Clinical trial NCT01951885
Conditions: Chronic Myelogenous Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Acute Biphenotypic Leukemia Myelodysplastic Syndrome Myeloproliferative Neoplasm Non-Hodgkin Lymphoma Hodgkins Disease Chronic Lymphocytic Leukemia Multiple Myeloma
Sponsor: Case Comprehensive Cancer Center
Start date: 2014-07-07; Completion date: 2021-08-11
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized clinical trial studies standard GVHD prophylaxis with tacrolimus and methotrexate compared to tacrolimus, mycophenolate mofetil and a reduced-dose methotrexate in patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplant. Both mycophenolate mofetil and reduced-dose methotrexate, in combination with a calcineurin inhibitor, have been shown to be safe and effective in GVHD prevention with less toxicity than standard dose methotrexate. It is not yet known, however, whether this combination of mycophenolate mofetil and reduced-dose methotrexate with tacrolimus is more effective than tacrolimus and standard dose methotrexate in preventing GVHD.

Detailed description:
Study Design This is a prospective randomized trial to determine the effectiveness of different doses of GVHD prophylaxis on mucositis, engraftment and aGVHD. Study consists of two study groups of 50 subjects each.

Group A will receive Tac and MTX (15 mg/m2 day +1, 10 mg/m2 day +3, +6, +11). Group B will receive Tac, Mini-dose MTX (5 mg/m2 on day +1, +3, +6) and MMF.

Arms: arm 1: Participants receive tacrolimus IV over 24 hours beginning on day -1 (or tacrolimus orally beginning on day -3) and then PO BID after engraftment with a taper from day 100 to day 180 (in the absence of GVHD). Patients also receive methotrexate IV on days 1, 3, 6, and 11. arm 2: Patients receive tacrolimus as in group A and methotrexate (low dose) IV on days 1, 3, and 6. Patients also receive oral mycophenolate mofetil BID beginning on day 1, with a taper from day 45 to day 100 (in the absence of GVHD).
Interventions: intervention 1: tacrolimus intervention 2: methotrexate intervention 3: Mycophenolate mofetil intervention 4: Methotrexate (low dose)
Intervention descriptions: intervention 1: Tacrolimus 0.03 mg/kg/day beginning day -1 or tacrolimus 0.03mg/kg/dose BID orally beginning on day -3. If Tac is administered intravenously, it will be given over 24 hours and will be converted to oral administration 2 times a day when the patient has engrafted and/or can tolerate oral medication. Levels of Tac will be obtained to maintain a recommended target serum level of 5-12 ng/mL intervention 2: MTX 15mg/m2 IV on day +1, followed by 10mg/m2 on day +3, +6, +11. If patient \< 10 kg then MTX will be given at 0.5 mg/kg IV on day +1. Then MTX will be given at 0.33 mg/kg on days +3, +6 and +11. intervention 3: Patients will receive Mycophenolate beginning on day +1. Patients \>40 kg will receive Mycophenolate 1000 mg twice a day. Mycophenolate should be given orally twice a day. IV formulation may be used if the patient cannot tolerate oral route. Patients \< 40 kg will receive MMF 45 mg/kg/day (15 mg/kg three times a day). MMF may be given orally or intravenously as per institutional protocol intervention 4: MTX 5mg/m2 IV on day +1, +3, +6. If patient\<10 kg MTX will be given at 0.17 mg/kg on day +1, +3, and +6.

Protocol documents:
Prot_SAP_002.pdf: 
 
C A S E C O M P R E H E N SI V E C A N C E R C E N T E R 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
S T U D Y N U M B E R:  C A S E 6 Z 1 3 
 
S T U D Y TI T L E:   
Tacr oli m us, 
mi ni- d ose 
Met h otre x ate a n d 
M yc o p h e n olate 
M ofet il 
vers us Tacr oli m us a n d 
Met h otre x ate f or t he Pre ve nti o n of Ac ute 
Graft- v ers us- H ost- Diseas e ( N C T 0 1 9 5 1 8 8 5)  
  
 
P RI N CI P A L I N V E S TI G A T O R:  Bett y Ha milt o n, M D 
De part me nt of He mat ol o gic O n c ol o g y a n d Bl o o d Dis or ders 
9 5 0 0 E ucli d A ve n ue C A 6  
  
  
  
 
C le vela n d, O H   4 4 1 9 5 
   
  
 
 
 
C O - PI:  
  
  
  
Ra bi Ha n na, M D 
De part me nt of Pe di atric He mat ol o g y/ O n c ol o g y 
9 5 0 0 E ucli d A ve n ue R 3 5  
  
  
  
 
C le vela n d, O H   4 4 1 9 5 
   
  
  
 
 
 
C O - I N V E S TI G A T O R:   
Matt Kala yci o, M D 
 
Bra d P o hl ma n, M D 
R o nal d S o bec ks, M D 
R o bert Dea n, M D 
Bria n Hill, M D 
  
  
  
  
Dee pa J a ga dees h, M D 
  
  
  
  
Aar o n Ger ds, M D 
  
  
  
  
Na v neet Maj h ail, M D 
  
  
  
  
Set h R otz, M D 
  
  
  
  
Illia B u ht oiar o v, M D 
  
  
  
  
Allis o n Wi nter, M D 
  
  
  
  
J ac k K h o uri, M D  
  
  
  
  
Faiz A n wer, M D   
  
  
   
 
 
S T A TI S TI CI A N:   
  
Lisa R y bic ki, M S  
  
  
  
  
Q ua ntitati ve Healt h Scie nces H S 1 - 0 8 
 
 
 
S P O N S O R:   
  
  
Cle vela n d Cli nic  
  
  
  
 
 
A G E N T S :         
  
  
Met h otre x ate, M yc o p he n ol ate M ofetil, T acr oli m us  
 


C A S E 6 Z 1 3  
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S C H E M A:   


C A S E  6 Z 1 3   
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T A B L E O F C O N T E N T S 
 
1. 0   
I N T R O D U C TI O N  
1. 1        All o ge n eic He m at o p oietic Ste m Cell Tra ns pla nt  
1. 2   
G V H D Pr o p h yla xis  
1. 3       Cli nical Data t o Date   
 
 
2. 0  
O B J E C TI V E S` 
2. 1   
Pri mar y O bj ecti ves 
2. 2   
Sec o n dar y O bj ecti ves 
 
3. 0  
S T U D Y D E SI G N 
3. 1       St u d y Desi g n 
3. 2       N u m ber of S u bje cts 
3. 3       Re place me nt of S u bjects 
3. 4   
E x pecte d D urati o n of S u bject Partici pati o n 
3. 4. 1    D ur ati o n of T hera p y 
3. 4. 2    D urati o n of F oll o w U p 
4. 0   
P A TI E N T S E L E C TI O N 
4. 1   
I n cl usi o n Criteria 
4. 2   
E x cl usi o n Criteria 
4. 3  
I n cl usi o n of W o me n a n d Mi n orities 
` 
5. 0   
R E GI S T R A TI O N 
5. 1   
Ra n d o mizati o n   
 
 
6. 0   
T R E A T M E N T P L A N 
6. 1  
A ge nt A d mi nistrati o n 
6. 1. 1 
Tacr oli m us ( Tac) A d mi nistrati o n 
6. 1. 2 
M yc o p h e n olate M of etil ( M M F) A d mi nistrati o n 
6. 1. 3 
Met h otre x ate ( M T X) A d mi nistrati o n 
6. 2  
Ge neral C o nc o mita nt Me dicati o ns a n d S u p p orti ve Care G ui deli nes 
 
6. 2. 1  
Gr o wt h Fact or S u p p ort 
  
6. 2. 2 
A ne mia 
  
6. 2. 3 
T hr o m b oc yt o p e nia 
 
6. 2. 4  
A nti micr o bial, A ntif u n gal, A nti viral Pr o p h yla xis 
  
6. 2. 5 
Fe ver 
  
6. 2. 6 
M o ut h Care 
 
  
6. 2. 7 
Ve n o us Access 
  
6. 2. 8 
N utriti o n 
 
6. 2. 9  
A ntie metics 
  
6. 2. 1 0 
Ma na ge me nt of Ac ute Graft Vers us H ost Disease 
6. 3   
D urati o n of T hera p y 
 
 


C A S E  6 Z 1 3   
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4  
7. 0  
D O S E D E L A Y S / D O S E M O DI FI C A TI O N S 
7. 1 A dj ust me nt of St u d y Me dicati o ns 
7. 1. 1  Ta cr oli m us 
7. 1. 2  M yc o p h e n olate M of etil 
7. 1. 3  Me t h otre x ate 
 
8. 0  
A D V E R S E E V E N T S: LI S T A N D R E P O R TI N G R E Q UI R E M E N T S  
 
8. 1  
A d ve rse E v e nts a n d P ote ntial Ris ks 
  
  
8. 1. 1 
Tacr oli m us 
 
  
8. 1. 2 
M yc o p h e n olate M of etil 
 
  
8. 1. 3 
Met h otre x ate 
8. 2  
Defi niti o ns 
 
8. 2. 1  
A d verse E v e nts 
 
8. 2. 2  Si g nifica nce of a n A d verse E ve nt 
 
8. 2. 3  Seri o us A d verse E v e nts 
 
8. 2. 4  
E x pecte d ness 
 
8. 2. 5  
Attri b uti o n 
8. 3  
Re p orti n g Pr oce d ures f or All A d verse E v e nts 
8. 4  
Seri o us A d verse E v e nt Re p orti n g Pr oce d ures 
 
8. 4. 1  F D A Re p orti n g 
8. 5  
Data Safet y T o xicit y C o m mittee    
 
 
9. 0  
P H A R M A C E U TI C A L I N F O R M A TI O N  
 
9. 1 I n v esti gati o nal A ge nts 
9. 2  
C o m mercial A ge nts 
9. 2. 1  
Met h otre x ate 
9. 2. 2  
M yc o p h e n olate 
9. 2. 3  
Tacr oli m us 
 
 1 0 . 0  
C O R R E L A TI V E / S P E CI A L S T U DI E S 
1 0. 1  
Researc h Sa m ple R e p osit or y 
   
1 0. 1. 1 Bac k gr o u n d a n d Rati o nal 
   
1 0. 1. 2 Patie nt Selecti o n 
   
1 0. 1. 3 Researc h Pla n/ St u d y Para meters 
   
1 0. 1. 4 S peci me n Ha n dli n g 
   
1 0. 1. 5 Pri vac y Pr ot ecti o n 
   
1 0. 1. 6 T y pes of La b orat or y St u dies t o Be Perf or me d 
   
1 0. 1. 7 Ris k 
 
 1 1. 0  
S T U D Y P A R A M E T E R S A N D C A L E N D A R 
1 1 . 1 
St u d y Para meters 
   
  
1 1. 1. 1 Prest u d y  
    
  
1 1. 1. 2 D uri n g h os pitaliz ati o n f or Tra ns pla nt 
   
  
1 1. 1. 3 P ost h os pitalizati o n f or Tra ns pla nt t o E n d of St u d y 
   
  
1 1. 1. 4 St u d y Para meter Ta ble 
   
  
1 1. 1. 5 St u d y Assess me nts 


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 1 2. 0  
M E A S U R E M E N T O F E F F E C T  
1 2. 1 
I n ci de nce, Le n gt h a n d Se verit y of M uc ositis  
 1 2. 2  
Rate of Ne utr o p hil a n d Platelet E n graft me nt 
 1 2. 3  
I n ci de nce of Ac ute G V H D 
 1 2. 4       Sec o n dar y o bje cti ve para m eters 
 
 1 3. 0  
R E C O R D S T O B E K E P T/ R E G U L A T O R Y C O N SI D E R A TI O N S 
1 3 . 1 
Data Re p orti n g 
 1 3. 2  
Re g ulat or y C o nsi derati o ns  
1 3. 2. 1 
Writte n I nf or m e d C o nse nt 
1 3. 2. 2 S u bject data Pr otecti o n 
1 3. 2. 3 Rete nti o n of Rec or ds 
1 3. 2. 4 A u dit a n d I ns pecti o ns 
1 3. 2. 5 Data Safet y a n d M o nit ori n g Pla n 
 
 1 4. 0   
S T A TI S TI C A L C O N SI D E R A TI O N S 
 
R E F E R E N C E S 
 
A P P E N DI C E S    
  
A P P E N DI X I 
 
Ac ute G V H D Sta gi n g a n d Gra di n g 
  
 
  
A P P E N DI X II 
  
C hr o nic G V H D Sc ori n g 
 
 
A P P E N DI X I II 
  
W orl d Healt h Or ga niz ati o n M uc ositis Gra di n g 
 
 
A P P E N DI X I V  
  
T BI A d mi nistrati o n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C A S E  6 Z 1 3   
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1. 0   
I N T R O D U C TI O N 
 
1. 1   
All o ge n eic He m at o p oietic Cell Tr a ns pl a nt 
 
All o ge n eic he mat o p oieti c cell tra ns pla ntati o n ( H C T) is a n effecti ve t hera p y f or a variet y of 
he mat ol o gic m ali g na n cies a n d b o ne marr o w fail ure s y n dr o mes.  H o we ver, it carries a 
si gnifica nt ris k f or treat me nt-relat e d m ortalit y, pri maril y d ue t o i nfecti o n, c o n diti o ni n g 
re gi me n-relate d t o xicities, a n d graft vers us h ost disease ( G V H D); w hic h c o nti n ues t o li mit its 
utilit y.  T he ris k of tra ns pla nt-relate d m ort alit y ( T R M) is i nfl ue nce d b y se v eral f act ors, 
i ncl u di n g patie nt a ge, disease re missi o n stat us, n u m ber of pri or c he m ot hera p y re gi me ns, c o-
m or bi d diseases, a n d c o n diti o ni n g re gi me n i nte nsit y. Si nce t he 1 9 8 0’s, s e veral a d va n ces ha v e 
re d uce d t h e ris k of T R M i n patie nts u n der g oi n g all o ge n eic H C T; i ncl u di n g m ore effecti ve 
a p pr oac h es f or pre ve nti o n of i nfecti o n, e n h a nce m e nts i n H L A t y pi n g a n d matc hi n g, a n d 
G V H D pr o p h yla ctic re gi me ns [ 1].  Des pite t his h o we ver, T R M re mai ns hi g h a n d G V H D 
remai ns a maj or ca use of m or bi dit y a n d m ortalit y a m o n gst all o ge n eic H C T patie nts.  E ve n 
wit h pr o p h yla ctic meas ur es, t he i nci de nce of ac ute G V H D is esti mate d t o b e 4 0- 5 0 % a m o n g 
patie nts fr o m H L A i de nti cal si bli n g d o n ors a n d u p t o 7 5 % i n patie nts recei vi n g u nrel ate d 
tra ns pla nts.  Treat me nt f or esta blis he d G V H D ca n be diffic ult, wit h a m ortalit y rate of 6 0-
8 0 %  i n patie nts wit h gra des 3- 4 ac ut e G V H D.  A p pr o xi matel y 4 0 % of patie nts wit h ac ute 
G H V D ha v e a d ura ble res p o nse t o c ortic oster oi d t hera p y, a n d t h ere h as bee n little c ha n ge i n 
t his res p o nse rate o v er t h e past 2 0 years des pite c h a n ges t o G V H D treat me nt re gi me ns [ 2]. 
T h us t he use of i m pr o ve d a n d effecti ve pr o p h yl a xis is of ut m ost i m p orta nce.  
 
1. 2  
G V H D Pr o p h yl a xis  
 
C urre ntl y, G V H D pr o p h yl a xis is base d o n a cal ci ne uri n i n hi bit ors (c ycl os p ori ne ( Cs A) or 
tacr oli m us ( Tac) als o c alle d F K- 5 0 6) a n d a s h ort c o urse of met h otre x ate ( M T X). Ot her 
o pti o ns i ncl u de ster oi ds, m yc o p h e n olate m ofetil ( M M F), a n d sir oli m us.  W hile t he 
co m bi nati o n of Tac a n d M T X has lar gel y b ee n s h o w n t o be s u peri or i n t he pre ve nti o n of 
a G V H D c o m pare d t o ot her re gi me ns, t o xicities fr o m t hese re gi me ns are a ca use of 
si g nifica nt m or bi dit y after all o ge neic tra ns pla nt.  
 
Met h otre x ate has ha d a l o n g hist or y of use as a c o m p o ne nt of G V H D pr o p h yla xis a ge nts i n 
H C T.  I nitiall y use d as a si n gle a ge nt, it has bee n s h o w n t o be c o m ple me ntar y i n c o m bi nati o n 
wit h ca lci ne uri n i n hi bit ors c ycl os p ori ne a n d tacr oli m us.  H o we ver, it als o ma y i ncreas e t he 
ris k of ot her c o m plicati o ns s uc h as m uc ositis, dela ye d ne utr o p hil a n d plat elet e n graft me nt 
a n d c o ntri b ute t o he patic a n d re nal t o xicities.  M uc ositis ca n be se vere a n d d e bilitati n g 
ne cessitati n g t he nee d f or t otal pare nteral n utriti o n ( T P N) a n d f urt heri n g tiss ue da ma ge 
c o ntri b uti n g t o G V H D.  As a res ult of se v ere m u c ositis, d oses of M T X m ust ofte n b e hel d, 
w hic h ma y f urt her decrease t he efficac y of G V H D pr o p h yl a xis.  
 
