tr a ns pla nt relate d m ortalit y ( T R M).  I n c o ntrast, less i nte nsi v e c o n diti o ni n g 
re gi me ns t hat rel y m or e si g nifica ntl y o n graft vers us disease ( G V D) effect t o treat disease are 
ge nerall y ass o ciate d wit h less t o xicit y, b ut are ass ociate d wit h hi g her rela pse ris k, partic ularl y 
a m o n g patie nts wit h hi g h ris k ac ute le u k e mias a n d M D S.  O pti mizi n g t he bala nce i n 
c o n diti o ni n g i nte nsit y t o ma xi mize disease c o ntr ol wit h o ut i ncreasi n g T R M is a n o n g oi n g 
c halle n ge i n H C T.  Tr e os ulfa n ( T R E O) is a b us ulfa n ( B U) a n al o g t hat has s e veral attracti ve 
c haracteristics as c o m par e d t o B U, i ncl u di n g less erratic p h ar mac o ki netics a n d p ote ntial f or 
hi g her a ntile u ke mic acti vit y.  T R E O is a p peali n g as a n a ge nt i n a re gi me n t hat is of less i nte nsit y 
t ha n c o n ve nti o nal m yel o a blati ve re gi me ns, b ut t h at is ca pa ble of ge nerati n g s ufficie nt a nti-
le u ke mic acti vit y t o i n d uce s ustai ne d re missi o ns i n hi g h-ris k patie nts.  T his pr ot oc ol will 
i n vesti gate t he effi cac y of a T R E O bas e d c o n diti o ni n g re gi me n pri or t o i nf usi o n of a n u nrelate d 
d o n or c or d bl o o d gr aft. 
 
2.  
B ac k gr o u n d a n d R ati o n ale 
 
 
  
E x perie nce wit h U C B T at t he F H C R C is gr o wi n g ra pi dl y.  Si nce Fe br uar y 2 0 0 6, 1 8 
patie nts ha ve bee n treat e d o n t he F H C R C sta n dar d m yel oa blati ve Pr ot oc ol 2 0 1 0 a n d 1 3 patie nts 
ha ve bee n treat e d o n t he F H C R C re d uce d-i nte nsit y c o n diti o ni n g ( RI C) Pr ot oc ol 2 0 1 2.   E ntr y 
criteria f or b ot h pr ot oc ols re q uires m or p h ol o gic blast c o u nts less t ha n 5 % f or A M L, A L L, a n d 
M D S, b ut mi ni mal resi d ual disease ( M R D) is all o we d.  Pr ot oc ol 2 0 1 0 is o pe n t o patie nts 4 5 a n d 
u n der, a n d c o n diti o ni n g is fl u dara bi ne ( F L U) 7 5 m g/ m 2, c ycl o p h os p ha mi de ( C Y) 1 2 0 m g/ k g, 
a n d T BI 1 3. 2 G y.  Pr ot oc ol 2 0 1 2 is o pe n t o patie nts a ge 7 0 a n d u n d er, a n d c o n diti o ni n g is F L U 
2 0 0 m g/ m 2, C Y  5 0 m g/ k g, a n d T BI 2 G y wit h t he a d diti o n of A T G 9 0 m g/ k g if t here w as n o 
e x p os ure t o si g nifica nt c he m ot hera p y i n t he t hree m o nt hs prece di n g U C B T.  Wit h a me dia n 
f oll o w- u p of 3 9 0 da ys a m o n g s ur vi v ors, 1 7/ 1 8 ( 9 4 %) patie nts treate d o n 2 0 1 0 re mai n ali ve a n d 
1/ 1 8 ( 6 %) patie nts has r ela pse d.   Se ve n of t hirtee n ( 5 4 %) patie nts treate d o n 2 0 1 2 re mai n ali ve 
a n d 5/ 1 3 ( 3 8 %) p atie nts ha ve rel a pse d. 
O utc o mes t o date i n t he m yel oa blati ve setti n g ha ve bee n e xtre mel y e n c o ura gi n g.  I n a 
hi g h-ris k p o p ulati o n, we ha ve o bser v e d o nl y o ne rela pse a m o n g 1 8 patie nts a n d o nl y o ne deat h 
d ue t o T R M.  Fiftee n of t hese patie nts recei ve d d o u ble c or d u nit tra ns pla ntati o ns (t hree patie nts 
recei v e d si n gle u nits).  T h o u g h t he data is preli mi nar y, e mer gi n g e vi de nce s u g gests t hat d o u ble 
u nit U C B T ma y be ass ociate d wit h re d uce d ris k of rela pse f or patie nts wit h g o o d disease c o ntr ol 
at t he ti me of tra ns pla ntati o n.  T he U ni versit y of Mi n nes ota has re p orte d t hat as c o m pare d t o 
si n gle u nit U C B T, t he i ntr o d ucti o n of d o u ble u nit U C B T  has mar ke dl y re d uce d t he ris k of 

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rela pse i n A M L p atie nts u n der g oi n g m yel oa blati v e c o n diti o ni n g i n m or p h ol o gic C R [ 7].  
Preli mi nar y a nal ysis of F H C R C data s u g gests t hat rela pse rate f oll o wi n g m yel oa blati ve d o u ble 
U C B T  ma y be l o wer t ha n t he rela pse rate f oll o wi n g c o n ve nti o nal d o n or m yel oa blati ve 
tra ns pla nt, b ut l o n ger f oll o w- u p a n d m ore p atie nts are nee de d t o c o nfir m t his o bser vati o n. 
I n o ur RI C a p pr oac h, use d f or ol der patie nts or p atie nts wit h si g nifica nt c o- m or bi dities, 
rela pse h as bee n a lar g er pr o ble m.  Fi ve of t hirtee n patie nts ha ve rela pse d.  F o ur of t hes e patie nts 
we nt t o U C B T wit h M R D or wer e a plastic f oll o wi n g c he m ot hera p y.  I n t he lar gest series of RI C 
U C B T re p orte d t o date, d escri bi n g o utc o mes i n 1 1 0 RI C U C B Ts perf or me d at t he U ni versit y of 
Mi n nes ota, rela pse was t he m ost c o m m o n ca use of deat h.  T he i n ci de nce of rela pse or 
pr o gressi o n f or t he 1 0 6 p atie nts tra ns pla nte d f or m ali g na nt diseases was 3 1 % ( 9 5 % CI, 2 1 %-
4 1 %) a n d disease pr o gr essi o n was t he m ost c o m m o n ca use of d eat h ( n = 2 7 vers us i nfecti o n n = 1 2 
a n d G V H D n = 6) [ 8].  Gi ve n t his a p pare nt i ncreas e d ris k of rel a pse f oll o wi n g RI C, c o u ple d wit h 
t he o bser vati o n t hat d o u ble u nit U C B T ma y re d uce t he ris k of rela pse a m o n g patie nts wit h g o o d 
disease c o ntr ol at t he ti m e of U C B T, a pre parati ve re gi me n wit h i m pr o ve d a nti-le u ke mic 
pr o perties b ut re d u ce d t o xicit y is partic ularl y a p peali n g. 
T R E O  is a n o vel a ge nt i n RIC re gi me n t h at ma y meet t hese criteria.  T R E O ( O vastat ®, 
L-treit ol- 1, 4- bis- met ha n es ulf o nate, di h y dr o x y b us ulfa n, T R E O; Me dac, Ha m b ur g, Ger ma n y) is a 
pr o dr u g of a bif u n cti o nal al k ylati n g a ge nt a n d a w ater-s ol u ble i ntra v e n o us B U a nal o g a p pr o v e d 
f or t hera p y of a d v a nce d o varia n carci n o ma i n E ur o pe. U n der p h ysi ol o gic c o n diti o ns, T R E O is 
s p o nta ne o usl y acti vate d i nt o e p o xi de s pecies t hat ca use cr oss-li n ki n g of D N A m olec ules a n d 
c yt ot o xicit y i n ra pi dl y pr oliferati n g cells, b ot h mali g na nt a n d n o n- mali g na nt, s uc h as n or mal 
he mat o p oietic cells [ 9, 1 0].  C o ntrar y t o B U, T R E O d oes n ot re q uire e nz y matic acti vati o n, t h us 
b y passi n g he patic meta b olis m. T he h y dr o x yl gr o u ps i n p ositi o ns 2 a n d 3 of t he m olec ule acc o u nt 
f or differe nces i n p har mac ol o gical acti vit y bet wee n T R E O a n d B U. B U directl y al k ylates 
n ucle o p h ylic ce nt ers, w hile T R E O i n d uces al k ylati o n of n ucle o p hilic ce nters b y i ntra m olec ular 
e p o xi de f or mati o n. Cli nical p har mac o ki netic st u dies ha ve de m o nstrat e d t hat T R E O has a si milar 
t ½ t o B U ( 1. 8 – 2 h o urs) a n d a hi g her, d os e-i n de p e n de nt, c u m ulati ve re nal e xcreti o n ( 5 0 % vs. 
2 0 %) [ 1 1, 1 2]. P har mac o ki netic st u dies of b ot h si n gle a n d m ulti ple i ntra ve n o us i nf usi o ns of 
T R E O ha ve de m o nstrat e d l o w i nter- patie nt a n d i nter- da y v aria bilit y. T here is a hi g h li near 
c orrel ati o n bet wee n t h e area u n der t he c ur ve a n d T R E O d ose (r 2 = 0. 9 2 2 7), w hic h c o m pares 
fa v ora bl y wit h t hat of oral a n d i ntra ve n o us B U [ 1 3, 1 4]. I n precli nical st u dies i n mice, rats, d o gs 
a n d pri mates, T R E O r es ulte d i n at least 1 0 ti mes l o wer ac ute a n d c hr o nic t o xicit y t ha n B U 
[ u n p u blis he d data, I n vesti gat or’s Br oc h ure].  Precli nical st u dies ha ve de m o nstrate d t he a ntit u m or 
acti vit y of T R E O a gai nst breast, l u n g a n d re nal cell carci n o ma, mela n o m a, m yel o ma, l y m p h o ma, 
c hr o nic m yel oi d le u ke mi a a n d ac ute le u ke mias. T R E O i n d uces cell deat h a n d a p o pt osis i n 
h u ma n A M L cells i n vitr o [ 1 5]. T he p ote nt i n vi v o acti vit y of T R E O a gai nst h u ma n B-cell a n d 
T-cell l y m p h o blasts has bee n de m o nstrat e d i n xe n o graft m o dels i n mice [ 1 6]. A si n gle d ose of 
3 0 0 0 m g/ k g T R E O or re peate d d oses of 1 0 0 0 m g/ k g f or 3 c o nsec uti ve da ys res ulte d i n s u peri or 
a ntile u ke mic acti vit y as c o m pare d t o ma xi m u m t olerate d d os es of B U or C Y i n t hese a ni mal 
m o dels. T he pr o n o u nce d effect of T R E O o n pri miti ve a n d c o m mitte d he mat o p oietic ste m cells 
a n d its i m m u n os u p pressi ve eff ects ha v e bee n d e m o nstrate d i n all o ge neic m uri ne tra ns pla nt 
m o dels [ 1 0]. At d oses 8 0- 8 8 % l o wer t h a n t h ose us e d f or h u ma ns i n cli nical trials, T R E O was at 
least as effecti ve as B U i n de pleti n g he mat o p oietic cell s u bsets. T R E O was ca pa ble of i n d uci n g 
f ull d o n or e n graft me nt a n d i m m u ne t olera nce acr oss M H C barriers. Marr o w s u p pressi o n is t he 
li miti n g t o xicit y f or c o n ve nti o nal c he m ot hera p y wit h T R E O at d oses o ver 1 0 g/ m 2 [ 1 7]. Wit h 
a ut ol o g o us ste m cell resc ue, t he T R E O d ose c o ul d be escal ate d u p t o 4 7 g/ m 2 bef ore d os e-

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li miti n g t o xicit y i ncl u di n g m uc ositis, diarr hea, der matitis or meta b olic aci d osis was o bser ve d 
[ 1 8]. Se ver e he pat ot o xicit y s uc h as ve n o- o ccl usi ve disease ( V O D), re n al, ne ur ol o gical or 
p ul m o nar y t o xicities k n o w n t o occ ur wit h ot her hi g h- d ose al k ylati n g a ge nts s uc h as B U ha ve n ot 
bee n o bser v e d wit h hi g h- d ose T R E O. 
Se veral ce nters o utsi de of t he U nite d States ha ve re p orte d e n c o ura gi n g o utc o mes i n s mall 
st u dies wit h T R E O base d RI C re gi me ns p erf or me d i n t he tra diti o nal d o n or setti n g [ 1 8- 2 4].   I n 
c olla b orati o n wit h Ore g o n Healt h a n d Scie n ce U ni versit y ( O H S U), t he F H C R C is partici pati n g 
i n t he first U nite d States trial of a T R E O bas e d re gi me n i n t he tra diti o nal d o n or setti n g.  Details 
of o utc o mes i n T R E O st u dies t o date are s u m marize d bel o w.  
 A t otal of 8 3 patie nts wit h he mat ol o gic mali g na ncies u n der g oi n g all o ge nei c H C T ha ve 
bee n treate d i n Me dac-s p o ns ore d st u dies of T R E O-c o ntai ni n g re gi me ns ( T a ble 1).   
 
T a ble 1. Preli mi n ar y res ults of st u dies of tre os ulf a n re gi me ns c o n d ucte d i n E ur o pe.  
 
 
Tre os ulf a n/ C ycl o p h os p h a mi de  
Tre os ulf a n/ Fl u d ar a bi ne  
N o. Patie nts  
2 7  
5 6  
A ge ( me d, r a n ge)  
4 4 ( 1 7 -6 4)  
5 0 ( 1 8 -6 6)  
Diseases  
1 0 A M L, 1 0 A L L, 2 C M L,  
3 M D S, 1 N H L, 1 H o d g ki n 
1 9 A M L, 1 A L L, 6 C M L,  
7 M D S, 8 N H L, 1 H o d g ki n, 
3 C L L, 1 1 m yel o ma  
M R D/ U R D  
1 8/ 9  
2 8/ 2 8  
Graft f ail ure  
1 ( 3 %)  
0  
Ac ute  G V H D  II -
I V 
6/ 2 7 ( 2 2 %)  
2 4/ 5 6 ( 4 3 %)  
C hr o nic G V H D  
3/ 1 5 ( 2 0 %)  
8/ 4 2 ( 1 9 %)  
1 -year O S  
6 7 %  
7 0 %  
1 -year P F S  
5 6 %  
5 3 %  
1 -year Rel a pse  
1 1 %  
1 5 %  
1 -year T R M  
3 3 %  
2 0 %  
T R M da y 2 0 0  
2 0 %  
1 5 %  
 
Tre os ulf a n a n d c ycl o p h os p h a mi de   
T we nt y-se ve n  patie nts,  me dia n  a ge  4 4  (ra n g e  1 7- 6 4)  years,  wit h  varie d  h e mat ol o gic 
mali g na ncies  recei ve d  t hree  d os es  of  1 2  or  1 4  g/ m 2  Tre os ulfa n  a n d  2  d oses  of  6 0  m g/ k g 
C ycl o p h os p ha mi de f oll o we d b y H L A -i de ntical si bli n g ( n = 1 8) or matc he d U R D ( n = 9) marr o w or 
P B S C  [ 1 9].  G V H D  pr o p h yla xis  was  wit h  c ycl os p ori ne  a n d  met h otre x ate.  T he  me dia n  ti me  t o 
ne utr o p hil e n graft me nt was 1 6 (r a n ge 1 1- 2 5) d a ys. O ne patie nt di d n ot e n graft pri or t o his d eat h 
fr o m  se psis  o n  da y  2 4.      Ac ute  G V H D  of  gra des  II-I V  a n d  e xte nsi ve  c hr o nic  G V H D  were 
o bser ve d  i n  6/ 2 7  ( 2 2 %)  a n d  3/ 1 5  ( 2 0 %)  e v al ua ble  patie nts,  res pecti vel y.  Si g nifica nt  t o xicities 
i ncl u de d  N CI  gr a de  3  ele vati o n  of  li ver  tra nsa mi nases  ( n = 1 2),  gra de  3  m uc ositis  ( n = 4), 
arr h yt h mia ( n = 1), gr a de 4 V O D ( n = 1) a n d A R D S ( n = 2). T hree ( 1 1 %) pati e nts die d fr o m rela pse. 
Ni ne ( 3 3 %) patie nts die d fr o m n o n-rela ps e ca uses, 6 fr o m i nfecti o n a n d 3 fr o m R R T ( 1 car di ac 
dec o m pe nsati o n/ m uc ositis, 1 car diac arrest, 1 m ulti or ga n fail ure). T he 1- y ear D F S is 5 6 %, wit h 
a me dia n f oll o w- u p of 1 2 m o nt hs. 
 
Tre os ulf a n a n d fl u d ar a bi ne 

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Pa ge 6  of 5 9  
Fift y -si x patie nts, me dia n a ge 5 0 (ra n ge 1 8- 6 6) y ears, wit h varie d h e mat ol o gic mali g na ncies 
recei v e d  t hree  d oses  of  1 0,  1 2  or  1 4  g/ m2  Tre os ulfa n  a n d  5  d oses  of  3 0  m g/ k g  Fl u dara bi ne 
f oll o we d b y H L A-i de nti cal si bli n g ( n = 2 8) or matc he d u nrelat e d ( n = 2 8)  marr o w or P B S C [ 2 0]. 
G V H D pr o p h yla xis was wit h c ycl os p ori ne wit h or wit h o ut t h y m o gl o b uli n ( u nrelate d reci pie nts 
o nl y). All patie nts e n gr afte d, wit h a m e dia n ti me t o ne utr o p hil e n graft me nt of 1 4 (ra n ge 1 0- 2 3) 
da ys. Ac ute G V H D of gr a des II-I V a n d e xte nsi ve c hr o nic G V H D w ere o bs er ve d i n 2 4/ 5 6 ( 4 3 %) 
a n d 8/ 4 2 ( 1 9 %) e val ua bl e patie nts, res pecti vel y. Si g nifica nt gra de 3 t o xicities i ncl u de d ele v ati o n 
of  bilir u bi n  or  li ver  tra nsa mi nases  ( n = 7),  diarr hea  ( n = 3),  m uc ositis  ( n = 2),  d ys p nea  ( 3)  a n d 
ele vati o n of creati ni ne ( n = 1). Ei g ht ( 1 5 %) patie nts die d fr o m rela pse. Ele ve n ( 2 0 %) patie nts die d 
fr o m n o n-rela ps e ca uses, 8 fr o m i nfecti o n, 2 fr o m G V H D wit h or wit h o ut i nfecti o n, a n d 1 fr o m 
R R T ( m y ocar dial i nfar cti o n). T he 1- year D F S is 5 3 %, wit h a me dia n f oll o w- u p of 2 1 m o nt hs. 
T hese r es ults s u g gest t hat t he c o m bi nati o n of Tre os ulfa n/ Fl u dara bi ne ma y res ult i n i m pr o ve d 
R R T  a n d  T R M  a n d  si milar  s ur vi val  c o m pare d  t o  Tre os ulfa n  / C ycl o p h os p ha mi de  or  B us ulfa n-
c o ntai ni n g  re gi me ns.  T he  rela pse  r ate  of  1 5 %  is  als o  pr o misi n g,  partic ularl y  w he n  c o nsi deri n g 
t hat  5 7 %  of  t he  patie nts  ha d  a d va nce d  diseas e.  T his  rate  of  rela pse  is  m uc h  l o wer  t ha n  t hat 
re p orte d wit h B us ulfa n/ Fl u dara bi ne st u dies w h ere 5 6- 5 7 % of t h e patie nts ha d a d va n ce d disease. 
O n g oi n g E ur o pea n p h ase I/II st u dies are e val u ati n g t he use of tre os ulfa n-c o ntai ni n g re gi me ns f or 
ot her diseases [ Me d a c, p ers o n al c o m m u nic ati o n, 2 0 0 7 ].    
 
E x perie nce wit h use of t re os ulf a n i n c hil dre n 
T he  e x perie n ce  wit h  t his  dr u g  i n  patie nts  of  pe diatric  a ge  is  li mite d.  Wac h o wia k  a n d 
c ollea g ues  c o n d u cte d  a  pil ot  st u d y  of  Tre os ulfa n-c o ntai ni n g  pre p arati ve  re gi me ns  f or  c hil dre n 
[ 2 3]. Ei g ht c hil dre n c o nsi dere d at hi g h ris k f or t o xicit y fr o m c o n ve nti o nal re gi me ns, of me dia n 
a ge 1 1 ( 4- 1 3) years, a n d dia g n osis of A M L ( n = 3), A L L ( n = 1), M D S ( n = 1), histi oc yt osis ( n = 1), 
Wis k ott- Al dric h  s y n dr o me  ( n = 1)  or  a de n ole u k o d ystr o p h y  ( n = 1)  were  st u die d.  T he y  recei v e d 
t hree d oses of Tre os ulf a n ( 1 0 or 1 2 g/ m2) i n c o m bi nati o n wit h ot her dr u gs i ncl u di n g Fl u dara bi ne, 
C ycl o p h os p ha mi de,  Mel p hala n  or  Et o p osi de,  f oll o we d  b y  H L A-i de ntical  si bli n g  marr o w  ( n = 7) 
or c or d bl o o d ( n = 1). G V H D pr o p h yla xis was wit h c ycl os p ori ne o nl y. All patie nts e n grafte d, wit h 
a me dia n ti me t o ne utr o p hil e n graft me nt of 1 9 (ra n ge 1 0- 2 2) da ys. Ac ute G V H D of gra d e II was 
o bser ve d i n 3 ( 3 8 %) pati e nts. E xte nsi ve c hr o nic G V H D w as o bser v e d i n 1 ( 1 3 %) patie nt. Se v ere 
or  fatal  t o xicities  wer e  n ot  o bser ve d.  T hree  p atie nts  de vel o pe d  mil d  m uc ositis  or  tra nsie nt 
ele vati o n  of  li ver  tra nsa mi nases  ( n = 2).  T w o  ( 2 5 %)  patie nts  rela pse d.  T h e  re mai ni n g  6  p atie nts 
are  ali ve  a n d  diseas e-fr ee,  wit h  a  me dia n  f oll o w- u p  of  1 2  m o nt hs.  Alt h o u g h  t he  n u m ber  of 
patie nts st u die d is s mall, t his st u d y s u g gests t hat t he use of Tre os ulfa n i n c hil dre n is feasi ble a n d 
relati vel y  saf e,  r es ulti n g  i n  mi ni mal  t o xicit y  or  p ost-tra ns pla nt  c o m plicati o ns  wit h o ut  a n 
i ncreas e d ris k f or rela ps e. C o ntrar y t o t he st u dies o n a d ult patie nts, t his st u d y di d n ot e v al uate t h e 
p ote ntial f or usi n g d oses of tre os ulfa n hi g her t ha n 1 2 g/ m 2 i n c hil dre n. P har mac o ki netic st u dies 
of Tre os ulfa n i n c hil dre n t o date ha ve b ee n li mite d.     
  
 
 
P h ase I/II st u d y of tre os ulf a n a n d fl u d ar a bi ne i n t he U nite d St ates  
I n  c olla b orati o n  wit h  Ore g o n  Healt h  a n d  Scie nce  U ni versit y  ( O H S U),  t he  F H C R C  has 
c o n d ucte d a st u d y t o d eter mi ne t he o pti m u m d ose of tre os ulfa n, i n c o m bi nati o n wit h fl u dara bi ne 
pri or t o all o ge nei c H C T wit h tra diti o nal d o n ors i n patie nts wit h A M L, A L L, or M D S. “ O pti mal” 
d ose was det er mi ne d b y safet y a n d efficac y, as d efi ne d b y i nci de n ce of se vere/fatal R R T, graft 

2 2 7 5. 0 0 
 
Pa ge 7  of 5 9  
fail ure a n d T R M. T hirt y-si x patie nts ( 8 c hil dre n a n d 2 8 a d ults > 1 8 years), wit h a me dia n of 4 1 
( 5- 5 8)  years,  a n d  dia g n ose d  wit h  A M L  i n  first  ( n = 1 9),  sec o n d  re missi o n  ( n = 7)  or  n ot  i n 
re missi o n ( n = 4), A L L i n sec o n d re missi o n ( n = 2) or M D S ( n = 4) h a ve b ee n treate d. Patie nts w ere 
c o nsi dere d  t o  be  at  hi g h  ris k  f or  T R M  beca use  of  a g gressi ve  t hera p y  f or  a  pri or  mali g na nc y, 
c o m or bi d c o n diti o ns or pre vi o us H C T. Patie nts recei ve d Tre os ulfa n at 1 2 ( n = 5) or 1 4 g/ m 2/ da y 
( n = 3 1) o n da ys - 6 t o - 4, a n d Fl u dara bi ne ( 3 0 m g/ k g/ da y) o n da ys - 6 t o - 2. G V H D pr o p h yla xis 
was  wit h  tacr oli m us  a n d  met h otre xate  ( n = 3 5)  or  c ycl os p ori ne  a n d  met h otre xate  ( n = 1).  D o n ors 
were  H L A - matc he d  si bli n gs  ( n = 1 9)  or  u nrelate d  v ol u nteers  ( n = 1 7);  s o urce  of  st e m  cells  were 
b o ne  marr o w  ( n = 7)  or  fil gras ti m- m o bilize d  peri p heral  bl o o d  cells  ( n = 2 9).  Ne utr o p hil 
e n graft me nt o cc urre d at a me dia n of 1 8 ( 1 1- 3 0) d a ys. Gra d e II-I V ac ute graft- vers us- h ost disease 
( G V H D)  was  o bs er ve d  i n  9  of  3 6  patie nts,  a n d  c hr o nic  G V H D  i n  8  of  2 3  e val ua ble  p atie nts 
s ur vi vi n g  be y o n d  p ost-tra ns pla nt  da y  8 0.  D ose-li miti n g  R R T  was  o bser ve d  i n  1  of  3 6  patie nts 
( m uc ositis re q uiri n g i nt u bati o n). Wit h a me dia n f oll o w- u p of 1 1 8 ( 2 0- 5 7 5) da ys, esti mate d o ne-
year  o ver all  a n d  disease-fr ee  s ur vi val,  rela ps e  a n d  T R M  are  8 3 %,  7 8 %,  2 2 %  a n d  0 %, 
respecti vel y.  Da y- 1 0 0  m ortalit y  o bser ve d  t o  dat e  is  6 %.  Tre os ulfa n/ Fl u d ara bi ne  s ee ms  t o  be  a 
well -t olerate d re gi me n wit h pr o misi n g disease c o ntr ol a n d l o w rates of R R T a n d T R M i n patie nts 
wit h ac ute le u ke mia a n d M D S.   
 
