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)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 130
Healthy volunteers: no

Brief summary:
This phase II trial studies how well giving treosulfan together with fludarabine phosphate and total-body irradiation (TBI) works in treating patients with hematological cancer who are undergoing umbilical cord blood transplant (UCBT). Giving chemotherapy, such as treosulfan and fludarabine phosphate, and TBI before a donor UCBT helps stop the growth of cancer cells and helps stop the patient's immune system from rejecting the donor's stem cells. When the stem cells from a related or unrelated donor, that do not exactly match the patient's blood, are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving cyclosporine (CsA) and mycophenolate mofetil (MMF) after the transplant may stop this from happening.

Detailed description:
PRIMARY OBJECTIVES:

I. Graft failure/rejection and secondary graft failure.

II. Day -200 non-relapse mortality.

SECONDARY OBJECTIVES:

I. Platelet engraftment by six months.

II. Grade II-IV and III-IV acute graft-versus-host disease (GVHD) at day 100 and one year.

III. Chronic GVHD.

IV. Clinically significant infections.

V. Overall survival.

VI. Relapse or disease progression.

VII. Immune reconstitution (Fred Hutchinson Cancer Research Center \[FHCRC\] only).

VIII. Emergence of a dominant unit (FHCRC only).

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM I (low risk for graft failure): Patients receive a conditioning regimen comprising fludarabine phosphate intravenously (IV) over 1 hour once daily (QD) on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0. Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or orally (PO) 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD.

ARM II (high risk for graft failure): Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I.

After completion of the study treatment, patients are followed up at 6 months and 1 and 2 years.

Arms:
arm 1: Patients receive a conditioning regimen comprising fludarabine phosphate IV over 1 hour QD on days -6 to -2 and treosulfan IV over 120 minutes on days - 6 to -4. Patients undergo TBI on day -1. Patients then undergo donor UCBT on day 0.

Patients receive GVHD prophylaxis comprising cyclosporine IV over 1 hour or PO 2-3 times daily on days -3 to 100, followed by a taper in the absence of GVHD. Patients also receive mycophenolate mofetil IV 3 times daily on days 0 to 40, followed by a taper in the absence of GVHD. arm 2: Patients receive a conditioning regimen, TBI, donor UCBT, GVHD prophylaxis, and mycophenolate mofetil as in Arm I.

Interventions: intervention 1: Cyclosporine intervention 2: Fludarabine Phosphate intervention 3: Laboratory Biomarker Analysis intervention 4: Mycophenolate Mofetil intervention 5: Total-Body Irradiation intervention 6: Treosulfan intervention 7: Umbilical Cord Blood Transplantation
Intervention descriptions: intervention 1: Given IV or PO intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV intervention 5: TBI administered day -1: 200 cGy (or escalated to 300 cGy, 400 cGy, or 450 cGy per protocol statistical section) intervention 6: Given IV intervention 7: Undergo single or double unit UCBT

Protocol document:
Prot_SAP_000.pdf: 
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  


2 2 7 5. 0 0 
Pa ge 1 of 5 9  
 
 
 
 
 
 
 
 
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 
 
Pa ge 2  of 5 9  
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: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
  
 


2 2 7 5. 0 0 
 
Pa ge 3  of 5 9  
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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Pa ge 5  of 5 9  
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 


2 2 7 5. 0 0 
 
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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Pa ge 8  of 5 9  
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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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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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 


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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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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. 


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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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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). 
 


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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. 
 


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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  


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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  


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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 


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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. 


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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 


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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 


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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. 


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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 
 


2 2 7 5. 0 0 
 
Pa ge 5 1  of 5 9  
 
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 


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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 


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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) 


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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 


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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. 


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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