Tacr oli m us is a n i m m u n os u p pressi ve macr oli de lact o ne t hat bl oc ks t he earliest ste ps of T-cell 
acti vati o n b y i n hi biti n g t he calci u m- d e pe n de nt si g nal tra ns d ucti o n pat h wa y.  Alt h o u g h t he 
m ec ha nis m of acti o n, p har mac o ki netics, a n d si de-effect pr ofile of t acr oli m us are si milar t o 
t h ose of c ycl os p ori ne, its i m m u n os u p pressi ve p ote nc y i n vitr o is 5 0 t o 2 0 0 ti mes greater t h a n 


C A S E  6 Z 1 3   
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t hat of c ycl os p ori ne.  Lar ge p h ase III st u dies c o m p ari n g Tac/ M T X v ers us Cs A/ M T X f or b ot h 
matc he d rel ate d a n d u nrelate d d o n ors ha ve b ee n p erf or me d a n d de m o nstrat e s u peri orit y of 
Tac/ M T X [ 3- 4].  
 
M yc o p h e n olate m of etil ( M M F) has bee n utilize d i n a n eff ort t o i m pr o ve G V H D pr o p h yla xis 
a n d re d uce t o xicit y. M M F is a n ester pr o dr u g of t he i m m u n os u p pressa nt m yc o p h e n olic aci d. 
M yc o p h e n olic aci d i n hi bits i n osi ne m o n o p h os p hate de h y dr o ge n ase, res ulti n g i n t he bl oc ka de 
of de n o v o p uri ne s y nt hesis, t here b y li miti n g pr oliferati o n of l y m p h oc ytes.  M M F is effecti ve 
i n pre ve nti n g G V H D i n a ni mal m o dels, a n d t he c o m bi nati o n of a calci ne uri n i n hi bit or a n d 
M M F is m ore effecti ve t ha n eit her a ge nt b y itself [ 5].  T he Cs A a n d M M F or Tac a n d M M F 
co m bi nati o ns are c o m m o nl y use d as G V H D pr o p h yl a xis i n patie nts u n der g oi n g re d u ce d 
i nte nsit y tra ns pla nts. M M F i n c o m bi nati o n wit h Cs A has bee n c o m p are d t o M T X a n d Cs A i n 
2 s mall pr os pecti ve ra n d o mize d st u dies f or G V H D pr o p h yl a xis i n patie nts u n der g oi n g 
m yel oa bl ati ve tra ns pla nt [ 6- 7].  T hese st u dies de m o nstrate d se veral be nefits i n t he M M F 
ar m, i ncl u di n g less s e vere m uc ositis, s h orter ti me t o ne utr o p hil a n d platelet e n graft me nt, a 
red ucti o n i n use of T P N a n d narc otic a nal gesia, a n d s h orter h os pitalizati o n ti mes.  T he 
co m bi nati o n of Tac a n d M M F has bee n e val u ate d as G V H D pr o p h yl a xis i n a d ults i n si n gle-
ar m p hase II trials w hic h ha ve s h o w n t he re gi me n t o be well t olerate d [ 8- 9].  
 
1. 3 
Cli n ic al D at a t o D ate  
 
T he gr o u p at M. D. A n d ers o n Ca ncer Ce nter has de vel o pe d a mi ni- d ose met h otre x ate re gi me n 
( 5 m g/ m2 I V o n da ys 1, 3, 6, a n d 1 1) i n a n eff ort t o re d uce m u c osal a n d he patic 
c o m plicati o ns a n d ha ve p u blis he d s mall st u dies o n its use i n c o m bi nati o n wit h b ot h Cs A a n d 
Tac [ 1 0- 1 1].  T hese st u dies ha ve de m o nstr ate d t he safet y a n d efficac y of t his re gi me n i n 
H L A matc he d a n d 1 a nti ge n mis matc h e d u nrel ate d d o n ors, wit h a n i nci de nce of gra de 2- 4 
ac ute G V H D of 3 3- 5 9 % a n d gra de 3- 4 ac ute G V H D of 1 7 %.  T ac a n d mi ni- d ose M T X 
( 5 m g/ m2 I V o n da ys 1, 3, a n d 6 o nl y) has bee n f urt her teste d i n c o m bi nati o n wit h a t hir d 
a ge nt [ 1 2- 1 3].  Miz u m ot o et al use d a c o m bi nati o n of Tac, mi ni- d ose M T X a n d M M F as 
G V H D pr o p h yla xis i n re d uce d-i nte nsit y tra ns pla nts a n d de m o nstrate d a s afe a n d well 
t olerate d pr ofile wit h a l o w i nci de nce of se vere gra de 3- 4 G V H D ( 5 %).  W hile t hese st u dies 
ha ve de m o nstrat e d t he safet y a n d efficac y of t hes e re gi me ns, t here h a ve b ee n n o st u dies 
directl y c o m pari n g mi ni- d ose M T X a n d sta n dar d d ose M T X base d G V H D pr o p h ylactic 
re gi me ns.   
 
2. 0    
O B J E C TI V E S 
 
2. 1    
Pri m ar y O bjecti ves  
 
 T o deter mi ne t he i nci de nce, le n gt h a n d se v erit y of m uc ositis fr o m Da y 0 u ntil da y of 
disc har ge or 
Da y 
+ 2 8 ( w hic he v er c o mes first) after all o ge n eic b o ne 
marr o w 
tra ns pla ntati o n c o m pari n g Tac, mi ni- d ose M T X a n d M M F wit h Tac a n d M T X. 
 
 T o st u d y rates of ne utr o p hil a n d platelet e n graft me nt c o m pari n g T ac, mi ni- d ose M T X 
a n d M M F vers us Tac a n d M T X 
 


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 T o st u d y t he i nci de n ce of ac ute g raft- v ers us- h ost disease i n H L A matc h e d relate d a n d 
u nre late d all o ge n eic b o ne marr o w tra ns pla ntati o n usi n g a m yel o a blati ve pre p arati ve 
re gi me n c o m pari n g T ac, mi ni- d ose M T X a n d M M F wit h Tac a n d M T X.  
 
2. 2   
Sec o n d ar y O bjecti ves 
 
 L e n gt h of h os pitalizati o n/ti me t o disc har ge 
 Use  of T P N (t otal pare nt eral n utriti o n)  
 L e n gt h of ti me o n c o nti n u o us i nf usi o n narc otics 
 In ci de nce of i nfecti o n i n t he first 1 0 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce of he p at ot o xicit y i n first 1 0 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce of ne p hr ot o xicit y i n first 1 0 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce of p ul m o nar y t o xicit y i n first 1 8 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce a n d se v erit y of gra de II-I V a n d III-I V ac ute G V H D  
 In ci de nce a n d se v erit y of c hr o nic G V H D  
 O ne  year rel a pse-free a n d o verall s ur vi val  
 
3 . 0   
S T U D Y D E SI G N 
 
3. 1  
St u d y Desi g n  
 
T his is a pr os pecti ve ra n d o mize d trial t o deter mi ne t he effecti ve ness of differe nt d oses of G V H D 
pr o p h yla xis o n m uc ositis, e n graft me nt a n d a G V H D.  St u d y c o nsists of t w o st u d y gr o u ps of 5 0 
s u bjects eac h.  
 
Gr o u p A will re cei ve Tac a n d M T X ( 1 5 m g/ m 2  da y + 1, 1 0 m g/ m2  da y + 3, + 6, + 1 1).   
Gr o u p B will recei ve Tac, Mi ni- d ose M T X ( 5 m g/ m 2  o n da y + 1, + 3, + 6) a n d M M F.  
 
3. 2  
N u m ber of S u bjects 
 
We pla n t o e nr oll 5 0 s u bjects i n eac h gr o u p f or a t otal of 1 0 0 s u bjects . 
 
3. 3 
Re pl ace me nt of S u bjects  
 
Patie nts w h o dr o p o ut pri or t o da y 1 0 0 st u d y e n d p oi nts ca n be e val u ate d, will be re place d s o 
t hat t here will be 5 0 e v al ua ble patie nts i ncl u de d i n t he st u d y i n eac h gr o u p.   
 
3. 4    
E x pecte d D ur ati o n of S u bject P arti ci p ati o n  
 
3. 4. 1    D ur ati o n of T her a p y 
 
In t he a bse n ce of graft vers us h ost disease, treat me nt ma y c o nti n ue u ntil da y 1 8 0 at t he 
discr eti o n of t he i n vesti gat or or u ntil o ne of t he f oll o wi n g criteria a p plies: 
 
 T he i n vesti gat or c o nsi ders it, f or safet y reas o ns, t o be i n t he best i nterest of t he patie nt. 


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 Ge neral or s pecific c h a n ges i n t he patie nt’s c o n diti o n re n der t he patie nt u nacce pta ble f or 
f urt her tr eat me nt i n t he j u d g me nt of t he i n v esti gat or.  
 
 Patie nt decisi o n t o wit h dra w fr o m tr eat me nt ( partial c o ns e nt) or fr o m t he st u d y (f ull 
c o nse nt), 
 
 P re g n a nc y d uri n g t he c o urse of t he st u d y f or a c hil d- beari n g partici pa nt 
 
 Deat h  
 
 T he PI reser ves t h e ri g ht t o te m p oraril y s us pe n d or pre m at urel y disc o nti n u e t his st u d y.  If 
t he rate of graft fail ure, w hic h will be m o nit or e d c o nti n u o usl y t hr o u g h o ut t he st u d y, 
e x cee ds 1 1 % (a p pr o xi matel y 2 0 % hi g h er t ha n w hat we t y picall y e x pect i n o ur pri or 
e x perie nce) i n eit her ar m at 6 m o nt hs, we will halt accr ual i n or der t o perf or m f urt her 
a nal ysis.   Graft fail ure is defi ne d as ha vi n g o ne of t he f oll o wi n g criteria i n a bse n ce of 
rela pse: 
 F ail ure t o reac h A N C > 5 0 0/ ul f or 3 c o nsec uti ve da ys i n p atie nt s ur vi vi n g a mi ni m u m 
of 2 8 da ys 
 Decrease of A N C t o < 1 0 0/ ul f or at least 3 c o nsec uti ve deter mi nati o ns after i nitial 
e n graft me nt wit h o ut rec o ver y bef ore rela pse, s ec o n d H C T or deat h 
 <  1 % d o n or T cells as assesse d b y a D N A- b ase d assa y t h at c o m p ares t he pr ofile of 
a m plifie d fra g me nt le n gt h p ol y m or p his ms (a m p F L P) or FI S H st u dies or V N T R of t he 
patie nt a n d d o n or o n da y + 2 8 or be y o n d 
 
T he date a n d reas o n f or disc o nti n uati o n m ust be d oc u me nte d.  E ver y eff ort s h o ul d be ma de 
t o c o m plete t he a p pr o priate assess me nts.  
 
3. 4. 2  D ur ati o n of F oll o w U p  
 
Patie nts will be f oll o we d f or 1 year after T- 0 ( date of i nf usi o n of H C T) or u ntil d eat h, 
w hic he ver occ urs first.  
 
T he cli nical c o urse of eac h e v e nt will be f oll o w e d u ntil res ol uti o n, sta bilizati o n, or u ntil it 
has bee n det er mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he ca use.  
 
Seri o us a d verse e ve nts t hat are still o n g oi n g at t he e n d of t he st u d y peri o d will necessitate 
f oll o w- u p t o det er mi ne t he fi nal o ut c o me.  A n y seri o us a d v erse e ve nt t h at occ urs after t he 
st u d y p eri o d a n d is c o nsi dere d t o b e p ossi bl y relate d t o t he st u d y tr eat me nt or st u d y 
partici pati o n will be rec or de d a n d re p orte d i m me diatel y. 
 
4 . 0  
P A TI E N T S E L E C TI O N 
 
Eac h of t he criteria i n t he c hec klist t hat f oll o ws m ust be met i n or der f or a patie nt t o b e 
c o nsi dere d eli gi ble f or t his st u d y.  Us e t he c hec klist t o c o nfir m a patie nt’s eli gi bilit y.  T he 


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c hec klist m ust be c o m plete d f or eac h patie nt a n d m ust be si g ne d a n d date d b y t h e treati n g 
p h ysicia n.   
 
4. 1  
I ncl usi o n Criteri a 
 
Patie nts m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt  
 
 
 P atie nts m ust ha ve o ne of t he f oll o wi n g d o c u me nt e d diseases:  
 
C hr o nic M yel o ge n o us Le u ke mia  
C hr o nic L y m p h oc ytic Le u ke mia  
M ulti ple M yel o ma  
M yel o d ys plasia  
M yel o pr oliferati ve dis or der  
N o n- H o d g ki n's L y m p h o ma  
H o d g ki n's Dise ase  
Ac ute M yel o ge n o us Le u ke mia  
Ac ute L y m p h o blastic Le u ke mia 
Ac ute Bi p h e n ot y pi c Le u ke mia 
 
 P atie nts m ust be u n der g oi n g a m yel o a blati ve all o ge neic he m at o p oietic cell tra ns pla nt 
wit h o ne of t he f oll o wi n g c o n diti o ni n g re gi me ns (see A P P E N DI X I V f or T BI 
ad mi nistrati o n g ui deli nes): 
 
 B us ulfa n ( > 1 2. 8 m g/ k g I V or P O) a n d c ycl o p h os p ha mi de ( > 1 2 0 m g/ k g)  
 
 B us ulfa n d ose m a y be a dj uste d acc or di n g t o p har mac o ki netics 
tar geti n g a dail y A U C of 5 0 0 0 µ m ol- mi n/ L, per i nstit uti o n sta n dar d of 
pra ctice.  
 T BI  ( > 1 2 0 0 c G y) a n d Et o p osi de ( 6 0 m g/ k g) 
 T BI  ( > 1 2 0 0 c G y) a n d c ycl o p h os p ha mi de ( 1 2 0 m g/ k g)  
 
 P atie nt’s disease stat us s h o ul d meet criteria as o utli ne d b y i nstit uti o nal master 
pr ot oc ol.  
 P atie nt’s d o n or m ust be a relate d or u nrelate d H L A 8/ 8 allele-le vel mat c h ( H L A- A,  
B,  C a n d D R B 1).  
 
 A ge  0- 7 0  
 A d ult p atie nts m ust ha ve a n E C O G perf or ma nce stat us of 0 or 1. Pe diatric patie nts m ust ha ve 
La ns k y sc ore > 6 0 %  
 Patie nts m ust ha ve a life e x pecta nc y of 1 0 0 da ys.  
 P atie nts m ust si g n writte n i nf or me d c o nse n t. 
 
4. 2  
E xcl usi o n Criteri a 
 
 Patie nts w h o ha ve u n der g o ne a n y pri or tr a ns pla nt.  
 P atie nts w h o are ser o p ositi ve f or h u ma n i m m u n o deficie nc y vir us ( HI V).  


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 Patie nts wit h a n y me dical ill ness or c o nc urre nt ps yc hi atric ill ness w hic h, i n t he 
i n vesti gat ors’ o pi ni o n, ca n n ot be a de q uat el y c o ntr olle d wit h a p pr o priate t h era p y.  
 P atie nts w h o are pre g na nt or lactati n g.  
 
4. 3 
I ncl usi o n of W o me n a n d Mi n orities 
 
B ot h me n a n d w o me n a n d me m bers of all races a n d et h nic gr o u ps are eli gi ble f or t his trial. 
 
5. 0   
R E GI S T R A TI O N 
 
All s u bjects w h o ha v e bee n c o nse nt e d are t o b e re gistere d i n t he O n C ore Data base.  F or t h os e 
s u bjects w h o are c o nse nt e d, b ut n ot e nr olle d, t he reas o n f or e x cl usi o n m ust be rec or de d. 
 
All s u bjects will be re gistere d t hr o u g h Cle vel a n d Cli nic a n d will be pr o vi de d a st u d y n u m ber 
b y t he St u d y C o or di nat or. 
 
5. 1     R a n d o miz ati o n 
 
Patie nts will be ra n d o mize d 1: 1 t o o ne of t he t w o G V H D pr o p h yla xis re gi me ns usi n g 
bl oc ke d ra n d o mizati o n wit h ra n d o m bl oc k sizes.  T he ra n d o mizati o n list will be ge n erate d 
bef ore  t h e start of t he st u d y b y t he st u d y statisticia n of t he st u d y usi n g a S A S ra n d o mizati o n 
pr o gra m; t he list will be ke pt i n a sec ure d l ocati o n w hic h will o nl y be accessi ble t o t he st u d y 
co or di nat or.  Ra n d o mizati o n will be stratifie d b y T BI i n t he pre parati ve re gi me n ( yes, n o), 
d o n or  relati o ns hi p (rel ate d, u nrelate d), a n d s o urce of he mat o p oietic cells ( P B S C, marr o w). 
 