Tre os ulf a n i n c or d tr a ns pl a nt 
W hile a T R E O bas e d U C B T re gi me n h ol ds a p peal, t w o si g nifica nt c o ncer ns s pecific t o t he 
U C B T setti n g i ncl u de pr o ba ble dela y e d e n graft m e nt a n d t he p ossi bilit y of graft fail ure.  I n 
Mi n nes ota’s i nitial eff ort at RI C U C B T, it perf or me d 2 1 tra ns pla nts f oll o wi n g c o n diti o ni n g wit h 
B U 8 m g/ k g, F L U 2 0 0 m g/ m 2, a n d 2 0 0 c G y T BI.  T his re gi me n was ass o ciate d wit h ne utr o p hil 
e n graft me nt at 2 6 da ys ( 1 2- 3 0) a n d t his dela ye d n e utr o p hil e n graft me nt res ulte d i n Mi n nes ota 
s witc hi n g t o t he F L U/ C Y/ T BI +/- A T G re gi me n t hat is t he basis f or F H C R C pr ot oc ol 2 0 1 2 [ 2 5]. 
T he s witc h t o a F L U/ C Y/ T BI r e gi me n i n Mi n nes ota res ulte d i n i nitial a ut ol o g o us he mat o p oietic 
rec o ver y, a n d a decreas e i n ti me t o ne utr o p hil e n graft me nt t o a me dia n of 1 2 da ys (ra n g e, 0- 3 2).  
Si milarl y, i n o ur e x perie nce, me dia n ti me t o e n graft me nt o n pr ot oc ol 2 0 1 2 is 1 1 da ys ( 6- 4 9) 
c o m pare d t o 2 5 da ys ( 1 4- 4 4) o n t he m yel oa blati ve U C B T F H C R C pr ot oc ol 2 0 1 0. Base d o n 
e x perie n ce i n t he tra diti o nal d o n or setti n g wit h T R E O base d re gi me ns [ 2 6], as well as 
Mi n nes ota’s e x perie nce wit h a n i nter me diate d os e B U base d re gi me n, we e x pect t hat a T R E O 
base d U C B T re gi me n will res ult i n pr ol o n ge d ne utr o pe nia.  Gi ve n t he ol der a ge a n d hi g h er 
c o m or bi dities of patie nts ge nerall y c o nsi d ere d f or RI C, t his pr ol o n ge d ne utr o pe nia is a 
si g nifica nt c o ncer n.  F or patie nts at hi g h-ris k f or rela pse, h o we v er, w e beli e ve t he p ote ntial 
be nefit of t he i ncreas e d a nti-le u ke mic affect o ut w ei g hs t he ris ks.   
O ur c o ncer n a b o ut graft f ail ure i n t he U C B T setti n g ste ms fr o m ot her ce nt ers’ e x perie n ce 
wit h B U/ F L U base d r e gi me ns. Mi n nes ota e x peri e nce d 4 graft fail ures i n t heir first 2 1 RI C 
patie nts recei vi n g B U/ F L U (al beit i n patie nts at ris k f or graft fail ure b y virt ue of less treat me nt 
bef ore tr a ns pla nt) [ 2 5].  D u ke has r ece ntl y re p ort e d ver y hi g h graft fail ures ( 6/ 1 0 graft fail ures) 
f oll o wi n g I V B U 5 2 0 m g/ m 2 ( mea n A U C 4 1 8 1 u m ol- mi n), F L U 1 6 0 m g/ m 2 [ 2 7].  S pai n, 
h o we ver, h as re p orte d g o o d e n graft me nt usi n g a t hi ote pa 1 5 m g/ k g, I V B U 9. 6 m g/ k g, F L U 1 5 0 
m g/ m 2, A T G 8 m g/ k g pre parati ve re gi me n [ 2 8].  Patie nts u n der g oi n g a n RI C re gi me n wit h c or d 
bl o o d as t he d o n or s o urce are at a n i ncreas e d ris k of graft fail ure.  T h o u g h T R E O is li kel y m ore 
i m m u n os u p pressi ve t ha n B U a n d ma y pr o m ote e n ha nce d e n graft me nt as c o m pare d t o B U, we 
belie ve t hat a T R E O/ F L U base d r e gi me n ma y re q uire a d diti o nal i m m u n os u p pressi ve t hera p y t o 
pr o m ote e n graft me nt.  We t heref ore pr o p ose a T R E O/ F L U re gi me n usi n g T R E O 4 2 g/ m 2 a n d 

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F L U 1 5 0 m g/ m 2 si milar t o t hat esta blis he d i n t he F H C R C/ O H S U P hase 1 st u d y i n t he tra diti o nal 
d o n or setti n g wit h t he a d diti o n of a si n gle d ose of 2 0 0 c G y T BI.  D ose escalati o n r ules are 
esta blis he d t o first i ncrease F L U t o 2 0 0 m g/ m 2 a n d t he n i ncreas e T BI t o 3 0 0, 4 0 0, a n d 4 5 0 c G y 
T BI i n t he e v e nt of e x cessi ve graft f ail ures.  
Pre vi o us e x perie n ce wit h RI C U C B T s u g gests t hat patie nts w h o ha ve ha d li mite d pri or 
t hera p y are at p artic ularl y greater ris k f or graft fail ure.  F or t h e p ur p oses of deter mi ni n g 
acce pta ble e n graft me nt r ates f oll o wi n g T R E O/ F L U/ T BI, p atie nts will be classifie d as l o w ris k 
f or graft fail ure ( Ar m 1) or hi g h ris k f or graft fail ure ( Ar m 2) as f oll o ws.  F or eac h ar m, a tr ue 
pr o ba bilit y of graft f ail ur e of 5 % ( or less) will be acce pte d wit h o ut d ose es calati o n. 
 
•  Ar m 1:  L o w-ris k patie nts i ncl u de t h ose w h o ha ve recei v e d ≥ 2 c ycl e s of m ultia ge nt 
c he m ot hera p y a n d at least o ne c ycle of t h era p y wit hi n t he 3 m o nt hs pre vi o us t o U C B T.   
 
•  Ar m 2:  Hi g h-ris k patie nts i ncl u de t h ose w h o ha ve recei v e d n o m ultia ge nt c he m ot hera p y 
or i m m u ne s u p pressi ve c he m ot hera p y i n t he 3 m o nt hs pri or t o tra ns pla nt or ha ve recei ve d 
o nl y a si n gle i n d ucti o n t hera p y.   
   
We belie v e t hat a T R E O/ F L U bas e d c o n diti o ni n g re gi me n ma y i m pr o ve o utc o mes f or 
ac ute le u k e mia a n d M D S U C B T patie nts u na ble t o t olerate hi g h- d ose m yel o a blati ve t hera p y b ut 
at hi g h ris k f or rela ps e.  I n a d diti o n t o p ossi bl y i m pr o vi n g o utc o mes f or t h ose RI C patie nts at 
hi g h-ris k f or rel a pse, a T R E O re gi me n w o ul d pr o vi de a hi g her i nte nsit y c h e m ot hera pe utic 
treat me nt o pti o n f or patie nts i neli gi ble f or hi g h d ose ra diati o n a n d t heref ore i neli gi ble f or 
F H C R C pr ot oc ol 2 0 1 0. E x perie nce wit h t he re gi m e n i n t his setti n g ma y lea d t o its e xte nsi o n t o a 
br oa der gr o u p of c or d patie nts.  
 
3.  
O bjecti ves 
 
A.   
Pri mar y O bjecti ve :  
 
T he pri mar y o bjecti ve of t his st u d y is t o s h o w t hat T R E O/ F L U/ T BI as a s ufficie nt 
c o n diti o ni n g re gi me n re d uces t he pr o b a bilit y of graft fail ure as c o m pare d t o a n hist orical 
be nc h mar k a n d t hat t he ris k of da y - 2 0 0 N R M is n ot hi g her t ha n a rele va nt hist orical 
be nc h mar k. Patie nts will be di vi de d i nt o t w o ar ms base d o n ris k of graft fail ure as 
descri be d a b o ve. 
 
Pri mar y e n d p oi nts are as liste d bel o w:  
1.  
G raft f ail ure/rej ecti o n a n d sec o n dar y graft fail ure.  Patie nts will be c o nsi dere d 
pri mar y graft fail ure/r ejecti o ns pr o vi de d t he y meet a n y criteria liste d bel o w: 
i. A bse nce of 3 c o nsec uti ve da ys wit h ne ut r o p hils ≥5 0 0/ ul c o m bi ne d 
wit h h ost C D 3 peri p heral bl o o d c hi meris m ≥ 5 0 % at da y 4 2  
ii. A bse nce of 3 c o nsec uti ve da ys wit h ne utr o p hils ≥5 0 0/ ul u n der a n y 
circ u msta nces at da y 5 5 
iii. Deat h aft er da y 2 8 wit h ne utr o p hil c o u nt < 1 0 0/ ul wit h o ut a n y e vi de nce 
of e n graft me nt ( < 5 % d o n or C D 3) 
i v. Pri mar y a ut ol o g o us c o u nt rec o ver y wit h < 5 % d o n or C D 3 peri p heral 
bl o o d c hi meris m at c o u nt rec o ver y a n d wit h o ut rel a pse 

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Sec o n dar y gr aft f ail ure is defi ne d as d ecli ne of n e utr o p hil c o u nt t o < 5 0 0/ ul wit h 
l oss of d o n or c hi meris m after d a y 5 5 
 
2.  
Da y - 2 0 0 n o n-rela pse m ortalit y 
 
B.   
Sec o n dar y E n d p oi nts: 
 
1.  
Platelet e n graft me nt b y si x m o nt hs  
2.  
Gra de II-I V a n d III-I V ac ute G V H D  at d a y 1 0 0 a n d o ne year 
3.  
C hr o nic G V H D     
4.  
Cli nicall y si g nifica nt i nfecti o ns   
5.  
O verall s ur vi val  
6.  
Rela pse or diseas e pr o gressi o n  
7. 
( F H C R C o nl y) I m m u ne rec o nstit uti o n 
8. 
( F H C R C o nl y) E mer g e n ce of a d o mi na nt u nit 
 
4.  
P atie nt Selecti o n  
 
A.   
I n cl usi o ns  
 
  
1.  Disease Criteria 
a.  
Ac ute M yel oi d Le u k e mia/ Ac ute L y m p h o blastic L e u ke mia, i ncl u di n g 
Bi p he n ot y pic Ac ute Le u ke mia or Mi xe d- Li nea ge Le u ke mia : M ust ha ve < 
5 % m or p h ol o gic marr o w blasts i n a n e val ua ble m arr o w s a m ple ( > 2 5 % of 
n or mal cell ularit y f or a ge c ollecte d less t ha n o n e m o nt h pri or t o start of 
c o n diti o ni n g.  Patie nts i n w hic h a de q u ate marr o w/ bi o ps y s peci me ns 
ca n n ot be o btai ne d t o d eter mi ne re missi o n stat us b y m or p h ol o gic 
assess me nt, b ut ha ve f ulfille d criteria of re missi o n b y fl o w c yt o metr y, 
rec o ver y of peri p heral bl o o d c o u nts wit h n o circ ul ati n g blasts, a n d/ or 
n or mal c yt o ge netics (if a p plica ble) ma y still be eli gi ble. Reas o na ble 
atte m pts m ust be ma de t o o btai n a n a de q u ate s peci me n f or m or p h ol o gic 
assess me nt, i ncl u di n g p ossi ble re peat pr o ce d ures. T hese patie nts m ust be 
disc usse d wit h t he Pri nci pal I n v esti gat or, Fili p p o Mila n o ( 6 6 7- 5 9 2 5 or 
pa ger, 3 1 4- 1 0 3 7) pri or t o e nr oll me nt.  Patie nts persiste ntl y a plastic f or 
greater t ha n o ne m o nt h si nce c o m pleti n g last c he m ot hera p y are als o 
eli gi ble wit h PI a p pr o v al.  
b.  
M yel o d ys plastic s y n dr o me ( M D S) : A n y 2 0 0 1 W H O classificati o n s u bt y p e 
( A p pe n di x I). R A E B - 2 p atie nts ma y pr ocee d directl y t o tra ns pla nt, b ut 
ma y als o be c o nsi dere d f or i n d ucti o n c he m ot hera p y bef ore tra ns pla nt.  
Patie nts wit h ≥2 0 % m or p h ol o gic marr o w blasts re q uire i n d ucti o n t hera p y 
t o re d uce m or p h ol o gic m arr o w blasts bel o w 5 % b ef ore tra ns pla nt.  
c.   
C hr o nic m yel o ge n o us le u ke mia: All t y pes, e xce pt refract or y blast crisis. 
C hr o nic p hase patie nts m ust ha ve faile d or b ee n i nt olera nt t o Glee vec or 
ot her t yr osi ne ki nase i n hi bit ors.    
 

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Pa ge 1 0  of 5 9  
2.  A ge, Or g a n F u n cti o n a n d Perf or ma nce Stat us Criteria 
a.  
S u bjects m ust be ≤ 6 5 years ol d.  Patie nts <  5 0 m ust ha ve perf or ma nce 
stat us sc ore: Kar n ofs k y (f or a d ults) ≥ 7 0 or E C O G 0- 1; La ns k y (f or 
c hil dre n) sc ore ≥ 5 0 ( A p p e n di x II).  Patie nts > 5 0 m ust ha ve Kar n ofs k y 
perf or ma n ce s c ore > 7 0 or E C O G 0- 1 a n d c o m or bi dit y i n de x < 5 
( Ap pe n di x II) .  
b.   
A de q uate car diac f u n cti o n defi ne d as a bse nce of d ec o m pe nsate d 
c o n gesti ve heart fail ure or u nc o ntr olle d arr h yt h mia A N D  
  i. 
left ve ntric ular ejecti o n fracti o n > 3 5 %  O R  
  ii. 
fracti o nal s h ort e ni n g > 2 2 % 
c.     
A de q uate p ul m o nar y f u n cti o n defi ne d as a bse nce of O 2 re q uire me nts a n d  
o ne of t he f oll o wi n g: 
i. 
D L C O c orrecte d ≥7 0 %  m m H g 
ii. 
D L C O c orrecte d b et wee n 6 0 % - 6 9 % m m H g a n d p O 2 ≥7 0 m m 
H g  
iii. 
D L C O c orrecte d b et wee n 5 0 % - 5 9 % m m H g a n d p O 2 ≥8 0 m m 
H g  
Pe diatric patie nts u na ble t o perf or m p ul m o nar y f u ncti o n tests m ust ha ve 
O 2 sat urati o n > 9 2 % o n r o o m air. Ma y n ot be o n s u p ple me ntal o x y ge n. 
d.   
A de q uate h e patic f u n cti o n.  Patie nts wit h cli nical or la b orat or y e vi de nce 
of li ver disease will be e val uate d f or t h e ca us e of li ver disease, its cli nical 
se verit y i n ter ms of li ver f u ncti o n, hist ol o g y, a n d t he de gree of p ort al 
h y perte nsi o n. Patie nts wit h f ul mi na nt li ver fail ure, cirr h osis wit h e vi de nce 
of p ortal h y perte nsi o n or bri d gi n g fi br osis, alc o h olic he patitis, es o p ha geal 
varices, a hist or y of blee di n g es o p ha geal varices, he patic e n ce p hal o pat h y, 
or c orr ecta ble h e patic s y nt hetic d ysf u ncti o n e vi de nce d b y pr ol o n gati o n of 
t he pr ot hr o m bi n ti me, ascites relate d t o p ort al h y perte nsi o n, bact erial or 
f u n gal a bscess, biliar y o bstr ucti o n, c hr o nic viral h e patitis wit h t otal ser u m 
bilir u bi n > 3 m g/ d L, a n d s y m pt o matic biliar y disease will be e xcl u d e d. 
e.  
A de q uate r e nal f u n cti o n defi ne d as creati ni ne < 2. 0 m g/ dl (a d ults) or 
esti mate d creati ni ne cleara nce > 4 0 ml/ mi n ( pe diatrics). All a d ults wit h a 
creati ni ne > 1. 2 or a hist or y of re n al d ysf u ncti o n m ust ha ve esti mate d 
creati ni ne clear a nce > 4 0 ml/ mi n.  
f.  
If rece nt m ol d i nfecti o n, e. g., As per gill us,  m ust be cleare d b y i nfecti o us 
disease t o pr ocee d. 
g.  
Pri or he mat o p oietic cell tra ns pla nt: M ust be > 3 m o nt hs after pre vi o us 
tra ns pla nt. 
 
B.   
E xcl usi o ns   
 
1.  
Pre g na nc y or breastfee di n g.  
2.  
E vi de nce of HI V i nf ecti o n or k n o w n HI V p ositi ve ser ol o g y. 
3.  
U nc o ntr olle d viral or b acterial i nfecti o n at t he ti m e of st u d y e nr oll me nt. 
4.  
Acti ve or r ece nt ( pri or 6 m o nt h) i n vasi ve f u n gal i nfecti o n wit h o ut I D c o ns ult a n d 
a p pr o val. 

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5.  
C N S  le u ke mic  i n v ol ve me nt  n ot  cleari n g  wit h  i ntrat hecal  c h e m ot hera p y  a n d/ or 
cra nial r a diati o n pri or t o i nitiati o n of c o n diti o ni n g ( da y – 6). 
 
5.  
D o n or Selecti o n 
 
 
C B d o n or selecti o n will be base d o n i nstit uti o nal g ui deli nes a n d i n ge neral s h o ul d be selecte d t o o pti mize 
b ot h H L A matc h a n d cell d ose. A d diti o nall y, C B grafts s hall c o nsist of o ne or t w o C B d o n ors base d o n, 
b ut n ot e xcl usi vel y deter mi ne d b y, cell d ose ( T N C/ k g a n d C D 3 4/ k g), H L A matc hi n g a n d disease stat us 
a n d i n dicati o n f or tra ns pla nt. Atte n di n g prefere nce will be all o we d f or si n gle vers us d o u ble u nit as well as 
t he de gree of mis matc hi n g base d o n patie nt s pecific fact ors, as l o n g as t he f oll o wi n g mi ni m u m criteria are 
met:  
 
A.  H L A matc hi n g:  
i. 
Mi ni m u m re q uire me nt: T he C B graft(s) m ust be matc he d at a mi ni m u m at 4/ 6 H L A- A, 
B, D R B 1 l oci wit h t he reci pie nt. T heref ore 0- 2 mis matc hes at t he A or B or D R B 1 l oci 
base d o n i nter me diate res ol uti o n A, B a nti ge n a n d D R B 1 allele t y pi n g f or deter mi nati o n 
of H L A- matc h is all o we d.  
ii. H L A - matc hi n g deter mi ne d b y hi g h res ol uti o n t y pi n g is all o we d per i nstit uti o nal 
g ui deli nes as l o n g as t he mi ni m u m criteria ( # A.i., a b o ve) are met.  
 
B.  Selecti o n of t w o C B u nits is ma n dat or y w he n a si n gle c or d bl o o d u nit d oes n ot meet t he 
f oll o wi n g criteria i n t he ta ble bel o w.   
 
 
Si n gle U nit All o we d f or:  
M atc h Gr a de  T N C D ose  
6 / 6 
≥ 2. 5 x 1 0 7/ k g 
5/ 6, 4/ 6  
≥ 4. 0 ( ± 0. 5) x 1 0 7/ k g 
 
If t w o C B u nits are use d, t he t otal cell d ose of t he c o m bi ne d u nits m ust be at least 3. 0 x 
1 0 7 T N C per kil o gra m reci pie nt wei g ht base d o n pre-cr y o preser vati o n n u m bers, wit h eac h C B 
u nit c o ntai ni n g a MI NI M U M of 1. 5 x 1 0 7 T N C/ k g.  
 
C.  T he mi ni m u m rec o m me n de d C D 3 4/ k g cell d ose s h o ul d be 2 x 1 05 C D 3 4/ k g, t otal d ose fr o m a 
si n gle or c o m bi ne d d o u ble.  
 
D.  T he u n ma ni p ulate d C B u nit(s) will be F D A lice nse d or will be o btai ne d u n der a se parate I N D, 
s uc h as t he Nati o nal Marr o w D o n or Pr o gra m ( N M D P) Pr ot oc ol 1 0- C B A c o n d ucte d u n der B B 
I N D- 7 5 5 5 or a n ot her I N D s p o ns ore d b y ( 1) a partici pati n g i nstit uti o n or ( 2) a n i n vesti gat or at 
F H C R C or o ne of t he partici pati n g i nstit uti o ns.  
 
E.  F H C R C o nl y : U p t o 5 % of t he u n ma ni p ulate d c or d bl o o d pr o d uct (s), w he n rea d y f or i nf usi o n, 
ma y be wit h hel d f or researc h p ur p oses as l o n g as t hres h ol ds f or i nf use d T N C d ose are met.  
T hese pr o d ucts will be use d t o c o n d uct st u dies i n v ol vi n g t he ki netics of e n graft me nt a n d 
i m m u n o bi ol o g y of d o u ble c or d tra ns pla ntati o n. 
 
         F.  U C B U nit E xcl usi o ns 
 
1.  
A n y c or d bl o o d u nits wit h < 1. 5 x 1 0 7 t otal n ucleate d cells per kil o gra m reci pie nt 
wei g ht. 

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2.   
A n y c or d bl o o d u nits wit h o ut f ull mater nal testi n g a n d ne gati ve res ults f or 
he patitis B, C, HI V, a n d H T L V- 1 vir uses. A n y a d diti o nal a vaila ble vir ol o g y 
res ults o n t he u nit itself will be re vie we d b ut are n ot ma n date d, c o m plete or 
al wa ys a vaila bl e. C or d bl o o d u nits are pres u me d t o be C M V ne gati ve re gar dless 
of ser ol o gic testi n g d ue t o passi ve tra ns missi o n of mater nal C M V a nti b o dies.  
 
6.  
E v al u ati o n a n d C o u nseli n g of P atie nt   
  
  
T he patie nt a n d d o n or u nits will be c o m pletel y e val uate d per st a n dar d practice.  T he pr ot oc ol 
will be disc usse d t h or o u g hl y wit h patie nt a n d care gi vers, a n d all k n o w n ris ks t o t he patie nt will 
be descri b e d.  T he pr o ce d ure a n d alter nati ve f or ms of t hera p y will be prese nte d as o bjecti vel y as 
p ossi ble a n d t he ris ks a n d hazar ds of t he pr o ce d ure e x plai ne d t o t he p atie nt or, i n t he case of 
mi n ors, t o t he patie nt's res p o nsi ble fa mil y me m bers. I nf or me d c o ns e nt fr o m t he patie nt will be 
o btai ne d usi n g a c o nse nt d oc u me nt a p pr o ve d b y t h e I nstit uti o nal Re vie w B oar d (I R B) of t h e 
Fre d H utc hi ns o n Ca ncer Researc h C e nter.  
 
7.  
Pr ot oc ol R e gistr ati o n  
 
F H C R C patie nts: Eli gi ble patie nts will be i de ntifie d b y t he Cli nical C o or di nat ors Office. Patie nts 
will be re gistere d wit h t h e Re gistrati o n Office ( 2 0 6- 6 6 7- 4 7 2 8) bet w ee n 8: 3 0 a m a n d 4: 0 0 p. m. 
Pacific ti me, M o n da y t hr o u g h Fri da y.  After h o urs, t he Re gistrati o n office ca n be reac h e d b y 
pa gi n g ( 2 0 6) 9 9 5- 7 4 3 7. 
 
 
8.  
Pl a n of Tre at m e nt  
 
A.   
C o n diti o ni n g Re gi me n 
 
T he st u d y has t w o ar ms, deter mi ne d b y ris k f or graft fail ure as o utli ne d bel o w: 
 
Ar m 1:  L o w-ris k patie nts i ncl u de patie nts w h o ha ve recei ve d ≥ 2 c y cle s of m ultia ge nt 
c he m ot hera p y a n d at least o ne c ycle of t h era p y wit hi n t he 3 m o nt hs pre vi o us t o U C B T.   
 
Ar m 2:  Hi g h-ris k patie nts i ncl u de patie nts w h o ha ve recei ve d n o m ultia ge nt c he m ot hera p y or 
i m m u ne s u p pressi ve c he m ot hera p y i n t he 3 m o nt hs pri or t o tra ns pla nt or h a ve recei ve d o nl y a 
si n gle i n d ucti o n t hera p y.   
 
C o n diti o ni n g re gi me n f or b ot h ar ms will be t he sa me i nitiall y.  As o utli ne d i n t he Statistical 
C o nsi derati o ns ( Secti o n 1 4), d ose escalati o ns will occ ur i n eit her ar m i f s ufficie nt e vi de nce e xists 
t o s u g gest t hat t he tr ue pr o ba bilit y of graft fail ure e xcee ds 5 %.  Ste p wise d ose escal ati o n if graft 
fail ures persist will be t o first i ncreas e fl u dara bi ne t o 2 0 0 m g/ m2 (a d mi nistere d at 4 0 m g/ m 2 
dail y da ys - 6 t o - 2), t he n t o escalate T BI t o 3 0 0 c G y, t he n t o 4 0 0 c G y, t he n t o 4 5 0 c G y.   

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Pa ge 1 3  of 5 9  
 
Da y – 6  
Fl u dara bi n e 3 0 m g/ m 2 I V o ver 1 h o ur*  
Tre os ulfa n 1 4 g/ m 2 I V o ver 2 h o urs  
Da y – 5  
Fl u dara bi n e 3 0 m g/ m 2 I V o ver 1 h o ur 
Tre os ulfa n 1 4 g/ m 2 I V o ver 2 h o urs  
Da y -4  
Fl u dara bi n e 3 0 m g/ m 2 I V o ver 1 h o ur  
Tre os ulfa n 1 4 g/ m 2 I V o ver 2 h o urs  
Da y – 3  
Fl u dara bi n e 3 0 m g/ m 2 I V o ver 1 h o ur 
Da y – 2  
Fl u dara bi n e 3 0 m g/ m 2 I V o ver 1 h o ur 
Da y – 1  
T BI 2 0 0 c G y  ( or escal ate d t o 3 0 0 c G y, 4 0 0 c G y, 
or 4 5 0 c G y per g ui deli nes o utli ne d i n t he statistical 
c o nsi derati o ns Sec ti o n 14 ) 
Da y 0  
U C B tra ns pla nt  
* Fl u dara bi ne will be i ncrease d t o 4 0 m g/ m 2 dail y da ys -6 t o -2 i n t he e ve nt of e xcessi ve graft fail ures  
 
1.   
Tre os ulfa n a d mi nistrati o n.  
a.  
F or patie nts f or patie nts w h ose b o d y s urface area ( B S A) > 1. 0 m2, 
T R E O will be a d mi nistere d i ntra ve n o usl y at a d os e of 1 4 g/ m 2/ da y o ver 
1 2 0 mi n utes f or t hree c o nsec uti ve da ys ( d a y – 6 t o – 4).  D oses of 1 4 
g/ m 2/ da y f or i nfa nts a n d s maller c hil dre n wit h l o w B S A res ults i n 
si g nifica ntl y hi g her tre os ulfa n e x p os ure ( A U C); t heref ore, t he f oll o wi n g 
B S A - de pe n de nt d osi n g sc he ma will be use d f or t h e treat me nt of i nfa nts 
a n d s maller c hil dre n w he n t heir B S A is ≤1. 0 m 2.  F or patie nts > 1 2 0 % of 
i deal wei g ht, B S A will be calc ul ate d usi n g a dj uste d wei g ht. 
 
B o d y s urf a ce a re a ( m 2) 
Tre os ulf a n d ose ( g/ m 2) 
 
≤ 0. 5  
1 0. 0  
 
> 0. 5 –  1. 0  
1 2. 0  
 
> 1. 0  
 
1 4. 0  
 
 
T R E O will be s u p plie d t o i n vesti gat ors b y Me dac G m b H, Ha m b ur g 
Ger ma n y u n d er a n i nstit uti o n-s p o ns ore d I N D of t h e U. S. F o o d a n d Dr u g 
A d mi nistrati o n (I N D 7 2, 4 7 9, A p pr o ve d 6/ 2 2/ 2 0 0 5, S p o ns or : Fre d H utc h). 
T he dr u g will be deli vere d b y c o urier t o eac h p artici pati n g ce nters’ 
p har mac y as a cli nical i n vesti gati o nal pr o d uct wit h a st u d y-s pecific l a bel 
o n t he glass vial, as a p pr o ve d b y t he F D A. T R E O is a vaila ble as a w hite 
cr ystalli ne p o w der i n vials of 1 0 0 0 m g a n d 5 0 0 0 m g. T he dr y pr o d u ct 
m ust be st ore d at r o o m te m perat ure a n d has a s h elf life of 5 years. T R E O 
m ust be diss ol ve d i n 2 0 ml ( 1 g vial) or 1 0 0 ml ( 5 g vial) of 0. 4 5 % s o di u m 
c hl ori de f or i njecti o n f or a fi nal c o nce ntrati o n of 5 0 m g/ ml. T he 0. 4 5 % 
s o di u m c hl ori de m ust be war me d t o 2 5- 3 0° C ( n ot hi g her) usi n g a w ar mer 
or water b at h. T he rec o nstit ute d s ol uti o n s h o ul d re mai n at r o o m 
te m perat ur e a n d be us e d t he da y of pre parati o n. T he rec o nstit ute d s ol uti o n 
s h o ul d n ot be st ore d i n a refri gerat or b eca us e cr yst allizati o n ma y occ ur at 
l o w te m perat ur es. Aci dic me dia d o n ot i nfl ue nce t he sta bilit y of 
tre os ulfa n. I n al kali ne a n d ne utral s ol uti o ns tre os ulfa n dec o m p oses t o 
met ha nes ulf o nic aci d a n d t hreit ol. T he rec o nstit ute d s ol uti o n has a 

2 2 7 5. 0 0 
 
Pa ge 1 4  of 5 9  
p h ysic oc he mical sta bilit y of 4 8 h o urs w he n st ore d at r o o m te m perat ure i n 
t he ori gi nal glass b ottle. 
 
2.  
Fl u dara bi n e a d mi nistrati o n. 
a.  
Fl u dara bi n e will be a d mi nistere d at a d ose of 3 0 m g/ m2 I V o ver o ne h o ur 
o nce dail y o n eac h of 5 c o nsec uti ve da ys f or a t otal d ose of 1 5 0 m g/ m 2.  
Patie nts > 1 2 0 % of i deal wei g ht, B S A will be calc ulate d usi n g a dj uste d 
wei g ht. 
b.  
If fl u dar a bi ne has b ee n escalate d t o 4 0 m g/ m 2, fl u dara bi ne d os e f or a d ult 
patie nts ( > 1 8 years ol d) wit h re nal i m pair me nt ( d efi ne d as Cr Cl < 
7 0 m L/ mi n ute per 2 4- h o ur) is 3 5 m g/ m 2 dail y f or fi ve c o nsec uti ve d a ys 
gi ve n as n ote d a b o ve. Patie nts > 1 2 0 % of i deal w ei g ht, B S A will be 
calc ulate d usi n g a dj uste d wei g ht. 
c.  
If fl u dar a bi ne has b ee n escalate d t o 4 0 m g/ m2, fl u dara bi ne d os e ma y als o 
be re d uce d t o 3 5 m g/ m 2 dail y if t here is pri or mali g na nc y i n v ol ve me nt of 
t he ce ntral n er v o us s yste m wit h i ntrat hecal c he m ot hera p y a n d/ or cra ni o-
s pi nal irra diati o n. Patie nts > 1 2 0 % of i deal wei g ht, B S A will be calc ulate d 
usi n g a dj uste d wei g ht. 
  
3.  
T otal B o d y Irra diati o n ( T BI) 
  
  
See A p pe n di x I V f or r a diati o n g ui deli nes 
 
B.   
I m m u n os u p pr essi ve T her a pies 
All patie nts will recei ve pr o p h yla xis f or G V H D wit h 2 dr u gs as f oll o ws: 
1.  
C ycl os p ori ne A 
a.  
Patie nts will recei ve c y cl os p ori ne A ( C S A) t hera p y be gi n ni n g o n Da y - 3 
mai ntai ni n g a tr o u g h le vel bet wee n 2 0 0 a n d 4 0 0 n g/ m L b y H P L C a nal ysis 
( 2 5 0 a n d 5 0 0 n g/ ml b y i m m u n oassa y). F or a d ults t he i nitial d ose will be 
2. 5 m g/ k g I V o v er 1 h o ur e ver y 1 2 h o urs. F or c hil dre n < 4 0 k g t he i nitial 
d ose will be 2. 5 m g/ k g I V o ver 1 h o ur e ver y 8 h o urs. 
b.  
D ose a dj ust me nts will be ma de o n t he basis of t o xicit y a n d l o w C S A 
le vels wit h a tr o u g h le vel of < 2 0 0 m g/ L ( H P L C).  O nce t he p atie nt ca n 
t olerate or al me dicati o ns, C S A will be c o n verte d t o a n oral f or m. C S A 
d osi n g will be m o nit ore d a n d altere d as cli nicall y a p pr o priate. 
c.  
Patie nts will recei ve C S A u ntil Da y + 1 0 0.  If t here is n o e vi de nce of 
G V H D, t he d ose will t he n be ta pere d 1 0 % per wee k starti n g o n Da y + 1 0 1 
a n d disc o nti n ue d n o s o o ner t ha n 6 m o nt hs p ost tra ns pla nt.  
 
2.  
M yc o p he n olate m of etil ( M M F ) 
a.  
All patie nts will recei ve M M F at t he d ose of 1 5 m g/ k g I V ( base d o n 
a dj uste d wei g ht) e v er y 8 h o urs wit h a ma xi m u m of 1 gra m/ d ose starti n g 4-
6 h o urs after i nf usi o n of U C B T o n Da y 0. If act ual b o d y wei g ht is < i deal 
wei g ht, calc ulati o n bas e d o n act ual wei g ht is all o we d. R o u n di n g of t he 
d ose t o t he near est 2 5 0 m g ca ps ule size is als o all o we d. O nce t he patie nt 
ca n t olerat e oral me dicati o ns, M M F ma y be c o n v erte d t o a n oral f or m.  
b.  
M M F will be gi ve n e ver y 8 hrs dail y u ntil da y 4 0 p ost tra ns pla nt a n d t he n 
i n t he a bse nce of G V H D, ta pere d b y 1 2 %/ wee k wit h M M F disc o nti n ue d 

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Pa ge 1 5  of 5 9  
after d a y + 9 6. If G V H D has bee n dia g n os e d, c o nti n ue d treat me nt a n d 
eli gi bilit y f or ac ute G V H D pr ot oc ols is at t he atte n di n g p h ysicia n’s 
discreti o n. It is rec o m me n de d i n t his setti n g t hat M M F be ta pere d after 
i nitiati o n of t hera p y f or ac ute G V H D h as bee n starte d a n d t here is 
d oc u me nte d res p o ns e. T his is at t he atte n di n g p h ysicia n’s discreti o n. 
c.         M M F d osi n g t o be m o nit ore d a n d altere d as cli nicall y a p pr o priate. 
d.  
Mar ke dl y l o w ( < 4 0 %) d o n or T cell c hi meris m after U C B T ma y i n dicate 
i m pe n di n g graft rejecti o n. M M F s h o ul d be c o nti n u e d at f ull d ose or, if 
M M F ta per h as bee n i niti ate d, rei nstit uti o n of f ull d ose M M F s h o ul d 
occ ur. If M M F h as bee n disc o nti n ue d, M M F s h o ul d be rei nitiate d at f ull 
d ose. 
 
C.   
U m bilical C or d Bl o o d Tra ns pla nt ( U C B T) 
1.  
Pr oce d ures f or r e q uesti n g, recei vi n g a n d c haracterizi n g t he c or d bl o o d u nit f or 
i nf usi o n will be acc or di n g t o i nstit uti o nal pr ot oc ol.  Pr oce d ures f or tra ns pl a ntati o n 
at o utsi de ce nters will be re vie we d a n d a p pr o ve d b y t he PI.  
2.  
F or F H C R C patie nts, t he c or d bl o o d u nit s h o ul d be t ha we d a n d i nf use d per 
F H C R C sta n dar d practice g ui deli nes. C or d bl o o d pr o d ucts s h o ul d be i nf us e d 
wit h o ut dela y as s o o n as t he pr o d uct arri ves o n t he u nit.  At t he F H C R C u p t o 5 % 
of c or d bl o o d pr o d u ct, w he n rea d y f or i nf usi o n, m a y be wit h hel d f or researc h 
p ur p oses as l o n g as t hres h ol ds f or i nf use d T N C d ose are m et.     
a.  
T he t ha we d pr o d uct (eit h er o ne or t w o u nits) will be deli vere d t o t he 
patie nt fl o or/ be dsi de w here t he pr o d u ct is d o u ble-c hec ke d b y a n urse wit h 
t he tec h n ol o gist fr o m t he Cell ular T hera p y L a b orat or y. Vis ual i ns pecti o n 
of t he pr o d uct is als o ma de at t his ti me. T he u nit(s) is verifie d acc or di n g t o 
1) t he i nf usi o n or der s h eets, 2) t he patie nt’s i de ntificati o n n u m ber o n t he 
cell pr o d uct, 3) t he pr o d u ct (cell) i de ntificati o n n u m ber a n d 4) t he p atie nt 
wrist ba n d.  
b.  
If t he c or d bl o o d u nit(s) fail t o pass i ns pecti o n or if t here is i ns uffici e nt 
i nf or mati o n t o verif y t he cell pr o d uct f or t h e patie nt, n otif y t he Direct or of 
t he Cell T hera p y L a b (( 2 0 6) 6 6 7- 4 0 0 4) a n d t h e PI, Fili p p o Mila n o ( 2 0 6) 
6 6 7- 5 9 2 5, pa ger ( 2 0 6) 3 1 4- 1 0 3 7) i m me diatel y. 
c.  
T he g oal i nf usi o n ti me of eac h c or d bl o o d u nit is 3 0 mi n utes, as cli nicall y 
p ossi ble. Pre- me dicati o ns (if a n y) pri or t o c or d bl o o d i nf usi o n will be at 
t he discreti o n of t he atte n di n g. U n der n o circ u msta nces is t he c or d bl o o d 
t o be irra diate d. N o me di cati o ns or fl ui ds s h o ul d be gi ve n pi g g y bac k 
t hr o u g h t he cat heter l u me n t hat is bei n g use d f or c or d bl o o d i nf usi o n. 
d.  
T he pr o d uct is i nf use d vi a I V dri p directl y i nt o t he ce ntral li ne acc or di n g 
t o sta n dar d practice. Filter t hr o u g h a bl o o d c o m p o ne nt a d mi nistrati o n filter 
set per Sta n dar d Practice G ui deli nes. 
e.   
Vital si g ns s h o ul d be m o nit ore d bef ore be gi n ni n g t he i nf usi o n a n d 
peri o dicall y d uri n g a d mi nistrati o n. N otif y t he atte n di n g p h ysicia n, fell o w 
or P A i m me diatel y if t he patie nt e x hi bits si g ns or s y m pt o ms of a reacti o n.  
f.  
Be na dr yl, e pi ne p hri n e, a n d h y dr oc ortis o ne s h o ul d be a vaila ble at t he 
be dsi de f or e m er ge n c y use if necessar y. O x y g e n wit h nasal pr o n gs f or 
sta n d b y use s h o ul d be prese nt i n t he r o o m. 

2 2 7 5. 0 0 
 
Pa ge 1 6  of 5 9  
g.  
If t he patie nt is a d o u ble c or d bl o o d reci pie nt, t he t w o u nits ma y be gi ve n 
c o nsec uti vel y wit h n o wait bet wee n i nf usi o n of t he u nits . H o we ver, 
i nf usi o n of t he sec o n d u nit will n ot  be gi n u ntil a n y ac ute t o xicities fr o m 
t he first u nit ha ve bee n c o ntr olle d. T he start a n d st o p ti me of eac h u nit 
s h o ul d be rec or de d o n t h e i nf usi o n rec or d.  
 
D.   
C N S pr o p h yla xis a n d treat me nt 
All patie nts wit h A L L, A M L or M D S-refract or y a ne mia wit h e xcess blasts ( R A E B) will ha ve a 
dia g n ostic l u m bar p u nct ure pri or t o t he pre parati ve re gi me n. All patie nts wit h A L L will recei v e 
pr o p h yla xis wit h i ntrat hecal t hera p y. Patie nts wit h A M L or R A E B will recei ve i ntrat hecal 
met h otre xate if t he cer e br os pi nal fl ui d is p ositi ve f or mali g na nt cells or if t he y ha ve pre vi o us 
hist or y of C N S le u ke mia. Cra nial ra diati o n will be a d mi nistere d f or p atie nts wit h acti ve C N S 
disease, as per eac h ce nter’s sta n dar d practice  g ui d eli nes. G ui deli nes f or a d mi nistrati o n of 
met h otre xate ( or alter n ati ve dr u g if patie nt ca n n ot recei v e met h otre xat e) are i ncl u de d i n 
A p pe n di x V. N ote: If a p atie nt d oes n ot clear C N S le u ke mia b y da y – 6, he/s he wil l n ot be 
eli gi ble t o e nter t he st u d y as descri be d i n Secti o n 4. B. 
 
E.   
Testic ular r a diati o n 
All male patie nts wit h A L L will recei ve e xter n al bea m testic ular irra diati o n pri or t o da y 0, 
per eac h ce nter’s sta n d ar d practice g ui d eli nes. Patie nts wit h A M L will recei ve testic ular 
ra diati o n at t he sa me d os e if t he y ha ve hist or y of testic ular i n v ol ve me nt or acti ve diseas e at t he 
ti me of pre-tr a ns pla nt e v al uati o n. 
 
F.   
S u p p orti ve Care 
Patie nts will recei ve tra nsf usi o ns, i nfecti o n pr o p h yla xis, a n d t hera p y acc or di n g t o i nstit uti o nal 
g ui deli nes ( A p pe n di x VI f or F H C R C i nfecti o n g ui deli nes).  
 
G.  
Gr o wt h Fact or S u p p ort  
 
Patie nts will be starte d o n G- C S F s u p p ort at 5 mc g/ k g (I V/ S Q)(r o u n d t o vi al size) dail y starti n g 
da y + 1 f oll o wi n g U C B i nf usi o n u ntil A N C > 2 5 0 0/ μ L f or 2 c o nsec uti ve d a ys. O nce a p atie nt has 
met t hese criteri a, t he A N C will be m o nit ore d a n d G- C S F restarte d if A N C falls t o < 1 0 0 0. 
 
H.       Ma na ge m e nt of Pr e-e n gr aft me nt I m m u ne R eacti o ns  
A well rec o g ni ze d cli nical e ntit y c o nsisti n g of s ki n ras h, fe v er, a n d, ofte n, l o ose st o ols a n d 
res pirat or y distress h as b ee n n ote d t o occ ur pri or t o e n graft me nt a m o n g c or d bl o o d patie nts, 
ge nerall y bet w ee n D a ys + 7 a n d + 2 1.  T his cli nical s y n dr o me li kel y i n v ol ves c yt o ki ne acti vati o n, 
a n d t h o u g h cli nicall y si milar t o ac ute or h y p erac ut e graft v ers us h ost diseas e, it a p pears t o b e a 
disti nct e ntit y, “ pre-e n gr aft me nt s y n dr o me.”   T his s y n dr o me is ofte n c o ntr olle d wit h brief 
ster oi d b ursts, t h us a v oi di n g a c o m mit me nt t o e xte n de d ster oi d e x p os ure. Patie nts s h o ul d be 
m o nit ore d car ef ull y f or t his s y n dr o me. 
 
If patie nts ha ve m o d erat e t o se vere s y m pt o ms as d escri be d a b o ve a n d alter n ati ve eti ol o gies (i.e., 
i nfecti o n) ha v e bee n e xcl u de d or ar e bei n g a p pr o priatel y e val uat e d, rec o m me n dati o ns f or 
ma na ge me nt are:  
1.  
F or patie nts n ot o n ster oi d t hera p y w he n t he s y n dr o me occ urs:  
met h yl pre d nis ol o ne s h o ul d be gi ve n at 1 m g/ k g I V q da y f or t hree d a ys.  If 
s y m pt o ms ha ve a bate d, ster oi ds s h o ul d be st o p pe d.  If s y m pt o ms persist, 1 m g/ k g 

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Pa ge 1 7  of 5 9  
ca n be c o nti n ue d t hr o u g h si x da ys t he n st o p pe d if s y m pt o ms ha ve a bate d.  If 
s y m pt o ms persist f or m ore t ha n si x da ys, t he patie nt s h o ul d be c o nsi dere d t o ha ve 
ac ute/ h y per ac ute G V H D a n d s h o ul d be treat e d wit h pr ol o n ge d ster oi ds as d ee me d 
a p pr o priate. 
 
2.  
F or patie nts alr ea d y o n st er oi ds f or ot her reas o ns w he n t he s y n dr o me o cc urs:  
met h yl pre d nis ol o ne s h o ul d be gi ve n at a d ose of 3- 5 m g/ k g I V ( ma x d ose 5 0 0 
m g) q 1 2 h o urs x 4 8 h o urs, f oll o we d b y a ra pi d ta per t o 1 m g/ k g I V q 1 2 h o urs.  
Patie nts s h o ul d be wea ne d after res p o nse as t olerat e d. 
 
9.  
E v al u ati o n (i n a d diti o n t o pr oce d ures a n d ev al u ati o ns liste d bel o w, a d diti o n al cli nic al 
ev al u ati o ns as directe d by t he cli nic al te a m m ay be c a pt ure d f or rese arc h p ur p oses)  
 
 
Refer t o F H C R C/ S C C A Sta n dar d Practice Ma n ual f or Pre- Tra ns pla nt E val uati o n G ui deli nes f or 
All o ge neic Tr a ns pla nt (r es ults of tests a n d/ or pr oce d ures c o n d u cte d as p er sta n dar d of care f or 
pre-tra ns pl a nt w or k u ps ma y be use d f or eli gi bilit y deter mi nati o n if c o n d u cte d wit hi n a n 
a p pr o priate wi n d o w pri or t o scree ni n g) See A p pe n di x XII f or s c he d ule of st u d y e val uati o ns. 
 
A.   
Patie nt Pre- St u d y Scree ni n g a n d E val uati o n Pr oce d ures 
1.  
Me dical hist or y, aller gies, pre vi o us c he m ot hera p y, pri or ra di ot hera p y, h or m o nal 
or i m m u n ot hera p y a n d res p o nse t o treat me nt, e n d- or ga n t o xicit y a n d i nfecti o ns. 
2.  
Kar n ofs k y / E C O G/La ns k y perf or ma n ce stat us ( A p pe n di x I I). 
3.  
P h ysical e xa mi nati o n. 
4.  
C o m plete bl o o d a n d platelet c o u nt wit h le u k oc yte differe ntial. 
5.  
Basic meta b olic a n d he p atic f u ncti o n pa nels. 
6.  
Uri nal ysis. 
7.  
Pre g na nc y test ( bl o o d or uri ne) i n fe mal es of c hil d beari n g p ote ntial. 
8.  
Viral titers ( H S V, C M V, HI V, H Bs A g, H Bc A b, H C V, H T L V 1/ 2). 
9.  
P C R f or C M V D N A m ust be d o ne wit hi n 2 wee ks pri or t o t he start of 
c o n diti o ni n g.  
1 0.  
B o ne marr o w as pirate ( +/- bi o ps y as cli nicall y i n dicate d) c ollecte d less t ha n o ne 
m o nt h pri or t o start of c o n diti o ni n g. 
1 1.  
Electr ocar di o gra m 
1 2.  
M U G A or ec h ocar di o gra p h y wit h meas ure me nt of t he left ve ntric ular ejecti o n 
fracti o n ( L V E F).  
1 3.  
C hest ra di o gra p h; C X R n ot re q uire d if c h est C T perf or me d   
1 4.  
P ul m o nar y f u ncti o n tests.  
1 5. 
D N A s peci me n fr o m pati e nt a n d fr o m U C B u nit(s) s u b mitte d t o Cli nical 
I m m u n o ge n etics La b or at or y ( CI L) ( F H C R C patie nts) f or c hi meris m st u dies. 
  
1 6.  
A c hest C T wit h o ut c o ntrast t o e xcl u de occ ult f u n gal i nfecti o n pri or t o tra ns pla nt 
f or patie nts wit h a hist or y of t he f oll o wi n g: 
•  hist or y of M D S or a hist or y of 2 or m ore c o nsec uti ve i n d ucti o ns/re-
i n d ucti o ns t o treat ac ute l e u ke mia  
•  pr ol o n ge d ne utr o pe ni a of at least 2 m o nt hs i m me diatel y prece di n g 
tra ns pla nt 
1 7.  
Pe diatric pretr a ns pla nt e v al uati o n c o nsi derati o ns:  f or c hil dre n t hat are n ot a ble t o 
c o o perat e t o ha ve a M U G A a n d/ or p ul m o nar y f u ncti o n tests, a n ec h ocar di o gra m 

2 2 7 5. 0 0 
 
Pa ge 1 8  of 5 9  
s h o ul d be atte m pte d a n d p ulse o xi metr y wit h e xercise t olera n ce o btai ne d. If n ot 
p ossi ble at all, it s h o ul d clearl y be d oc u m e nte d i n t he p h ysicia n’s n ote. 
1 8.  
C o m or bi dit y I n de x sc or e t o be c o m plete d b y res earc h staff ( A p pe n di x III).  
1 9.  
Cli nical i m m u ne rec o nstit uti o n st u dies (see secti o n 9 . F). 
2 0.       L y m p h oc ytes s u bset e n u merati o n ( T cell s u bset wit h B a n d N K c ells) s h o ul d be 
d o ne after a p atie nt si g ns t he c o nse nt f or m. 
2 1. 
F H C R C o nl y :  Bl o o d Sa m ples f or H ost a n d D o n or I m m u n ol o gic I nt eracti o n 
St u dies (see secti o n 9. E). 
2 2. 
F H C R C o nl y:  I m m u ne Rec o nstit uti o n Researc h St u d y (see secti o n 9. F) 
 
B.   
Patie nt E val uati o ns fr o m Da y 0 u ntil E n graft me nt (t hr o u g h Da y 3 0)  
See Secti o n 9. G bel o w f or st u dy ev al u ati o n wi n d o ws a n d A p pe n dix XII f or sc he d ule of st u dy 
ev al u ati o ns. 
1.  
P h ysical e xa mi nati o ns dail y or as cli nicall y i n dicate d.  
2.  
C o m plete bl o o d a n d platelet c o u nt dail y, or as cli nicall y i n dicate d, u ntil t he 
a bs ol ute ne utr o p hil c o u nt ( A N C) > 5 X 1 0 8/ L f or 3 c o nsec uti ve meas ure me nts. 
Le u k oc yte diff er e ntial is t o be perf or m e d dail y if W B C c o u nt > 5 0 0. 
3.  
Basic meta b olic pa nel dail y or as cli nicall y i n dicate d (at least t wice wee kl y).  
4.  
C M V P C R s ur veilla nce as cli nicall y i n dicate d per i nstit uti o nal g ui deli nes 
( A p pe n di x VI). 
5.  
Uri nal ysis as cli nicall y i n dicate d. 
6.  
C hest ra di o gra p hs as cli nicall y i n dicate d. 
7.  
B o ne marr o w as pirate ( +/- as cli nicall y i n dicate d) o n Da y 2 8 f or assess me nt of 
u n derl yi n g disease a n d U C B e n graft me nt. Da y 2 8 B M s peci me n s u b mitte d at all 
ce nters f or w h ole b o n e marr o w c hi meris m st u dies.  Please n ote if patie nt is a 
d o u ble c or d bl o o d reci pie nt.  Ot her tests o n B M t hat are disease a p pr o priat e o n 
Da y 2 8.  
8.   
Da y 2 8 peri p h eral bl o o d f or c hi meris m st u dies (as p ossi ble s orte d f or C D 3, C D 1 4, 
C D 3 3, C D 5 6 cells). 
9. 
F H C R C o nl y :  
a.   F or patie nts w h o recei ve d a si n gle c or d bl o o d u nit – peri p heral bl o o d f or 
c hi meris m st u dies (s orte d f or C D 3, C D 1 4, C D 3 3, C D 5 6 cells) o n Da y 2 8.  
b.   F or patie nts w h o recei ve t w o c or d bl o o d u nits, peri p heral bl o o d f or c hi meris m 
st u dies (s orte d f or C D 3, C D 1 4, C D 3 3, C D 5 6 cells) o n Da y 1 4 a n d 2 8.  
1 0.  
G V H D e v al uati o n ( A p pe n di x VII ) w ee kl y or as cli nicall y i n dicate d. 
1 1.  
Cli nical i m m u ne rec o nstit uti o n st u dies (see secti o n 9. F). 
1 2. 
F H C R C o nl y:  Bl o o d sa m ples f or H ost a n d D o n or I m m u n ol o gic I nt eracti o n 
St u dies (see secti o n 9. E) 
1 3. 
F H C R C o nl y:  I m m u ne Rec o nstit uti o n Researc h St u dies.  (see secti o n 9. F) 
 
C.   
Patie nt E val uati o ns fr o m E n graft me nt t o Da y 1 0 0  
See Secti o n 9. G bel o w f or st u dy ev al u ati o n wi n d o ws a n d A p pe n dix XII f or sc he d ule of st u dy 
ev al u ati o ns. 
1.  
P h ysical e xa mi nati o ns wee kl y a n d/ or as cli nicall y i n dicate d. 
2.  
Kar n ofs k y / E C O G/La ns k y perf or ma n ce o n ce bet w ee n Da y 8 0 a n d 1 0 0 ( A p pe n di x 
II).  

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Pa ge 1 9  of 5 9  
3.  
C o m plete bl o o d a n d platelet c o u nt wit h le u k oc yte differe ntial at least wee kl y 
a n d/ or as cli nicall y i n dicate d. 
4.  
Basic meta b olic pa nel at least wee kl y a n d as cli nicall y i n dicate d. 
5.  
C M V P C R s ur veilla nce as cli nicall y i n dicate d per i nstit uti o nal g ui deli nes 
( A p pe n di x VI).   
6.  
Uri nal ysis as cli nicall y i n dicate d (at least o nce pri or t o d/c wit h uri ne 
creati ni ne/al b u mi n rati o). 
7.  
C hest ra di o gra p hs as cli nicall y i n dicate d. 
8.  
Peri p heral bl o o d f or c hi meris m st u dies (s orte d f or C D 3, C D 3 3, C D 5 6) ( F H C R C 
patie nt s) o n Da ys 5 6 a n d 8 0.   
9.  
B o ne marr o w as pirate a n d bi o ps y Da y 8 0 ( or pri or t o de part ure) f or all patie nts 
f or assess me nt of disease rela pse, c hi meris m a n d U C B e n graft me nt. D N A B M 
s peci me n s u b mitte d f or c hi meris m st u dies. Please n ote if patie nt is a d o u ble c or d 
bl o o d reci pie nt.  
1 1.  
G V H D e v al uati o n ( A p pe n di x VII) w ee kl y a n d as cli nicall y i n dicate d. 
1 2.  
E B V viral l oa d as cli nicall y i n dicate d t hr o u g h da y 1 0 0 or disc har g e fr o m 
tra ns pla nt ce nter (see A p pe n di x VIII). If ≥ 1 0 0 0 c o pies/ m L of wh ole bl o o d refer 
t o A p pe n di x VIII f or ma na ge me nt. 
1 3.  
Cli nical i m m u ne rec o nstit uti o n st u dies (see secti o n 9. F). 
1 4. 
F H C R C o nl y:  Bl o o d sa m ples f or H ost a n d D o n or I m m u n ol o gic I nt eracti o n 
St u dies (see secti o n 9. E). 
1 5. 
F H C R C o nl y:  I m m u ne Rec o nstit uti o n Researc h St u dies (see secti o n 9. F).  
 
D.   
Patie nt E val uati o ns at 6 m o nt hs, 1 year a n d 2 years 
See Secti o n 9. G bel o w f or st u dy ev al u ati o n wi n d o ws a n d A p pe n dix XII f or sc he d ule of st u dy 
ev al u ati o ns. 
1.  
P h ysical e xa mi nati o ns at 6 m o nt hs, 1 year a n d 2 y ears. 
2.  
Kar n ofs k y / E C O G/La ns k y perf or ma n ce stat us ( A p pe n di x II) at 6 m o nt hs, 1 year 
a n d 2 years. 
3.  
C o m plete bl o o d c o u nt wit h le u k oc yte differe ntial a n d ser u m c h e mistr y at 6 
m o nt hs, 1 year a n d 2 years a n d as cli nicall y i n dicate d. 
4.  
C M V s ur veilla nce as cli nicall y i n dicate d per i nstit uti o nal g ui deli nes ( A p pe n di x 
VI).  
5.  
C hest ra di o gra p hs as cli nicall y i n dicate d. 
 
6.  
Peri p heral bl o o d f or c hi meris m st u dies (s orte d f or C D 3, C D 3 3, C D 5 6) ( F H C R C 
patie nts) at 6 m o nt hs, 1 year a n d 2 y ears. 
7.  
B o ne marr o w as pirate a n d bi o ps y at 1 year a n d, as cli nicall y i n dicate d, at 2 years 
f or assess me nt of U C B e n graft me nt a n d e vi de nce of rec urre nt disease. D N A B M 
s peci me n s u b mitte d f or c hi meris m st u dies. Please n ote if patie nt is a d o u ble c or d 
bl o o d reci pie nt.  
8.  
G V H D e v al uati o n ( A p pe n di x VII) at 6 m o nt hs, 1 year a n d 2 y ears. 
9.  
A ut o ps y re p ort, if a v aila ble, if deat h occ urs bef ore t he 2 year f oll o w- u p. 
1 0.  
Cli nical i m m u ne rec o nstit uti o n st u dies (see secti o n 9 . F). 
1 1. 
F H C R C o nl y : I m m u ne Rec o nstit uti o n Researc h St u dies at 1 year a n d 2 y ears 
(see secti o n 9. F). 
 

2 2 7 5. 0 0 
 
Pa ge 2 0  of 5 9  
E. 
Rese arc h St u dies (resear c h bl o o d sa m ples ma y be use d i nterc ha n g ea bl y, a n d a m o u nt of 
bl o o d t o be dra w n ma y b e re d uce d at t he i n vesti gat or/atte n di n g p h ysicia n’s discreti o n a n d 
as dictate d b y patie nt saf et y):   
 
F H C R C o nl y:  H ost a n d D o n or I m m u n ol o gic I nteracti o n St u dies  
F or patie nts lar g er t ha n 2 0 k g: 
 
F or p atie nts 2 1- 3 0 k g 
1.  
Pri or t o t he start of c o n diti o ni n g (a n d after c o nse nt o btai ne d) : 2 0 ml of peri p heral 
bl o o d will be c ollecte d i n gree n t o p t u bes t o ge n erate E B V tra nsf or me d L C L li nes 
fr o m t he patie nt f or researc h st u dies e val uati n g d o n or/ h ost i m m u n ol o gic 
reacti o ns.  
2.  
P ost tra ns pla ntati o n o n u p t o fi ve occasi o ns, 2 0 ml of peri p heral bl o o d ma y be 
c ollecte d i n gree n t o p t u bes t o assa y f or i m m u ne me diate d res p o nses o cc urri n g 
bet wee n t he h ost a n d d o n ors.  Ti mi n g of sa m ple c ollecti o n will be at i n vesti gat or 
discreti o n a n d res ear c h st aff will i nitiate t he or ders.    
3.  
Please se n d sa m ples t o D 2- 3 3 5; c o ntact De nis e Zie gler: p h o ne ( 2 0 6) 6 6 7- 5 7 6 2.  
4.   
Sa m ples s h o ul d be dra w n o n M O N D A Y t hr o u g h F RI D A Y O N L Y.  
 
F or p atie nts l ar ger t h a n 3 0 k g 
1.   
Pri or t o t he start of c o n diti o ni n g (a n d after c o nse nt o btai ne d) : 3 0 ml of peri p heral 
bl o o d will be c ollecte d i n gree n t o p t u bes t o ge n erate E B V tra nsf or me d L C L li nes 
fr o m t he patie nt f or researc h st u dies e val uati n g d o n or/ h ost i m m u n ol o gic 
reacti o ns.  
2.  
P ost tra ns pla ntati o n o n u p t o fi ve occasi o ns, 3 0 ml of peri p heral bl o o d ma y be 
c ollecte d i n gree n t o p t u bes t o assa y f or i m m u ne me diate d res p o nses o cc urri n g 
bet wee n t he h ost a n d d o n ors.  Ti mi n g of sa m ple c ollecti o n will be at i n vesti gat or 
discreti o n a n d res ear c h st aff will i nitiate t he or ders.    
3.  
Please se n d sa m ples t o D 2- 3 3 5; c o ntact De nis e Zie gler: p h o ne ( 2 0 6) 6 6 7- 5 7 6 2.  
4.   
Sa m ples s h o ul d be dra w n o n M O N D A Y t hr o u g h F RI D A Y O N L Y.  
 