6. 0  
T R E A T M E N T P L A N 
 
6. 1  
A ge nt A d mi nistr ati o n 
 
6. 1. 1 
T acr oli m us ( T ac) A d mi nistr ati o n:  
 
Patie nts i n b ot h gr o u p A a n d B will recei ve Tac 0. 0 3 m g/ k g/ da y i ntra ve n o usl y be gi n ni n g o n 
da y - 1 or ta cr oli m us 0. 0 3 m g/ k g/ d ose BI D orall y b e gi n ni n g o n da y - 3.  If T ac is a d mi nistere d 
i ntra ven o usl y, it will be gi ve n o v er 2 4 h o urs a n d will be c o n verte d t o or al a d mi nistrati o n 2 
ti mes a da y w he n t he p atie nt has e n grafte d a n d/ or ca n t olerat e oral me dicati o n. 
 
Le v els of Tac will be o bt ai ne d t o mai ntai n a rec o m me n de d tar get ser u m le vel of 5- 1 5 m g/ m L or 
pe r i nstit uti o n g ui deli nes. D ose a dj ust me nts of Tac will be ma de acc or di n g t o Secti o n 7. 1. 1 
be l o w. 
 
I n t he a bse n ce of G V H D, Tac ma y start t o be t a pere d a p pr o xi matel y at d a y + 1 0 0 a n d s h o ul d 
be ta pere d off b y d a y + 1 8 0, per i n vesti gat or’s dis creti o n. 
 
 
 


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6. 1. 2  M yc o p he n ol ate M ofetil ( M M F) A d mi nistr ati o n: 
 
Patie nts i n gr o u p B o nl y will recei ve M M F be gi n ni n g o n da y + 1.  Patie nts > 4 0 k g will 
recei v e M M F 1 0 0 0 m g t wice a d a y. M M F s h o ul d be gi v e n orall y t wice a d a y. I V f or m ulati o n 
ma y b e  use d if t he p atie nt ca n n ot t olerate oral r o ut e. Patie nts < 4 0 k g will rec ei ve M M F 4 5 
m g/ k g/ da y ( 1 5 m g/ k g t hr ee ti mes a da y).  M M F m a y b e gi ve n orall y or i ntra ve n o usl y as per 
i nstit uti o nal pr ot oc ol 
 
I n t he a bse n ce of G V H D, M M F ma y be ta pere d after da y + 4 5 a n d st o p pe d b y da y + 1 0 0 at t he 
discreti o n of t he p h ysicia n a n d per i nstit uti o nal g ui deli nes f or ta per.   
6. 1. 3  M et h otre x ate ( M T X) A d mi nistr ati o n: 
 
Gr o u p A  
M T X will be gi ve n at 1 5 m g/ m
2 I V o n da y + 1.  T h e n M T X will be gi ve n at 1 0 m g/ m2 o n 
da ys + 3, + 6 a n d + 1 1. D ose a dj ust me nts of M T X will be ma de acc or di n g t o Secti o n 7. 1. 3 
be l o w. 
 
If patie nt < 1 0 k g t he n M T X will be gi ve n at 0. 5 m g/ k g I V o n da y + 1.  T h e n M T X will be 
gi ve n at 0. 3 3 m g/ k g o n d a ys + 3, + 6 a n d + 1 1. 
 
Gr o u p B 
M T X will be gi ve n at 5 m g/ m
2 I V o n da ys + 1, + 3 a n d + 6. 
 
If patie nt < 1 0 k g t he n M T X will be gi ve n at 0. 1 7 m g/ k g o n da ys + 1, + 3 a n d + 6. 
 
6. 2  
Ge ner al C o nc o mit a nt Me dic ati o ns a n d S u p p orti ve C are G ui deli nes 
 
Patie nts s h o ul d recei ve f ull s u p p orti ve care t hr o u g h o ut t he st u d y i ncl u di n g tra nsf usi o ns of bl o o d 
a n d bl o o d pr o d ucts, c yt o ki nes, a nti bi otics, a ntie metics, Mes na, bla d der was hes a n d/ or h y drati o n 
t o pre ve nt he m orr ha gic c ystitis, etc. w he n a p pr o priate.  
 
T he f oll o wi n g t h era pies a n d/ or me dicati o ns s h o ul d be a v oi de d d uri n g t he st u d y peri o d:  
•  
A mi p h osti ne  
•  I L- 1 1( Ne u me ga ®)  
•  
S ucralfate i n s us pe nsi o n f or m ( use of s ucralf ate ta blets is n ot pr oscri be d)  
•  
P o vi d o ne-i o di ne ri nses  
•  
Ot her i n vesti gati o nal a ge nts  
•  
C yt ot o xic dr u gs ot her t ha n t h ose s pecifie d i n t he pr ot oc ol ( E xce pti o n: I ntr at hecal 
met h otre x ate or c yt osi nara bi n osi de f or s u bjects wit h ce ntral ner v o us s yste m 
i n v ol ve me nt) 
•  
A T G s u p pressi o n/ Ca m pat h, or Rit u xi ma b as a pr o p h ylactic a ge nt f or G V H D ( ma y 
o nl y be us e d t o treat a G V H D se verit y gra des 3- 4 refract or y t o ster oi ds )  
 


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Patie nts will n ot be re m o ve d fr o m st u d y if ta ki n g o ne of t he a b o v e me dicati o ns b ut t he 
me dicati o n, d ose, dates t a ke n, reas o n f or t a ki n g it, etc. will be rec or de d.  
 
B el o w are ge neral g ui deli nes b ut 
ma y var y de pe n di n g o n i nstit uti o nal a n d pr o gra m 
g ui deli nes. 
 
6. 2. 1. G r o wt h F a ct or S u p p ort  - C ol o n y sti m ulati n g fact ors ( G-C S F)  
 
N o gr o wt h fact or s u p p ort will b e r o uti nel y gi ve n u nless i n dicate d per sta n dar d i nstit uti o nal 
g ui deli nes.  
.  
6. 2. 2  A ne mi a 
 
Tra nsf usi o ns of re d bl o o d cells are i n dicate d f or t he s y m pt o matic ma na ge me nt of a ne mia. A n 
atte m pt will be ma de t o mai ntai n t he he m o gl o bi n > 8. 0 g/ dl.  All bl o o d pr o d ucts m ust be 
irra diate d ( 1 5 0 0 – 3 0 0 0 c G y) a n d le u k ore d uce d b y filtrati o n.  
 
6. 2. 3  T hr o m b oc yt o pe ni a 
 
Pr o p h yla ctic platelet tra nsf usi o ns s h o ul d be gi ve n t o mai ntai n t he platelet c o u nt > 1 0, 0 0 0/ ul 
or a b o ve a platelet le vel at w hic h si g ns of blee di n g are k n o w n t o occ ur, w hic he ver is greater. 
All as piri n-c o ntai ni n g dr u gs are c o ntr ai n dicate d.  
 
6. 2. 4  A nti m ic r o bi al, A ntif u n g al, A nti vir al Pr o p h yl a xis 
 
A nti bacterial, a ntif u n gal , p ne u m oc ystis jir o veci, a n d a nti viral pr o p h yla xis is rec o m me n de d 
an d will be use d acc or di n g t o i nstit uti o nal a n d pr o gra m g ui d eli nes. 
 
C M V s ur veilla nce a n d e m piric treat me nt will be base d o n i nstit uti o nal a n d pr o gra m 
g ui deli nes.  
 
6. 2. 5  F e v er:  
 
A g gressi ve dia g n ostic a n d t hera pe utic ma na ge me nt of fe ver i n t he n e utr o p e nic patie nt is 
ma n dat or y.  T he f oll o wi n g are rec o m me n de d g ui deli nes f or t he ma na ge me nt of fe ver, b ut 
ma y als o be treate d acc or di n g t o i nstit uti o nal a n d pr o gra m g ui deli nes.  At t he o nset of fe ver 
( 3 8º C), t he patie nt s h o ul d be t h or o u g hl y e x a mi ne d a n d c ult ure d. Br oa d-s p ectr u m a nti bi otics 
s h o ul d be i nitiate d t o i ncl u de c o vera ge of gra m- p ositi ve (i ncl u di n g sta p h yl o c occ us) a n d 
g ra m- ne gati ve (i ncl u di n g pse u d o m o nas) or ga nis ms.  V oric o naz ole s h o ul d be use d 
em piricall y f or persiste nt fe vers ( > 3 da ys). 
 
6. 2. 6  M o ut h C are 
 
A m o ut h care pr ot oc ol per i nstit uti o n prefere nce is rec o m me n de d t o b e e m pl o ye d usi n g a 
co m bi nati o n of m o ut h was h a n d ot her a nti- bacteri al s ol uti o ns t o mi ni mize t he ris k of m uc ositis 
a n d disse mi nati o n of oral pat h o ge ns.  


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6. 2. 7  Ve n o us access 
 
Tri ple l u me n Hic k ma n cat heters or Br o viac cat heters i n pe diatric patie nts, will be rec o m me n de d 
t o facilitate i ntra ve n o us a d mi nistrati o n of dr u gs a n d t he use of pare nteral h y perali me ntati o n. 
 
6. 2. 8  N utr iti o n 
 
I nitiati o n of T P N will be left t o t he discreti o n of t he atte n di n g p h ysicia n; h o we ver ge neral 
g ui deli nes s h o ul d be use d as f oll o ws:  
 
 In a d ult patie nts, it is rec o m me n de d t hat t he T P N s u p p ort tea m s h o ul d be 
c o ns ulte d re gar di n g p ot e ntial i nitiati o n of T P N if:  
o  t here is less t ha n 5 0 % of e nteral i nta ke f or > 7 d a ys  
o  pa tie nt has se vere gra de 3- 4 W H O m uc ositis f or > 5 da ys 
 In p e diatric p atie nts, T P N is rec o m me n de d if t h e c hil d :  
o  ha s less t ha n 5 0 % of e nteral i nta ke f or > 3 da ys  
o  ha s l ost > 1 0 % of his a d missi o n wei g ht  
o  ha s se vere gra d e 3- 4 W H O m uc ositis t hat is e x pecte d t o last m ore t ha n 5 da ys  
o  is sh o wi n g si g ns of n utriti o nal deficie nc y wit h a preal b u mi n < 1 5 
 
6. 2. 9  A ntie metics 
 
A ntie metics will be use d base d o n i nstit uti o n a n d pr o gra m g ui deli nes. Sta n dar d a ntie metic 
t hera pies i ncl u de o n da ns etr o n, l oraze pa m, pr oc hl or perazi ne a n d met ocl o pra mi de w hic h ca n 
be c o nsi de re d eit her as sc he d ule d or as n ee de d m e dicati o n. 
 
6. 2. 1 0  M a n a ge me nt of Ac ute Gr aft- Vers us- H ost Dise ase:  
 
If ac ute graft- v ers us- h ost disease d e vel o ps, t he pri mar y tea m will e val u ate ac ute G V H D sta ge 
an d gra de a n d start t he p atie nt o n pre d nis o ne or e q ui vale nt i ntra ve n o us m et h yl pr e d nis o ne ( M P) 
d ose base d o n o verall gra de.  Refer t o A p pe n di x I f or Ac ute G V H D Gra di n g Scale.  Bi o ps y 
s h o ul d be o btai ne d w he n e ver p ossi ble.   
 
T he  g oal of gl uc o c ortic oi d t hera p y is t o c o ntr ol t he ac ute ma nifestati o ns of G V H D a n d t he n t o 
ta per t he d oses of pre d nis o ne ( or 
M P) as s o o n as p ossi ble.  Literat ure de m o nstr ates t hat 
pr ol o n ge d use of hi g h- d ose gl uc o c ortic oi ds f or t he treat me nt of ac ute G V H D is ass ociate d wit h 
a n i ncrease d ris k f or i nfecti o n, rela pse a n d deat h. 
 
Treat me nt of mil d ac ut e G V H D 
 i ncl u des ras h < 5 0 % of t he t otal b o d y s urface area (s ki n < sta ge 3 a n d n ot pr o gressi n g 
rapi dl y wit hi n 6- 2 4 h o urs), a n ore xia, na usea, e mesis, or diarr hea < 1. 0 L/ d a y ( GI  sta ge 
1 or less) a n d n o li ver i n v ol ve me nt (sta ge 0) 
 ca n treat patie nt wit h pre d nis o ne at 1 m g/ k g ( or e q ui vale nt M P), al o n g wit h b u des o ni de 
at 3 m g orall y t wi ce d ail y a n d b ecl o met has o ne 1 m g orall y f o ur ti mes dail y d e pe n di n g 
o n patie nts u p per a n d l o wer gastr oi ntesti nal s y m pt o ms 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
1 5  
 rec o m me n de d d urati o n of 5 0 da ys wit h a ta per o ver 1- 2 wee ks [ 1 4] 
 S u g geste d d urati o n a n d d osi n g of i nitial pre d nis o ne ( or M P) tr eat me nt is at least 1 0 
da ys wit h a s u bse q u e nt ta per acc or di n g t o patie nt res p o nse. If t he p atie nt has a ra pi d 
res p o nse t o t hera p y, t he n t he ster oi d ta per ma y occ ur m or e ra pi dl y e v er y 3 d a ys as 
s u g geste d i n T a ble A bel o w: 
 
T A P E R S C H E D U L E A ( mil d GI-tract G V H D wit h mi ni mal diarr hea) 
  
D a y  
A M d ose ( m g/ k g)  
P M d ose ( m g/ k g)  
1 -1 0  
0. 5  
0. 5  
1 1  
0. 2 5  
0. 2 5  
1 3  
0. 1 2 5  
0. 1 2 5  
1 5  
0. 0 6 2 5  
0. 0 6 2 5  
1 7 -7 9  *  
C o nti n ue 0. 0 6 2 5  
0  
8 0  
st o p 
0  
 
* Da y 5 0 B u d es o ni de/ bel c o met has o ne ma y b e st o p pe d or ta per e d ra pi dl y, o ver 1- 2 wee ks. 
 
 If t he p atie nt has a sl o wer res p o ns e a n d i m pr o ve me nt i n his s y m pt o ms, it is 
rec o m me n de d t o ta p er e v er y 5 da ys , as s u g geste d i n Ta ble B b el o w: 
  
T A P E R S C H E D U L E B ( mil d GI-tract G V H D wit h 1 0- 2 0 ml/ k g diarr hea; ma x. 5 0 0- 1 0 0 0  ml/ da y) 
  
D a y  
A M d ose ( m g/ k g)  
P M d ose ( m g/ k g)  
Bef ore ta p er  
0. 5  
0. 5  
1  
0. 5  
0. 4  
6  
0. 5  
0. 3  
1 1  
0. 5  
0. 2  
1 6  
0. 5  
0 . 1 
2 1  
0. 5  
0  
2 6  
0. 4  
0  
3 1  
0. 3  
0  
3 6 –  till da y X 
0. 2  
0  
Da y of ta per  
M g/ k g/ da y ( A M d os e o nl y)  
 
1  
0. 2 ( n ot t o e x cee d 2 0 m g)  
 
2  
0. 1 ( n ot t o e x cee d 1 0 m g)  
 
3  
0. 2 5 ( n ot t o e x cee d 2 5 m g)  
 
4  
0. 0 5 ( n ot t o e x cee d 5 m g)  
 
5  
0. 3 ( n ot t o e x cee d 3 0 m g)  
 
6  
0  
 
7  
0. 2 ( n ot t o e x cee d 1 5 m g)  
 
8  
0  
 
9  
0. 1 5 ( n ot t o e x cee d 1 0 m g)  
 
1 0  
0  
 
1 1  
0. 1 ( n ot t o e x cee d 5 m g)  
 
1 2  
S T O P  
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
1 6  
Treat me nt of m or e t ha n mil d gra des of ac ut e G V H D 
 I n cl u des ras h c o v eri n g > 5 0 % of t h e b o d y s urface area (s ki n sta ge 3) or pr o gressi n g 
ra pi dl y wit hi n 6- 2 4 h o urs, diarr hea ≥ 1 L da y or 5 5 6- 8 3 3 ml/ m 2/ da y f or pe diatri c 
patie nts ( GI sta ge 2), or ser u m bilir u bi n ≥ 2. 0 m g/ d L i n t he a bs e nce of n o n- G V H D 
ca uses f or h y p er bilir u bi n e mia, or ≥ 3. 0 m g/ d L if ot her ca uses of h y p er bilir ui bi ne mia 
are prese nt besi des G V H D 
 T reate d wit h 2 m g/ k g/ da y of pre d nis o ne or e q ui val e nt M P 
 S u g geste d d urati o n of i nitial pre d nis o ne ( or M P) is 1 4 da ys f oll o we d b y a ta per o ver 6 
wee ks 
 
I n t h e case of n o n-res p o nsi ve, or ster oi d refract or y a G V H D ( defi ne d as n o res p o nse after 5 da ys 
of hi g h d ose st er oi ds), sec o n d li ne G V H D t hera pies will be base d o n p h ysici a n discreti o n, 
i ncl u di n g st o p pi n g of st u d y me dicati o ns a n d wit h dra wal fr o m t he st u d y. 
 
Tacr oli m us a n d 
m yc o p he n olate (i n t he a p pr o priate treat me nt gr o u p) s h o ul d ot her wise be 
c o nti n ue d d uri n g t h e treat me nt of ac ute G V H D.  
 
If starte d o n pre d nis o ne, P ne u m oc ystis pr o p h yla xis will be gi n as well, wit h eit her aer os olize d 
pe nta mi di ne or oral tri met ha pri m-s ulfa met h o x az ole ( Bactri m). If pre d nis o ne is > 4 0 
m g, 
pr o p h yla ctic a nti-f u n gal s h o ul d be starte d.  
 
6. 3   
D ur ati o n of T her a p y   
 
St u d y m e dicati o ns will be gi v e n u p t o 1 8 0 da ys.  A dj ust me nts will be ma de acc or di n g t o 7. 1 
bel o w.  I n t he a bs e nce of a G V H D, ta p er ca n be gi n at da y 1 0 0 f or Tac a n d Da y 4 5 f or M M F 
acc or di n g t o g ui deli nes i n 6. 1. 1 a n d 6. 1. 2 a b o ve. 
 
After 1 8 0 da ys of t hera p y, it will be at t he discreti o n of t he i n vesti gat ors h o w t hese patie nts are 
t o be treate d if graft vers us h ost disease de vel o ps.  T he y m a y c o nti n ue T ac a n d/ or M M F  or ot her 
t hera pe utic a ge nts t o treat graft- vers us- h ost diseas e.  
 
7. 0   
D O SI N G D E L AY S / D O S E M O DI FI C A TI O N S 
 
7. 1  
A dj ust me nt of St u d y Me dic ati o ns:  
 
A n y G V H D pr o p h yl a xis me dicati o n c ha n ge will be rec or de d al o n g wit h t he reas o n it was 
re d uce d or wit h hel d. 
 
7. 1. 1  T acr oli m us  
 
Le v els of tacr oli m us will be dra w n t wi ce per wee k w hile h os pitalize d t he n wee kl y or m o nt hl y 
t hereafter u nless a c ha n ge i n me dicati o n or re nal f u ncti o n mi g ht res ult i n a n ac ute c h a n ge i n 
le vel.  T he tar get ser u m l e vel f or ta cr oli m us is 5- 1 0 m g/ m L.  D ose a dj ust m e nts are b ase d o n 
cli nical j u d g me nt of t h e treati n g p h ysicia n after c o nsi deri n g cli nical t o xicit y, ser u m le vels, 
G V H D, c o n c o mita nt dr u g use a n d t he rate of rise or decli ne of t h e ser u m le vel.  
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
1 7  
7. 1. 2  M yc o p he n ol ate M ofetil 
 
M M F  has b ee n ass ociat e d wit h GI t o xicit y, i ncl u di n g na us ea, v o miti n g, a b d o mi nal pai n a n d 
diarr hea, n ot relate d t o G V H D.  If s y m pt o ms occ ur, w or k u p f or G V H D s h o ul d occ ur. A d ose 
re d ucti o n ma y be i nstit ute d f or 4 8- 7 2 h o urs.  If GI t o xicit y d oes n ot res ol v e wit hi n 4 8- 7 2 h o urs 
of st o p pi n g t he st u d y dr u g, t o xicit y is li kel y n ot relate d t o t he st u d y me dicati o n a n d t h e dr u g 
s h o ul d be restarte d. M M F has als o b ee n ass ociat e d wit h m yel os u p presi o n.  If t he A N C re mai ns 
or decreases t o less t ha n 1 0 0 0/ ul after e n graft me nt, 
M M F ma y be re d uce d or hel d at t he 
p h ysicia n’s discreti o n.  D ose a dj ust me nts are b ase d o n t he cli nical j u d g me nt of t he treati n g 
p h ysicia n after c o nsi deri n g cli nic al t o xicit y a n d G V H D.  
  
7. 1. 3 
M et h otre x ate  
 
M T X WI L L N O T be d os e a dj uste d or hel d f or ne utr o pe nia.  M T X ma y be h el d or d ose re d uce d 
if creati ni ne cleara nce is decrease d b y > 5 0 % bas eli ne, if t he patie nt is e x perie nci n g cli nical si g ns 
of ve n o- occl usi ve diseas e, a n d if t he patie nt h as se vere m u c ositis ( oral ulcerati o n, si g nifi ca nt 
e de ma) c o m pr o misi n g res pirat or y f u ncti o n or necessitati n g paret neral h y perali me ntati o n.  
F urt her g ui d eli nes f or d ose a dj ust me nts f or li ver a n d re nal t o xicit y are as f oll o ws:  
 
D ose a dj ust me nts f or li ver t o xicit y:  
Bilir u bi n ( m g/ dl)    
  
M T X d ose 
< 3. 0   
  
  
  
1 0 0 % 
3. 1 - 5. 0  
  
  
  
5 0 % 
> 5. 0   
  
  
  
h ol d M T X 
 
D ose  a dj ust me nt f or re nal t o xicit y: 
Creati ni ne cleara n ce ( ml/ mi n)  
M T X d ose 
> 5 0   
  
  
  
1 0 0 % 
1 0 – 5 0  
  
  
  
5 0 % 
< 0   
  
  
  
h ol d M T X 
 
W he n creati ni ne cl eara nce is ≤ 6 0 ml/ mi n ute, a d mi nister Le u c o v ori n at a d ose of 1: 1 
( Le uc o v ori n: Met h otr e x ate) I V o n ce, 2 4 h o urs after t he d ose of M T X. 
 
P atie nts wit h ple ural, pericar dial or ascetic eff usi o n(s) m ust be m o nit ore d cl osel y f or i ncrease d 
d ura ti o n of M T X t o xicit y ( m uc ositis a n d re nal i ns ufficie nc y) a n d c o nsi d ere d f or le uc o v ori n 
t hera p y. 
 
8. 0   
A D V E R S E E V E N T S: LI S T A N D R E P O R TI N G R E Q UI R E M E N T S 
 
T he f oll o wi n g is a list of A Es ( Secti o n 8. 1) a n d t he re p orti n g re q uire me nts ass ociate d wit h 
o bser ve d A Es ( Secti o ns 8. 3 a n d 8. 4).    
 
T he cli nical c o urse of eac h e ve nt will be f oll o we d u ntil res ol uti o n, sta bilizati o n, or u ntil it is has 
be e n deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he ca use.  
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
1 8  
Seri o us a d verse e ve nts t hat are still o n g oi n g at t he e n d of t he st u d y p eri o d will necessitate 
f oll o w- u p t o deter mi ne t he fi nal o utc o me.  A n y s eri o us a d verse e v e nt t hat occ urs after t he st u d y 
peri o d a n d is c o nsi d ere d t o be p ossi bl y relate d t o t he st u d y tr eat me nt or st u d y p artici pati o n will 
be rec or de d a n d re p orte d i m me diatel y. 
 
8. 1   
A d verse E ve nts a n d P ote nti al Ris ks 
 
P lease refer t o t he pac ka ge i nsert(s) f or t he c o m pre he nsi ve list of a d vers e e ve nts.  Ma n y of t hese 
t o xicities are rec o g niz e d t o xicities of tra ns pla ntati o n a n d will n ot b e c o nsi dere d a d verse eff ects 
i n t he c o nte xt of t his st u d y. F or e x a m ple, re-a d missi o ns are c o m m o n after all o ge neic 
tra ns pla ntati o n, a n d reas o ns f or rea d missi o ns m ost c o m m o nl y i ncl u de fe ver wit h or wit h o ut 
i nfecti o n.  
U nless i n patie nt h os pitalizati o ns are t h o u g ht t o be d ue t o o ne of t he st u d y 
me dicati o ns, t he y will n ot be re p orte d as s eri o us a d verse e ve nts.  Tra ns pla nt relate d a d v erse 
e ve nts w hic h ma y b e i nfl ue nce d b y G V H D pr o p h yla xis will be s p ecificall y e val u ate d p er 
sec o n dar y o bj ecti ves ( e. g. i nci de nce of re n al, li ver, a n d p ul m o n ar y t o xicities).  
 
8. 1. 1  
T acr oli m us 
 
T he re are ma n y well des cri be d t o xic effects of tacr oli m us. Pri mar y t o xicities i n lar ge c o ntr olle d 
trials 
were re versi ble re nal i ns ufficie n c y, t hr o m b otic 
micr oa n gi o pat h y, 
h y p erte nsi o n, 
h y per gl yce mia, h y p o ma g nes ae mia, h y p o kale mi a, o p p ort u nistic i nfecti o n, a n d ne ur ol o gic 
t o xicit y.  I n a d diti o n t here ma y be a n i nf usi o n al t o xicit y fr o m t he dil ue nt.  
 
8. 1. 2  
M yc o p he n ol ate M ofetil 
 
T he  use of m yc o p he n olate m ofetil has bee n ass o ciate d wit h m yel os u p presi o n, i ncrease d ris k of 
o p p ort u nistic i nfecti o n a n d GI t o xicit y i ncl u di n g diarr hea, a b d o mi nal pai n a n d v o miti n g, n ot 
relate d t o G V H D.  Gastr oi ntesti nal blee di n g a n d b o wel perf orati o n ha ve b ee n descri be d 
i nfre q ue ntl y.  
 
8. 1. 3  Met h otre x ate 
 
T he m ost fre q ue ntl y re p orte d a d verse reacti o ns ass ociate d wit h met h otre x ate use as G V H D 
pr o p h yla xis i ncl u de ulc erati ve st o matitis, le u k o pe nia a n d s u p presse d he mat o p oiesis, he patic a n d 
ne p hr ot o xicit y, na us ea, a n d a b d o mi nal distress.  Ot her fre q u e ntl y re p ort e d a d verse effects are 
malaise, fati g u e, c hills a n d fe ver, a n d dizzi ness.  Met h otre x ate ma y be ass ociate d wit h i ncreas e d 
rates of p ul m o nar y c o m plicati o ns after tra ns pl a ntati o n.  
 
8. 2 
Dr u g I nter acti o ns 
 
8. 2. 1 
M et h otre x ate 
 
Met h otre x ate is partiall y b o u n d t o ser u m al b u mi n, a n d t o xicit y m a y be i ncreas e d beca use of 
dis place me nt b y certai n dr u gs, s uc h as salic yl ates, p he n yl b utaz o ne, p he n yt oi n a n d s ulf o na mi des. 
Re nal t u b ular tra ns p ort is als o di mi nis he d b y pr o be neci d; use of met h otre x ate wit h t his dr u g 
s h o ul d be caref ull y m o nit ore d.  


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
1 9  
 
Oral a nti bi otics s uc h as tetrac ycli ne, c hl ora m p he nic ol, a n d n o na bs or ba ble br oa d-s pectr u m 
a nti bi otics, ma y d ecrease i ntesti nal a bs or pti o n of met h otre x ate or i nterfere wit h t he e nter o h e patic 
circ ulati o n b y i n hi biti n g b o wel fl ora a n d s u p pressi n g meta b olis m of t he dr u g b y bacteria. 
Pe nicilli ns ma y re d u ce t he re n al cleara nce of m et h otre x ate; i ncreas e d ser u m c o nce ntr ati o ns of 
met h otre x ate wit h c o nc o mita nt he mat ol o gic a n d gastr oi ntesti nal t o xicit y ha v e bee n o bser ve d 
wit h hi g h a n d l o w d ose met h otre x ate. Use of met h otre x ate wit h pe nicilli ns s h o ul d be caref ull y 
m o nit ore d.  
 
8. 2. 2 
M yc o p he n ol ate M ofetil 
 
M M F acti vit y is decreas e d wit h oral a d mi nistrati o n of a ntaci ds a n d c h olest yra mi ne. Ac ycl o vir or 
ga n cicl o vir bl o o d le vels ma y i n crease d uri n g c o-a d mi nistrati o n wit h M M F d ue t o c o m petiti o n 
f or t u b ular secreti o n of t hese dr u gs, es peciall y if re nal i m pair me nt is prese nt. Pr o be neci d ma y 
als o a u g me nt m yc o p he n olic aci d ( M P A) le vels d ue t o i n hi biti o n of t u b ular secreti o n. Hi g h d oses 
of salic ylates ( or ot her hi g hl y pr otei n b o u n d dr u gs) ma y i ncreas e t he free fracti o n of M P A a n d 
e x a g gerate t he p ote ntial f or m yel os u p pressi o n. 
 
8. 2. 3 
T acr oli m us 
 
Tacr oli m us is e xte nsi vel y meta b olize d b y t he c yt oc hr o me P- 4 5 0 ( C Y P 3 A 4) s yste m.  
Care s h o ul d be ta ke n w h e n dr u gs or ot her s u bsta nces t hat are meta b olize d b y C Y P 3 A 4 are 
a d mi nistere d c o nc o mita ntl y wit h tacr oli m us. Gra p efr uit j uice a n d ot h er dri n ks c o ntai ni n g 
ber ga m otti n ( Fresc a, S q uirt, S u n ny Deli g ht) re d uces t he C Y P 3 A 4- me diate d meta b olis m of 
tacr oli m us a n d ma y i ncrease its le vels.   
 
Dr u gs t hat ma y i ncrease t acr oli m us bl o o d c o nce ntr ati o ns i ncl u de:  
 
 C alci u m c ha n nel bl oc kers: diltiaze m, nicar di pi ne, nife di pi ne, vera pa mil 
 A ntif u n ga l a ge nts: ket oc o naz ole, cl otri maz ole, fl uc o naz ole, itrac o naz ole 
 Ma cr oli de a nti bi otics: clarit hr o m yci n, er yt hr o m yci n, tr olea n d o m yci n 
 Ga str oi ntesti nal pr o ki netic a ge nts: cisa pri d e, met o cl o pra mi de 
 Ot he r dr u gs: br o m ocri pti ne, ci meti di ne, c ycl os p ori ne, da naz ol, et hi n yl estra di ol, 
o me praz ole, nefaza d o ne, HI V- pr ot ease i n hi bit ors (e. g. rit o na vir, i n di na vir). 
 
Dr u gs t hat ma y decreas e tacr oli m us c o nce ntr ati o ns i ncl u de: 
 
 A ntic o n v ulsa nts: ca r ba m aze pi ne, p he n o bar bital, p he n yt oi n 
 A nti bi otics: rifa b uti n, rifa pe nti ne 
 Her bal pre p arati o ns: St. J o h n’s 
W ort ( h y p eric u m perf orat u m) c o ul d res ult i n re d uce d 
tacr oli m us c o nce ntr ati o ns.  
 
D ue t o e xtre me i nteracti o ns wit h v oric o naz ole, tacr oli m us d oses s h o ul d be l o were d b y 5 0 % 
w he n c o n c o mita nt t hera p y wit h v oric o naz ole is i nitiate d. It is rec o m me n de d t hat dr u gs wit h 
k n o w n i nteracti o ns wit h tacr oli m us be a v oi de d w he n cli nicall y feasi ble. W he n t hese me dicati o ns 
are re q uire d, d os e m o dificati o ns of tacr oli m us ma y be re q uir e d.  


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
2 0  
 
8. 2   
Defi niti o ns  
 
8. 2. 1  
A d verse E ve nts   
 
A n  a d verse e ve nt  ( A E) is a n y u nfa v ora bl e or u ni nte n de d e ve nt, p h ysical or ps yc h ol o gical, 
ass ociate d wit h a researc h st u d y, w hic h ca uses har m or i nj ur y t o a res earc h partici pa nt as a res ult 
of t he partici pa nt’s i n v ol ve me nt i n a researc h st u d y.  T he e ve nt ca n i ncl u de a b n or mal la b orat or y 
fi n di n gs, s y m pt o ms, or disease ass ociate d wit h t he res earc h st u d y.  T he e v e nt d oes n ot 
necessaril y ha v e t o ha ve a ca usal relati o ns hi p wit h t he researc h, a n y ris k ass ociate d wit h t he 
researc h, t he researc h i nt er ve nti o n, or t he researc h assess me nts.  
 
A d verse e ve nts ma y b e t he res ult of t he i nter ve nti o ns a n d i nteracti o ns use d i n t he researc h; 
t he c ollecti o n of i de ntifia ble pri vate i nf or mati o n i n t he researc h; a n u n derl yi n g disease, 
dis or der, or c o n diti o n of t he s u bject; a n d/ or ot her circ u msta nces u nrelat e d t o t he researc h or 
a n y u n d erl yi n g disease, dis or der, or c o n diti o n of t he s u bject.  
E xter n al a d verse e v e nts are a d v erse e ve nts e x perie nce d b y s u bj ects e nr olle d i n m ultice nter 
cli nical trials at sites ot her t ha n t he site(s) o ver w hic h t he I nstit uti o nal Re vie w B oar d has 
j uris dicti o n.  
I nter n al a d verse e ve nts are a d vers e e ve nts e x perie nce d b y s u bj ects e nr olle d at t he site(s) 
u n der t he I R B’s j uris dicti o n f or eit her m ultice nter or si n gle-ce nter res earc h pr ojects.  
 