F.  
I m m u ne Rec o nstit uti o n after U C B T 
See Secti o n 9. G bel o w f or st u dy ev al u ati o n wi n d o ws a n d A p pe n dix XII f or sc he d ule of st u dy 
ev al u ati o ns. 
          Cli nical St u dies (t o be perf or me d as p ossi ble): 
1.  
Q ua ntitati ve i m m u n o gl o b uli n le vels (I g G, I g A, I g M) will be assesse d at D a y 2 8, 
5 6, 1 0 0, 6 m o nt hs, 1 year a n d 2 years. 
2.  
T otal T l y m p h oc ytes a n d s u bset e n u merati o n ( L y m p h oc ytes pa nel) will be 
assesse d pr e-tra ns pla nt a n d at Da y 2 8, 5 6, 1 0 0, 6 m o nt hs, 1 year a n d 2 years. 
 
F H C R C o nl y: I m m u ne Rec o nstit uti o n Researc h St u dies:  
1.  
Sa m ples will be c ollecte d f or i m m u n o p he n ot y pic e val uati o n of i m m u ne 
rec o nstit uti o n will be perf or me d o nce pri or t o t he start of c o n diti o ni n g, t he n o n 
Da y 2 8, 5 6, 1 0 0, 6 m o nt hs, 1 year a n d 2 y ears. C ollect o ne 1 0 ml t u be. Se n d 1 0 
ml ( Na He pari n gree n t o p) t o t he Di gel La b. Mai n c o ntact: De n ise Zi e gler: p h o ne 
( 2 0 6) 6 6 7- 5 7 6 2. 
 

2 2 7 5. 0 0 
 
Pa ge 2 1  of 5 9  
G.   
St u d y E val uati o n Wi n d o ws 
 
T he tar get dates f or p ost-tra ns pla nt st u d y e val uati o ns are o utli ne d i n t he ta ble bel o w: 
 
E v al u ati o n D ate P ost Tr a ns pl a nt  
Wi n d o w  
Da y + 7  
+  3 da ys  
Da y + 1 4  
+  2  da ys  
Da y + 2 1  
± 2  da ys  
Da y + 2 8  
±  3 da ys  
Da y + 5 6  
 ± 7 da ys  
Da y + 8 0  
 ± 7 da ys  
Da y + 1 0 0  
 ± 7 da ys  
Da y + 1 8 0  
+  3 0 da ys  
1 year  
*  
2 year  
*  
 
* E ver y eff ort will be ma de t o c o m plete t he 1 year a n d 2 year e val uati o ns as cl ose t o t hese dates as p ossi ble, ta ki n g i nt o 
c o nsi derati o n patie nt’s circ u msta nces at t hese ti me p oi nts. 
  
N O T E:  I n certai n cli nical circ u msta nces (e. g., rela pse or ter mi nal ill ness) st u d y tests ma y be 
o mitte d at t he p h ysicia n’s or PI’s discreti o n .  
 
1 0.  
Dr u gs, Irr a di ati o n a n d M arr o w A d mi nistr ati o n - T o xicities a n d C o m plic ati o ns. 
A.   
Treat me nt- Relat e d T o xicities 
F or t he p ur p os es of t his pr ot oc ol, t o xicit y will be gra de d usi n g t he m o difie d N CI 
c o m m o n t o xicit y scale ( A p pe n di x I X) 
 
 
 
 
 
 
1.  P ote nti al t o xicities ass o ci ate d wit h t he C o n diti o ni n g Re gi me n 
 
Tre os ulf a n 
 
Ver y C o m m o n ( > 1 0 %)  
C o m m o n ( 1 -9 %)  
U nc o m m o n ( 0. 1 -
0. 9 %)  
Rare/ U n k n o w n  

2 2 7 5. 0 0 
 
Pa ge 2 2  of 5 9  
•  
I nfecti o n 
( bacterial/f u n gal/ viral) 
•  
L o weri n g all bl o o d 
c o u nts lea di n g t o 
a ne mia, i ncrease d ris k 
f or i nfecti o ns a n d 
blee di n g 
•  
M uc ositis 
(i nfla m mati o n li ni n g of 
m o ut h w hic h ma y be 
pai nf ul) 
•  
Diarr hea, na usea, 
v o miti n g 
•  
A b d o mi nal pai n 
•  
Fe ver ( ofte n ass ociate d 
wit h ver y l o w w hite 
bl o o d c o u nt) 
•  
I ncrease d bilir u bi n * * 
•  
Fati g ue/let har g y * * 
•  
Itc hi n g s ki n * 
•  
Ras h  
•  
Al o pecia (te m p orar y hair 
l oss) 
•  
Ele vate d li ver f u ncti o n 
tests 
•  
D ys p ha gia ( diffic ult 
s wall o wi n g) 
•  
Decrease d a p petite * * 
•  
I ns o m nia * * 
•  
Hea dac he/ dizz y * * 
•  
Heart r h yt h m 
a b n or malities * * 
•  
Hi g h bl o o d press ure * * 
•  
S h ort ness of breat h * * 
•  
Gastritis/c o nsti pati o n * * 
•  
Ge neralize d pai n 
( m uscles a n d b o ne) * * 
•  
A b n or mal ki d ne y 
f u ncti o n * * 
•  
Hi g h bl o o d 
gl uc ose * * 
•  
C o nf usi o n * * 
•  
Peri p heral 
ne ur o pat h y * * 
•  
L o w bl o o d 
press ure * * 
•  
P ne u m o nitis * * 
•  
Se vere s ki n 
ras h wit h 
blisters a n d 
sl o u g hi n g of 
s ki n * * 
•  
Dr y m o ut h * * 
•  
Se vere li ver 
f u ncti o n 
a b n or malit y * * 
•  
Aci d osis, 
electr ol yte 
a b n or malities 
•  
Li ver fail ure/se vere 
li ver t o xicit y 
•  
Dr y e yes 
•  
Ki d ne y fail ure 
•  
Heart fail ure * *  
•  
M uscle 
wea k ness * * 
•  
E nce p hal o pat h y * * 
•  
Hi g h or L o w bl o o d 
press ure * 
 
* Ris ks u ni q ue t o Pe diatric Patie nts 
* * Ris ks u ni q ue t o A d ult Patie nts 
     
T here h a ve bee n is olate d re p orts of seiz ure i n i nfa nts ( 4 m o nt hs of a ge or less) after    
recei vi n g tr e os ulfa n c o m bi ne d wit h fl u dara bi ne as i n t his st u d y or wit h c ycl o p h os p ha mi de 
(a n ot her c he m ot her a p y dr u g t hat is n ot bei n g use d i n t his st u d y). Ver y y o u n g c hil dre n will be 
ver y cl osel y w atc he d f or si g ns of ne ur ol o gic si de effects. 
  
Fl u d ar a bi ne  
C o m m o n  
2 1 -1 0 0 pe o ple  o ut of 1 0 0  
Less Fre q ue nt  
5 -2 0 pe o ple o ut of 1 0 0  
U nc o m m o n  
< 5 pe o ple o ut of 1 0 0  
Se vere s u p pressi o n of bl o o d c o u nts  
Diarr hea  
A n ore xia 
M uc ositis 
Na usea/ v o miti n g 
St o matitis  
Oste o p or osis 
D ys uria 
C hills  
Fe ver 
GI blee di n g 
Peri p heral e de ma 
Ne ur ot o xicit y  
A gitati o n a n d c o nf usi o n 
Bl urre d visi o n 
Peri p heral ne ur o pat h y 
Heari n g l oss  
Hea dac he 
Cere bellar s y n dr o me 
Bli n d ness 
C o ma  
Wea k ness 
De pressi o n 
I ns o m nia 
He m orr ha gic c ystitis (e xce pt i n F A) 
A b n or mal re nal f u ncti o n test 
A ut oi m m u ne he m ol ytic a ne mia 
Dee p ve n o us t hr o m b osis 
A ne ur ys ms  

2 2 7 5. 0 0 
 
Pa ge 2 3  of 5 9  
Pr uritic s ki n ras h  
A b n or mal li ver f u ncti o n/ Li ver fail ure 
C o nsti pati o n 
Tra nsie nt isc he mic attac k 
D ys p ha gia 
M yal gia 
Art hral gia 
Re nal fail ure  
 
T ot al B o d y Irr a di ati o n ( T BI) *  
C o m m o n  
Occ urs i n 2 1 -1 0 0 pe o ple o ut of 1 0 0  
Less Fre q ue nt  
Occ urs i n 5 -2 0 pe o ple o ut of e ver y 1 0 0  
•  
Na usea (feeli n g sic k t o st o mac h)  
•  
Fati g ue (feeli n g tire d) 
•  
T he irra diati o n d ose use d ma y  res ult 
i n sterilit y 
 
•  
M uc ositis (te m p orar y da ma ge t o t he li ni n g of t he 
m o ut h) 
•  
S u p pressi o n of bl o o d c o u nts 
•  
Te m p orar y hair l oss    
•  
V o miti n g (t hr o wi n g u p)  
•  
Diarr hea (l o ose st o ols) 
•  
Pai nf ul s welli n g of t he par oti d gla n d (a gla n d u n der t he 
c hi n) f or a fe w da ys   
•  
Cataracts (a n o pacit y or w hite ni n g of t he le ns) ma y 
de vel o p i n t he e ye 
•  
Sec o n dar y ca ncers 
 
* T hese si de effects ma y be see n m or e sli g htl y m ore c o m m o nl y at t he 4 0 0 c G y a n d 4 5 0 c G y 
d ose le vels.  Re gar di n g r ec o ver y of testic ular f u ncti o n f oll o wi n g ra diati o n e x p os ure, s per m 
c o u nts n or mall y ret ur n t o pre- T BI le v els. T his ta kes a b o ut 2 1/ 2 years f or p atie nts gi ve n 3 0 0 c G y 
T BI. It ta k es a b o ut 5 years f or patie nts gi ve n 4 0 0- 4 5 0 c G y T BI. C o ntrace pti ve tec h ni q ues m ust 
be use d f or at least o ne y ear after tr a ns pla nt t o mi ni mize t he ris k of c o ncei vi n g ge neticall y 
da ma ge d offs pri n g. 
 
2.  
T o xicities p ote nti all y ass oci ate d wit h t he i nf usi o n of t he U C B gr aft 
 
P ote ntial t o xicities ass ociate d wit h t he i nf usi o n i ncl u de D M S O t o xicit y a n d si de effects fr o m re d 
cells. D M S O t o xicit y a n d si de effect of re d cells m a y i ncl u de c h a n ges i n heart rate, r h yt h m or 
f u ncti o n, c ha n ges i n bl o o d press ure, c ha n ges i n o x y ge nati o n, fe ver, c hills, s weats, 
na usea/ v o miti n g, diarr hea, a b d o mi nal cra m pi n g, hea dac he, aller gic reacti o n, prese nce of D M S O 
taste a n d o d or, he m o gl o bi n uria, a n d ac ut e re n al fail ure.   
 
3.  
P ote nti al t o xicities ass o ci ate d wit h I m m u n os u p pressi ve T her a pies 
C ycl os p ori ne A 
Ne p hr ot o xicit y  
T hr o m b otic t hr o m b oc yt o pe nic p ur p ura  
Seiz ures  
Electr ol yte i m bala nces  
H y perte nsi o n  
Parest hesias/ ne ur o pat h y  
Hirs utis m  
Gi n gi val h y per plasia  
I ncrease d ris k of rela pse 
I ncrease d ris k of o p p ort u nistic i nfecti o n 

2 2 7 5. 0 0 
 
Pa ge 2 4  of 5 9  
 
M yc o p he n ol ate M of etil ( M M F) 
Pa nc yt o pe nia  
H y perte nsi o n  
Hea da c he 
Dizzi ness  
I ns o m nia 
H y per gl yce mia  
Electr ol yte i m bala nces  
Ras h  
Le g cra m ps/ b o ne pai n  
Na usea/ diarr hea  
S p o nta ne o us a b orti o n  
Birt h defects  
Pr o gressi ve m ultif ocal le u k oe nce p hal o pat h y  
 
 
T o xicities ass oci ate d wit h Gr o wt h F act or ( G- C S F, Ne u p o ge n)  
B o ne pai n  
I ns o m nia 
Hea dac hes  
D ys p nea  
B o d y ac hes  
Ras h  
Fati g ue   
E de ma  
Na usea/ v o miti n g  
 
 
1 1.  
Pr ot oc ol E nr oll m e nt a n d S peci al C o nsi der ati o ns   
 
Pr ojecte d T ar get Accr u al 
E T H NI C A N D G E N D E R DI S T RI B U TI O N C H A R T 
 
 
T A R G E T E D / P L A N N E D E N R O L L M E N T:  N u m ber of S u bjects  
Et h nic Cate g or y 
 
Se x / Ge n der  
 
Fe m ales  
M ales  
T ot al  
His pa nic or Lati n o  
1 1  
1 3  
2 4  
N ot His pa nic or Lati n o  
4 9  
5 7  
1 0 6  
Et h nic Cate g or y T otal of All S u bjects *  
6 0  
7 0  
1 3 0  
R aci al C ate g ories  
A merica n I n dia n / Alas ka Nati ve   
3 
3 
6 
Asia n  
1 3  
1 0  
2 3  
Nati ve Ha waiia n or Ot her Pacific Isla n der   5 
6 
1 1  
Blac k or Africa n A merica n  
8 
8 
1 6  
W hite  
3 1  
4 3  
7 4  
Racial Cate g ories:  T otal of All S u bjects *  
6 0  
7 0  
1 3 0  
 
1 2.   G ui deli nes f or A d verse E ve nt R e p orti n g 
 
A.   
M o nit ori n g t he Pr o gress of Trial a n d t he Safet y of Partici pa nts 
 
T his is a P hase 2 cli nical trial t hat is m o nit ore d b y t he pri nci pal i n vesti gat or ( PI), Fili p p o Mila n o, 
M. D. T he PI re vie ws t he o utc o me of t he data f or eac h i n di vi d ual patie nt o n a n o n g oi n g basis. 

2 2 7 5. 0 0 
 
Pa ge 2 5  of 5 9  
T he PI of t he st u d y will ha ve pri mar y res p o nsi bilit y f or e ns uri n g t hat t he pr ot oc ol is c o n d ucte d as 
a p pr o ve d b y t he Scie ntifi c Re vie w C o m mittee a n d I nstit uti o nal Re vie w B o ar d. T he PI will 
e ns ure t hat t he m o nit ori n g pla n is f oll o we d a n d t h at all data re q uire d f or o v ersi g ht of m o nit ori n g 
are acc uratel y r e p orte d t o t he Data a n d Safet y M o nit ori n g C o m mittee, t hat all a d verse e ve nts are 
re p orte d acc or di n g t o t he pr ot oc ol g ui deli nes, a n d t hat a n y a d vers e reacti o ns reflecti n g patie nt 
safet y c o n cer ns are a p pr o priatel y re p ort e d. T he PI will pers o nall y re vie w wit h t he Researc h 
N urse t he cli nical c o urse of all t he e nr olle d p atie nts at least t wice m o nt hl y.  
  
 
B.   
Re p orti n g of A d vers e E v e nts 
 
1)  
A d verse E v e nt Defi niti o ns 
 
a.  
A d verse E v e nt 
A n A d verse E ve nt ( A E) is a n y u nt o war d me dical occ urre nce i n a cli nical i n vesti gati o n s u bject 
a d mi nistere d a me dici nal pr o d uct; t he e ve nt d oes n ot necessaril y ha v e a ca usal relati o ns hi p wit h 
st u d y dr u g a d mi nistrati o n or usa ge. A n a d vers e e ve nt ca n t heref ore be a n y u nfa v ora bl e a n d 
u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease te m p orall y 
ass ociate d wit h t he use of a me dici nal pr o d u ct, w het her or n ot c o nsi dere d relate d t o t he 
me dici nal pr o d uct. 
 
b.  
Seri o us A d verse E v e nt  
A seri o us a d verse e v e nt ( S A E) is defi ne d as a n u nt o war d me dical occ urre n ce t hat res ults i n a n y 
of t he f oll o wi n g o utc o mes: 
•  Deat h. 
• Life -t hreate ni n g sit uati o n (ie, wit h a n i m me diate ris k of deat h fr o m t he e ve nt as it 
occ urr e d b ut n ot i ncl u di n g a n e ve nt t hat, ha d it occ urre d i n a m ore seri o us f or m, 
mi g ht ha ve ca use d d eat h). 
• 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. I n p atie nt 
h os pitalizati o n c o m prises f or mal a d missi o n t o a h os pital f or me dical reas o ns, f or 
a n y le n gt h of ti me, w het her or n ot h os pitalizati o n e xte n ds o ver ni g ht. H o w e ver, 
h os pital a d missi o ns f or a d mi nistrati o n of t he st u d y dr u g, pr oce d ures re q uire d b y 
t he st u d y pr ot oc ol, or t u m or-relate d di a g n ostic pr oce d ures are n ot c o nsi dere d 
seri o us. H os pitalizati o ns c o m m o nl y ass ociate d wit h tra ns pla nt i ncl u di n g, b ut n ot 
li mite d, t o fe brile ne utr o pe nia, fe v ers, i nfecti o ns, a n d gastr oi ntesti nal t o xicities 
will n ot be rec or d e d as seri o us a d verse e ve nts as t h e maj orit y of patie nts recei vi n g 
re d uce d i nte nsit y tra ns pl a nts are h os pitalize d.  
•  Persiste nt or si g nifica nt disa bilit y/i nca pacit y or 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. 
•  C o n ge nital a n o mal y/ birt h defect. 
•  A n i m p orta nt me dical e v e nt t hat re q uires i nter ve nti o n t o pre ve nt o ne of t he a b o ve 
o utc o mes. 
 
c.  
U ne x pect e d A d verse E ve nt 
A n u ne x pect e d a d verse e ve nt is defi ne d as a n e ve nt t hat has a nat ure or se v erit y, or fre q ue nc y 
t hat is n ot c o nsiste nt wit h t he a p plica ble i n vesti gat or br oc h ure.  “ U n e x pecte d,” as use d i n t his 
defi niti o n, refers t o a n a d verse dr u g e x peri e nce t h at has n ot bee n pre vi o usl y o bser ve d a n d 

2 2 7 5. 0 0 
 
Pa ge 2 6  of 5 9  
re p orte d r at her t h a n a n e x perie nce t hat has n ot bee n a ntici pate d bas e d o n t he p har mac ol o gical 
pr o perties of t he st u d y dr u g. 
 
2)  
M o nit ori n g a n d rec or di n g A Es 
Gra de 3 or 4 a d verse e v e nts ( or hi g hl y u n us ual gra de 2 a d v erse e ve nts) a n d all S A Es, w hic h 
occ ur fr o m t he start of st u d y treat me nt ( pre-tra ns pla nt c o n diti o ni n g) t hr o u g h Da y + 1 0 0 p ost 
tra ns pla nt will be assesse d b y t he i n vesti gat or or q ualifie d desi g nee a n d rec or de d o n t he Case 
Re p ort F or m ( C R F).  Cli nicall y si g nifica nt A Es b e y o n d Da y 1 0 0 ma y als o be ca pt ure d at t he 
discreti o n of t he i n vesti g at or. W he n a s u bject e x p erie nces rela ps e or graft fail ure a n d g oes o n t o 
f urt her tr eat me nt off pr ot oc ol, a d vers e e ve nts will n o l o n ger be c ollecte d wit h t he e xce pti o n of 
deat h. T he i n vesti gat or s h o ul d atte m pt t o esta blis h a dia g n osis of t he e ve nt o n t he basis of si g ns, 
s y m pt o ms a n d/ or ot her cli nical i nf or mati o n. I n s uc h cases, t he dia g n osis s h o ul d be d oc u me nte d 
as t he a d verse e v e nt a n d/ or seri o us a d verse e v e nt a n d n ot descri be d as t he i n di vi d ual si g ns or 
s y m pt o ms. T he f oll o wi n g i nf or mati o n s h o ul d be rec or de d: 
• De scri pti o n of t he a d v ers e e ve nt usi n g c o ncis e me dical ter mi n ol o g y 
•  Descri pti o n as t o w het her or n ot t he a d verse e v e nt is seri o us  
•  T he start date ( date of a d verse e v e nt o nset) 
•  T he ma xi m u m se verit y ( gra de) of t he a d v erse e ve nt  
•  A descri pti o n of t he p ote ntial relate d ness of t h e a d verse e v e nt t o st u d y dr u g or a 
st u d y pr oce d ur e  
 
3)  
Gra di n g of t he s e verit y of a n A d verse E ve nt 
All A Es will be gra de d i n se verit y acc or di n g t o t he m o difie d (f or H S C T) N CI C o m m o n T o xicit y 
Criteria f or A d v erse E v e nts ( C T C A E) Versi o n 3 . 0 A p pe n di x I X 
( htt ps://cte p.ca ncer. g o v/ pr ot oc ol de vel o p me nt/electr o nic _a p plicati o ns/ d ocs/ctcae v 3. p df).  If a 
C T C A E criteri o n d oes n ot e xist, t he i n vesti gat or s h o ul d use t he gra de or a djecti ves: Gra d e 1 
( mil d), Gra de 2 ( m o derat e), Gr a de 3 (s e vere), Gra de 4 (life-t hreate ni n g), or Gra de 5 (fatal) t o 
descri be t he m a xi m u m i nte nsit y of t he a d vers e e ve nt.  
 
4)  
Attri b uti o n of A d verse E ve nt 
Ass ociati o n or relat e d ness t o t he st u d y a ge nt will be assesse d b y t he i n v esti gat or as f oll o ws: 
•  Defi nite:  T he e v e nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m e x p os ure t o t he 
i n vesti gati o nal a ge nt, has bee n pre vi o usl y des cri be d i n ass ociati o n wit h t he 
i n vesti gati o nal a ge nt, a n d ca n n ot reas o na bl y be attri b ute d t o ot her fact ors s uc h as 
t he patie nt’s cli nical state, ot her t hera p e utic i nter v e nti o ns or c o nc o mita nt 
me dicati o ns; A N D t he e v e nt disa p pears or i m pr o ves wit h wit h dra wal of t he 
i n vesti gati o nal a ge nt a n d/ or re-a p p ears o n re-e x p os ure (e. g., i n t he e ve nt of a n 
i nf usi o n reacti o n). 
•  Pr o ba ble:  T he e v e nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m e x p os ure t o 
t he i n vesti gati o nal a ge nt a n d has bee n pre vi o usl y bee n descri be d i n ass oci ati o n 
wit h t he i n vesti gati o nal a ge nt O R ca n n ot reas o na bl y be attri b ute d t o ot her fact ors 
s uc h as t he patie nt’s cli nical state, ot her t hera p e utic i nter ve nti o ns or c o n c o mita nt 
me dicati o ns. 
•  P ossi ble:  T he e ve nt f oll o ws a reas o na ble te m p oral se q ue nce fr o m e x p os ure t o t he 
i n vesti gati o nal a ge nt, b ut c o ul d be attri b uta ble t o ot her fact ors s uc h as t he 

2 2 7 5. 0 0 
 
Pa ge 2 7  of 5 9  
patie nt’s cli nical state, ot her t hera pe utic i nter v e nti o ns or c o nc o mita nt 
me dicati o ns. 
•  U nli kel y:  T o xicit y is d o u btf ull y relate d t o t he i n vesti gati o nal a ge nt(s).  T h e e ve nt 
ma y be attri b uta ble t o ot her fact ors s uc h as t h e patie nt’s cli nical state, ot her 
t hera pe utic i nter v e nti o ns or c o nc o mita nt me dicati o ns. 
•  U nrelate d:  T h e e ve nt is clearl y relate d t o ot her fact ors s uc h as t he p atie nt’s 
cli nical state, ot her t hera pe utic i nter ve nti o ns or c o nc o mita nt me dicati o ns. 
 
F or ge n eral A E assess me nt, a n A E is c o nsi dere d relate d if it is assesse d as defi nitel y, pr o ba bl y, 
or p ossi bl y relate d; u nrel ate d if it is assesse d as u nli kel y relate d or u nrelate d. F or det er mi nati o n 
of I N D safet y r e p orti n g, A E attri b uti o n will be assesse d acc or di n g t o t he s us pecte d a d v erse 
reacti on defi niti o n descri be d i n 2 1 C F R 3 1 2. 3 2 as a n A E f or w hic h t here is a reas o n a ble 
p ossi bilit y t hat t he dr u g ca use d t he a d v erse e ve nt w here “reas o na ble p ossi bilit y” mea ns t here is 
e vi de nce t o s u g gest a ca usal relati o ns hi p bet wee n t he dr u g a n d t he A E. S us pecte d a d v erse 
reacti o ns t hat are b ot h seri o us a n d u ne x pecte d will be re p orte d t o t he F D A as a n I N D s afet y 
re p ort, i n acc or da n ce wit h re g ulati o ns u n der 2 1 C F R 3 1 2. 3 2. 
 
5)  
A d verse E v e nt Re p orti n g Peri o d 
A Es will be m o nit ore d a n d rec or d e d i n st u d y-s pecific cas e re p ort f or ms ( C R Fs) fr o m t he ti me of 
first e x p os ure t o a n i n vesti gati o nal pr o d uct i n t his st u d y t hr o u g h da y + 1 0 0 p ost-tra ns pla nt. T he 
start of t he a d verse e v e nt re p orti n g f or a st u d y s u bject will c oi nci de wit h si g ni n g of t he i nf or me d 
c o nse nt.  A Es wit h a n o nset date pri or t o t he first e x p os ure t o a n i n vesti gati o nal pr o d uct will n ot 
be rec or de d, e xce pt i n t h e case of cli nicall y si g nifica nt w orse ni n g of t he A E d uri n g t he s pecifie d 
m o nit ori n g ti me fra me. S A Es t hat occ ur after t h e st u d y-s pecific i nf or m e d c o nse nt is si g ne d b ut 
pri or t o t he first d ose of t he i n vesti gati o nal pr o d uct will be c ollecte d o nl y if t he y are c o nsi dere d 
b y t he i n vesti gat or t o be ca usall y rel ate d t o t he st u d y re q uire d pr oce d ures. A s u bject wit h dra w n 
fr o m t he st u d y beca us e of a n a d verse e v e nt m ust be f oll o we d u ntil t he cli nical o utc o me fr o m t he 
a d verse e ve nt is deter mi ne d. 
T o xicities meeti n g t he st u d y st o p pi n g r ule criteria will be re p orte d t o t he I R B wit hi n 1 0 da ys of 
st u d y staff a ware n ess. All ot her S A Es a n d deat hs n ot meeti n g t he e x pe dite d re p orti n g criteria 
will be re p orte d t o t he I R B as part of t he a n n u al c o nti n uati o n re vie w re p ort t o t he I R B.  
 
6)  
A d verse E v e nt Re p orti n g Re q uire me nts 
A.  
Researc h Site Re p orti n g Re q uire me nts 
Classificati o n of a n e ve nt as seri o us or n o n-s eri o us (see Secti o n 1 2. B. 1) det er mi nes t he re p orti n g 
pr oce d ur es t o be f oll o we d b y t he site f or re p orti n g t he e ve nt t o t he S p o ns or. T he i n vesti gat or 
m ust re p ort e ve nts t o t he F H C R C I R B i n acc or da n ce wit h t he p olicies of t h e I R B. 
 
Site t o S p o ns or re p orti n g re q uire me nts f or a d verse e ve nts are s u m marize d i n Ta ble bel o w: 
 
Cl assific ati o n  
Re p orti n g Ti me  
Re p orti n g Acti o n  
C o nt act I nf or m ati o n  
Seri o us 
A d verse 
E ve nt 
( S A E) 
Fatal or 
life-
t hreate ni n g 
Wit hi n 2 4 h o urs of 
researc h tea m * 
a war e ness 
E mail n otificati o n t o 
S p o ns or’s Me dical 
M o nit or & I SI O C 
A d mi nistrat or  
Me dical M o nit or e mail:  
ks ba ker @fre d h utc h. or g 
I SI O C e mail: 
I SI O C @fre d h utc h. or g 

2 2 7 5. 0 0 
 
Pa ge 2 8  of 5 9  
All S A Es 
Wit hi n 2 b usi ness 
da ys of res earc h 
tea m * a ware ness 
S u b mit c o m plete d 
I nstit uti o n-
S p o ns ore d I N D S A E 
Re p orti n g F or m 
si g ne d b y PI or 
desi g nate d s u b-
I n v esti gat or 
I SI O C e mail: 
I SI O C @fre d h utc h. or g 
N o n-seri o us A d verse 
E ve nt 
Per C R F c o m pleti o n 
g ui deli nes 
Rec or d i nf or mati o n 
o n a p pr o priate C R Fs 
N/ A  
 
* Researc h tea m is defi ne d as t he i n di vi d uals liste d o n t he dele gati o n of a ut h orit y l o g. P h ysicia ns liste d o n t he 
st u d y’s dele gati o n of a ut h orit y l o g as tra ns pla nt ser vice atte n di n g p h ysicia ns dele gate d a ut h orit y t o a d mi nister 
i nf or me d c o nse nt will n ot be c o nsi dere d part of t he researc h tea m u nless a d diti o nal res p o nsi bilities relate d t o t he 
c o n d uct of t he st u d y ha ve bee n dele gate d t o t he m b y t he Pri nci pal I n vesti gat or.   
 