8. 2. 2       T he si g nific a nce of a n a d verse e ve nt is use d t o descri be t he patie nt/e ve nt o utc o me 
or acti o n criteri a ass o ciate d wit h e v e nts t hat p os e a t hreat t o a patie nt’s life or f u ncti o ni n g 
(i.e., m o derate, s e vere or life t hreate ni n g).  Bas e d o n t he Nati o nal Ca ncer I nstit ute G ui deli nes 
f or t he Ca ncer T hera p y E val uati o n Pr o gra m, se v erit y ca n be defi ne d b y t he f oll o wi n g gra des 
of e ve nts: 
  
 
Gr a des 1 
are 
mil d a d verse e ve nts (e. g., 
mi n or e ve nt re q uiri n g n o s pecific 
me di cal 
i nter ve nti o n; as y m pt o matic la b orat or y fi n di n gs o nl y; mar gi nal cli nical rele va nce). 
 
Gr a des 2 are m o derate a d verse e ve nts (e. g., mi ni mal i nter ve nti o n; l ocal i nter ve nti o n; n o n-
i n vasi ve i nter ve nti o n; tra nsf usi o n; electi ve i nter ve nti o nal ra di ol o gical pr oce d ure; t hera pe utic 
e n d osc o p y or o perati o n). 
 
Gr a des 3 are se v ere a n d u n desira ble a d verse e ve nts (e. g., si g nifica nt s y m pt o ms re q uiri n g 
h os pitaliz ati o n or i n vasi ve i nter ve nti o n; tra nsf usi o n; electi ve i nter ve nti o nal ra di ol o gical 
pr oce d ure; t hera p e utic e n d osc o p y or o perati o n). 
 
Gr a des 4  are life t hreat e ni n g or disa bli n g a d v erse e ve nts (e. g., c o m plicate d b y ac ute, life-
t hreate ni n g 
meta b olic 
or car di o vas c ular c o m plicati o ns s uc h as circ ulat or y fail ure, 
he m orr ha ge, se psis; life –t hreate ni n g p h ysi ol o gi c c o nse q ue n ces; nee d f or i nte nsi ve care or 
emer ge nt i n vasi ve pr oce d ure; e mer ge nt i nter ve nti o nal ra di ol o gical pr oce d ure, t hera p e utic 
e n d osc o p y or o perati o n). 


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Gr a des 5 are fatal a d v ers e e ve nt r es ulti n g i n deat h.     
 
8. 2. 3    Seri o us A d verse E vent s  
 
A seri o us a d verse e ve nt ( S A E) is a n y a d verse e x perie nce occ urri n g at a n y d os e t hat res ults 
i n a n y of t h e f oll o wi n g o utc o mes:  
 R es ults i n de at h.   
 Is a life-t hre ate ni n g a d v erse e x perie nce.  T he t er m life-t hreat e ni n g i n t he defi niti o n 
of seri o us refers t o a n a d verse e v e nt i n w hic h t h e s u bject was at ris k of deat h at t he 
ti me of t he e ve nt.  It d oes n ot refer t o a n a d verse e ve nt w hic h h y p ot h eticall y mi g ht 
ha ve ca use d deat h if it were m or e se vere.  
 R e q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n.  
A n y a d verse e ve nt lea di n g t o h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n will be 
c o nsi dere d as Seri o us, U N L E S S at least o ne of t h e f oll o wi n g e x pectati o ns is met:  
o  T he  a d missi o n res ults i n a h os pital sta y of l ess t ha n 1 2 h o urs O R 
o  T he  a d missi o n is pre- pla n ne d (i.e., el ecti ve or s c h e d ule d s ur ger y arra n ge d 
pri or t o t he start of t he st u d y) O R  
o  T he  a d missi o n is n ot ass ociate d wit h a n a d v erse e ve nt, please refer t o 
Secti o n 8. 1. 
o  H o w e ver it s h o ul d be n ote d t hat i n vasi ve treat me nt d uri n g a n y 
h os pitaliz ati o n ma y f ulfill t he criteria of “ m e dicall y i m p orta nt ” a n d as 
s uc h ma y b e re p orta ble as a seri o us a d v erse e ve nt de pe n da nt o n cli nical 
j u d g me nt.  I n a d diti o n w here l ocal re g ul at or y a ut h orities s pecificall y 
re q uire a m ore stri n ge nt defi niti o n, t he l ocal re g ul ati o n ta kes prece de nt.  
 Res ults i n persiste nt or si g nific a nt dis a bilit y/i nc a p acit y .  T he defi niti o n of 
disa bilit y is a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life’s 
f u ncti o ns. 
 Is a c o n ge nit al a n o m al y/ birt h defect .  
 Is a n i m p ort a nt me dic al e ve nt.  I m p orta nt me dical e ve nts t hat ma y n ot res ult deat h, 
be life-t hreat e ni n g, or re q uire h os pitalizati o n ma y be c o nsi d ere d a seri o us a d verse 
e x perie nce w h e n, base d u p o n a p pr o priate m e dical j u d g me nt, t he y ma y je o par dize t he 
patie nt or s u bject a n d m a y re q uir e me di cal or s ur gical i nter ve nti o n t o pre ve nt o ne of 
t he o utc o mes liste d i n t his defi niti o n.  E x a m ples of s uc h me dical e ve nts i ncl u de 
aller gic br o nc h os pas m re q uiri n g i nte nsi ve tr eat me nt i n a n e mer ge n c y r o o m or at 
h o me, bl o o d disease or dis or ders, or c o n v ulsi o ns t hat d o n ot res ult i n i n patie nt 
h os pitaliz ati o n, or t he de vel o p me nt of dr u g de p e n de nc y or dr u g a b use. 
 
8. 2. 4  E x pecte d ness 
 
A d verse E v e nts ca n b e E x pecte d or U ne x pecte d. 
 
A n e x pecte d a d verse e ve nt  is a n e ve nt pre vi o usl y k n o w n or a nti ci pate d t o res ult fr o m 
partici pati o n i n t he res earc h st u d y or a n y u n derl yi n g diseas e, dis or der, or c o n diti o n of t he 


C A S E  6 Z 1 3   
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2 2  
s u bject.  T he e ve nt is us uall y liste d i n t he I n vesti gat or Br oc h ure, c o nse nt f or m or res earc h 
pr ot oc ol.  
 
A n u ne x pecte d a d verse e ve nt is a n a d v erse e ve nt n ot pre vi o usl y k n o w n or a ntici pate d t o res ult 
fr o m t he res earc h st u d y or a n y u n derl yi n g diseas e, dis or der, or c o n diti o n of t he s u bject.  
 
8. 2. 5  At tri b uti o n 
 
Attri b uti o n is t he relati o ns hi p bet wee n a n a d v erse e ve nt or seri o us a d v erse e ve nt a n d t he st u d y 
dr u g.  Attri b uti o n will be assi g ne d as f oll o ws: 
 Defi nite – T he A E is clearl y relate d t o t he st u d y dr u g. 
 Pr o ba ble –  T he A E is li k el y relate d t o t he st u d y dr u g. 
 P ossi ble – T he A E ma y b e relate d t o t he st u d y dr u g. 
 U nli kel y – T he A E is d o u btf ull y rel ate d t o t he st u d y dr u g. 
 U nrelate d – T h e A E is cl earl y N O T relate d t o t he st u d y dr u g. 
 
8. 3    
Re p orti n g Pr oce d ures f or All A d verse E ve nts 
 
All partici pati n g i n vesti gat ors will assess t he occ urre nce of A Es t hr o u g h o ut t he s u bject’s 
partici pati o n i n t he st u d y.  S u bjects will be f oll o we d f or t o xicit y f or 3 0 d a ys after tr eat me nt wit h 
tacr oli m us or m yc o p he n olate has bee n disc o nti n ue d, ta pere d or u ntil deat h, w hic he ver occ urs 
first.  If patie nt c o nti n ues o n tacr oli m us or m yc o p he n olate f or treat me nt of c o nti n ue d G V H D past 
the e n d p oi nt of st u d y ( 1 year after i nf usi o n of H C T), a d verse e ve nts will n o l o n ger b e re p orte d.  
T he  cli nical c o urs e of eac h e ve nt will be f oll o we d u ntil res ol uti o n, sta bilizati o n, or u ntil it has 
bee n deter mi ne d t hat t he st u d y treat me nt or partici pati o n is n ot t he ca use.   
 
T o xicities of t he bl o o d/ b o ne marr o w, g ut, li ver a n d s ki n will be e val uate d se paratel y si nce t h e y 
are li kel y t o be affecte d b y G V H D. G V H D se verit y will be deter mi ne d cli nicall y, h o we v er 
bi o psies of affecte d are str o n gl y e n c o ura ge d w he n e v er p ossi ble.  
 
Gra de 4- 5 seri o us a d v ers e e ve nts will be re p orte d acc or di n g t o t he l ocal I R B’s p olicies a n d 
pr oce d ures.  
 
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t hat seri o us a d verse e v e nts o bser ve d b y t he 
i n vesti gat or or re p orte d b y t h e s u bject w hic h occ ur after t he s u bject has starte d tr eat me nt wit h 
t he first st u d y dr u g ( da y - 1) are f ull y rec or de d i n t he s u bject’s case re p ort f or m, s u bject’s me dical 
rec or ds, a n d/ or a n y ot her i nstit uti o nal re q uire m e nt.  S pecific t o xicities, i ncl u di n g la b orat or y 
val ues a n d e v e nts o utli ne d i n sec o n dar y o bjecti v es will be ca pt ure d p er pr ot oc ol; a n d will n ot 
necessaril y b e c o nsi dere d as part of a d verse e v e nt re p orti n g as t hese are e x pecte d t o xicities p ost 
tra ns pla nt, b ut 
ma y be i nfl ue nce d b y G V H D a n d G V H D pre ve nti o n a p pr oac hes. S o urce 
d oc u me ntati o n m ust be a vaila ble t o s u p p ort all a d verse e v e nts.  
 
T he  i n vesti gat or will pr o vi de t he f oll o wi n g f or seri o us a d verse e ve nts: 
 De scri pti o n of t he e v e nt 
 Gra de of t o xicit y  
 Attri b uti o n of relate d ness t o t he i n vesti gati o nal a ge nt 


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2 3  
 
I n t his st u d y, d escri pti o ns a n d gra di n g scales f o u n d i n t he N CI C o m m o n Ter mi n ol o g y Criteria 
f or A d verse E v e nts ( C T C A E) versi o n 4. 0 a vaila ble at htt p://cte p.ca ncer. g o v  will be utilize d f or 
A E  re p orti n g.  
 
I n v esti gati ve sites will re p ort a d verse e ve nts t o t heir res pecti ve I R B acc or di n g t o t he l ocal I R B’s 
p olicies a n d pr oce d ures i n re p orti n g a d verse e v e nts. 
 
8. 4    
Seri o us A d verse E ve nt Re p orti n g Pr oce d ures 
 
Seri o us a d verse e ve nts t hat occ ur be gi n ni n g wit h t he first d a y of t he st u d y dr u g a d mi nistrati o n, 
d uri n g treat me nt, or wit hi n 3 0 da ys of t h e last d os e of treat me nt, or u p t o st u d y e n d p oi nt m ust b e 
rep orte d t o t he Cle vel a n d Cli nic Pri nci pal I n vesti gat or.   
 
In v esti gati ve sites will re p ort seri o us a d verse e v e nts t o t heir res pecti ve I R B acc or di n g t o t he 
l ocal I R B’s p olicies a n d pr oce d ures i n re p orti n g s eri o us a d verse e v e nts. 
 
8. 4. 1  F D A Re p orti n g 
 
 
 
N/ A  
 
8. 5  
D at a S afet y T o xicit y C o m mittee 
 
It is t he C ase C o m pre he nsive C a ncer Ce nter Pri nci pal I n vesti gat or’s res p o nsi bilit y t o e ns ure 
t hat A L L seri o us a d verse e ve nts are re p orte d t o t he Case C o m pre he nsi ve Ca ncer Ce nter’s Dat a 
S afet y T o xicit y C o m mittee. T his s u b missi o n is si m ulta ne o us wit h t heir s u b missi o n t o ot her 
Re g ulat or y b o d y.  
 
 
 9. 0   
P H A R M A C E U TI C A L I N F O R M A TI O N    
 
A list of t he a d verse e ve nts a n d p ote ntial ris ks ass ociate d wit h t he i n vesti gati o nal or 
c o m mercial a ge nts a d mi nistere d i n t his st u d y ca n be f o u n d i n Secti o n 8. 0.    
 
 
9. 1  
I n vesti g ati o n al A ge nts  
 
  
N/ A 
 
9. 2      C o m merci al A ge nts 
 
A ge nts are liste d i n al p ha betical or der. 
 
9. 2. 1  Met h otre x ate  ( N S C # 7 4 0) 
 
C he mical na me:    
Met h otre x ate  


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F or m ulati o n:   
Met h otre x ate is a vaila ble as t he s o di u m salt f or pare nteral use i n 
2 0 m g, 5 0 m g, a n d 1 g vi als as t he l y o p hilize d p o w der. Li q ui d 
met h otre x ate s o di u m i njecti o n pr o d ucts, a n d ta blets f or oral 
ad mi nistrati o n are als o a vaila ble. 
T o xicit y:   
A d verse reacti o ns i ncl u de dizzi ness, dr o wsi ness, ge n eral b o d y 
disc o mf ort, hea dac he, l oss of a p petite, mil d hair l oss, m uc ositis, 
na usea, v o miti n g, diarr hea, m yel os u p pressi o n, s ki n ras hes, 
itc hi n g, pi g me ntati o n c ha n ges, i m pair e d re n al a n d he patic 
f u ncti o n.  
Ma n ufact ur er:    
I m m u ne x 
S u p plier:   
Patie nt or 3 r d Part y 
Me c ha nis m of Acti o n:    
Met h otre x ate is a n a nti meta b olite a n d has its pri nci ple   
 
mec ha nis m of acti o n t he c o m petiti ve i n hi biti o n of di h y dr of ol ate 
re d uctas e. 
 
9. 2. 2 
M yc o p he n ol ate  ( N S C # 6 1 4 4 3) 
 
C he mical na me:    
M yc o p h e n olate m of etil 
F or m ulati o n:   
M yc o p h e n olate is a vaila ble i n ca ps ule f or m, 2 5 0 m g or ta blets of 
5 0 m g.  Li q ui d f or ms are als o a vaila ble a n d c o me i n 5 0 0 m g vials 
( 2 0 m L). 
T o xicit y:   
A d verse reacti o ns i ncl u de a n xiet y, bac k pai n, c o nsti pati o n, 
diarr hea, dizzi ness, hea dac he, l oss of a p petite, le u k o pe nia, se psis, 
na usea, v o miti n g, tre m or, tr o u ble slee pi n g a n d i ncreas e d 
i nci de nce of i nfecti o ns. 
Ma n ufact ur er:    
R oc he 
S u p plier:   
Patie nt or 3 r d part y 
M ec ha nis m of Acti o n:    
M yc o p h e n olate is ra pi dl y a bs or be d f oll o wi n g oral a n d I V 
a d mi nistrati o n a n d h y dr ol yz e d t o f or m M P A, w hic h is t he acti ve 
meta b olite.  
M P A is a p ote nt, selecti ve, u n c o m petiti ve a n d 
re versi ble i n hi bit or of i n osi ne m o n o p h os p hate de h y dr o ge nas e 
(I M P D H), a n d t heref ore i n hi bits t he de n o v o pat h wa y of 
g ua n osi n e n ucl e oti de s y nt hesis wit h o ut i nc or p orati o n i nt o D N A.  
Beca use T- a n d B-l y m p h oc yt es are criticall y d e pe n de nt f or t heir 
pr oliferati o n o n de n o v o s y nt hesis of p uri n es w hereas ot her cell 
t y pes ca n utilize sal va ge pat h w a ys, M P A h as p ote nt c yt ostatic 
effects o n l y m p h oc ytes.  M P A i n hi bits pr oliferati ve res p o nses of 
T- a n d 
B-l y m p h o c ytes t o b ot h 
mit o ge nic a n d all os pecific 
sti m ulati o n.  
 
9. 2. 3 
T acr oli m us  ( N S C # 7 7 8 6 5) 
 
C he mical na me :   
F K 5 0 6  
F or m ulati o n:  
Ca ps ule, oral: 0. 5 m g, 1 m g, 5 m g.  I njecti o n, s ol uti o n: 5 m g/ ml ( 1 
ml).   


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T o xicit y:  
A d verse reacti o ns i ncl u de bac k p ai n, c o nsti pati o n, diarr hea, 
diz zi ness, hea dac h e, j oi nt pai n, l oss of a p petite, na usea, st o mac h 
pai n or u pset, tr o u ble sle e pi n g, v o miti n g, wea k n ess. 
Me c ha nis m of Acti o n:   
Bi n ds t o t he F K B P- 1 2 pr otei n a n d f or ms a c o m ple x wit h 
calci u m- de p e n de nt pr otei ns, t here b y i n hi biti n g calci ne uri n 
p h os p hatase acti vit y a n d res ulti n g i n decrease d c yt o ki ne 
pr o d ucti o n.  T his a ge nt e x hi bits p ote nt i m m u n os u p pressi ve 
acti vit y a n d pre ve nts t he acti vati o n of T-l y m p h oc ytes i n res p o nse 
t o a nti ge nic or mit o ge nti c sti m ulati o n.  
 
1 0. 0  
C O R R E L A TI V E / S P E CI A L S T U DI E S  
 
1 0. 1  
Re se arc h S a m ple Re p osit or y 
 
 
T he p ur p ose of t his c orrelati ve st u d y is t o i m pr o ve o ur u n dersta n di n g of G V H D b y  st ori n g 
sa m ples of bl o o d/tiss ue of t he reci pie nt t o use i n vari o us la b orat or y st u dies. 
 
1 0. 1. 1 B ac k gr o u n d a n d R ati o n al: 
 
G V H D is a c o m ple x disease w hic h arises w he n d o n or T cells res p o n d t o ge neticall y d efi ne d 
a n d dis parate pr otei ns o n h ost cells; t he m ost i m p orta nt of w hic h are h u ma n le u k oc yt e 
a nti ge ns ( H L As), w hic h are hi g hl y p ol y m or p hic a n d are e n c o de d b y t he m aj or 
hist oc o m pati bilit y c o m pl e x ( M H C).  G V H D is oft e n ass ociate d wit h a graft vers us le u ke mia 
( G V L) effect, b ut se parati n g t he t w o is ofte n a c halle n ge.  T h e pat h o ge n esis u n derl yi n g 
G V H D is a c o m ple x, m ulti-ste p pr ocess.  T here are ma n y fact ors w hic h are n ot f ull y 
u n de rst o o d w hic h deter mi ne w het her G V H D occ urs a n d t he stre n gt h of t he reacti o n.  T h ese 
i ncl u de t he t y p e a n d pr o p erties of tra ns pla nt e d T cells, hist oc o m pati bilit y a nti ge n 
mis matc hi n g, i nteracti o ns bet wee n T cells a n d e n d ot helial cells, si g nali n g e ve nts occ urri n g 
bet wee n i m m u ne cells, i n d ucti o n of pr o-i nfla m mat or y c yt o ki n es, a n d a m o u nt of B li nea ge-
s pecific pr o ge nit or cells.  Ac ute G V H D re q uir es t he earl y tr affi c ki n g of d o n or nai ve T cells 
t o reci pie nt sec o n d ar y l y m p h oi d tiss ue w here t he y u n der g o acti vati o n a n d e x pa nsi o n, a n d 
t heir s u bse q ue nt mi grati o n t o tar get or ga ns w h ere t he y elicit i nj ur y [ 1 5- 1 7].  T he st u d y of 
t hese pr ocesses t hr o u g h l a b orat or y st u dies i ncl u di n g t he meas ure m e nt of c yt o ki ne pr o d u cti o n 
a n d c yt o ki ne rece pt ors, d eter mi nati o n of he mat o p oietic cell s u bt y p es b y fl o w c yt o m etr y, a n d 
deter mi nati o n of H L A a nti ge n t y pes b y ge n ot y pi n g ma y h el p el uci date a n d se parat e t he 
detri me ntal a n d be n eficial effects c o nferre d b y d o n or- deri ve d T cells a n d i m pr o ve o ur 
u n dersta n di n g of G V H D.  
 
 
1 0. 1. 2 P ati e nt Selecti o n :  
 
Cle vela n d cli nic patie nts e nr olle d i n t he trial ma y be as ke d t o partici pate i n t his st u d y t o 
c ollect bl o o d a n d tiss ue sa m ples f or la b orat or y researc h p ur p oses.   
 
 
 


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1 0. 1. 3 Res e arc h Pl a n/ St u d y P ar a meters:  
 
Researc h i n graft vers us h ost disease de pe n ds o n t he rea d y a vaila bilit y of sa m ples of bl o o d, 
tiss ue (s ki n, GI tr act, a n d li ver bi o psies) a n d b o ne marr o w of tra ns pla nt reci pie nts a n d d o n ors 
f or i n vitr o st u dies.  Assa ys ma y i ncl u de p h e n ot y pic a nal ysis b y fl o w c yt o metr y a n d 
hist oc he mical met h o ds, m olec ular bi ol o gi c deter mi nati o n of s pecific D N A a n d R N A s peci es, 
an d ge ne e x pressi o n a nal ysis.  
 
I n a d diti o n, re p osit ories of plas ma, ser u m, D N A, R N A a n d w h ole cell pre p arati o ns ma y be 
i n val ua ble i n retr os pecti ve a nal ysis.  C orrelati o n of cli nical data, s uc h as a ge, se x, la b orat or y 
res ults, c yt o ge netics, b o n e marr o w m or p h ol o g y, tr eat me nt, pr o gressi o n, c o- m or bi dities, etc. 
ma y b e use d as n ee de d.  T his data will o nl y be li n ke d t o researc h s a m ple n u m ber.  
 
Reci pie nts will ha ve 1 0 ml of peri p heral bl o o d o btai ne d b y v e ni p u nct ure i n 1 gree n t o p 
he pari nize d t u be f or a baseli ne s peci me n pri or t o tra ns pla ntati o n.  If a b o ne marr o w s peci me n 
is perf or me d, a 1 0 ml as pirate sa m ple i n a gree n t o p t u be will be c ollecte d at t hat ti me.  After 
trans pla ntati o n, 1 0- 2 0 ml (i n 1- 2 gree n t o p h e pari nize d t u bes) of peri p heral bl o o d ma y be 
o btai ne d ar o u n d tr a ns pla nt da y + 1 0 0 ( +/- 1 4 d a ys) , + 1 8 0 ( +/- 3 0 d a ys)( or ti me of 
i m m u n os u p pressi o n wit h dra wal), a n d + 3 6 5 ( +/- 3 0 da ys) t hr o u g h t he patie nt’s ce ntral v e n o us 
cat heter or b y ve ni p u nct ure.  A d diti o nal bl o o d sa m ples fr o m patie nts ma y b e c ollecte d at 
time of cli nical dia g n osis or bi o ps y- pr o ve n G V H D.  
 
If p ossi ble, wit h t he de vel o p me nt of G V H D s o me of t he bi o ps y s p eci me ns fr o m t he or ga n 
i n v ol ve d (i ncl u di n g s ki n, li ver, or GI tr act bi o ps y) ma y als o be f urt her assesse d if t here is 
ade q uate tiss ue.  
 
F or t h ose patie nts w h o re q uire a d o n or l y m p h oc yt e i nf usi o n ( D LI) or s u bse q ue nt i nf usi o n of 
a d diti o nal he mat o p oietic ste m cells p ost-tra ns pla nt a f oll o w- u p peri p heral bl o o d sa m ple will 
be o btai ne d pri or t o pr o ce d ure as well as a gai n ar o u n d da y + 1 0 0 ( +/- 1 4 da ys), a n d + 3 6 5 ( +/-
3 0 da ys)  after re-i nf usi o n.  
 
T he c ollecti o n of A L L bl o o d A N D  tiss ue s peci me ns f or t he sa m ple re p osit or y will o nl y be 
c ollecte d w h e n cli nical s peci me ns are c ollect e d t o mi ni mize patie nt disc o mf ort.  
 
1 0. 1. 4 S peci me n H a n dli n g: 
 
Tiss ue:   
Bi o ps y mat erial ( b o ne marr o w or G V H D affect e d tiss ue) ma y b e fr oze n i n li q ui d nitr o ge n 
a n d st ore d i n defi nitel y at - 8 0 oC f or m olec ul ar ge n etic st u dies if re q uir e d as dee m e d b y 
s pecific st u d y.  Ot her wise, r o uti ne s peci me n fi x ati o n (i n f or mali n a n d ot her a p pr o priate 
fi x ates) f or c o n ve nti o nal hist ol o g y a n d i m m u n o hist oc he mistr y/ FI S H, pres er vati o n i n tiss ue 
c ult ure me dia f or fl o w c yt o metr y, a n d a n al ysis of fres h sterile tiss ue f or c yt o ge n etics.  P ost-
pr oc ure m e nt pr ocessi n g o n b ot h fr oze n a n d f or m ali n-fi x e d paraffi n-e m be d de d tiss ues will be 
perf or me d.  Deri vati ve D N A a n d R N A ma y be e xtracte d o n t hese tiss ue sa m ples f or rele va nt 
assa ys f or i n vesti gat ors.   
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
2 7  
Bl o o d: 
T he pr ot oc ol f or bl o o d pr ocessi n g a n d st ora ge is as f oll o ws:  Peri p h eral bl o o d will be 
o btai ne d i n gree n t o p he pari nize d t u bes. F or eac h 1 0 ml of w h ole bl o o d, a p pr o xi matel y 4- 5 
ml of ser u m or plas ma ca n be d eri ve d.  T hese will be di vi de d i nt o 0. 5 ml ali q u ots.  E x cess 
m o n o n uclear cells will be fr oze n a n d st or e d i n ali q u ots f or fl o w c yt o metri c a nal ysis or D N A 
e xtracti o n.  Gl ycer ol will be a d de d t o a fi nal c o n ce ntrati o n of 1 0 % ( w/ v) as a cr y o pr otecta nt 
a n d s peci me ns will be fr oze n at - 8 0 oC i n ali q u ots of 1 0 ml a n d st ore d u ntil use.  
 
S peci me ns will be c ollecte d after t h e patie nt si g ns t he writte n, i nf or me d c o nse nt.  S peci me ns 
will o nl y b e o btai ne d at t he ti me r o uti ne cli nical s peci me ns are c ollect e d t o mi ni mize patie nt 
disc o mf or t.  Patie nts ma y ref use c ollecti o n of s peci me ns at a n y ti me.  S peci me ns will be 
st ored i n defi nitel y or u ntil a patie nt wit h dra ws fr o m t he st u d y.  
 
D N A/ bl o o d sa m ples fr o m all B M T d o n ors are st ore d i n a re gistr y u n d er I R B 0 9- 5 9 1 All o ge n 
L a b orat ories Re gistr y/ D ata base.  T hes e s peci me ns/ data ma y be s hare d/teste d/c o m bi ne d wit h 
t his st u d y t o gai n a d diti o nal i nf or mati o n. 
 
1 0. 1. 5  Pri v a c y Pr otecti o n:  
 
S peci me ns all ocate d t o t his researc h pr oject will be assi g ne d a researc h I D n u m ber, w hic h 
will be t he o nl y i de ntifier pr o vi de d t o i n vesti gat ors w he n t he y are gi v e n s peci me ns.  T he ke y 
li n ki n g t he researc h I D n u m ber wit h t he patie nt i de ntificati o n ( na me, C C F I D n u m ber a n d 
date of birt h) will be l ocate d i n O n C ore w hic h is a sec ure d, pass w or d pr otecte d data base. 
Occasi o nall y c h art re vie w will be necessar y.  F or t his p ur p ose, a C o-I n vesti gat or will be 
pr o vi de d wit h patie nt n a me a n d I D n u m ber f or t he p ur p ose of a bstracti n g perti ne nt hist orical 
i nf or mati o n.  T he i nf or m ati o n will be rec or de d wit h o nl y t he res earc h I D n u m ber.   
 
1 0. 1. 6  T y pes of L a b or at or y St u dies t o Be Perf or me d: 
 
Bl o o d, s ur gical s pe ci me ns a n d b o ne marr o w fr o m patie nts ma y b e utilize d f or di verse 
p ur p oses.  D N A/ bl o o d sa m ples fr o m all B M T d o n ors are st or e d i n a re gistr y u n der I R B 0 9-
5 9 1 All o ge n La b orat ori es Re gistr y/ Data base.  T h ese s peci me ns/ dat a ma y be s hare d t o gai n 
ad diti o nal i nf or mati o n. 
 
T his i ncl u des st u dies of he mat o p oiesis a n d i m m u ne rec o nstit uti o n, meas ure me nts of c yt o ki n e 
pr o d ucti o n a n d c yt o ki ne rece pt ors; deter mi nati o n of he mat o p oietic cell s u bt y pes b y fl o w 
c yt o metr y a n d i de ntificati o n of T cell re p ert oire a n d a nti ge ns.  S o me st u di es ma y b e ge n etic 
i n nat ure, as f or e x a m ple deter mi nati o n of H L A a nti ge n t y pes b y ge n ot y pi n g.  Cells as w ell 
as ser u m are ofte n b a n ke d f or se veral ye ars f or f ut ure st u dies, t he nat ur e, w hic h ca n n ot be 
precisel y pre dicte d.  H o we ver, t he f oll o wi n g list c o nsists of e x a m ples of researc h t hat is 
c urre ntl y perf or me d o n bl o o d, s ur gic al s peci me ns a n d b o ne marr o w: 
  
 
 Usi n g  Fl o w c yt o metr y a n al ysis f or pr otei ns o n t he s urface or i nsi de of cells. 
 Usi n g  fl o w c yt o m etr y a n d cell c ult ure tec h ni q ues t o i de ntif y l y m p h o c yte t y pes a n d 
t heir f u ncti o n i n disease i ncl u di n g T C R usa ge a n d c yt o ki ne s ecreti o n p he n ot y pe. 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
2 8  
 Meas uri n g i m m u nit y t o mali g na nt cells, n or mal cells, vir uses, bacteri a, a n d f u n gi 
usi n g fl o w c yt o metr y, P C R tec h ni q ues, c yt o ki ne releas e assa ys, pr olif erati o n assa ys 
a n d c yt ot o xicit y assa ys.  S o me tec h ni q ues will re q uire c ult ure of cells f or s e veral 
wee ks.   
 De tecti o n of vir al D N A or R N A. 
 C orrelati o n of cli nical dat a, s uc h as a ge, se x, la b orat or y res ults, c yt o ge n etics, b o ne 
marr o w m or p h ol o g y, treat me nt, pr o gressi o n, tra nsf usi o n re q uire me nts, past me dical 
hist or y, c o- m or bi dities, etc. as nee d e d f or f ut ure pr ojects.  T hese d ata will o nl y be 
li n ke d t o t he researc h sa m ple n u m ber. 
 Ge ne e x pressi o n a n al ysis.  
 Im m u n o hist oc he mistr y f or pr otei ns e x presse d i n or o n t he s urface of cells. 
 A na l ysis of c hr o m os o mal defects usi n g arra y- b ase d c o m parati ve a n d ot her m olec ular 
met h o ds. 
 A na l ysis of discrete c ha n ges i n t he D N A se q u e nces deri ve d fr o m bl o o d, tiss ue, a n d 
b o ne marr o w usi n g hi g h de nsit y S N P arra ys:  
 S N P ge n ot y pi n g i n bl o o d a n d marr o w 
 S N P arra y- b ase d ka y ot y pi n g i n bl o o d a n d marr o w 
 
T hese st u dies d o n ot i ncl u de a n y t hera pe utic ma ni p ulati o ns. 
 
1 0. 1. 7  Ris ks: 
 
T he ris ks of t his trial are mi ni mal t o patie nts.  Tra ns pla nt patie nts will ha ve ce ntral ve n o us 
cat heters i n pla ce fr o m w hic h m ost of t heir bl o o d s peci me ns ca n b e o btai ne d, t h us a v oi di n g 
t he p ote ntial mi n or disc o mf ort fr o m ve ni p u nct ure.  N o b o ne marr o w as pirati o ns/ bi o psies or 
s ur geries/tiss ue bi o psies will be perf or me d s ol el y f or res earc h p ur p oses.  T he y will o nl y be 
pe rf or me d if alrea d y me dicall y i n dicat e d.  
 