T he i nf or mati o n i n t he I nstit uti o n- S p o ns ore d I N D S A E Re p orti n g F or m m ust matc h or be 
rec o ncile d wit h t he i nf or mati o n rec or d e d i n t he a d verse e v e nts secti o n of t h e C R F a n d st u d y 
data base. F or e xa m ple, t he sa me a d v erse e ve nt ter m s h o ul d be use d o n b ot h f o r ms. 
T he i n vesti gat or m ust re p ort e ve nts t o t he F H C R C I R B i n acc or da nce wit h t he p olicies of t he 
I R B.  
 
B.       F H C R C S p o ns or Re p orti n g Re q uire me nts 
T he s p o ns or ass u mes r es p o nsi bilit y f or I N D s afet y re p orti n g t o t he F D A a n d partici pati n g 
i n vesti gat ors, i n acc or d a nce wit h re g ulati o ns u n d er 2 1 C F R 3 1 2. 3 2. 
Eac h seri o us a d vers e e ve nt re p ort recei ve d fr o m t he i n vesti gat or will be e v al uate d b y t he 
Me dical M o nit or w h o will assess t he seri o us ness of t he e ve nt (s ee Secti o n 1 2. B. 1. b), t he 
e x pecte d n ess of t he e v e nt (see Secti o n 1 2. B. 1.c), a n d t he relati o ns hi p t o partici pati o n i n t he st u d y 
(see Secti o n 1 2. B. 4). F or re g ulat or y r e p orti n g p ur p oses, t he S p o ns or will deter mi ne e x p ecte d n ess 
relati n g t o tre os ulfa n usi n g safet y i nf or mati o n s pecifie d i n t he tre os ulfa n i n vesti gat or br oc h ure. 
A n e ve nt will be classifie d as relate d if eit her t he i n vesti gat or or t he S p o ns or deter mi nes t hat t he 
e ve nt ma y be r elate d t o t he st u d y dr u g. 
 
T he S p o ns or or its desi g nee will pr o vi de all i n vesti gat ors wit h a safet y letter n otif yi n g t he m of a n 
e ve nt t hat meets F D A I N D Safet y Re p orti n g criteria. I n v esti gat ors will be re q ueste d t o pr o vi de 
writte n n otificati o n of saf et y re p ort t o t he F H C R C I R B as s o o n as is practical, c o nsiste nt wit h 
I R B re q uire me nts. 
 
Refer t o A p pe n di x XI  f or a list of p ote ntial a d vers e e ve nts ass oci ate d or e x pecte d wit h 
he mat o p oietic cell tra ns pla ntati o n.  All c olla b orati n g PIs ha v e f ulfille d all NI H re q uire me nts f or 
trai ni n g i n h u ma n s u bjects pr otecti o n.    
 
C.   
Pla ns f or ass uri n g data acc urac y a n d pr ot oc ol c o m plia nce 
C olla b orati n g sites se n d si g ne d c o nse nts a n d eli gi bilit y f or ms t o F H C R C st u d y staff wit h s o urce 
d oc u me nts de m o nstrati n g eli gi bilit y. C R Fs  are re vie we d f or a d here nce t o t he pr ot oc ol, acc urac y, 

2 2 7 5. 0 0 
 
Pa ge 2 9  of 5 9  
a n d c o m plete ness b y t he F H C R C st u d y staff. Q ueries are se nt t o t he c olla b orati n g i n vesti gat ors if 
C R Fs are i nacc ur ate or i n c o m plete. T he st u d y is m o nit ore d u n der t he F H C R C M o nit ori n g Pla n. 
T he F H C R C Data a n d Safet y M o nit ori n g Pla n details t he f ull sc o pe a n d e xt e nt of m o nit ori n g a n d 
pr o vi des f or i m me diate acti o n i n t he e ve nt of t he disc o ver y of maj or d e viati o ns.  
 
D.   
O versi g ht a n d Re vie w of Safet y M o nit ori n g 
A n a n n ual re vi e w of t he pr o gress of t he st u d y wit h res pect t o t he m o nit ori n g pla n will be  
perf or me d b y a D ata a n d Safet y M o nit ori n g C o m mittee ( D S M C). As part of t he a n n ual re n e w al 
pr ocess, t he PI will s u b mit a n acc o u nti n g of patie nt e nr oll me nt a n d o utc o mes defi ni n g t he 
m o nit ori n g pla n i n s ufficie nt detail as t o per mit verificati o n of t he re p ort t hr o u g h c hart a u dit. T he 
I R B pr o vi des a fi nal le vel of a n n ual re vi e w. A p pr o val b y t he D S M C is a necessar y b ut n ot 
s ufficie nt c o n diti o n f or fi nal a p pr o val b y t he I R B. T he I R B will re vie w t he sa me c o nti n uati o n 
a p plicati o n a n d materi als t hat are r e vie w e d b y t he D S M C, a n d ma ke a n i n d e pe n de nt ass ess me nt 
of t he pr o gress of t he trial a n d deter mi ne w h et her t he percei ve d ris k- b e nefit rati o c o nti n ues t o be 
acce pta ble. 
 
1 3.    Rec or ds 
 
Cli nical Statistics mai ntai ns a patie nt data bas e at F H C R C t o all o w st ora ge a n d retrie v al of patie nt 
data c ollecte d fr o m a wi de variet y of s o urces.  T h e i n vesti gat or will e ns ure t hat data c ollect e d 
c o nf or m t o all esta blis he d g ui deli nes f or c o di n g, c ollecti o n, ke y e ntr y a n d v erificati o n.  Eac h 
patie nt is assi g ne d a u ni q ue patie nt n u m ber t o ass ure patie nt c o nfi de ntialit y.  Patie nts will n ot be 
referre d t o b y t his n u m ber, b y na me, or b y a n y ot her i n di vi d ual i de ntifier i n a n y p u blicati o n or 
e xter nal pr ese ntati o n.   T h e lice nse d me dical rec or ds de part me nt, affiliate d wit h t he i nstit uti o n 
w here t he p atie nt recei ves me dical care, mai ntai ns all ori gi nal i n patie nt a n d o ut patie nt c h art 
d oc u me nts.  Patie nt researc h files are ke pt i n a l o c ke d r o o m.  T he y are mai ntai ne d b y t he 
F H C R C data c ollecti o n staff w hic h is s u per vise d b y a n A. R. T.  Access is restricte d t o pers o n n el 
a ut h orize d b y t he Di visi o n of Cli nical Researc h . 
 
1 4.  
St atistic al C o nsi der ati o ns 
 
T he g oal of t his st u d y is t o s h o w t hat t he pr o ba bilit y of graft fail ure usi n g T R E O/ F L U/ T BI as a 
s ufficie nt c o n diti o ni n g re gi me n is statisticall y si g nifica ntl y less t ha n t he fi x e d hist orical 
be nc h mar k of 1 0 %. I n a d diti o n, we h o pe t o s h o w t hat pr o ba bilit y of da y- 2 0 0 N R M is c o nsiste nt 
wit h a tr ue pr o ba bilit y t hat d oes n ot e xcee d 2 5 %.   
 
T he ori gi nal r ule f or escalati o n of F L U/ T BI bas e d o n e xcess graft fail ure will n ot be i n place i n 
t he m o difie d pr ot oc ol; h o we ver t he st o p pi n g r ule f or da y- 2 0 0 N R M will be e x pa n de d t o 
acc o m m o date t he i n creas e i n accr ual. I n p artic ular, a tr ue da y- 2 0 0 N R M of 2 5 % will be 
c o nsi dere d e xcessi ve, a n d t his assess me nt will be ma de se paratel y f or eac h treat me nt ar m. T h e 
e x pa n de d st o p pi n g r ules will be assesse d after e v er y 1 0 t h e nr olle d patie nt bec o mes eli gi ble f or 
e val uati o n. T he c urre nt distri b uti o n of patie nts e nr olle d t o t he t w o differe nt ar ms is 3 4 t o Ar m 1 
a n d 4 0 t o Ar m 2. Gi ve n t hese t otals, we e x p ect fe wer t ha n a t otal of 8 0 patie nts o n eit her ar m b y 
t he ti me a t otal of 1 3 0 has bee n reac h e d.  T heref ore, t he e x pa n d e d st o p pi n g r ules f or T R M will 
be assesse d after t h e 4 0t h a n d 5 0t h patie nts ha ve b ee n e nr olle d t o Ar ms 1 a n d 2, res pecti vel y. I n 
partic ular, t his r ule w o ul d be tri g gere d i n a partic ular ar m if a n y of t he f oll o wi n g occ urs:  1 3 

2 2 7 5. 0 0 
 
Pa ge 3 0  of 5 9  
N R M e ve nts a m o n g t he first 4 0 ( or fe w er) p atie nts; 1 6 a m o n g t he first 5 0 ( or fe w er) p atie nts; 1 9 
a m o n g t he first 6 0 ( or f e wer) p atie nts; 2 2 a m o n g t he first 7 0 ( or fe wer) pati e nts; 2 4 a m o n g t he 
first 8 0 ( or fe wer) patie nts. If t he tr ue pr o ba bilit y of N R M is 0. 1 5, t he pr o ba bilit y of st o p pi n g 
after 5 0 or 7 0 patie nts is a p pr o xi matel y . 0 0 5 a n d . 0 0 5, res pecti vel y. If t he tr ue pr o ba bilit y of da y-
2 0 0 N R M is 0. 4 0, t he st o p pi n g pr o ba bilities are a p pr o xi matel y . 7 7 a n d . 8 5, res pecti vel y 
(esti mate d fr o m 5, 0 0 0 si m ulati o ns). 
 
Sec o n dar y e n d p oi nts will be e val uat e d a n d i ncl u de o verall s ur vi val ( wit h 6 5 patie nts i n a n ar m, 
we ca n b e 8 0 % certai n t h at esti mate d o ne- y ear s ur vi val is wit hi n at least 0. 0 8 of t he tr ue o ne- year 
s ur vi val), n o n-r ela pse m ortalit y, platelet e n graft me nt, ac ute a n d c hr o nic G V H D, rel a pse, 
pr o gressi o n-free s ur vi val, a n d cli nicall y si g nifica nt i nfecti o ns. Eac h of t h ese will be treate d as a 
ti me-t o-e ve nt e n d p oi nt, a n d Ka pla n- Mei er a n d c u m ulati ve i nci de nce esti m ates will be use d t o 
s u m marize eac h, as a p pr o priate.   
 
1 5. 
Refere nces  
 
1.  
K urtz ber g, J., M. L a u g hli n, M. L. Gra ha m, et al., Place ntal bl o o d as a s o urce of 
he mat o p oietic ste m cells f or tra ns pla ntati o n i nt o u nrelate d reci pie nts. N E n gl J Me d, 
1 9 9 6. 3 3 5( 3): 1 5 7- 6 6. 
2.  
Gl uc k ma n, E., V. R oc ha, A. B o yer- C ha m mar d, et al., O utc o me of c or d- bl o o d 
tra ns pla ntati o n fr o m rel ate d a n d u nrel ate d d o n ors. E ur oc or d Tra ns pla nt Gr o u p a n d t he 
E ur o pea n Bl o o d a n d Marr o w Tra ns pla nt ati o n Gr o u p. N E n gl J Me d, 1 9 9 7. 3 3 7( 6): 3 7 3-
8 1. 
3.  
R u bi nstei n, P., C. Carrier, A. Scara d a v o u, et al., O utc o mes a m o n g 5 6 2 reci pie nts of 
place ntal- bl o o d tr a ns pla nts fr o m u nrelate d d o n ors. N E n gl J Me d, 1 9 9 8. 3 3 9( 2 2): 1 5 6 5-
1 5 7 7. 
4.  
R u bi nstei n, P., J. K urtz ber g, F. L o b eriza, et al., C o m paris o n of U nrel ate d C or d Bl o o d a n d 
U nrelate d B o ne M arr o w Tra ns pla nts f or L e u ke mi a i n C hil dre n: A C olla b orati ve St u d y of 
t he Ne w Y or k Bl o o d Ce nter a n d t he I nt er nati o nal B o ne Marr o w Tra ns pla nt Re gistr y. 
Bl o o d, 2 0 0 1. 9 8: 8 1 4a. 
5.  
Wa g ner, J. E., J. N. Bar ker, T. E. De F or, et al., Tra ns pla ntati o n of u nrelate d d o n or 
u m bilical c or d bl o o d i n 1 0 2 patie nts wit h mali g na nt a n d n o n mali g na nt diseases: i nfl ue nce 
of C D 3 4 cell d ose a n d H L A dis parit y o n treat me nt-relate d m ortalit y a n d s ur vi val. Bl o o d, 
2 0 0 2. 1 0 0( 5): 1 6 1 1- 8. 
6.  
Bar ker, J. N., T. P. Kr e ps ki, T. E. De F or, et al., Searc hi n g f or U nrelate d D o n or 
He mat o p oietic Ste m Cells: A vaila bilit y a n d S pee d of U m bilical C or d Bl o o d vers us B o ne 
Marr o w. Bi ol Bl o o d Marr o w Tra ns pla nt, 2 0 0 2. 8: 2 5 7- 2 6 0. 
7.  
Ver neris M R, Br u nstei n C, Def or T E, et al.  Ris k of rela pse after u m bilical c or d bl o o d 
tra ns pla ntati o n i n patie nts wit h ac ute le u ke mia: m ar ke d re d ucti o n i n reci pie nts of t w o 
u nits.  Bl o o d.  2 0 0 5; 1 0 6: A 3 0 5. 
8.  
Br u nstei n C G, Bar ker J N, Weis d orf DJ, et al.  U m bilical c or d bl o o d tra ns pl a ntati o n after 
n o n- m yel oa blati ve c o n diti o ni n g: i m pact o n tra ns pla nt o utc o me i n 1 1 0 a d ults wit h 
he mat ol o gical disease.  Bl o o d. 2 0 0 7; 1 1 0: 3 0 6 4- 7 0. 
9.  
Feit P W, Rastr u p- A n d ers e n N, Mata g n e R. St u dies o n e p o xi de f or mati o n fr o m ( 2 S, 3 S)-
t hreit ol 1, 4- bis met ha nes ulf o nate. T he pre parati o n a n d bi ol o gical acti vit y of ( 2 S, 3 S)- 1, 2-
e p o x y- 3, 4- b uta n e di ol 4- met ha nes ulf o nate. J M e d C he m 1 9 7 0; 1 3: 1 1 7 3- 5. 

2 2 7 5. 0 0 
 
Pa ge 3 1  of 5 9  
1 0.   
Pl oe mac her R E, J o h ns o n K W, R o m b o uts EJ, et al. A d diti o n of tre os ulfa n t o a 
n o n m yel oa blati ve c o n diti o ni n g re gi me n res ults i n e n ha nce d c hi meris m a n d i m m u n ol o gic 
t olera nce i n a n e x peri me ntal all o ge neic b o ne marr o w tra ns pla nt m o del. Bi ol Bl o o d 
Marr o w Tra ns pla nt 2 0 0 4; 1 0: 2 3 6- 4 5. 
1 1.  
Hil ger R A, Harstri c k A, E ber har dt W, et al. Cli nical p har mac o ki netics of i ntra ve n o us 
tre os ulfa n i n patie nts wit h a d va nce d s oli d t u m ors. Ca ncer C he m ot her P har mac ol. 
1 9 9 8; 4 2: 9 9- 1 0 4. 
1 2.  
Hil ger R A, Ba u m gart J, Sc he ule n M E, et al. P har mac o ki netics of tre os ulfa n i n a 
m yel oa blati ve c o m bi nati o n wit h c ycl o p h os p ha mi de pri or t o all o ge nei c he mat o p oietic 
ste m cell tra ns pla ntati o n. I nt J Cli n P har mac ol T h er 2 0 0 4; 4 2: 6 5 4- 6 5 5. 
1 3. 
Li n dle y C, S hea T, Mc C u ne J, et al. I ntrai n di vi d u al varia bilit y i n b us ulfa n 
p har mac o ki netics i n p atie nts u n der g oi n g a b o ne marr o w tra ns pl a nt: assess me nt of a test 
d ose a n d first d ose str ate g y. A ntica ncer Dr u gs 2 0 0 4; 1 5: 4 5 3- 4 5 9. 
1 4.  
Sc h uler U S, Re n ner U D, Kr osc hi ns k y F, et al. I ntra ve n o us b us ul p ha n f or c o n diti o ni n g 
bef ore a ut ol o g o us or all o ge neic h u ma n bl o o d ste m cell tra ns pla ntati o n. Br J Hae mat ol 
2 0 0 1; 1 1 4: 9 4 4- 9 5 0. 
1 5.  
Sc h mi d maier R, Oelleric h M, Ba u m gart J, et al. Tre os ulfa n-i n d u ce d a p o pt osis i n ac ute 
m yel oi d le u ke mia cells is acc o m pa ni e d b y tra nsl ocati o n of pr otei n ki nase C delta a n d 
e n ha nce d b y br y ostati n- 1. E x p He mat ol 2 0 0 4; 3 2: 7 6- 8 6. 
1 6.  
Fic ht ner I, Bec ker M, Ba u m gart J. A ntile u kae mic acti vit y of tre os ulfa n i n x e n o graft e d 
h u ma n ac ute l y m p h o blastic le u kae mias ( A L L). E ur J Ca ncer 2 0 0 3; 3 9: 8 0 1- 7.  
1 7.  
Harstric k A, Wil ke H, E b e n har dt W, et al. A p has e I d os e escalati o n trial of i ntra ve n o us 
tre os ulfa n i n refract or y ca ncer. O n k ol o gie 1 9 9 6; 1 9: 1 5 3- 1 5 6. 
1 8.  
Sc he ule n M E, Hil ger R A, O ber h off C, et al. Cli nical p hase I d os e escalati o n a n d 
p har mac o ki netic st u d y of hi g h- d ose c he m ot hera p y wit h tre os ulfa n a n d a ut ol o g o us 
peri p her al bl o o d ste m cell tra ns pla ntati o n i n patie nts wit h a d va nce d mali g na ncies. Cli n 
Ca ncer Res 2 0 0 0; 6: 4 2 0 9- 1 6. 
1 9.  
H oller E, Tre ns c hel R, Cas per J, et al. Tre os ulfa n/ c ycl o p h os p ha mi de c o n diti o ni n g i n 
hi g h- ris k le u ke mia patie nts. A cli nical p hase I p h ar mac o ki netic st u d y. B o ne Marr o w 
Tra ns pla nt 2 0 0 3; 3 1( S u p pl 1): P 6 4 2 [a bstract]. 
2 0.  
Cas per J, K na uf W, Kief er T, et al. Tre os ulfa n a n d fl u dara bi ne: a ne w t o xi cit y- red uce d 
c o n diti o ni n g re gi me n f or all o ge neic he mat o p oieti c ste m cell tra ns pla ntati o n. Bl o o d. 
2 0 0 4; 1 0 3: 7 2 5- 3 1. 
2 1. 
S h i m o ni A, Har da n I, S he m- T o v N, et al..  Fl u dara bi ne a n d tre os ulfa n: a n o vel m o difie d 
m yel oa blati ve re gi me n f or all o ge neic h e mat o p oietic ste m-cell tra ns pla ntati o n wit h 
effecti ve a ntile u ke mia acti vit y i n patie nts wit h ac ute m yel oi d le u ke mia a n d 
m yel o d ys plastic s y n dr o mes.  Le u k L y m p h o ma. 2 0 0 7; 4 8: 2 3 5 2- 9. 
2 2.  
H ol o wiec ki J, Gie bel S, Beela n D, et al.  P has e II M ultice nter Trial T o E val uate t he 
Safet y a n d Efficac y of L o w- T o xicit y Tre os ulfa n/ Fl u dara bi n e C o n diti o ni n g Pri or t o 
All o ge neic Hae mat o p oietic Ste m Cell Tra ns pla ntati o n i n Patie nts wit h Ac ute M yel oi d 
Le u ke mia.  Bl o o d 2 0 0 7; 1 1 0: a 6 2 1. 
2 3  
Wac h o wi a k J, C h y bic ka A, K o walcz y k J, et al. D oes tre os ulfa n- base d pre p arati ve 
re gi me n all o w saf e a n d effecti ve all o ge neic H S C T f or a d va n ce d h e mat ol o gic 
mali g na ncies i n c hil dre n de m o nstrati n g hi g h ris k of c o n ve nti o nal re gi me n relate d 
t o xicit y? B o ne Marr o w Tra ns pla nt 2 0 0 3; 3 1( S u p pl 1): 1 9 3[a bst].  

2 2 7 5. 0 0 
 
Pa ge 3 2  of 5 9  
2 4.  
Kr o ger N, S hi m o ni A, Za beli na T, et al.  Re d uce d-t o xicit y c o n diti o ni n g wit h tre os ulfa n, 
fl u dara bi ne a n d A T G as pre parati ve re gi me n f or all o ge neic ste m cell tra ns pla ntati o n 
(all o S C T) i n el derl y patie nts wit h sec o n dar y ac ut e m yel oi d le u ke mia (s A M L) or 
m yel o d ys plastic s y n dr o me ( M D S).  B o ne Marr o w Tra ns pla nt. 2 0 0 6; 3 7: 3 3 9- 3 4 4. 
2 5.  
Bar ker, J N, Weis d orf DJ, De F or T E, et al., Ra pi d a n d c o m plete d o n or c hi meris m i n a d ult 
reci pie nts of u nr elate d d o n or u m bilical c or d bl o o d tra ns pla ntati o n after re d u ce d-i nte nsit y 
c o n diti o ni n g. Bl o o d, 2 0 0 3; 1 0 2( 5): 1 9 1 5- 1 9 1 9. 
2 6.  
Bla u I W, Sc h mi dt- Hie ber M, Lesc hi n ger N, et al.  E n graft me nt ki netics a n d 
he mat o p oietic c hi meris m after re d uce d-i nte nsit y c o n diti o ni n g wit h fl u dara bi ne a n d 
tre os ulfa n bef ore all o ge n eic ste m cell tra ns pla nt ati o n.  A n n He mat ol. 2 0 0 7; 8 6( 8): 5 8 3- 9. 
2 7.  
H or witz M, C h ute J, Gas parett o C, et al.  M yel oa blati ve i ntra ve n o us b us ulfa n/fl u dara bi n e 
c o n diti o ni n g d oes n ot facilitate e n graft me nt of d u al u m bilical c or d bl o o d grafts i n a d ult 
reci pie nts. Bl o o d 2 0 0 7; 1 1 0:a 2 0 0 7.  
2 8.  
Sa nz J, Arcese W, Her n a n dez- B ol u da J C, et al.  L o w tra ns pla nt-relate d m ortalit y i n 
patie nts wit h he mat ol o gic mali g na ncies u n der g oi n g u m bilical c or d bl o o d tra ns pla ntati o n 
wit h t hi ote pa, o nce dail y i ntra ve n o us b us ulfa n, fl u dara bi ne, a n d a nti-t h y m o c yte gl o b uli n. 
 Bl o o d 2 0 0 7; 1 1 0:a 6 1 8. 

2 2 7 5. 0 0 
 
Pa ge 3 3  of 5 9  
A P P E N DI X I: W H O cl assific ati o n a n d criteri a f or t he m yel o d ys pl astic s y n dr o mes ( M D S) 
  
 
Dis or der  
 
Peri p her al Bl o o d  
 
B o ne M arr o w  
 
Refr act or y A ne mi a ( R A)  
A ne mi a  
N o or r are bl asts  
  
Er yt hr oi d d ys pl asi a o nl y  
< 5 perce nt bl asts  
< 1 5 perc e nt ri n ge d si der o bl asts  
Refr act or y A ne mi a wit h Ri n ge d Si der o bl asts 
( R A R S) 
A ne mi a  
N o bl asts  
  
Er yt hr oi d d ys pl asi a o nl y  
< 5 perce nt bl asts  
1 5 perce nt ri n ge d si der o bl asts  
Refr act or y C yt o pe ni a wit h M ultili ne a ge 
D ys pl asi a ( R C M D)  
Bi - or  p a n -c yt o pe ni a  
N o or r are bl asts  
N o A uer r o ds  
M o n oc ytes 
< 1, 0 0 0/ µ L  
D ys pl asi a i n 
1 0 perce nt of cells i n 
t w o or m ore m yel oi d cell li nes 
N o A uer r o ds  
< 5 perce nt bl asts  
< 1 5 perce nt ri n ge d si der o bl asts  
Refr act or y C yt o pe ni a wit h M ultili ne a ge 
D ys pl asi a a n d Ri n ge d Si der o bl asts ( R C M D -
R S)  
Bi - or p a n -c yt o pe ni a  
N o or r are bl asts  
N o A uer r o ds  
M o n oc ytes 
< 1, 0 0 0/ µ L  
D ys pl asi a i n 
1 0 perce nt o f cells i n 
t w o or m ore m yel oi d cell li nes 
N o A uer r o ds  
< 5 perce nt bl asts  
1 5 % ri n ge d si der o bl asts 
Refr act or y A ne mi a w it h E xcess Bl asts-1 
( R A E B-1)  
C yt o pe ni as  
< 5 % bl astss 
N o A uer r o ds  
M o n oc ytes 
< 1, 0 0 0/ µ L  
U nili ne a ge or m ultili ne a ge d ys pl asi a  
5- 9 perce nt bl asts  
N o A uer r o ds  
  
Refr act or y A ne mi a wit h E xcess Bl asts -2 
( R A E B-2)  
C yt o pe ni as  
5- 1 9 % bl asts 
A uer r o ds ±  
M o n oc ytes 
< 1, 0 0 0/ µ L  
U nili ne a ge or m ultili ne a ge d ys pl asi a  
1 0 -1 9 perce nt bl asts  
A uer r o ds ±  
  
M D S -U ncl assifie d ( M D S -U)  
C yt o pe ni as  
N o or r are bl asts  
N o A uer r o ds  
U nili ne a ge d ys pl asi a i n gr a n ul oc ytes 
or m e g a k ar y oc ytes  
N o A uer r o ds  
< 5 perce nt bl asts  
M D S wit h del( 5 q) " 5 q - s y n d r o m e " 
A ne mi a  
< 5 perce nt bl asts  
Pl atelets us u all y 
n or m al or i ncre ase d  
N or m al t o i ncre ase d m e g a k ar y oc ytes 
wit h h y p ol o b ul ate d n uclei  
N o A uer r o ds  
< 5 perce nt bl asts Is ol ate d del( 5 q)  
 
 

2 2 7 5. 0 0 
 
Pa ge 3 4  of 5 9  
A P P E N DI X II:  
    Perf o r m a nce St at us Sc ales  
 
 
E C O G Perf or m a nce St at us  Sc ale  
 
 
K ar n ofs k y Perf or m a nce Sc ale  
Gra de  
Descri pti o ns  
Perce nt  
Descri pti o n  
0 
N or mal acti vit y.  F ull y acti ve, a ble t o 
carr y o n all pre-disease perf or ma nce 
wit h o ut restricti o n.  
1 0 0  
N or mal, n o c o m plai nts, n o e vi de nce of 
disease.  
9 0  
A ble t o carr y o n n or m al acti vit y; mi n or 
si g ns or s y m pt o ms of disease. 
1 
S y m pt o ms, b ut a m b ulat or y.  Restricte d i n 
p h ysicall y stre n u o us acti vit y, b ut 
a m b ulat or y a n d a ble t o carr y o ut w or k of 
a li g ht or se de ntar y nat ure (e. g., li g ht 
h o use w or k, office w or k).  
8 0  
N or mal acti vit y wi t h eff ort; s o me si g ns or 
s y m pt o ms of disease. 
7 0  
Cares f or self, u na ble t o carr y o n n or mal 
acti vit y or t o d o acti ve w or k. 
2 
I n be d < 5 0 % of t he ti me.  A m b ulat or y 
a n d ca pa ble of all self -care, b ut u na ble t o 
carr y o ut a n y w or k acti vities.  U p a n d 
a b o ut m o re t ha n 5 0 % of wa ki n g h o urs. 
6 0  
Re q uires occasi o nal assista nce, b ut is a ble 
t o care f or m ost of his/ her nee ds. 
5 0  
Re q uires c o nsi dera ble assista nce a n d 
fre q ue nt me dical care. 
3 
I n be d > 5 0 % of t he ti me.  Ca pa ble of o nl y 
li mite d self-care, c o nfi ne d t o be d  or c hair 
m ore t ha n 5 0 % of wa ki n g h o urs.  
4 0  
Disa ble d, re q uires s pecial care a n d 
assista nce.  
3 0  
Se verel y disa ble d, h os pitalizati o n i n dicate d. 
 Deat h n ot i m mi ne nt.  
4 
1 0 0 % be dri d de n.  C o m pletel y disa ble d.  
Ca n n ot carr y o n a n y self -care.  T otall y 
c o nfi ne d t o be d or c hair. 
2 0  
Ver y sic k, h os pitalizati o n i n dicate d. Deat h 
n ot i m mi ne nt.  
1 0  
M ori b u n d, fatal pr ocesses pr o gressi n g 
ra pi dl y. 
5  
Dea d.  
0  
Dea d.  
 