1 1. 0   
S T U D Y P A R A M E T E R S A N D C A L E N D A R  
 
1 1 . 1 
St u d y P ar a meters 
1 1 . 1.1  Pre- St u d y 
All e val uati o ns 
m ust b e c o m plete d < 4 2 da ys pri or t o a d mi nistrati o n of 
m yel oa bl ati ve 
c o n diti o ni n g re gi me n gi v e n f or all o ge n eic he mat o p oietic ste m cell tra ns pla nt. 
 Inf or me d c o ns e nt 
 De m o gra p hics 
 Me dical hist or y 
 C o m plete p h ysical e x a m 
 Dise ase ass ess me nt of t u m or or site i n v ol ve d i ncl u di n g b o ne marr o w bi o ps y a n d as pirate 
 P erf or ma nce stat us ( E C O G f or a d ults, La ns k y f or pe diatrics) 
 La b orat or y st u dies: 
 
C o m plete bl o o d c o u nt ( C B C) wit h differe ntial 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
2 9  
 
He patic e nz y mes: A S T, A L T, al kali ne p h os p hatase, t otal bilir u bi n, creati ni ne  
 
ß - H C G f or w o me n of c hil d beari n g p ote ntial 
 
P T/ P T T  
 P ul m o nar y f u ncti o n testi n g wit h D L C O if pt > 6 years of a ge  
 C M V scree ni n g  
 H I V scree ni n g 
See St u d y Para meters Ta ble f or s pecific ti me p oi nts f or st u d y ass ess me nts 
1 1. 1. 2 D ur i n g h os pit aliz ati o n f or Tr a ns pl a nt 
 L a b orat or y st u dies: 
 
C o m plete bl o o d c o u nt ( C B C) wit h differe ntial 
 
He patic e nz y mes: A S T, A L T, al kali ne p h os p hatase, t otal bilir u bi n, creati ni ne  
 
P T/ P T T  
 C M V D N A testi n g  
 M uc ositis gra di n g 
 Ac ute G V H D m o nit ori n g 
 Or ga n t o xicit y assess me nt 
 P eri p heral bl o o d c hi meris ms (a p pr o xi matel y  1, 2, 3, 6, 9 a n d 1 2 m o nt hs or as cli nicall y 
i n dicate d) 
See St u d y Para meters Ta ble f or s pecific ti me p oi nts f or st u d y ass ess me nts 
1 1. 1. 3  P ost h os pit aliz ati o n f or Tr a ns pl a nt t o E n d of St u d y 
Sa me assess me nts as a b o ve ( d uri n g h os pitalizati o n f or tra ns pla nt) ; See St u d y Para meters Ta bl e 
f or s pecifi c ti me p oi nts f or st u d y ass ess me nts 
 
 
 
 
 
 
 
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 0  
1 1. 1. 4  St u d y P ar a meters T a ble 
Re q uire d Assess me nts   Pre -st u d y ( < 
4 2 da ys pri or 
All o -H S C T)  
D uri n g I nitial 
H os pitalizati o n  f or 
All o -H S C T  
P ost H os pitalizati o n f or 
All o -H S C T t o St u d y E n d 
P oi nt  
T u m or c hara cteristics 
/ Site of i n v ol ve me nt  
X  
 
As cli nicall y i n dicate d  
E C O G / La ns k y  
X  
 
Q visits u ntil 1 year  
B o ne Marr o w 
As pirate / Bi o ps y  
X  
 
Da y 1 0 0 ( o pti o nal) or a s 
cli nicall y i n dicat e d  
C B C a n d diff  
X  
Dail y u ntil A N C 
> 5 0 0, plt > 2 0, 0 0 0, 
t he n Q wee kl y u ntil 
n or mal  
Q  wee kl y u n til da y 1 0 0 a n d 
t he n at at f oll o w u p visits 
He patic e nz y mes 
( A S T, A L T, Al k 
P h os, T otal Bili)  
X  
Dail y  u ntil  
disc har ge  
At f oll o w u p visits  
Creati ni ne  
X  
Dail y  u ntil 
disc har ge  
At f oll o w u p visits  
P T/ P T T  
X  
Q wee kl y  
As cli nicall y i n dicate d  
C M V D N A  
X  
Q wee kl y  
Wee kl y  u ntil D 1 0 0, t he n 
as cli nicall y i n dicate d  
HI V scree ni n g  
X  
 
 
P F T st u dies ( > 6 y o)  
X  
 
da y 1 0 0 a n d  as n ee de d  
P B c hi meris m  
 
X  (if patie nt is still 
i n h os pital at a n y 
ti me p oi nt) 
A p pr o xi matel y 1, 2, 3, 6, 9, 
1 2 m o nt hs or as cli nicall y 
i n dicate d 
H C G (fe male of 
c hil d beari n g a ge)  
X  
 
 
Tac le vels  
 
2 X / wee k  or as 
cli nicall y i n dicat e d  
A s cli nicall y i n dicate d 
Ac ute G V H D 
M o nit ori n g  
 
1 X  / wee k starti n g 
D + 7  
Q wee kl y u ntil da y 1 0 0  
C hr o nic G V H D 
m o nit ori n g  
 
 
After D 1 0 0, at least e ver y 
3 m o nt hs  
M uc ositis gr a di n g 
 
3 X  / w k D 0 t o D  
+ 2 8 or D/ C  ( w hic h 
e ver occ urs first) 
 
Or ga n T o xicit y 
assess me nt  
 
Q wee kl y  
Q visits u ntil  1 year  
1 1. 1. 5 St u d y  Assess me nts 
E n gr aft me nt  
Ne utr o p hil e n graft me nt will be meas ure d b y t he n u m ber of da ys t o reac h a n e utr o p hil c o u nt of 
greater t ha n or e q ual 5 0 0/ ul f or t hree c o nsec uti v e la b orat or y val ues o btai ne d o n differe nt da y.  
T he da y of e n graft me nt will be t he first da y of t h e t hree c o nsec uti ve la b orat or y v al ues 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 1  
 
Platelet e n graft me nt will be meas ure d b y t he n u m ber of da ys t o reac h a pl atelet c o u nt of greater 
t ha n or e q ual 2 0, 0 0 0/ ul f or t hree c o nsec uti ve la b orat or y val ues o btai n e d o n differe nt da ys 
i n de pe n de nt of platelet tr a nsf usi o ns t he pri or 7 d a ys.  T he da y of e n graft m e nt will be t h e first d a y 
of t he t hree c o nsec uti ve l a b orat or y v al u es. 
 
Ac ute Gr aft- V ers us- H ost Dise ase  
Ac ute graft- v ers us- h ost disease will be m o nit ore d dail y a n d will be d o c u m e nte d 1 X / wee k fr o m 
da y + 7 w hile p atie nt is h os pitaliz e d f or tra ns pla nt.  After disc h ar ge fr o m h os pital, Ac ute G V H D 
will be m o nit ore d a n d d oc u me nte d at a mi ni m u m of e ver y 2 1 da ys till da y + 1 0 0 ( or m or e if 
cli nicall y i n dicate d).  A c ute graft- v ers us- h ost dise ase will be gra de d acc or di n g t o t he ta ble s h o w n 
i n A p pe n di x 1. S ki n, gastr oi ntesti nal, a n d/ or li ver bi o psies will be o btai ne d, w he n a p pr o priat e, t o 
facilitate t he dia g n osis.  T he t y p e a n d d urati o n of i m m u n os u p pressi ve treat me nt gi v e n f or 
a G V H D will be rec or de d. 
 
C hr o nic Gr aft- V ers us- H ost Dise ase 
After d a y 1 0 0, patie nts will be assesse d at least e ver y 3 m o nt hs ( +/- 1 4 da ys) f or c G V H D.  
c G V H D will be gra d e d as mil d, m o derate, or se vere bas e d o n t he Nati o nal I nstit utes of Healt h 
C o nse ns us De vel o p me nt Pr oject acc or di n g t o t he ta ble s h o w n i n A p pe n di x II.  T he t y pe a n d 
d ura ti o n of i m m u n os u p pressi ve treat me nt gi ve n f or c G V H D will be rec or de d.   
 
M uc ositis   
M uc ositis will be gra d e d 3 ti mes per wee k ( M o n- We d- Fri) b y t he mi d -le vel pr o vi der or 
tra ns pla nt p h ysicia n fr o m da y 0 u ntil da y + 2 8 or d a y of disc har ge ( w hic he ver occ urs first) 
acc or di n g t o t he W H O gra di n g scale s h o w n i n A p pe n di x III. 
 
T ot al P are nter al N utriti o n ( T P N) 
Start a n d st o p dates of T P N will be rec or de d.  
 
I V P ai n Me dic ati o ns 
Start a n d st o p dates f or t he nee d f or c o nti n u o us I V i nf usi o n of narc otics f or se vere m uc ositis 
pai n i n t he f or m of i ntra v e n o us i nf usi o n or patie nt c o ntr olle d a nal gesi a ( P C A) will be 
rec or de d.  
 
Le n gt h of H os pit aliz ati o n  
Le n gt h of h os pitaliz ati o n will be meas ure d fr o m d ate of tra ns pla nt t o dat e of disc har ge.  
 
Or g a n T o xicit y    
Inf or mati o n re gar di n g re nal, he patic a n d p ul m o nar y f u ncti o n will be c ollecte d at st u d y e ntr y 
a n d will be assesse d t hr o u g h o ut t he ti me t hat t he patie nt re mai ns o n G V H D pr o p h yl a xis.  
Patie nts will be assesse d at least wee kl y u ntil da y 1 0 0 p ost tra ns pla nt a n d t he n at f oll o w u p 
visi ts f or 1 year p ost tra ns pla nt f or or ga n t o xicit y.  
A pa tie nt will be c o nsi dere d t o ha ve li ver d ysf u ncti o n s h o ul d t he patie nt ha ve a t otal bilir u bi n 
≥ 3 X t he u p per li mit of n or mal a n d A S T, A L T or al kali ne p h os p hatase ≥ 5 X t he u p per li mit 
of n o r mal. 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 2  
He patic ve n o- occl usi ve disease will be dia g n ose d acc or di n g t o criteria set f ort h b y Mc D o nal d 
et al [ 1 8].  Patie nt m ust ha ve t he prese nce, bef ore da y 2 0 after tra ns pla nt, of at least t w o of 
t he foll o wi n g feat ur es:  
 B ilir u bi n greater t ha n or e q ual t o 2 m g/ d L  
 He pat o me gal y a n d ri g ht u p per q ua dra nt pai n 
 Asc ites a n d/ or u ne x plai ne d wei g ht gai n greater t h a n 2 % fr o m b aseli ne.  
A patie nt will be c o nsi dere d t o ha ve re nal d ysf u ncti o n s h o ul d t he patie nt ha v e a ser u m 
creati ni ne ≥ 3 X t h e baseli ne val ue, creati ni ne cl eara nce or G F R ≤ 4 0 % of baseli ne or dial ysis 
de pe n de n ce. 
A patie nt will b e c o nsi d ere d t o ha ve p ul m o nar y t o xicit y bas e d o n t h e f oll o wi n g criteria ( usi n g 
C T C A E v 4): 
 B r o nc h o p ul m o nar y he m orr ha ge, gra de 3 or hi g her 
 P ul m o nar y e d e ma, gra de 3 or hi g h er 
 R es pirat or y fail ure, gra d e 4 or hi g her 
O ver all S ur vi v al a n d Rel a pse- Free S ur vi v al    
B ot h o verall s ur vi val a n d rela pse-free s ur vi val will be assesse d o ne year fr o m t he da y of ste m 
cell i nf usi o n, T- O or deat h, w hic h e ver is first.  O ne- year-rela pse-free a n d o verall s ur vi val will 
be  defi ne d b y CI B M T R criteria f or i n di vi d ual diseases.  S us pici o n f or rel a pse s h o ul d be 
co nfir me d b y b o ne m arr o w bi o ps y a n d d ate of bi o ps y s h o ul d ser ve as dat e of rela pse.  Bi o ps y is 
str o n gl y e n c o ura ge d b ut n ot re q uire d if t here are c o m pelli n g me dical r eas o ns w h y bi o ps y is n ot 
feasi ble or u n o btai n a ble or if rela ps e is ot her wise e vi de nt a n d c o nfir me d b y peri p heral bl o o d 
fl o w c yt o m etr y. 
 
E v al u ati o n of C hi meris m   
D o n or c hi meris m will be assesse d b y a n al ysis of si n gle-ta n de m re p eats o n w h ole marr o w a n d i n 
l y m p h oc yte e nric he d or s orte d C D 3 + T cells a n d C D 3 3 + gra n ul oc ytes fr o m t he bl o o d de pe n di n g 
o n i nstit uti o n practice.  Bl o o d will be o btai ne d f or d o n or c hi meris m “ B M E a nal ysis ” at 
ap pr o xi matel y 1, 2, 3, 6, 9 a n d 1 2 m o nt hs or as cli nicall y i n dicat e d.  
 
I nfecti o ns 
D oc u me nte d bacterial, viral a n d f u n gal i nfecti o ns will be rec or de d f or 1 ye ar aft er 
tra ns pla ntati o n.  
 
1 2 . 0  
M E A S UR E M E N T O F E F F E C T   
 
1 2. 1  
I nci de nce, Le n gt h a n d Se verit y of M uc ositis 
 
T h e i nci de n ce, l e n gt h a n d se verit y of m uc ositis fr o m da y 0 t o d a y 2 8 ( or disc har ge date if earlier) 
after all o ge n eic b o ne marr o w tra ns pl a ntati o n c o m pari n g Tac, mi ni- d ose M T X a n d M M F wit h 
Tac a n d M T X will be det er mi ne d.  


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 3  
  
1 2. 2  
R ate of Ne utr o p hil a n d Pl at elet E n gr aft me nt 
 
N u m ber of da ys t o e n graft me nt, f or b ot h ne utr o p hil a n d platelet after all o ge n eic b o ne marr o w 
tra ns pla ntati o n c o m pari n g T ac, 
mi ni- d ose 
M T X a n d 
M M F 
wit h Tac a n d 
M T X 
will be 
deter mi ne d.  
 
1 2. 3  
I nci de nce of Ac ute G V H D 
  
T he  i nci de nce a n d s e verit y of gra de II-I V a n d III-I V ac ut e G V H D aft er all o ge n eic b o ne marr o w 
tra ns pla ntati o n c o m pari n g T ac, 
mi ni- d ose 
M T X a n d 
M M F 
wit h Tac a n d 
M T X will be 
deter mi ne d.   
 
1 2. 4  
S ec o n d ar y o bjecti ve p ar a meters  will als o be c o m pare d i n t he Tac, mi ni- d ose M T X a n d 
M M F  wit h t he Tac a n d M T X: 
 L e n gt h of h os pitaliz ati o n 
 L e n gt h of use of T P N 
 In ci de nce of i nfecti o n i n t he first 1 0 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce of he p at ot o xicit y i n t he first 1 0 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce of ne p hr ot o xicit y i n t he first 1 0 0 da ys p ost-tra ns pla ntati o n 
 In ci de nce of p ul m o nar y t o xicit y i n t he first 1 8 0 da ys p ost-tra ns pl a ntati o n 
 In ci de nce a n d se v erit y of c hr o nic G V H D 
 O ne  year rel a pse-free s ur vi val 
 O ve rall s ur vi val 
 C hi meris m res ults 
 
 
1 3. 0  
R E C O R D S T O B E K E P T / R E G U L A T O R Y C O N SI D E R A TI O N S  
 
A d verse e ve nt lists, g ui d eli nes, a n d i nstr ucti o ns f or A E re p orti n g ca n be f o u n d i n Secti o n 8. 0 
( Ad vers e E ve nts: List a n d Re p orti n g Re q uir e me nts). 
 
1 3. 1 
D at a Re p orti n g  
 
T he O n C or e D ata base will be utilize d, as re q uire d b y t he Case C o m pre he nsi ve Ca ncer 
Ce nter, t o pr o vi de d ata c ollecti o n f or accr ual e ntr y O n C ore is a Cli nical Trials Ma na ge m e nt 
S yste m h o use d o n sec ure ser vers m ai ntai ne d at Case Wester n R eser ve U ni versit y.  O n C ore 
pr o perl y use d is c o m plia nt wit h Title 2 1 C F R Part 1 1.  Access t o data t hr o u g h O n C ore is 
restricte d b y user acc o u nts a n d assi g n e d r oles.   
 
Da ta will be e ntere d i nt o t he Ca ncer Ce nt er Cli nical Trials O nc ore Dat a bas e.  T he 
In v esti gat or will e ns ure t hat t he rec or ds a n d d oc u me nts pertai ni n g t o t he c o n d uct of t he st u d y 
a n d t he distri b uti o n of t he pr ot oc ol t hera p y, t hat is c o pies of C R Fs a n d s o urce d oc u me nts 
( ori gi n al d oc u me nts, data, a n d rec or ds [e. g., h os pit al rec or ds; cli nical a n d office c h arts; 
la b orat or y n otes; S A E re p orts]) be retai ne d b y t he I n v esti gat or f or as l o n g as nee de d t o 
c o m pl y wit h nati o nal a n d i nter nati o nal re g ulati o ns ( ge nerall y 2 years after disc o nti n ui n g 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 4  
cli nical de vel o p me nt).  T he rec or ds of t his st u d y will be ke pt pri vate.  I nf or mati o n t hat ma y 
be  gai ne d fr o m t his st u d y will be use d f or researc h a n d e d ucati o nal p ur p oses o nl y.  I n a n y 
re p ort t hat mi g ht get p u blis he d, n o i nf or mati o n will be i ncl u de d t hat w o ul d all o w f or 
i de ntificati o n of t he patie nt.  At a n y ti me t he I n v esti gat or ma y b e s u bject t o a fiel d a u dit b y 
reg ulat or y a ut h orities (e. g., F D A, T P P, E M E A) i n or der t o vali date t h e partici pati o n of 
s u bjects i n t he st u d y.  T h eref ore, caref ul atte nti o n s h o ul d be pai d t o seei n g t hat all st u d y 
d oc u me nts/rec or ds are c o m plete, acc urate, a n d file d a n d retai ne d b y t h e I n v esti gat or. 
 