 
L a ns k y Pl a y Perf or m a nce St at us Sc ale  
 
L a ns k y Pl a y Perf or m a nce Sc ale   
 
 
 
Sc ore 
 
Descri pti o n  
1 0 0  
F ull y acti ve, n or mal  
9 0  
Mi n or restricti o ns i n p h ysicall y stre n u o us acti vit y  
8 0  
Acti ve, b ut tires m ore q uic kl y  
7 0  
B ot h, greater r estricti o ns of, a n d less ti me s pe n d i n pla y acti vities  
6 0  
U p a n d ar o u n d, b ut mi ni mal acti ve pla y, kee ps b us y wit h q uieter acti vi ties 
5 0  
Gets dresse d b ut lies ar o u n d m uc h of t he da y, n o acti ve pla y; a ble t o partici pate i n 
 
 
 
 
4 0  
M ostl y i n be d; partici pates i n q uiet acti vities  
3 0  
I n b e d; nee ds assista nce e ve n f or q ui et pla y 
2 0  
Ofte n slee pi n g; pla y e ntir el y l i mite d t o ver y passi ve acti vities 
1 0  
U nres p o nsi ve  
0  
Dea d  
 

2 2 7 5. 0 0 
 
Pa ge 3 5  of 5 9  
A P P E N DI X III:  T he He m at o p oietic Cell Tr a ns pl a nt- C o m or bi dit y I n de x ( H C T- CI)  
 
I nstr ucti o ns: Circle a p plica ble sc ores a n d pr o vi de act ual val ue or ca use of' c o -m or bi dit y.  
C o m or bi dities 
Defi niti o ns 
 
H C T -CI 
wei g hte d sc ores  
Act ual La b 
Val ues/ C o m me nts 
Arr h yt h mia  
Atrial fi brillati o n or fl utter, sic k si n us  
s y n dr o me, 
a n d v e ntri uclar arr h yt h mias  
1  
 
Car diac  
C or o nar y arter y disease , c o n gesti ve heart 
fail ure, m y ocar dial i nfarcti o n, or E F< 5 0 %  
1  
 
I nfla m mat or y 
b o wel disease  
Cr o h n's disease or ulcerati ve c olitis  
1  
 
Dia betes *  
Re q uiri n g treat me nt wit h i ns uli n or oral  
h y p o gl yce mics, b ut n ot diet al o ne  
1  
 
Cere br o -vasc ular 
disease  
Tra nsie nt isc he mic attac k or cere br o -vasc ular  
Acci de nt  
1  
 
 
 
Ps yc hiatric  
Dist ur ba nc e 
De pressi o n a n xiet y re q uiri n g ps yc hiatric 
c o ns ult 
or treat me nt  
1  
 
He patic -mil d *  
C hr o nic he patitis, Bilir u bi n  > U L N - 1. 5 X 
U L N,  
or A S T/ A L T > U L N -2. 5 X U L N  
1  
 
 
O besit y *  
Patie nts wit h a b o d y mass i n de x > 3 5 k g/  m2 
1  
 
 
 
I nfecti o n * 
Re q uiri n g c o nti n uati o n of a nt i-micr o bial  
Treat me nt after da y 0  
1  
 
 
 
R he u m at ol o gic 
S L E, R A, p ol y m y ositis, mi xe d C T D  
P ol y m yal gia r he u matica  
2  
 
 
Pe p tic ulcer *  
Re q uiri n g treat me nt  
2  
 
M o derate/ se vere 
re nal * 
ser u m creati ni ne > 2 m g/ dl, o n dial ysis, or pri or 
re nal tra ns pla ntati o n 
2  
 
 
M o dera te 
p ul m o nar y *  
D L C O  a n d/ or F E V, > 6 5 % -8 0 % or  
Dis pe n d o n sli g ht acti vit y  
2  
 
 
Pri or s oli d t u m or  
Tre ate d at a ny ti me p oi nt i n t he p atie nt's p ast  
hist ory, excl u di n g n o n -mel a n o m a ski n c a ncer  
3  
 
 
 
Heart val ve 
disease *  
E xce pt mitral val ve pr ola pse  
3  
 
 
Se vere p ul m o nar y *  
D L C O a n d/ or F E V 1 < 6 5 % or  
D ys p nea at rest re q uiri n g o x y ge n  
3  
 
M o derate/se vere  
He patic  
Li ver cirr h osis, Bilir u bi n > 1. 5 X U L N or  
A S T/ A L T > 2. 5 X U L N  
3  
 
 
 
 
Ple ase pr o vi de                       K ar n ofs k y perf or m a nce 
Sc o re = _ _ _ _ _ _ _ _ _ _ _ _ _ _ %  
     ( K P S):  
T ot al S c ore 
= _ _ _ _ _ _ _ _ _ _ 
 
 
C o m plete d b y ( pri nt): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D ate 
c o m plete d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
* C o m or bi dit y is c urre ntl y acti ve or patie nt re q uires me dical treat me nt +  
O n e o r m ore vessel-c or o n ar y arter y ste n osis, re q uiri n g me dical treat me nt, ste nt, or b y p ass g raft  

2 2 7 5. 0 0 
 
Pa ge 3 6  of 5 9  
E F i n dicates ejecti o n fracti o n; U L N, u p per li mit of n or mal; S L E, s yste mic l u p us er yt he mat os us;  R A, r h e u mat oi d art hritis; C T D , c o n necti v e 
tiss u e disease; 
D L C O, dif f usi o n ca pacit y of car b o n m o n o xi de; F E V1, f orce d e x pirat or y v ol u me i n o ne sec o n d; A S T, as p artate a mi n otra nsferase; A L T, ala ni ne 
a mi n otra nsferase 

2 2 7 5. 0 0 
 
Pa ge 3 7  of 5 9  
A P P E N DI X I V:  G ui deli nes f or T ot al B o d y Irr a di ati o n  
All patie nts w h o ha ve ha d pre vi o us ra diati o n t hera p y or T B I s h o ul d be see n b y Ra diati o n 
O nc ol o g y pri or t o e ntra n ce o n t he pr ot oc ol f or a p pr o val f or a d diti o nal T BI. T BI ma y b e 
deli vere d b y l ocal g ui deli nes pr o vi de d t he effecti ve d ose is e q ui vale nt t o w hat is rec o m me n de d 
i n t he T BI G ui deli nes. 
 
Patie nts i neli gi ble f or t his pr ot oc ol i ncl u de t h ose w h o ha ve ha d pre vi o us irra diati o n t o areas of 
t he b o d y s uc h t hat t he Ra diati o n O nc ol o gist feels t hat e ve n a relati vel y s mall d ose of t otal b o d y 
irra diati o n ( T BI) ca n n ot safel y be gi ve n. 
 
F or patie nts pr e vi o usl y e x p ose d t o t otal b o d y irra diati o n ( T BI), t h e Ra diati o n O nc ol o gist will 
deter mi ne w het h er t he p atie nt ca n saf el y recei ve a d diti o nal T BI base d o n pri or e x p os ure hist or y. 
I n a d diti o n, t he treati n g Ra diati o n O nc ol o gist, al o n g wit h t he atte n di n g p h ysicia n, will deter mi ne 
t he nee d f or l u n g a n d/ or ki d ne y s hiel di n g fr o m t he ra diati o n bea m t o pre ve nt e xcessi ve t o xicit y 
a n d a gai n bas e d o n t he hist or y of e x p os ure. N o ot her or ga ns ma y be s hiel de d. 
 
 
T BI d osi n g g ui deli nes 
 
D ose le vel 1: 
T he treat me nt d ose re gi me n will be 2 0 0 c G y i n o ne fracti o n. N o l u n g s hiel di n g or ki d ne y 
s hiel di n g will be use d f or t his T BI sc he me u nl ess patie nts ha ve e x p erie n ce d pre vi o us irra diati o n 
(see l u n g s hiel di n g bel o w). 
 
D ose le vel 2: 
T he sec o n d d os e le vel will be 3 0 0 c G y i n o ne fracti o n f or t he first T BI d ose le vel. N o l u n g 
s hiel di n g or ki d ne y s hiel di n g will be use d f or t his T BI sc h e me u nless patie nts ha ve e x perie nce d 
pre vi o us irra diati o n (s ee l u n g s hiel di n g bel o w). 
 
D ose le vel 3: 
T he t hir d d ose le vel will be 4 0 0 c G y i n o ne fracti o n. L u n g s hiel di n g will be use d f or t his T BI 
sc he me as o utli ne d bel o w. 
 
D ose le vel 4: 
T he f o urt h d ose le v el will be 4 5 0 c G y i n o ne fracti o n f or patie nts > 7 years ol d. Patie nts ≤ 7 
years ol d will recei ve 2 2 5 c G y BI D o ver o ne da y. L u n g s hiel di n g will be use d f or t his T BI 
sc he me as d escri be d b el o w. 
 
M o dalit y: 
Hi g h- e ner g y p h ot o ns wit h e ner g y ≥ 6 M V p h ot o ns s h o ul d be utilize d. Alt h o u g h t here is n o u p per 
li mit o n t he e ner g y as l o n g as t he s ki n d ose re q uire me nts ca n be met, it is rec o m me n de d t hat 
1 8 M V or l o wer b e use d. T he selecti o n of e ner g y is deter mi ne d b y t he d ose u nif or mit y criteri o n. 
 
 
 
Tar get V ol u me: 

2 2 7 5. 0 0 
 
Pa ge 3 8  of 5 9  
T he t otal b o d y will be treate d i ncl u di n g t he hea d a n d feet i n o ne fi el d (e xce pt i n certai n 
circ u msta nces). Car e s h o ul d be ta ke n t o e ns ure t hat t he patie nt is e ntirel y wit hi n t he 9 0 % is o d os e 
decre m e nt li ne of t he bea m (i.e., n ot i n t he pe n u m bra re gi o n of t h e bea m). 
 
Tar get D ose: 
T he prescri pti o n p oi nt is defi ne d as t he p oi nt al o n g t he l o n git u di nal a xis of t he patie nt at t he 
mi dli ne at t he le vel of t he u m bilic us (see Prescri pti o n P oi nt 2 ). N o tiss ue i n h o m o ge neit y 
c orrecti o n will be ma de i n t he calc ulati o n of d os e t o t he prescri pti o n p oi nt. T he a bs or be d d ose 
al o n g t he patie nt’s hea d t o t oe a xis (li ne f or me d b y t he i ntersecti o n of t he mi dsa gittal pla ne a n d 
t he mi dc or o nal pla ne) s hall be wit hi n 1 0 % of t he prescri be d d os e. T he d os e at select e d 
a nat o mical p oi nts s hall be calc ul ate d a n d t hes e cal c ulati o ns are t o be s u b mitte d as part of t he 
q ualit y ass ura nce. M eas ure me nts of patie nt di me nsi o ns nee de d f or t h e cal c ulati o n of t he 
prescri pti o n d ose will be ma de at t he ti me of t he si m ulati o n f or l u n g bl oc ks. 
 
Meas ure me nt a n d cal c ulati o ns of re q uire d m o nit or u nits ma y be necessar y f or eac h treat me nt a n d 
will be perf or me d f or b ot h t he e x pect e d u pri g ht treat me nt p ositi o n ( A P- P A fiel ds) a n d t he 
recli ni n g, lateral d ec u bit us p ositi o n ( A P- P A fiel ds) or lateral fiel d tec h ni q ues. Pe diatric patie nts 
ma y be treat e d pr o ne a n d s u pi ne u n der a n est hesia b y A P- P A fiel ds. I n t h e e ve nt t he patie nt 
pr o ves t o o ill t o recei ve a fracti o n i n t he u pri g ht p ositi o n, d ose calc ulati o n m a y be pre-cal c ulate d 
t o per mit treat me nt i n t he lateral dec u bit us p ositi o n). 
 
D ose p oi nt calc ulati o ns: 
1. He a d ( P oi nt 1) : t his refere n ce p oi nt is defi ne d al o n g t he l o n git u di nal a xis of t he s k ull at t he 
greatest mi d -se p arati o n (i m me diatel y s u peri or t o t he nasal bri d ge). T he d e pt h s h o ul d be ta ke n as 
mi d wa y bet wee n t h e e ntr a nce a n d e xit p oi nts of t he o p p ose d ra di ati o n bea ms. 
2. Nec k ( P oi nt 2) : t his refere n ce p oi nt is defi ne d al o n g t he patie nt’s l o n git u di nal a xis at t he le vel 
of C 3/ C 4 (a p pr o xi mate mi d- nec k, b ut c h ose n f or t he t hi n nest mi d-se parati o n of t he nec k). T he 
p oi nt is ta ke n t o be mi d wa y bet wee n t he e ntra nce a n d e xit p oi nt of t he bea m. 
3. U p per Me di asti n u m ( P oi nt 3) : t his refere n ce p oi nt is defi ne d al o n g t he patie nt’s l o n git u di nal 
a xis at t he le vel of t he a n gle of L o uis. T he refere n ce p oi nt is mi d wa y bet wee n t he e ntra n ce a n d 
t he e xit p oi nts of t he o p p ose d bea ms. 
4. L o wer Me di asti n u m ( P oi nt 4) : t his refere nce p oi nt is defi ne d al o n g t he patie nt’s l o n git u di nal 
a xis at t he le vel of t he xi p hister nal n otc h. T he refere nce p oi nt is mi d wa y bet wee n t he e ntra n ce 
a n d e xit p oi nts of t he o p p ose d bea ms 
5. U m bilic us ( P oi nt 5) : T H E P R E S C RI P TI O N P OI N T is defi ne d al o n g t he patie nt’s 
l o n git u di nal a xis at t he le vel of t he u m bilic us. T he prescri pti o n p oi nt is mi d wa y bet wee n t he 
e ntra nce a n d e xit p oi nts of t he o p p ose d bea ms. 
6. K nee ( P oi nt 6): t his refere n ce p oi nt is defi ne d al o n g t he mi dli ne i n t he mi d pla ne of t he k nee 
at t he le vel of t he p atella. 
7. A n kle ( P oi nt 7) : t his refer e nce p oi nt is defi ne d al o n g t he mi dli ne at t he mi d pla ne of t he a n kle 
at t he le vel of t he lat eral malle ol us. 
8. S hiel de d L u n g D ose ( P oi nt 8) : t his refere n ce p oi nt is l ocate d o n t he ri g ht c hest wall u n der t he 
l u n g bl oc k. It is ce ntere d ( b ot h me dial/lateral a n d ce p hal oca u da d) u n d er t h e l u n g bl oc k as 
pr ojecte d o n t he p atie nt’s s ki n. T he de pt h s h o ul d be ta ke n as mi d wa y b et wee n t he e ntra n ce a n d 
e xit p oi nts of t he o p p ose d ra diati o n bea ms. D ose meas ure me nts at t his l ocati o n will be ta ke n 
d uri n g a fracti o n wit h l u n g s hiel di n g i n place. 

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9. U ns hiel de d L u n g D ose ( P oi nt 9) : T his refere n ce p oi nt is t he sa me as p oi nt 8. D ose 
meas ure me nts at t his l ocati o n will be ta ke n d uri n g a fracti o n wit h o ut l u n g s hiel di n g i n place. T he 
de pt h s h o ul d be ta ke n as mi d wa y bet wee n t h e e ntra nce a n d e xit p oi nts of t he o p p ose d ra di ati o n 
bea ms. 
 
Pr escri pti o n P oi nts/ D ose M o nit ori n g P oi nts: 
1. He a d ( P oi nt 1):  t his prescri pti o n p oi nt/ d ose m o nit ori n g p oi nt is defi ne d al o n g t he l o n git u di nal 
a xis of t he s k ull at t he gr eatest mi d-se parati o n (i m me diatel y s u peri or t o t he nasal bri d ge). T h e 
de pt h s h o ul d be ta ke n as mi d wa y bet wee n t h e e ntra nce a n d e xit p oi nts of t he o p p ose d ra di ati o n 
bea ms. Prescri pti o n p oi nt meas ure d eac h fracti o n A P/ P A. 
2. U m bilic us ( P oi nt 2) : t he prescri pti o n p oi nt/ d ose m o nit ori n g p oi nt is defi ne d al o n g t he 
patie nt’s l o n git u di nal a xis at t he le vel of t he u m bilic us. T he pres cri pti o n p oi nt is mi d wa y 
bet wee n t he e ntra n ce a n d e xit p oi nts of t he o p p ose d bea m. Prescri pti o n p oi nt meas ure d eac h 
fracti o n A P/ P A. 
3. A n kle ( P oi nt 3) : t his d ose m o nit ori n g p oi nt is defi ne d al o n g t he mi dli ne at t he mi d pla ne of t he 
a n kle.  
 
D ose Defi niti o n: 
T he a bs or be d d ose is s pecifie d as ce nti gra y (c G y)- t o- m uscle. 
 
D ose Rate: 
A mi d- pla ne d ose r ate of bet wee n 6 a n d 1 5 c G y p er mi n ute is re q uire d. 
 
D ose U nif or mit y: 
T he o bjecti ve is t o kee p t he d ose t hr o u g h o ut t he b o d y, defi ne d t o e xte n d t o wit hi n 2 m m of t he 
s ki n s urface, t o at least 9 0 % of t he pres cri pti o n d ose. I n a d diti o n, t he brai n d ose s hall n ot e xcee d 
1 0 7 % of t he pr escri pti o n d ose. F or s o me A P/ P A treat me nts, partial tra ns missi o n l u n g bl oc ks will 
be use d t o li mit t he o verall t otal l u n g d ose. T he d ose at t he mi d p oi nt of t he t hic kest part of t he 
b o d y w hile i n t he treat me nt p ositi o n s h o ul d be deter mi ne d a n d if n ecess ar y, m o dificati o ns ma de 
t o t he treat me nt t o raise t he d ose i n t his re gi o n t o at least 9 0 % of t he prescri pti o n d ose. 
 
I n or der t o satisf y t he re q uire me nt t hat t he s ki n d ose at a de pt h of 2 m m is wit hi n at least 9 0 % of 
t he prescri pti o n d ose, b ea m s p oilers or ot her e q uall y effecti ve de vices s h o ul d be use d. T he fiel d 
size s hall be s uc h t hat n o part of t he patie nt e xte n ds i nt o t he p orti o n of t he pe n u m bra re gi o n 
w here t he d os e is less t ha n 9 0 % of t he ce ntral a xis d ose. 
 
Treat me nt Tec h ni q ue: 
Patie nts will be treate d usi n g A P/ P A fiel ds i n a n u pri g ht seate d or sta n di n g p ositi o n i n a T BI 
p ositi o ni n g de vice. Treat me nt will be deli vere d wit h e q uall y wei g hte d parallel o p p ose d p ortals, 
wit h eac h treat me nt i ncl u di n g b ot h A P a n d P A fiel ds. If t he patie nt is u na bl e t o t olerate t he 
u pri g ht p ositi o n, acce pta ble alter nate arra n ge me nts will i ncl u de e q uall y wei g hte d A P- P A or 
lateral parallel o p p ose d fi el ds deli vere d t o t he p atie nt i n a lateral d ec u bit us p ositi o n o n a 
treat me nt c o uc h or g ur ne y. 
 
C ha n ges i n patie nt p ositi o ni n g after t he p atie nt has starte d T BI are disc o ura ge d. W h e n 
u na v oi da ble, t o e ns ur e c o m plia nce t o t he o verall d ose a n d l u n g s hiel di n g para meters, a p pr o priat e 

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c ha n ges i n l u n g bl oc ki n g a n d d ose recalc ul ati o n will be re q uire d. Y o u n g p atie nts re q uiri n g 
a nest hesia will be treate d i n a n A P/ P A c o nfi g urati o n at e xte n de d dista nce.  
 
D ose Calc ulati o n f or t he Prescri pti o n P oi nt: 
T he calc ul ati o n of t he treat me nt ti me or t he m o nit or u nits f or t he pres cri be d d ose ca n be carrie d 
o ut usi n g sta n dar d tec h ni q ues. H o we v er, T BI pres e nts s pecial pr o ble ms relati ve t o t he r o uti ne 
treat me nt sit uati o n i n t hat t he fiel d sizes are m uc h lar ger a n d t he treat me nt dista nces m uc h 
l o n ger. T he T BI perce nt de pt h d ose ( P D D) or Tiss ue Ma xi m u m Rati o ( T M R) a n d o ut p ut fact ors 
s h o ul d be meas ure d u n d er T BI tr eat me nt c o n diti o ns f or a ra n ge of p h a nt o m sizes t o esta blis h t he 
data base f or T BI bea m- o n ti me calc ulati o ns or t o vali date t he cal c ulati o n met h o d ol o g y. 
 
T y picall y, a cal c ulati o n met h o d ol o g y will be a d o pte d w hic h uses P D D or T M R a n d o ut p ut 
fact ors meas ure d u n d er sta n dar d c o n diti o ns b ut t he n m o difie d t o acc o u nt f or t he lar ger treat me nt 
dista nce. F or e xa m ple, m o difie d val ues f or i n v erse s q uare c orrecte d perce nt a ge de pt h d ose or 
tiss ue-air rati os a n d tiss u e p ha nt o m rati os are necessar y f or s o me treat me nt u nits w he n t he 
patie nt is p ositi o ne d at a l o n g dista nce fr o m t he p h ot o n s o urce a n d n ear t he fl o or or o ne w all of 
t he r o o m. Als o, s o me de viati o n fr o m a n e xact i n verse s q uare decrease wit h dista nce has bee n 
de m o nstrate d f or cert ai n ge o metries. 
 
Meas ure me nts of d ose at t he ce nter of a p h a nt o m a b o ut t he size of t he t y pical patie nt s h o ul d be 
perf or me d a n d c o m pare d t o t he calc ulate d d os e. If differe n ces are f o u n d, a d diti o nal c orrecti o n 
fact ors s h o ul d be i ntr o d u ce d t o t he calc ulati o n met h o d. 
 
Critical Or ga n D ose P oi nts: 
T he re q uir e d d ose calc ul ati o ns s h o ul d be perf or m e d f or  at least 3 p oi nts refere n ce d a b o ve, 
i ncl u di n g t he d ose m o nit ori n g p oi nts. T he mi dli ne d ose at t hese l ocati o ns s h o ul d be rec or de d o n 
t he T BI S u m mar y F or m. T he d ose ca n be calc ulat e d base d o n t he t hic k n ess at eac h l o cati o n a n d 
fact ors a p pr o priate t o t he T BI tr eat me nt c o n diti o ns. 
 
It is rec o m me n de d t hat e ntra nce a n d e xit T L Ds or di o des be place d o n t h e patie nt at eac h 
re q uire d d ose assess me nt l ocati o n. T he mi dli ne d ose ca n be calc ul ate d fr o m t hese meas ure me nts 
ma ki n g t he a p pr o priat e c orrecti o ns t o t he rea di n gs a n d t he n a vera gi n g t he c orrect e d val ues. 
I n y o u n g er patie nts it is als o rec o m me n de d t hat T L Ds or di o des be place d u n der neat h t he l u n g 
bl oc ks t o d oc u me nt t he tr a ns missi o n d ose a n d scatter d ose. 
 
L u n g S hiel di n g: 
L u n g s hiel di n g s hall be use d i n all patie nts w h o recei ve a d os e ≥ 4 0 0 c G y t otal T BI. O n e half 
val ue la yer tra ns missi o n ( H V L) bl oc ks will be us e d f or D ose Le v els 3 a n d 4 . I n a d diti o n, f or 
patie nts recei vi n g 2 0 0 or 3 0 0 c G y of T BI w h o h a v e recei ve d pre vi o us irra di ati o n, t he treati n g 
Ra diati o n O nc ol o gist will deter mi ne w het her t he p atie nt ca n safel y recei ve a d diti o nal T BI bas e d 
o n pri or e x p os ure hist or y. I n a d diti o n, t he treati n g Ra diati o n O nc ol o gist, al o n g wit h t he atte n di n g 
p h ysicia n, will deter mi ne t he nee d f or l u n g a n d/ or ki d ne y s hiel di n g fr o m t he ra diati o n bea m t o 
pre ve nt e x cessi ve t o xicit y a n d a gai n bas e d o n t he hist or y of e x p os ure. If t h e l u n gs s h o ul d be 
s hiel de d, o ne half v al ue l a yer l u n g bl oc ks will be use d t o decrease t he p h ot o n c o ntri b uti o n t o t he 
l u n g d ose t o a p pr o xi matel y half t hat of t he pres cri pti o n p oi nt. 
 

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I n t he e ve nt t hat t he Ra di ati o n O nc ol o gist feels it is necessar y, o ne half val ue la yer P O S T E RI O R 
ki d ne y bl oc ks ma y  be us e d t o decr ease t h e p h ot o n c o ntri b uti o n t o t he ki d ne ys t o a p pr o xi matel y 
7 5 % t hat of t he pres cri pti o n p oi nt. 
 
L u n g- Bl oc k Desi g n: 
L u n g bl oc ks will c o nfir m t o t he f oll o wi n g g ui deli nes: T he lateral e d ges will be 1. 0 – 1. 5 c m fr o m 
t he i n ner b or der of t he ri bs; t he i nferi or e d g es will be 1. 0 – 1. 5 c m fr o m t he d o me of t he a pe x of 
t he dia p hra g m; t he s u peri or b or ders will be 1. 0 – 1. 5 c m bel o w t he cla vi cles; t he me dial b or der 
2. 0 – 2. 5 c m fr o m t he lat eral e d g es of t he t h oracic verte bral b o dies. N o c o nt o uri n g of t he l u n g 
s hiel ds will be d o ne ar o u n d t he hil u m u nless t here is a resi d ual a b n or m al hilar a de n o p at h y, i n 
w hic h case t h e mar gi ns ar o u n d t he hilar mass will be 1. 0 – 1. 5 c m. 
 
L u n g- Bl oc k Ti mi n g: 
L u n g bl oc ks will be e m pl o ye d f or t he treat me nt(s) liste d bel o w. S h o ul d patie nt i nfir mit y 
precl u de u pri g ht p ositi o ni n g d uri n g a fracti o n w he n l u n g s hiel di n g is prescri be d, t hat patie nt ma y 
be treate d i n t he l ateral d ec u bit us p ositi o n wit h o ut l u n g s hiel di n g, a n d l u n g s hiel di n g ca n be 
deferre d u ntil t he ne xt treat me nt fracti o n. F or c hil dre n recei vi n g T BI u n der a nest hesia, 
treat me nts will be perf or me d i n a m o difie d s u pi ne a n d pr o ne p ositi o n, wit h t he a p pr o priat e l u n g 
s hiel di n g as s pecifie d i n t he pr ot oc ol. 
 
L u n g bl oc ks will be use d f or t he first fracti o n of t h e first i ncre m e ntal d ose escalati o n o ver 3 0 0 
c G y, i.e., 4 0 0 c G y f or o n e fracti o n, or 4 5 0 c G y f or o ne fracti o n, or b ot h fracti o ns f or pe diatric 
patie nts treate d wit h 2 2 5 c G y x 2. T his sc he ma is calc ulate d t o deli ver a n o mi nal d ose of 
a p pr o xi matel y 2 0 0 c G y f or D ose Le vel 3 ( 4 0 0 x 5 0 % = 2 0 0); a n d 2 2 5 c G y f or D ose Le v el 4 
( 4 5 0 x 5 0 % = 2 2 5 c G y). N o c o m pe nsat or y electr o n b o ost of t hat p orti o n of t he c hest wall 
s hiel de d b y t he l u n g bl oc ks is re q uire d. 
 

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A P P E N DI X V: I ntr at hec al Di a g n ostics a n d T her a pe utics 
 
Dise ase:  
I nter ve nti o n: 
A L L –  re missi o n or rela pse  
• P ositi ve c yt ol o g y o n L P  
• Pre vi o us hist or y of p ositi ve C N S 
• Ne gati ve hist or y a n d c yt ol o g y  
L u m bar p u nct ure wit h t hera p y  
2 pre-tra ns pla nt I T a n d 6 p ost-tra ns pla nt + cra nial X R T 
2 pre-tra ns pla nt I T a n d 6 p ost-tra ns pla nt 
2 pre -tra ns pla nt I T a n d 4 p ost-tra ns pla nt 
A M L –  re missi o n or rela pse  
• P ositi ve c yt ol o g y o n L P  
• Pre vi o us hist or y of p ositi ve C N S  
• Ne gati ve hist or y a n d c yt ol o g y  
Dia g n ostic l u m ba r p u nct ure 
2 pre-tra ns pla nt I T a n d 6 p ost-tra ns pla nt 
2 pre-tra ns pla nt I T a n d 6 p ost-tra ns pla nt 
N o t hera p y  
M D S  
• R A E B 
• R A or R A R S 
 
Treat as A M L 
N o L P or I T t hera p y i n dicate d  
 
 
Met h otre x ate 
 
St a n d ar d i ntr at hec al met h otre x ate d osi n g (ser u m cre ati ni ne < 1. 5 b aseli ne)  
A ge  
L u m bar P u nct ure  
O m ma ya Reser v oir ( 1/ 2 of L u m bar P u nct ure D ose)  
A ge < 2 yrs  
4 m g  
2 m g  
A ge 2 -3 yrs  
6 m g  
3 m g  
A ge ≥ 4 yrs  
1 2 m g  
6 m g  
 
M o nit ori n g of ser u m met h otre xate le vels 
1. Re nal i ns ufficie nc y: if ser u m creati ni ne is 1. 5 t o 2 ti mes t he pre-tra ns pla nt baseli ne, a d mi nister 
I ntrat hecal 
met h otre xate a n d f oll o w ser u m le vels. 
2. Me ni n geal I nfla m mati o n: patie nts wit h acti ve me ni n geal i nfla m mati o n ( d ue t o mali g na nt disease 
a n d/ or pri or t hera p y) ma y ha ve si g nifica nt lea ka ge of met h otre xate i nt o t he s yste mic circ ulati o n; s uc h 
patie nts ma y re q uire m o nit ori n g of ser u m met h otre xate le vels, partic ularl y d uri n g t he p osttra ns pla nt  
peri o d, t o a v oi d marr o w t o xicit y. 
3. S us pecte d met h otre xate t o xicit y: m o nit ori n g of ser u m met h otre xate le vel f oll o wi n g i ntrat hecal 
t hera p y is a p pr o priate i n patie nts w h o ha ve ha d s us pecte d s yste mic met h otre xate t o xicit y ( he mat ol o gic or 
he patic) f oll o wi n g pre vi o us i ntrat hecal d oses. 
4. Si g nifica nt acc u m ulati o ns of t hir d s pace fl ui d (e. g. ascites, ple ural or pericar dial eff usi o ns) ma y be 
ass ociate d wit h i m paire d cleara nce of met h otre xate. T he decisi o n t o a d mi nister I ntrat hecal met h otre xate 
i n t hese cli nical setti n gs s h o ul d be ma de b y t he atte n di n g p h ysicia n. M o nit ori n g of ser u m met h otre xate 
le vels is a p pr o priate w he n met h otre xate is a d mi nistere d i n t he setti n g of cli nicall y e vi de nt t hir d s pace 
fl ui d acc u m ulati o n, si nce t he effecti ve half-life of t he dr u g ma y be pr ol o n ge d. 
5. Le uc o v ori n s h o ul d be gi ve n if t he met h otre xate le vel e xcee ds 0. 0 4 micr o m olar at 2 4 h o urs. D osi n g is 
1 0 m g/ m 2 e ver y 6 h o urs I V or P O (ta blets a vaila ble as 5 m g, 1 0 m g, 2 5 m g), a n d s h o ul d be c o nti n ue d 
u ntil a met h otre xate le vel < 0. 0 4 micr o m olar is d oc u me nte d. I V a n d oral d oses are bi oe q ui vale nt. 
6. Li ver d ysf u ncti o n: If a d mi nisteri n g I ntrat hecal met h otre xate i n t he setti n g of li ver d ysf u ncti o n wit h 
bilir u bi n > 2 0 m g/ dl, m o nit or ser u m met h otre xate le vels. 
7. Met h otre xate le vels a n d/ or a ut o matic le uc o v ori n resc ue are n ot r o uti nel y i n dicate d i n patie nts wit h 
n or mal re nal f u ncti o n recei vi n g pr o p h ylactic t hera p y. 
 
 
 
Alter n ati ve I ntr at hec al t her a p y – c yt ar a bi ne ( Ar a- C)  

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Alter nati ve i ntrat hecal t hera p y wit h c ytara bi ne ( Ara- C) s h o ul d be c o nsi dere d i n t he f oll o wi n g 
circ u msta nces: 
1. Si g nifica nt re nal i ns ufficie nc y wit h ser u m creati ni ne > 2 x baseli ne. 
2. T o xicit y wit h pre vi o us d oses of I ntrat hecal met h otre xate has bee n de m o nstrate d. 
3. Persiste nt t hir d s pace fl ui d c ollecti o ns (ascites or ple ural eff usi o n). 
4. Me ni n geal i nfla m mati o n felt t o be sec o n dar y t o met h otre xate t hera p y. 
5. Si g nifica nt li ver d ysf u ncti o n. 
 
St a n d ar d I ntr at hec al C yt ar a bi ne ( Ar a- C) D osi n g 
A ge  
L u m bar P u nct ure  
O m ma ya Reser v oir  
A ge < 2 yrs  
1 6 m g  
1 6 m g  
A ge 2 -3 yrs  
2 0 m g  
2 0 m g  
A ge ≥ 4 yrs  
2 4 m g  
2 4 m g  
 
 
Alter n ati ve I ntr at hec al t her a p y – Tri ple T her a p y wit h Met h otre x ate, H y dr oc ortis o ne, a n d 
c yt ar a bi ne ( Ar a- C)  
Tri ple i ntrat hecal t hera p y wit h met h otre xate, h y dr oc ortis o ne ( h y dr oc ortis o ne), a n d c ytara bi ne ( Ara- C) is  
s o meti mes gi ve n t o patie nts w h o ha ve C N S disease t hat is refract or y or p o orl y res p o nsi ve t o m o n ot hera p y 
wit h eit her met h otre xate or c ytara bi ne ( Ara- C). S uc h patie nts s h o ul d be treate d t wice wee kl y u ntil t heir 
s pi nal 
fl ui d ( C S F) bec o mes ne gati ve f or mali g na nt cells. 
 
St a n d ar d Tri ple I ntr at hec al D osi n g 
A ge  
L u m bar P u nct ure  
O m ma ya Reser v oir  
 
Met h otre xate  H y dr oc ortis o ne  
Ara -C  
met h otre xate  
H y dr oc ortis o ne  
Ara -C  
A ge < 2 
yrs  
4 m g  
8 m g  
1 6 m g  
2 m g  
8 m g  
1 6 m g  
A ge 2 -3 
yrs  
6 m g  
1 0 m g  
2 0 m g  
3 m g  
1 0 m g  
2 0 m g  
A ge ≥ 4 
yrs  
1 2 m g  
1 2 m g  
2 4 m g  
6 m g  
1 2 m g  
2 4 m g  
 
 
 
 
 
 
 
 
 
 

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 A P P E N DI X VI:  I nfecti o n Tre at m e nt a n d Pr o p h yl a xis G ui deli nes  
 
 
 
 
 
C M V scree ni n g a n d pre-e m pti ve tre at me nt 
 
C M V. p df
 
 
A nti -f u n g al tre at me nt 
 
A ntif u n g al _ T h er a p y.
p df
 
 
 
P C P pr o p h yl a xis 
 
P C P. p df
 
 
H S V a n d V Z V pr o p h yl a xis a n d tre at me nt 
 
H S V a n d V Z V. p df
 
 
 
 
 

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 A P P E N DI X VII :  
G V H D St a gi n g a n d Gr a di n g  
 
A C U T E G V H D A S S E S S M E N T  
 
St a gi n g b y I n di vi d u al Or g a n I n v ol ve me nt 
 
 
S KI N:   
meas ure d b y ras h first a p peari n g ge nerall y bet wee n 1 0 a n d 7 0 da ys after tra ns pla nt. (e xcl u des ras hes 
of k n o w n viral or ot her ori gi n) 
 
St a ge  
Descri pti o n  
1  
Mac ul o pa p ular ras h  < 2 5 % B S A 
2  
Mac ul o pa p ular ras h 2 5 – 5 0 % B S A 
3  
Ge neralize d er yt hr o der ma  
4 
Ge neralize d er yt hr o der ma wit h 
b ull o us f or mati o n a n d des q ua mati o n 
 
LI V E R *: 
meas ure d b y t otal ser u m bilir u bi n  
 
St a ge  
Descri pti o n  
1  
2. 0 – 2. 9 m g/ d L 
2  
3. 0 – 5. 9 m g/ d L 
3  
6. 0 – 1 4. 9 m g/ d L 
4  
> 1 5. 0 m g/ d L 
 
G U T * *: 
i ncl u des o nl y diarr hea occ urri n g after Da y + 2 1 
 
Sc ore 
A d ult  
Pe di atric * * * 
1 
u p per GI (a n ore xia, na usea, v o miti n g) 
wit h diarr hea of < 1 0 0 0 m L/ da y 
u p per GI (a n ore xia, na usea, v o miti n g) 
wit h diarr hea of < 5 5 5 m L/ m 2/ da y 
2  
1 0 0 0 – 1 4 9 9 m L/ da y diarr hea  
5 5 6- 8 3 3 m L/ m 2/ da y diarr hea 
3  
> 1 5 0 0 m L/ da y diarr hea 
> 8 3 3 m L/ m 2/ da y diarr hea 
4 
se vere a b d o mi nal cra m pi n g, blee di n g or ile us ca use d b y G V H D 
 
* 
I n cases w here a n ot her ca use of h y per bilir u bi ne mia a nte date d t he o nset of ras h, t he li ver sc ore s h o ul d be 
decrease d b y o ne sta ge. 
* *  I n cases w here pea k GI s y m pt o ms are e xacer bate d b y a ca use ot her t ha n G V H D, t he g ut sc ore s h o ul d be 
decrease d b y o ne sta ge. 
* * *  Pe d iatric patie nts < 1 7 years of a ge 

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A C U T E G V H D A S S E S S M E N T  
 
O ver all Gr a de  
 
T he deter mi nati o n of a n o verall G V H D gra de s h o ul d be base d o n t he or ga n sta ge, res p o nse t o treat me nt a n d 
w het her G V H D was a maj or ca use of deat h. 
 
 
 
O ver all 
Gr a de 
 Or g a n St a ge  
Q u alif yi n g C o n diti o ns  
A d diti o n al Q u alif yi n g C o n diti o ns 
I  
Sta ge 1 - 2 s ki n   
N o li ver or g ut 
I n dicates t hat t he pr o p h ylactic 
i m m u n os u p pressi ve re gi me n was n ot 
s ufficie nt t o pre ve nt all ma nifestati o ns of 
a G V H D. 
II 
Sta ge 3 s ki n  
  
or  
Sta ge 1 li ver  
  
or  
Sta ge 1 g ut 
N/ A  
I n dicates t hat t he pr o p h ylactic 
i m m u n os u p pressi ve re gi me n was n ot 
s ufficie nt t o pre ve nt all ma nifestati o ns of 
a G V H D, b ut gl uc oc ortic oi d treat me nt after 
t he o nset of G V H D was ge nerall y s ufficie nt 
t o c o ntr ol t he disease. 
III 
Sta ge 4 s ki n  
  
or  
Sta ge 2- 4 li ver  
  
or  
Sta ge 2- 4 g ut  
 
wit h o ut  G V H D as a maj or 
c o ntri b uti n g ca use of deat h 
 
 
I n dicates t hat t he pr o p h ylactic 
i m m u n os u p pressi ve re gi me n was n ot 
s ufficie nt t o pre ve nt all ma nifestati o ns of 
a G V H D a n d t hat a d diti o nal treat me nt after 
t he o nset of G V H D di d n ot rea dil y c o ntr ol 
t he disease. 
I V 
Sta ge 4 s ki n  
  
or  
Sta ge 2- 4 li ver  
  
or  
Sta ge 2- 4 g ut  
 
wit h  G V H D as a maj or 
c o ntri b uti n g ca use of deat h 
 
 
G V H D was resista nt t o b ot h t he pr o p h ylactic 
i m m u n os u p pressi ve re gi me n a n d a n y 
a d diti o nal treat me nt after t he o nset of t he 
disease. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A P P E N DI X  VII:    
G V H D St a gi n g a n d Gr a di n g (c o nti n ue d)  
 
C H R O NI C G V H D 
I n t he p ast, a n y ma nif estati o n of G V H D t hat w as prese nt ( or c o nti n ue d) at 1 0 0 da ys after H C T or 
t hereafter w as ar bitr aril y defi ne d as c hr o nic G V H D e ve n if t he cli nical ma nifestati o n was 
i n disti n g uis ha ble fr o m t hat of ac ute G V H D. A d va nces i n H C T practice i n t he past 2 deca des ha v e 
pr of o u n dl y altere d t h e pr ese ntati o n a n d nat ural hist or y of b ot h ac ute a n d c hr o nic G V H D a n d bri n g 
pre vi o us defi niti o ns i nt o q uesti o n. F or i nsta nce, ac ute G V H D ma y prese nt b e y o n d 3 m o nt hs i n patie nts 
w h o ha ve r ecei v e d re d u ce d-i nte nsit y c o n diti o ni n g w hereas ma nifestati o ns of ac ute a n d c hr o ni c G V H D 
ca n be pr ese nt si m ulta ne o usl y. T heref ore, t he c urre nt c o nse ns us is t hat cli nical ma nifestati o ns, a n d n ot 
t he ti me t o s y m pt o matic o nset after tr a ns pla ntati o n, deter mi ne w het h er t he cli nical s y n dr o me of G V H D 
is c o nsi dere d ac ute or c hr o nic.1   
 
C hr o nic G V H D will t her ef ore b e defi n e d acc or di n g t o t he Nati o nal I nstit utes of Healt h C o nse ns us 
De vel o p me nt  Pr oject o n Criteria f or Cli nical Trials i n C hr o nic Graft- v ers us- H ost Disease.  Di a g n osis 
of c hr o nic G V H D will re q uire t he pres e nce of at l east 1 dia g n ostic cli nical si g n of c hr o nic G V H D or 
prese nce of at least 1 disti ncti ve ma nifestati o n c o nfir me d b y perti ne nt bi o ps y or ot her rel e va nt tests 
after t he e xcl usi o n of ot her p ossi ble dia g n oses.  C hr o nic G V H D will be des cri be d as mil d, m o derate, or 
se vere as gra d e d acc or di n g t o t he attac he d Or ga n Sc ori n g S heet.  S y m pt o ms de vel o pi n g after d a y 1 0 0 
b ut c o nsiste nt wit h ac ute G V H D o nl y will be c o nsi dere d persiste nt, rec urre nt, or late- o nset ac ute 
G V H D.   S y m pt o ms c o nsiste nt wit h b ot h c hr o nic a n d ac ute G V H D occ urri n g after d a y 1 0 0 will be 
c o nsi dere d o v erla p c hr o nic G V H D s y n dr o me.   
 
a. Fili p o vic h A H, Weis d orf D, Pa vletic S, et al.  Nati o nal I nstit utes of H ealt h C o nse ns us  
De vel o p me nt Pr oject o n Criteria f or Cli nical Trials i n C hr o nic Graft- v ers us- H ost- disease: 
1. Dia g n osis a n d Sta gi n g W or ki n g Gr o u p Re p ort.  Bi o Bl o o d a n d Marr o w Tra ns pla nt 
2 0 0 5; 1 1: 9 4 5- 9 5 5.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C hr o nic G V H D Or ga n S c ori n g S heet 

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S C O R E 0  
S C O R E 1  
S C O R E 2  
S C O R E 3  
 
 
 
 
 
 P E R F O R M A N C E S C O R E :  
 
 
  K P S   E C O G   L P S  
   As y m pt o matic 
a n d f ull y acti v e 
( E C O G 0; K P S or 
L P S 1 0 0 %)  
   S y m pt o matic, f ull y 
a m b ulat or y, restricte d o nl y i n 
p h ysicall y stre n u o us acti vit y 
( E C O G 1, K P S or L P S 8 0-9 0 %)  
   S y m pt o matic, 
a m b ulat or y, ca p a ble of 
self-care, > 5 0 % of 
wa ki n g h o urs o ut of b e d 
( E C O G 2, K P S or L P S 
6 0 -7 0 %)  
   S y m pt o matic, li mite d self -care, 
> 5 0 % of wa ki n g h o urs i n be d 
( E C O G 3-4, K P S or L P S < 6 0 %)  
 
 
 
 
 
S KI N  
Cli nic al fe at ures:  
   Mac ul o pa p ular ras h  
   Lic he n pla n us -li ke 
feat ures 
   Pa p ul os q ua m o us 
lesi o ns or ic ht h y osis 
  H y per pi g me ntati o n  
   H y p o pi g me ntati o n  
   Kerat osis pilaris  
   Er yt h e ma 
   Er yt hr o der ma  
   P oi kil o der ma  
   Scler otic feat ures  
   Pr urit us 
   Hair i n v ol ve me nt  
   Nail i n v ol ve me nt  
% B S A 
 I n v ol ved 
   N o S y m pt o ms  
   < 1 8 % B S A wit h disease si g ns 
b ut N O  scler otic feat ures 
   1 9 -5 0 % B S A O R 
i n v ol v e me nt wit h 
s u p erficial scler otic 
feat ures “ n ot hi d e b o u n d ” 
(a ble t o pi n c h) 
   > 5 0 % B S A O R  dee p scler otic 
feat ures “ hi d e b o u n d” ( u na ble t o 
pi n c h) O R  i m p aire d m o bilit y, 
ulcerati o n or se v ere pr urit us  
    A b n or m ality prese nt b ut N O T   t h o u g ht t o re prese nt G V H D 
 
 
 
 
 
M
O U T H  
Di a g n ostic/ disti n ctive 
fe at ures 
   Prese nt  
   A bse nt  
 
   N o s y m pt o ms  
       
   Mil d s y m pt o ms wit h disease 
si g ns b ut n ot li miti n g oral i nta k e 
si g nifica ntl y 
   M o derate s y m pt o ms 
wit h disease si g ns wit h  
p artial li mitati o n of oral 
i nta k e 
   Se v ere s y m pt o ms wit h disease 
si g ns o n e x a mi n ati o n wit h  maj or 
li mitati o n of oral i nta ke 
   A b n or m ality prese nt b ut N O T  t h o u g ht t o re prese nt G V H D 
 
 
 
 
 
E Y E S  
Mea n tear test ( m m):  
   > 1 0  
   6- 1 0  
   < 5 
   N ot d o ne  
   N o s y m pt o ms  
   Mil d dr y e y e s y m pt o ms n ot 
affecti n g A D L (re q uiri n g 
e y e dr o ps < 3 x p er d a y) O R  
as y m pt o matic si g ns of  
k erat o c o nj u n cti vitis sicca  
   M o derate dr y e ye 
s y m pt o ms p artiall y 
affecti n g A D L (re q uiri n g 
dr o ps > 3 x p er d a y or 
p u n ctal pl u gs), 
WI T H O U T  visi o n 
i m p air me nt 
   Se v ere dr y e y e s y m pt o ms 
si g nifica ntl y affecti n g A D L 
(s pecial e y e ware t o relie ve pai n) 
O R  u n a ble t o w or k beca use of 
o c ular s y m pt o ms O R  l oss of visi o n 
ca use d b y k erat o c o nj u ncti vitis 
sicca 
   A b n or m ality prese nt b ut N O T   t h o u g ht t o re prese nt G V H D 
 
 
 
 
 
GI  T R A C T  
   N o s y m pt o ms  
   S y m pt o ms s u c h as n a usea, 
v o miti n g ,a n ore xia, d ys p h a gia, 
a b d o mi n al p ai n or diarr h ea 
wit h o ut si g nifica nt wei g ht l oss 
( < 5 %) 
   S y m pt o ms ass o ciate d 
wit h mil d t o m o d erate 
wei g ht l oss ( 5 -1 5 %)  
  S y m pt o ms ass o ciate d wit h 
si g nifica nt wei g ht l oss > 1 5 %, re q uire  
n utriti o n al s u p ple me nt  
f or m ost cal orie n ee ds O R  es o p ha gea  
dilati o n  
   A b n or m ality prese nt b ut N O T  t h o u g ht t o re prese nt G V H D 
 

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S C O R E 0  
S C O R E 1  
S C O R E 2  
S C O R E 3  
 
 
 
 
 
L I V E R 
 
   N or mal L F T  
  Ele v ate d Bilir u bi n, 
A P *, A S T or A L T < 2 x 
U L N  
   Bilir u bi n > 3 m g/ dl or 
Bilir u bi n, e n z y mes 2 -5 x 
U L N   
   Bilir u bi n or e n z y mes > 5 x U L N  
   A b n or m ality prese nt b ut N O T  t h o u g ht t o re prese nt G V H D 
 L U N G S ‡    
  P F Ts n ot d o ne  
 
F E V 1  
 
D L C O  
   N o s y m pt o ms  
 
 
 
 
   F E V 1 > 8 0 % O R     
     L F S = 2  
   Mil d s y m pt o ms 
(s h ort n ess of breat h after 
cli m bi n g o n e fli g ht of 
ste ps) 
 
   F E V 1 6 0 -7 9 % O R  
     L F S 3 - 5 
   M o derate s y m pt o ms 
(s h ort n ess of breat h after 
wal ki n g o n flat gr o u n d)  
 
   F E V 1 4 0 -5 9 % O R   
     L F S 6 - 9 
   Se v ere s y m pt o ms (s h ort ness    
   of breat h  at rest; re q uiri n g 0 2) 
 
 
 
   F E V 1 < 3 9 % O R  
     L F S 1 0 -1 2  
   A b n or m ality prese nt b ut N O T   t h o u g ht t o re prese nt G V H D 
 
 
 
 
 
J OI N T S A N D F A S CI A  
   N o s y m pt o ms  
   Mil d ti g ht n ess of 
ar ms or le gs, n or mal 
or mil d d ecrease d 
ra n g e of m oti o n 
( R O M) A N D  n ot 
affecti n g A D L 
   Ti g ht ness of ar ms or le gs 
O R  j oi nt c o ntract ures, 
er yt h e ma t h o u g ht d u e t o 
fasciitis, m o derate decrease 
R O M A N D  mil d t o 
m o derate li mitati o n of A D L  
   C o ntract ures WI T H  si g nifica nt 
d ecrease of R O M  A N D si g nifica nt 
li mitati o n of A D L ( u na ble t o tie 
s h o es, b utt o n s hirts, dress self etc.)  
   A b n or m ality prese nt b ut N O T   t h o u g ht t o re prese nt G V H D 
 
 
 
 
 
G E NI T A L T R A C T  
Di a g n ostic/  
Disti nctive fe at ures : 
  Prese nt  
  A bse nt  
  N ot e xa mi ne d  
    N o s y m pt o ms  
  S y m pt o matic wit h 
mil d si g ns o n e xa m 
A N D  n o effect o n 
c oit us a n d mi ni mal 
disc o mf ort wit h 
g y n ec ol o gic e x a m  
  S y m pt o matic wi t h 
m o d erate si g ns o n e x a m 
A N D  wit h mil d d ys p are u nia 
or disc o mf ort wit h 
g y n ec ol o gic e x a m  
  S y m pt o matic WI T H  a d va nce d 
si g ns (strict ure, la bial a g gl uti nati o n or 
se v ere ulcerati o n) A N D  se vere pai n 
wit h c oit us or i n a bilit y t o i nsert 
v a gi n al s p ec ul u m  
   A b n or m a lity prese nt b ut N O T   t h o u g ht t o re prese nt G V H D 
 
Ot her i n dic at ors, cli nic al m a nifest ati o ns or c o m plic ati o ns rel ate d t o c hr o nic G V H D (c hec k all t h at a p pl y):  
 Wei g ht l oss                                 
 Br o n c hi olitis o bli tera ns            
 Br o n c hi olitis o blitera ns wit h or g a nizi n g p n e u m o nia  
 
 Es o p ha geal strict ure or we b       
 Pericar dial Eff usi o n              
 Ple ural Eff usi o n(s)                           
 Ascites (ser ositis)  
 
 Ne p hr otic s y n dr o me                   
 Peri p h eral Ne ur o p at h y              
 M yast he nia Gra vis                           
 P ol y m y ositis    
 
 Mala bs or pti o n                 
 Car diac c o n d u cti o n d efects       
 C or o n ar y arter y i n v ol v e me nt           
 Car di o m y o p at h y       
 
 E osi n o p hilia > 5 0 0/ micr oliter     
 Ot h e r: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _               
  N o ne  
 
Bi o ps y o bt ai ne d : 
Yes     
N o       Or g a n s yste m(s) bi o psie d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ G V H D c o nfir m e d b y hist ol o g y: 
Yes    
N o  
 
O V E R A L L se verit y of G V H D :  
 
 N o G V H D     
 Mil d                  
 M o der ate         
 Se v ere  
 
C h a n ge fr o m pre vi o us e v al u ati o n : 
 N o G V H D     
 I m pr o ve d          
 St a ble              
 W o rse             
 N/ A ( b aseli ne)  
 
C o m plete d b y ( pri nt): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ D ate c o m plete d: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
Si g n at ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
‡     P ul m o n ar y s c ori n g  s h o ul d b e perf or me d usi n g b ot h t h e s y m pt o m a n d p ul m o nar y f u n cti o n t esti n g ( P F T) s cal e w h e n e v er p ossi bl e.  W he n dis cre pa nc y e xists bet w ee n 
p ul m o n ar y s y m pt o m or P F T s c ores t h e hi g h er v al ue s h o ul d be use d f or fi n al s c ori n g.  Sc ori n g usi n g t h e L u n g F u n cti o n Sc ore ( L F S) is preferre d, b ut if D L C O 
(car b o n m o n o xi de diff usi o n ca p acit y c orrecte d f or h e m o gl o bi n) is n ot a vail a bl e, gra di n g usi n g F E V 1 (f orce d e x pirat or y v ol u me) s h o ul d b e us e d. T h e L F S is a gl o b al 
ass ess me nt of l u n g f u n cti o n after t h e di a g n osis of br o nc hi olitis o blit era ns h as alrea d y b ee n esta blis h e d.2 8 T h e p erce nt pre dicte d F E V 1 a n d D L C O (a dj ust e d f or 
h e mat o crit b ut n ot al v e olar v ol u me) s h o ul d be c o n verte d t o a n u meri c sc ore as f oll o ws: > 8 0 % = 1; 7 0 -7 9 % = 2; 6 0 -6 9 % = 3; 5 0 -5 9 % = 4; 4 0 -4 9 % = 5; < 4 0 % = 6. 
T h e L F S = F E V 1 s c ore + D L C O s c ore, wit h a p ossi bl e ra n ge of 2 -1 2.  
 

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A P P E N DI X VIII:  
E B V Vir al L o a d M o nit ori n g a n d M a n a ge me nt 
1.  M o nit ori n g of E B V viral l oa d: m o nit or E B V viral l oa d e ver y 2 wee ks b et w ee n Da y 3 0 a n d Da y 
1 0 0 or disc har g e fr o m tra ns pla nt ce nter  
•  If viral l oa d p ositi ve ( ≥ 1 0 0 0 c o pies/ m L of w h ole bl o o d) 
i. C o m plete p h ysical e xa m l o o ki n g f or peri p heral a d e n o pat h y a n d s ple n o me g al y 
ii. C T c hest, a b d o me n, a n d pel vis, if p ossi ble wit h c o ntrast  
iii. If n o acti ve G V H D start ta peri n g i m m u ne s u p pressi o n. If E B V viral l oa d sta ble 
or i ncreasi n g tr y t o ta per all i m m u ne s u p pressi o n o ver 3- 5 w ee ks. 
i v. Re peat viral l oa d w ee kl y X 2 ( 7 a n d 1 4 da ys) 
v.  Start Ac ycl o vir 1 0 m g/ k g I V TI D or 8 0 0 m g P O 5 x dail y (if n ot alrea d y o n it) 
vi.  Bi o ps y a n y ne w s us pici o us lesi o ns or a de n o pat h y w he ne ver feasi ble. If e n o u g h 
material a vaila bl e, t he bi o ps y sa m ple s h o ul d als o be se nt f or fl o w c yt o metr y. 
vii.  B o ne marr o w bi o ps y s h o ul d be o btai ne d if cli nicall y i n dicate d (e. g. falli n g 
c o u nts) a n d, i n a d diti o n t o re g ular e val uati o n, be s e nt f or fl o w c yt o metr y. 
2.  I nter ve nti o n: pree m pti ve a n d acti ve rit u xi ma b treat me nt 
•  Ne gati ve p h ysical a n d/ or C T’s: rit u xi ma b 3 7 5 m g/ m 2 si n gle d ose 
i. If viral l oa d f alls: bac k t o m o nit ori n g 
•  Ne gati ve p h ysical a n d/ or C T’s: rit u xi ma b 3 7 5 m g/ m 2 si n gle d ose 
i. If viral l oa d sta ble or cli m bi n g treat as ite m “c” b el o w 
•  P ositi ve p h ysical a n d/ or C T’s: rit u xi ma b 3 7 5 m g/ m 2 4 d oses 
3.  Treat me nt f or patie nts wit h prese ntati o n as a g gressi ve l y m p h o ma a n d/ or n ot res p o n di n g t o 
rit u xi ma b al o ne 
•  T his patie nts s h o ul d be c o nsi dere d f or m ultia ge nt c he m ot hera p y wit h rit u xi ma b 
 

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A P P E N DI X I X:  A d a pt e d fr o m C O M M O N T O XI CI T Y C RI T E RI A ( C T C) 
A L L E R G Y/I M M U N O L O G Y  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Aller gic reacti o n/ h y perse nsiti vit y  
(i ncl u di n g dr u g fe ver) 
S y m pt o matic br o nc h os pas m,  re q uiri n g 
pare nteral me dicati o n(s),  wit h or 
wit h o ut urtic aria; aller g y  relate d 
e de ma/a n gi oe de ma 
A na p h yla xis  
Vasc ulitis Re q uiri n g ster oi ds  
  
Re q uiri n g ster oi ds  
Isc he mic c ha n ges or re q uiri n g a m p utati o n 
 
Aller g y/I m m u n ol o g y –  Ot her  
(s pecif y): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Se vere  
Life -t hreate ni n g or disa bli n g 
B L O O D/ B O N E M A R R O W  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
He m ol ysis (e. g., i m m u ne  
he m ol ytic a ne mia, dr u g  relate d 
he m ol ysis, ot her)  
Re q uiri n g tra nsf usi o n a n d/ or  
me dical i nter ve nti o n (e. g.,  
ster oi ds) 
Catastr o p hic c o nse q ue nces of he m ol ysis  
(e. g., re nal fail ure, h y p ote nsi o n, 
br o nc h os p as m, e mer ge nc y 
s ple nect o m y) 
F or B M T st u dies, if s pecifie d  
i n t he pr ot oc ol. 
 
 
 
F or pe diatric B M T st u dies, if  
s pecifie d i n t he pr ot oc ol. 
> 4 u p R B C i n 2 4 h o urs  
 
 
 
 
> 3 0 m L/ k g i n 2 4 h o urs  
He m orr ha ge or he m ol ysis ass ociate d  wit h 
life-t hreate ni n g a ne mia; me dical 
i nter ve nti o n re q uire d t o i m pr o ve 
he m o gl o bi n  
He m orr ha ge or he m ol ysis ass ociate d  wit h 
life-t hreate ni n g a ne mia; me dical 
i nter ve nti o n re q uire d t o i m pr o ve 
he m o gl o bi n  
C A R DI O V A S C U L A R –  A R R H Y T H MI A  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Car di o vasc ular/ Arr h yt h mia - 
Ot her (s pecif y): _ _ _ _ _ _ _ _ _ _ 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
S y m pt o matic, a n d re q uiri n g  
treat me nt of u n derl yi n g ca use 
Life -t hreate ni n g (e. g., arr h yt h mia 
ass ociate d wit h C H F, h y p ote nsi o n,  
s y nc o pe, s h oc k) 
C A R DI O V A S C U L A R –  G E N E R A L  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Car diac le ft ve ntric ular f u ncti o n 
 
C H F res p o nsi ve t o treat me nt  
Se vere or refract or y C H F or re q uiri n g  
i nt u bati o n 
Car diac tr o p o ni n I (c T nI)  
 
Le vels c o nsiste nt wit h u nsta ble  
a n gi na as defi ne d b y t he 
ma n ufact urer  
Le vels c o nsiste nt wit h m y ocar dial  
i nfarcti o n as defi ne d 
Car diac tr o p o ni n T (c T n T)  
≥ 0. 1 - < 0. 2 n g/ m L  
≥ 0. 2 n g/ m L  
H y p ote nsi o n  
Re q uiri n g t hera p y a n d s ustai ne d  
me dical atte nti o n, b ut res ol ves  
wit h o ut persisti n g p h ysi ol o gic  
c o nse q ue nces 
 
 S h oc k (ass ociate d wit h aci de mia a n d  
i m pairi n g vital or ga n f u ncti o n d ue t o 
tiss ue h y p o perf usi o n) 
M y ocar d itis 
C H F res p o nsi ve t o treat me nt  
Se vere or refract or y C H F  
Pericar dial eff usi o n/  pericar ditis  
 
Wit h p h ysi ol o gic c o nse q ue nces  
Ta m p o na de ( drai na ge or pericar dial  
wi n d o w re q uire d)  
S y nc o pe (fai nti n g) is gra de d  i n t he 
Ne ur ol o g y cate g or y.  
 
- 
- 
T hr o m b osis/e m b ol is m 
Dee p vai n t hr o m b osis, re q uiri n g  
E m b olic e ve nt i ncl u di n g 

2 2 7 5. 0 0 
 
Pa ge 5 2  of 5 9  
a ntic oa g ula nt t hera p y  
p ul m o nar ye m b olis m  
Vei n/arter y o perati ve i nj ur y is  
gra de d as O perati ve i nj ur y of  
vei n/arter y i n t he  
Car di o v asc ular ( ge neral)  
cate g or y. 
Ot her (s pecif y): _ _ _ _ _ _ _ _ _ _ _  
 
 
 
Car di o v asc ular/ Ge neral –  
 
Se vere  
Life -t hreate ni n g or disa bli n g 
C O A G U L A TI O N  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
DI C ( disse mi nate d i ntra vasc ular  
c oa g ulati o n) 
 
Als o c o nsi der  
Platelets.  
 
N ote: M ust h ave i ncre ase d fi bri n  
s plit pr o d ucts or D-di mer i n or der 
t o gr a de as DI C 
La b orat or y fi n di n gs prese nt wit h  
n o blee di n g  
La b orat or y fi n di n gs a n d blee di n g  
T hr o m b otic micr oa n gi o pat h y  
(e. g., t hr o m b otic t hr o m b oc yt o pe nic 
p ur p ura/ T T A or  
he m ol ytic ure mic s y n dr o me/ H U S)  
 
Als o c o nsi der  
He m o gl o bi n, platelets, creati ni ne.  
 
N ote: M ust h ave m icr o a n gi o p at hic 
c h a n ges o n bl o o d s me ar (e. g., 
sc hist ocytes, hel met cells, re d cell 
fr a g me nts). 
La b orat or y fi n di n gs prese nt  
wit h o ut cli nical c o nse q ue nces  
E vi de nce of R B C destr ucti o n wit h  
creati ni ne ( > 3 x U L N) n ot 
re q uiri n g dial ysis 
La b orat or y fi n di n gs a n d c li nical 
c o nse q ue nces, (e. g., C N S  
he m orr ha ge/ blee di n g or  
t hr o m b osis/e m b olis m or re nal fail ure) 
re q uiri n g t hera pe utic i nter ve nti o n 
 
E vi de nce of R B C destr ucti o n wit h  re nal 
fail ure re q uiri n g dial ysis a n d/ or 
e nce p hal o pat h y. 
C oa g ulati o n - Ot her (s pecif y):  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Se vere  
Life -t hreate ni n g or disa bli n g 
C O N S TI T U TI O N A L S Y M P T O M S  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Wei g ht gai n ass ociate d wit h  
Ve n o -Occl usi ve Disease ( V O D)  
f or B M T st u dies, if s pecifie d i n 
t he pr ot oc ol. 
 
Als o c o nsi der  
Ascites E de ma, Ple ural  eff usi o n 
( n o n-mali g na nt).  
> 1 0 % or as ascites  
> 1 0 % or fl ui d rete nti o n res ulti n g i n  
p ul m o nar y fail ure  
D E R M A T O L O G Y/ S KI N  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Er yt he ma m ultif or me (e. g.,  
Ste ve ns -J o h ns o n s y n dr o me, t o xic 
e pi der mal necr ol ysis)  
Se vere or re q uiri n g I V f l ui ds (e. g., 
ge neralize d ras h or pai nf ul  
st o matitis) 
Life -t hreate ni n g (e. g., e xf oliati ve or 
ulcerati n g der matitis or re q uiri n g  
e nteral or pare nteral n utriti o nal  s u p p ort) 
Ras h/ des q ua mati o n ass ociate d  
wit h graft vers us h ost disease  
( G V H D) f or B M T st u dies, if 
s pecifie d i n t he pr ot oc ol. 
S y m pt o matic ge neralize d  
er yt hr o der ma or s y m pt o matic  
mac ular, pa p ular or vesic ular  
er u pti o n, wit h b ull o us f or mati o n,  
Ge neralize d e xf oliati ve der matitis  or 
ulcerati ve der matitis or b ull o us  f or mati o n 

2 2 7 5. 0 0 
 
Pa ge 5 3  of 5 9  
or des q ua mati o n c o veri n g ≥5 0 % of  
b o d y s urface area.  
G A S T R OI N T E S TI N A L  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Ascites ( n o ne -mali g na nt)  
S y m pt o matic, re q uiri n g  t hera pe utic 
parace ntesis  
Life -t hreate ni n g p h ysi ol o gic 
C o nse q ue nces  
C olitis  
 
Als o c o nsi der  
He m orr ha ge/ blee di n g wit h gra de  
3 or 4 t hr o m b oc yt o pe nia,  
he m orr ha ge/ blee di n g wit h o ut  
gra de 3 or 4 t hr o m b oc yt o pe nia,  
mele na/ GI blee di n g, rectal  
blee di n g/ he mat oc hezia,  
h y p ote nsi o n.  
A b d o mi nal p ai n, fe ver, c ha n ge i n  
b o wel ha bits wit h ile us or  
perit o neal si g ns, a n d ra di o gra p hic or 
bi o ps y d oc u me ntati o n  
Perf orati o n or re q uiri n g s ur ger y or  t o xic 
me gac ol o n  
Diarr hea ass ociate d wit h graft  
vers us h ost disease ( G V H D) f or  
B M T st u dies, if s pecifie d i n t he  
pr ot oc ol.  
 
F or pe di atric B M T st u dies, if  
s pecifie d i n t he pr ot oc ol. 
 
Als o c o nsi der  
He m orr ha ge/ blee di n g wit h gra de  
3 or 4 t hr o m b oc yt o pe nia,  
he m orr ha ge/ blee di n g wit h o ut  
gra de 3 or 4 t hr o m b oc yt o pe nia,  
pai n, de h y drati o n, h y p ote nsi o n.  
> 1 5 0 0 m L of diarr hea/ da y  
 
 
 
 
> 1 5 m L/k g of di arr he a/ d ay  
Se vere a b d o mi nal pai n wit h or  wit h o ut 
ile us 
D u o de nal ulcer (re q uires  
ra di o gra p hic or e n d osc o pic 
d oc u me ntati o n)  
U nc o ntr olle d b y o ut patie nt  
me dical ma na ge me nt; re q uiri n g  
h os pitalizati o n  
Perf orati o n or blee di n g, re q uiri n g  
e mer ge nc y s ur ger y  
Gastric ulcer (re q uires  
ra di o gra p hic or e n d osc o pic 
d oc u me ntati o n)  
 
Als o c o nsi der  
He m orr ha ge/ blee di n g wit h gra de  
3 or 4 t hr o m b oc yt o pe nia,  
he m orr ha ge/ blee di n g wit h o ut  
gra de 3 or 4 t hr o m b oc yt o pe nia.  
Blee di n g wit h o ut perf orati o n,  
u nc o ntr olle d b y o ut patie nt me dical  
ma na ge me nt; re q uiri n g  
h os pitalizati o n or s ur ger y  
Perf orati o n or blee di n g, re q uiri n g  
e mer ge nc y s ur ger y v  
Gastritis  
 
Als o c o nsi der  
He m orr ha ge/ blee di n g wit h gra de  
3 or 4 t hr o m b oc yt o pe nia,  
he m orr ha ge/ blee di n g wit h o ut  
gra de 3 or 4 t hr o m b oc yt o pe n ia. 
U nc o ntr olle d b y o ut -patie nt  
me dical ma na ge me nt; re q uiri n g  
h os pitalizati o n or s ur ger y  
Life -t hreate ni n g blee di n g, re q uiri n g 
e mer ge nc y s ur ger y  
Pa ncreatitis  
 
Als o c o nsi der  
H y p ote nsi o n.  
 
A b d o mi na l pai n wit h pa ncreatic 
e nz y me ele vati o n 
C o m plicate d b y s h oc k (ac ute  
circ ulat or y fail ure) 

2 2 7 5. 0 0 
 
Pa ge 5 4  of 5 9  
N ote: A myl ase is gr a de d i n  
t he M E T A B O LI C/ L A B O R A T O R Y 
c ate g ory. 
M uc ositis  
 
N ote: R a di ati o n -rel ate d m uc ositis 
is gr a de d as M uc ositis d ue t o 
r a di ati o n. 
Pai nless er yt he ma, e de ma, or  
ulcers pre ve nti n g s wall o wi n g or  
re q uiri n g h y drati o n or pare nteral  
( or e nteral) n utriti o nal s u p p ort 
Se vere ulcerati o n re q uiri n g  
pr o p h ylactic i nt u bati o n or res ulti n g  i n 
d oc u me nte d as pirati o n  p ne u m o nia  
T y p hlitis  
(i nfla m mati o n of t he cec u m) 
 
Als o c o nsi der  
He m orr ha ge/ blee di n g wit h gra de  
3 or 4 t hr o m b oc yt o pe nia , 
he m orr ha ge/ blee di n g wit h o ut  
gra de 3 or 4 t hr o m b oc yt o pe nia,  
h y p ote nsi o n, fe brile ne utr o pe nia.  
A b d o mi nal pai n, diarr hea, fe ver,  
a n d ra di o gra p hic or bi o ps y  
d oc u me ntati o n  
Perf orati o n, blee di n g or necr osis or  ot her 
life-t hreate ni n g c o m plicati o n 
re q uiri n g s ur gical i nter ve nti o n (e. g., 
c ol ost o m y) 
H E M O R R H A G E  
N otes:  
Tr a nsf usi o n i n t his secti o n ref ers t o p R B C i nf usi o n.  
F or a ny blee di n g wit h gr a de 3 or 4 pl atelets ( < 5 0, 0 0 0), al w ays gr a de He m orr h a ge/ blee di n g wit h gr a de 3 or 4 
t hr o m b ocyt o pe ni a. Als o c o nsi der Pl atelets, Tr a nsf usi o n: p R B Cs, a n d Tr a nsf usi o n: pl atelets i n a d diti o n t o gr a di n g severity 
by gr a di n g t he site or ty pe of blee di n g.  
 
If t he site or ty pe of He m orr h a ge/ blee di n g is liste d, als o use t he gr a di n g t h at i nc or p or ates t he site of blee di n g: N S 
He m orr h a ge/ ble e di n g, He m at uri a, He m ate mesis, He m o ptysis, He m orr h a ge/ blee di n g wit h s ur gery, Mele n a/l o wer GI 
blee di n g, Petec hi ae/ p ur p ur a ( He m orr h a ge/ blee di n g i nt o ski n), Rect al blee di n g/ he m at oc hezi a, V a gi n al blee di n g.  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
He m orr ha ge/ blee di n g w it h gra de 
3 or 4 t he o m b oc yt o pe nia  
 
Als o c o nsi der  
Platelets, he m o gl o bi n, tra nsf usi o n:  
platelets, tra nsf usi o n: p R B Cs, site  
or t y pe of blee di n g.  
 
If t he site is n ot liste d, gra de as 
He m orr ha ge – Ot her (s pecif y  
site): _ _ _ _ _ _ _ _ _ _ _ 
 
N ote: T his a dverse eve nt m ust be  
gr a de d f or a ny blee di n g wit h  
gr a de 3 or 4 t hr o m b ocyt o pe ni a.  
Re q uiri n g tra nsf usi o n  
Catastr o p hic blee di n g, re q uiri n g  maj or 
n o n -electi ve i nter ve nti o n 
C N S he m orr ha ge/ blee di n g  
Blee di n g n ote d o n C T or ot her  
sca n wit h n o cli nical c o nse q ue nces 
He m orr ha gic str o ke or he m orr ha gic  
vasc ular e ve nt ( C V A) wit h  ne ur ol o gic 
si g ns a n d s y m pt o ms 
He m o pt ysis  
Re q uiri n g tra nsf usi o n  
Catastr o p hic blee di n g, re q uiri n g  maj or 
n o n -electi ve i nter ve nti o n 
Mele na/ GI blee di n g  
Re q uiri n g tra nsf usi o n  
Catastr o p hic blee di n g, re q uiri n g  maj or 
n o n -electi ve i nter ve nti o n 
Rectal blee di n g/ h e mat oc hezia  
Re q uiri n g tra nsf usi o n  
Catastr o p hic blee di n g, re q uiri n g  maj or 
n o n -electi ve i nter ve nti o n 
Va gi nal blee di n g  
Re q uiri n g tra nsf usi o n  
Catastr o p hic blee di n g, re q uiri n g  maj or 
n o n -electi ve i nter ve nti o n 

2 2 7 5. 0 0 
 
Pa ge 5 5  of 5 9  
He m orr ha g e –  Ot her (s pecif y  
site): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Re q uiri n g tra nsf usi o n  
Catastr o p hic blee di n g, re q uiri n g  maj or 
n o n -electi ve i nter ve nti o n 
H E P A TI C  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Bilir u bi n  
 
Bilir u bi n ass ociate d wit h graft  
vers us h ost disease ( G V H D) f or  
B M T st u dies, if s pecifie d i n t he  
pr ot oc ol.  
> 3. 0 –  1 0. 0 x U L N  
 
> 6 - < 1 5 m g/ 1 0 0 m L  
> 1 0. 0 x U L N  
 
> 1 5 m g/ 1 0 0 m L  
I N F E C TI O N/ F E B RI L E N E U T R O P E NI A 
A d verse E ve nt  
 
Gr a de 3  
Gr a de 4  
Fe brile ne utr o pe nia (fe ver or  
u n k n o w n ori gi n wit h o ut cli nicall y  
or micr o bi ol o gicall y d oc u me nte d 
i nfecti o n). 
Prese nt  
Life -t hreate ni n g se psis (e. g., se ptic s h oc k) 
I nfecti o n/ Fe brile Ne utr o pe nia –  
Ot her (s pecif y): _ _ _ _ _ _ _ _ _ _ _ _ _ _  
Se vere  
Life -t hreate ni n g or disa bli n g 
N E U R O L O G Y  
A p h asi a, rece ptive a n d/ or ex pressive, is gr a de d u n der S peec h i m p air me nt i n t he N E U R O L O G Y c ate g ory. 
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
C N S cere br o vasc ular isc he mia  
Tra nsie nt isc he mic e ve nt or attac k  
( TI A) 
 
Per ma ne nt e ve nt (e. g.,  
cere bral vasc ular acci de nt)  
 
Le u k oe nce p hal o pat h y ass ociate d  
ra di ol o gical fi n di n gs 
 
Se vere i ncrease i n S A S ; se vere 
ve ntric ul o me gal y; near t otal w hite  
matter T 2 h y peri nte nsities or  diff use 
l o w atte n uati o n ( C T); f ocal w hite 
matter necr osis (c ystic)  
Se vere i ncrease i n S A S;  
se vere ve ntric ul o me gal y; 
diff use l o w atte n uati o n wit h  
calcificati o n ( C T); diff use 
w hite mat ter necr osis ( M RI) 
 
Seiz ure(s)  
Seiz ure(s) i n w hic h c o nsci o us ness is 
altere d  
 
Seiz ures of a n y t y pe w hic h  
are pr ol o n ge d, re petiti ve, or  
diffic ult t o c o ntr ol (e. g.,  
stat us e pile ptic us, i ntracta ble 
e pile ps y) 
P U L M O N A R Y  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
A d ult Re s pirat or y Distress 
S y n dr o me  
( A R D S) 
 
- 
Prese nt  
A p nea  
Prese nt  
Re q uiri n g i nt u bati o n  
Car b o n m o n o xi de diff usi o n ca pacit y 
( D L C O) 
> 2 5 - < 5 0 % of pretreat me nt or  
n or mal val ue  
 
< 2 5 % of pretreat me nt or  
n or mal val ue  
 
F E V 1  
> 2 5 - < 5 0 % of pretreat me nt or  
n or mal val ue  
< 2 5 % of pretreat me nt or  
n or mal val ue  
 
H y p o xia  
Decrease d O 2 sat urati o n at rest,  
re q uiri n g s u p ple me ntal o x y ge n 
 
Decrease d O 2 sat urati o n,  
re q uiri n g press ure s u p p ort 
( C P A P) or assiste d 
Ve ntilati o n  
R E N A L/ G E NI T O U RI N A R Y  

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Pa ge 5 6  of 5 9  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Creati ni n e 
 
N ote: A dj ust t o a ge -a p pr o pri ate  
levels f or pe di atric p atie nts 
> 3. 0 - 6. 0 x U L N  
> 6. 0 x U L N  
 
Re nal fail ure  
 
Re q uiri n g dial ysis, b ut re versi ble  
Re q uiri n g dial ysis a n d irre versi ble  
S E C O N D A R Y M A LI G N A N C Y  
A d verse E ve nt  
Gr a de 3  
Gr a de 4  
Sec o n dar y Mali g na nc y –  Ot her  
(s pecif y t y pe): _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Excl u des met ast asis fr o m i niti al  
pri m ary.  
- 
Prese nt  
 

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A P P E N DI X X:  F H C R C I R B P olicies 
 
htt p://e xtra net.f hcrc. or g/ E N/secti o ns/ir o/ir b/ p olic y/i n de x. ht ml  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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A p pe n di x XI:  A d verse E ve nts Ass oci ate d or E x pecte d wit h He m at o p oietic Cell Tr a ns pl a nt ati o n 
 
1. Graft vers us h ost disease:  G V H D is a maj or t o xicit y ass ociate d wit h t he i nf usi o n of all o ge neic d o n or ste m 
cells.  G V H D ma y be ac ute or c hr o nic a n d ma y affect m ulti ple or ga n s yste ms, i ncl u di n g t he s ki n, li ver, a n d GI 
tract. 
 
2. O p p ort u nistic i nfecti o ns, i ncl u di n g viral a n d f u n gal i nfecti o ns, ca n res ult i n se vere p ul m o nar y, ne ur ol o gic, 
he patic a n d ot her or ga n d ysf u ncti o n, a n d p ossi ble deat h. 
 
3. Gastr oi ntesti nal t o xicit y. Na usea a n d v o miti n g ca n be a ntici pate d d uri n g t he e ntire c o urse of a blati ve t hera p y. 
M uc ositis a n d diarr hea s h o ul d be e x pecte d. Pre d nis o ne ca n ca use GI blee di n g. 
 
4. Car diac t o xicit y. Car di ot o xicit y (c o n gesti ve heart fail ure, pericar dial eff usi o n, E K G c ha n ges) is u nc o m m o nl y 
ass ociate d wit h t he c he m ot hera p y a ge nts a n d T BI use d i n t he re gi me n a n d t hese se q uelae ma y pr o ve let hal. 
 
5. P ul m o nar y t o xicit y. Diff use i nterstitial p ne u m o nitis of u n k n o w n eti ol o g y a n d diff use al ve olar he m orr ha ge 
occ ur wit h s o me re g ularit y after B M T a n d i nterstitial fi br osis occ urs m uc h m ore rarel y. B ot h are well- descri be d 
c o m plicati o ns of i nte nsi ve c he m ot hera p y a n d T BI re gi me ns a n d ma y pr o ve let hal. 
 
6. He patic t o xicit y. Ve n o- occl usi ve disease of t he li ver is a c o m m o n t o xicit y of hi g h- d ose c he m ora di ot hera p y 
a n d ma y res ult i n deat h. C ycl os p ori ne ma y ca use ele vati o n of A L T/ A S T. 
 
7. Re nal d ysf u ncti o n. C he m ora di ot hera p y ma y u nc o m m o nl y ca use re nal d ysf u ncti o n. M ore c o m m o nl y, 
ne p hr ot o xicit y res ults fr o m c ycl os p ori ne a n d ge nerall y res p o n ds t o d ose re d ucti o n. Rarel y, i di o pat hic or 
calci ne uri n i n hi bit or-ass ociate d he m ol ytic- ure mic s y n dr o me ma y occ ur a n d ma y be pr o gressi ve a n d fatal. A 
s y n dr o me of m o derate re nal i ns ufficie nc y a n d he m ol ysis has bee n see n 5- 7 m o nt hs p ost H S C T after i nte nsi ve 
m ulti-a ge nt c o n diti o ni n g pl us T BI. 
 
8. He m orr ha gic c ystitis, ma nifeste d eit her as gr oss or micr osc o pic he mat uria, is a c o m m o n t o xicit y after hi g h-
d ose c he m ora di ot hera p y, b ut us uall y ass ociate d wit h re gi me ns t hat i ncl u de c ycl o p h os p ha mi de. He m orr ha gic 
c ystitis ma y pre dis p ose t o a l o n g-ter m i ncrease d ris k of bla d der ca ncer. 
 
9. Ce ntral ner v o us s yste m t o xicit y. Ra diati o n a n d c he m ot hera p y ca n ca use C N S t o xicit y, i ncl u di n g seiz ures, 
de presse d me ntal stat us, or le u k oe nce p hal o pat h y. Calci ne uri n i n hi bit ors ca n ca use seiz ures or ot her C N S 
t o xicit y. 
 
1 0. Marr o w a plasia. Se vere ne utr o pe nia, t hr o m b oc yt o pe nia, a n d a ne mia, is e x pecte d t o occ ur f or a peri o d of 7 t o 
4 2 da ys f oll o wi n g i nf usi o n of marr o w. Tra nsf usi o n of platelets a n d re d bl o o d cells is e x pecte d as s u p p orti ve 
care. Tra nsf usi o n of bl o o d pr o d ucts ma y be ass ociate d wit h ac q uisiti o n of HI V or a he patitis vir us. Ne utr o pe nia 
ma y i ncrease t he ris k f or ac q uiri n g seri o us i nfecti o n. T hr o m b oc yt o pe nia ma y i ncrease t he ris k of life-t hreate ni n g 
he m orr ha ge. He m orr ha gic or i nfecti o us c o m plicati o ns d uri n g t he e x pecte d peri o d of a plasia ma y res ult i n deat h. 
 
1 1. Miscella ne o us. Al o pecia a n d sterilit y are e x pecte d c o m plicati o ns of t he pr o gra m as a w h ole. Cataract 
de vel o p me nt is p ossi ble after T BI a n d/ or ster oi ds. Deficie ncies of gr o wt h h or m o ne, t h yr oi d h or m o ne, a n d se x 
h or m o nes are p ossi ble after T BI. Calci ne uri n i n hi bit ors ca n ca use tra nsie nt gi n gi val h y per plasia, tre m or, seiz ure, 
h y perte nsi o n, hea dac he, d ysest hesia a n d hirs utis m. Ster oi d t hera p y ca n als o c o ntri b ute t o fl ui d rete nti o n, eas y 
br uisi n g, h y perte nsi o n, ase ptic necr osis of b o ne a n d i ncrease d s usce pti bilit y t o i nfecti o n. M M F ca n ca use 
s p o nta ne o us a b orti o ns a n d birt h defects. H os pitalizati o n d uri n g c o n diti o ni n g a n d rec o ver y peri o d is e x pecte d t o 
be 5- 9 wee ks i n d urati o n. 

2 2 7 5. 0 0 
 
Pa ge 5 9  of 5 9  
A P P E N DI X XI I:  Sc he d ule of St u d y E v al u ati o ns 
 
Scree n  
Da y 1 t o e n graft me nt  
Da ys 3 1 -1 0 0  
L o n g -Ter m F oll o w -u p  
dail y  
wee kl y  
 
Da y 1 4 * * *  
( ±2  da ys)  
Da y 2 8  
( ± 3 da ys) 
wee kl y  
 
Da y 5 6  
( ± 7 da ys) 
Da y 8 0  
( ± 7 da ys) 
Da y 1 0 0  
( ± 7 da ys)  
6 m o nt hs ( + 3 0 
da ys)  
1 year  
2 years  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y  
X  
 
 
 
 
 
 
 
 
 
 
 
P h ysical e xa m  
X  
X  
 
 
 
X  
 
 
 
X  
X  
X  
Perf or ma n ce stat us   
X  
  
 
 
 
 
 
X   
Da y 8 0 -1 0 0  
 
X 
X 
X 
Hei g ht/ Wei g ht  
X  
 
 
 
 
 
 
X  
 
 
 
 
G V H D e v al uati o n  
 
 
X  
 
 
X  
 
 
 
X  
X  
X  
A d verse e ve nt s  
 
X  
 
 
 
X  
 
 
 
 
 
 
C B C wit h diff  
X  
X  
 
 
 
X  
 
 
 
X  
X  
X  
Basic M eta b olic Pa nel  
X  
X  
 
 
 
X  
 
 
 
X  
X  
X  
He p atic F u ncti o n Pa nel  
X  
As cli nicall y i n dicate d or per sta n dar d practice  
Viral scree ni n g 
i ncl u di n g C M V P C R  
Per sta n dar d practice  
C M V S ur veilla nce b y  
P C R  
P er st a n d ar d practice 
Pre g na n c y test  
X  
 
 
 
 
 
 
 
 
 
 
 
E B V m o nit ori n g  
 
 
 
 
 
 
See A p pe n di x VIII  
 
 
 
 
 
Uri n al ysis  
X  
As cli nicall y i n dicate d or per sta n dar d practice  
E K G  
X  
As cli nicall y i n dicate d or per sta n dar d practice  
M U G A or 
ec h ocar di o gra m 
X 
As cli nicall y i n dicat e d or p er sta n d ar d practice 
C hest x -ra y or C T 
X  
As cli nicall y i n dicate d or per sta n dar d practice  
P F T  
X 
As cli nicall y i n dicate d or per sta n dar d practice  
B o n e marr o w b x/as p  * *  
X  
 
 
 
X  
 
 
X  
 
 
X  
 
C hi meris m –  B M  
 
 
 
 
X  
 
 
X  
 
 
X  
 
C hi meris m – P B   
  
  
 
  
X 
F H C R C  
X 
 
X  
X 
 
X 
X 
X 
I g G, I g A, I g M (as 
p ossi ble)  
  
  
 
 
X 
 
X  
 
X 
X 
X 
X 
H ost/ d o n or st u dies  
( F H C R C) 
I n vesti gat or discreti o n ( See Secti o n 9. E) 
L y m p h o c yte  p a nel (as 
p ossi ble)  
X  
  
 
 
X 
 
X  
 
X 
X  
X  
X  
I m m u n o p he n ot y pic 
é v al u ati o n ( F H C R C) 
X  
  
 
 
X 
 
X  
 
X 
X 
X 
X 
 
C h ec k Secti o n 9 :  E val u ati o n  f or d etails.  E ver y eff ort will be ma de t o c o m pl ete t h e 1 - a n d 2 -year e v al u ati o ns as cl os e t o t h es e d at es as p ossi ble, t a ki n g i nt o c o nsi derati o n p ati e nt’s circ u mst a n ces at t h es e ti me p oi nts.   
* *as cli ni call y i n dicat e d    * * * F or p ati e nts w h o recei v e d d o u bl e c or d bl o o d u nits  
N O T E:  I n certai n circ u mst a n ces (e. g., rel a ps e or t er mi nal ill ness), st u d y e v al uati o ns ma y b e o mitte d at t he p h ysi cia n’s or P I’s discreti o n