1 3. 2 
Re g ul at or y C o nsi der ati o ns  
T he st u d y will be c o n d ucte d i n c o m plia nce wit h I C H g ui deli nes a n d wit h all a p plica ble fe d eral 
(i ncl u di n g 2 1 C F R p arts 5 6 & 5 0), state or l ocal la ws.  
1 3. 2. 1 Wr itte n I nf or me d C o nse nt 
Pr o visi o n of writte n i nf or me d c o nse nt m ust be o btai ne d pri or t o a n y st u d y-relate d pr oce d ures.  
T he Pri nci pal I n v esti gat or will e ns ure t hat t he s u bject is gi ve n f ull a n d a de q uate oral a n d writte n 
i nf or mati o n a b o ut t he n at ure, p ur p ose, p ossi ble ris ks a n d b e nefits of t he st u d y as well as t he 
s u bject’s fi na ncial res p o nsi bilit y.  S u bjects m ust als o be n otifie d t hat t he y are free t o disc o nti n ue 
fr o m t he st u d y at a n y ti me.  T h e s u bject s h o ul d be gi v e n t he o p p ort u nit y t o as k q uesti o ns a n d 
all o we d ti me t o c o nsi der t he i nf or mati o n pr o vi de d.  
T he  ori gi nal, si g ne d writte n I nf or me d C o nse nt F or m m ust be ke pt wit h t he Researc h C hart i n 
co nf or ma n ce wit h t he i nstit uti o n’s sta n dar d o perati n g pr oce d ures.  A c o p y of t he si g n e d writte n 
I nf or me d C o nse nt F or m m ust be gi ve n t o t h e s u bj ect. 
1 3. 2. 2 S u bject D at a Pr otecti o n  
I n acc or da nce wit h t he Healt h I nf or mati o n P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A), a 
s u bject m ust si g n a n a ut h orizati o n t o release me di cal i nf or mati o n t o t he s p o ns or a n d/ or all o w t he 
s p o ns or, a re g ulat or y a ut h orit y, or I nstit uti o nal Re vie w B oar d access t o s u bject’s me dical 
i nf or mati o n t hat i ncl u des all h os pital rec or ds rele va nt t o t he st u d y, i n cl u di n g s u bjects’ m e dical 
hist or y. 
 
1 3. 2. 3  Rete nti o n of Rec or ds 
 
T he  Pri nci pal I n v esti gat or of T he Cle vela n d Cli nic s u per vises t he rete nti o n of all d oc u me ntati o n 
of a d v erse e ve nts, rec or ds of st u d y dr u g recei pt a n d dis pe nsati o n, a n d all I R B c orres p o n de nce f or 
as l o n g as nee de d t o c o m pl y wit h nati o nal a n d i nter nati o nal re g ulati o ns.  N o rec or ds will be 
destr o ye d u ntil t he Pri nci pal I n v esti gat or c o nfir ms destr ucti o n is per mitte d.  
 
1 3. 2. 4 A u dits a n d I ns pecti o ns 
A ut h oriz e d re prese nt ati ves of t he s p o ns or, a re g ulat or y a ut h orit y, a n I n de pe n d e nt Et hics 
C o m mittee (I E C) or a n I nstit uti o nal Re vie w B oar d (I R B) ma y visit t he Ce nter t o p erf or m a u dits 
or i ns pecti o ns, i ncl u di n g s o urce dat a verificati o n.  T he p ur p os e of a n a u dit or i ns pecti o n is t o 
s yste maticall y a n d i n d e pe n de ntl y e x a mi ne all st u d y-relate d acti vities a n d d oc u me nts t o 
deter mi ne w het h er t hes e acti vities were c o n d u cte d, a n d data were rec or de d, a n al yse d, a n d 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 5  
acc uratel y re p orte d acc or di n g t o t he pr ot oc ol, G o o d Cli nical Practice ( G C P), g ui deli nes of t he 
I nter nati o nal C o nfere nce o n Har m o nizati o n (I C H), a n d a n y a p plica ble re g ul at or y re q uir e me nts. 
1 3. 2. 5  D at a S afet y a n d M o nit ori n g Pl a n 
T his pr ot oc ol will a d here t o t he p olicies of t he Cas e C o m pre he nsi ve Ca n cer Ce nter Data a n d 
S afet y M o nit ori n g Pla n i n acc or da nce wit h N CI re g ul ati o ns.  
 
1 4. 0     S T A TI S TI C A L C O N SI D E R A TI O N S 
 
C o nsi deri n g t he p ote ntial f or misse d d oses of met h otre x ate or ot her dr u g, t his i n vesti gati o n 
will be base d o n a n i nte nt t o treat a nal ysis.  T his st u d y h o pes t o s h o w a re d ucti o n i n t he 
i nci dence of s e vere m uc ositis a n d ti me t o ne utr o p hil a n d platelet e n graft me nt w hile n ot 
i ncreasi n g t he i nci d e nce or se verit y of ac ute G V H D i n t he all o ge neic H C T p o p ulati o n.  
 
O ur c urre nt rat e of se v ere ( gra d e 3- 4) m u c ositis is 4 1 %. Ni net y-f o ur ( 4 7 i n eac h gr o u p) 
w o ul d be  nee d e d t o de m o nstrate a 2 5 % i m pr o ve me nt i n m uc ositis t o 1 6 %, base d o n a o n e-
si de d test wit h 5 % si g nifi ca nce a n d 8 0 % p o wer.  
 
O ur c urre nt esti mate of mea n da y t o ne utr o p hil e n graft me nt is 1 9 da ys.  O ne h u n dre d patie nts 
( 5 0 i n eac h gr o u p) w o ul d be nee d e d t o de m o nstrat e a 4 da y i m pr o ve m e nt i n ti me t o 
ne utr o p hil e n graft me nt b ase d o n a o ne-si de d test wit h 5 % si g nifica n ce a n d 8 0 % p o wer.  
 
O ur c urre nt perce nt of p atie nts ac hie vi n g pl atelet e n graft me nt b y da y 2 1 is 2 6 %. Ni net y-ei g ht 
( 4 9 i n eac h gr o u p) w o ul d be nee d e d t o de m o nstrat e a 2 5 % i m pr o ve m e nt i n platelet 
e n graft me nt t o 5 1 %, b ase d o n a o ne-si de d test wit h 5 % si g nifica nce a n d 8 0 % p o wer.  
 
O ur c urre nt rat e of a n y ac ute G V H D b y d a y 6 0 is 6 2 %.  If t he h azar d rati o bet wee n tr eat me nt 
ar ms is at m ost 1. 7, t he n we will c o ncl u de t hat t he ne w treat me nt d o es n ot si g nifica ntl y 
i ncreas e ac ut e G V H D.  F ort y-fi ve patie nts per gr o u p are nee de d t o det ect t his hazar d rati o 
usi n g a o n e-si de d n o n-i nf eri orit y l o g-ra n k test wit h 5 % si g nifica nce a n d 8 0 % p o wer. 
 
T heref ore, t his st u d y re q uires 1 0 0 patie nts t o ha ve a mi ni m u m of 8 0 % p o wer t o a d dress all of  
t he pri mar y o bjecti ves.  
 
O verall s ur vi val a n d pr o gressi o n-free s ur vi val will be esti mate d usi n g t he Ka pla n- Mei er 
met h o d a n d c o m pare d bet wee n patie nts r ecei vi n g T ac a n d M T X vers us Tac, mi ni- M T X, a n d 
M M F usi n g t he l o g-ra n k test.  H os pital sta y will be c o m pare d bet wee n gr o u ps usi n g t he 
W ilc o x o n ra n k s u m test.  T P N a n d 1 0 0- da y i nci de nce of c o m plicati o ns will be c o m pare d 
usi n g t he C hi-s q uare test.  Ac ute a n d c hr o nic G V H D will be esti mate d usi n g c u m ulati ve 
i nci de nce met h o ds a n d c o m pare d usi n g t he Pe pe- M ori test.   


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 6  
R E F E R E N C E S  
1.  H or a n J T et al. Re d uci n g t he Ris k f or Tra ns pla ntati o n- Relate d M ortalit y aft er All o ge neic 
He mat o p oietic Cell Tra ns pla ntati o n: H o w M uc h Pr o gress Has Bee n M a de? J C O 2 0 1 1; 
2 9: 8 0 5 - 8 1 3 
2.  W eis d orf D et al. Treat me nt of m o derat e/se vere ac ute graft- vers us- h ost disease after 
all o ge n eic b o ne m arr o w tra ns pla ntati o n: a n a n al ysis of cli nical ris k feat ures a n d o utc o me. 
Bl o o d 1 9 9 0; 7 5: 1 0 2 4- 1 0 3 0 
3.  R ata nat harat h or n V et al. P hase III st u d y c o m p ari n g met h otre x ate a n d t acr oli m us 
( pro graf, F K 5 0 6) wit h met h otre x ate a n d c ycl os p ori ne f or graft- v ers us- h ost disease 
pr o p h yla xis after H L A-i d e ntical si bli n g b o ne marr o w tra ns pla ntati o n. Bl o o d  1 9 9 8; 9 2: 
2 3 0 3- 2 3 1 4 
4.  Na s h R A et al. P hase 3 st u d y c o m p ari n g met h otre x ate a n d tacr oli m us wit h met h otre x ate 
a n d c ycl os p ori ne f or pr o p h yla xis of ac ute graft- v ers us- h ost disease after marr o w 
tra ns pla ntati o n fr o m u nrelate d d o n ors. Bl o o d  2 0 0 0; 9 6: 2 0 6 2- 2 0 6 8 
5.  Y u C, et a l. S y ner gis m bet wee n m yc o p h e n olate m ofetil a n d c ycl os p ori ne i n pre ve nti n g 
g raft- vers us- h ost disease a m o n g let h all y irra diate d d o gs gi ve n D L A- n o ni de ntical 
u nre late d marr o w grafts. Bl o o d.  1 9 9 8; 9 1: 2 5 8 1- 2 5 8 7.  
6.  Kie hl M G et al. M yc o p h e n olate m ofetil i n c o m bi nati o n wit h c ycl os p ori ne A ( Cs A) +/- 
pr e d nis ol o ne vers us Cs A, met h otre x ate +/- pre d nis ol o ne f or t he pr o p h yla xis of ac ute 
G V H D after all o g nei c tra ns pla ntati o n — M M F, a n e w o pti o n i n G V H D pr o p h yla xis. 
Bl o o d.  2 0 0 3; 1 0 2: 2 6 5 0a  
7.  B ol well B et al. A pr os p ecti ve ra n d o mize d trial c o m pari n g c ycl os p ori ne a n d s h ort c o urse 
met h otre x ate wit h c ycl os p ori ne a n d m yc o p he n ol ate m ofetil f or G V H D pr o p h yla xis i n 
m yel oa bl ati ve all o ge neic b o ne marr o w tra ns pla ntati o n. B o ne M arr o w Tr a ns pl a nt  2 0 0 4; 
3 4: 6 2 1 - 6 2 5 
8.  S a br y W et al. Graft - v ers us- h ost disease pr o p h yla xis wit h tacr oli m us a n d m yc o p h e n olate 
m ofetil i n H L A- m atc he d n o n m yel oa bl ati ve tra ns pl a nt reci pie nts is ass ociat e d wit h ver y 
l o w i nci de nce of G V H D a n d n o nrela ps e m ortalit y. Bi ol Bl o o d M arr o w Tr a ns pl a nt  2 0 0 9 
A u g ; 1 5( 8): 9 1 9- 2 9 
9.  Nie t o Y et al. Tacr oli m us a n d m yc o p he n olate m of etil after n o n m yel oa blati ve matc he d-
si bli n g d o n or all o ge nei c ste m-cell tra ns pla ntati o ns c o n diti o ne d wit h fl u dara bi ne a n d l o w-
d ose t otal b o d y irra diati o n. Bi ol Bl o o d M arr o w Tr a ns pl a nt  2 0 0 6; 1 2: 2 1 7- 2 2 5.  
1 0.  Prze pi or ka D et al. Tacr oli m us a n d mi ni d ose met h otre x ate f or pre v e nti o n of ac ute graft-
ve rs us- h ost disease after matc he d u nrel ate d d o n or marr o w tra ns pl a ntati o n. Bl o o d  1 9 9 6; 
8 8: 4 3 8 3 - 4 3 8 9 
1 1.  Prze pi or ka D et al.  Tacr oli m us a n d mi ni d ose met h otre x ate f or pre v e nti o n of ac ute graft-
vers us- h ost disease after H L A- mis matc he d marr o w or bl o o d ste m cell tra ns pla ntati o n. 
B o ne M arr o w Tr a ns pl a nt  1 9 9 9; 2 4: 7 6 3- 7 6 8 
1 2.  Mc D o nal d G B et al.  V e n o- occl usi ve diseas e of t h e li ver a n d m ulti or ga n fail ure after b o ne 
marr o w tra ns pl a ntati o n: a c o h ort st u d y of 3 5 5 patie nts. A n n I nter n Me d  1 9 9 3; 1 1 8( 4): 2 5 5 
1 3. Miz u m ot o C. et al. M yc o p h e n olate m of etil c o m bi ne d wit h tacr oli m us a n d mi ni d ose 
met h otre x ate after u nrelate d d o n or b o ne marr o w tr a ns pla ntati o n wit h re d uce d-
i nte nsit y c o n diti o ni n g.  I nt J He m at ol. 2 0 0 9; 8 9: 5 3 8- 5 4 5. 
  


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 7  
1 4. H oc ke n ber y D M et al. A ra n d o mize d, place b o -c o ntr olle d trial of oral becl o met has o ne 
di pr o pi o nate as a pre d nis o ne -s pari n g t hera p y f or gastr oi ntesti nal graft-v ers us -h ost 
disease. Bl o o d. 2 0 0 7; 1 0 9 : 4 5 5 7– 4 5 6 3.  
1 5.  Beil hac k A et al. I n vi v o a nal ysis of earl y e ve nts i n ac ute graft- vers us- h ost disease re v eal 
seq ue ntial i nfiltrati o n of T-cell s u bsets. Bl o o d  2 0 0 5; 1 0 6( 3): 1 1 1 3- 1 1 2 2 
1 6.  Pa n os kaltsis -M ortari A et al . In vi v o i ma gi n g of graft -vers us -h ost -disea s e i n mice. Bl o o d  
2 0 0 4; 1 0 3( 9): 3 5 9 0 -3 5 9 8  
1 7.  W ys o c ki C A et al. Le u k o c yt e mi grati o n a n d graft- vers us- h ost disease. Bl o o d  2 0 0 5; 
1 0 5( 1 1): 4 1 9 1- 4 1 9 9 
1 8.  P ar mar S, et al. Pr o p h yla xis of Graft- Vers us- H ost Disease i n U nrelate d D o n or 
Tra ns pla ntati o n wit h Pe nt ostati n, Tacr oli m us, a n d Mi ni- Met h otre x ate: A P hase I/II 
c o ntr olle d, A da pti vel y R a n d o mize d St u d y. J Cli n O nc. 2 0 1 1; 2 9: 2 9 4- 3 0 2.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 8  
A P P E N DI X I 
 
A C U T E G R A F T V S. H O S T DI S E A S E G R A DI N G S C A L E  
 
Ac ute G V H D St a gi n g: 
 
Sta ge  
S ki n  
Li ver  
I ntesti ne 
0  
N o ras h  
Bilir u bi n <  2 m g/ dl  
< 5 0 0 m L diarr hea per da y  
1  
Mac ul o pa p ular ras h 
< 2 5 % of b o d y s urface  
Bilir u bi n 2 -3 
m g/ dl  
> 5 0 0 -1 0 0 0 m L diarr hea per 
da y or persiste nt 
na usea / v o miti n g/a n ore xia 
2  
Mac ul o pa p ular ras h 2 5 -
5 0 % of b o d y s urface  
Bilir u bi n 3. 1 -6 
m g/ dl  
> 1 0 0 0 -1 5 0 0 m L 
diarr hea per da y  
3  
Mac ul o pa p ular ras h > 5 0 % 
b o d y s urface area or 
Ge neralize d er yt hr o der ma  
Bilir u bi n 6. 1 -
1 5  
m g/ dl  
> 1 5 0 0 m L diarr hea per 
da y  
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  
Bilir u bi n > 1 5 
m g/ dl  
> 2 0 0 0 m L diarr hea  per 
da y or  se vere a b d o mi nal 
pai n +/ -ile us 
 
Ac ute G V H D Gr a di n g:  
  
 
Gra de  
S ki n  
Li ver  
GI  
I 
Sta ge 1 -2  
0  
0  
II 
Sta ge 3  or  
Sta ge 1 or  
Sta ge 1  
III 
---- 
Sta ge 2 -3  
Sta ge 2 -4  
I V 
Sta ge 4  
Sta ge 4  
N A  
 
C o n versi o n c hart f or sta gi n g t he v ol u me of Di arr h ea i n Pe diatric Patie nts: ( S o urce 
ada pte d fr o m t he m o difie d ke yst o n e criteri a G V H D re p orti n g f or m) a n d t h e pe diatric 
G U T G V H D st a gi n g is b ase d o n t he CI B M T R/ C T N tec h nical ma n u al of practice v ersi o n 
2 ( Se p, 2 0 0 5). 
 
 
S T A G E  
  
  
  
 
S T O O L V O L U M E   
    0  
  
  
  
  
n o ne or diarr h ea < 2 8 0 ml/ m2/ da y  
    1  
 
 
 
 
2 8 0 -5 5 5 ml/ m 2/ day  
    2  
  
  
  
  
5 5 6- 8 3 3 ml/ m 2/ day 
    3  
 
 
 
 
> 8 3 3 ml/ m 2/ day  
    4  
  
  
  
  
se vere a b d o mi nal pai n, w/ or w/ o ut ili us 
 
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
3 9  
A P P E N DI X II 
 
C H R O NI C G V H D S C O RI N G:  usi n g NI H c o nse ns us criteria 
 
 
 
Sc ore 0  
Sc ore 1  
Sc ore 2  
Sc ore 3  
Perf or m a nce Sc ore:  
 
 
K P S  E C O G  L P S  
  As y m pt o matic  
a n d f ull y acti ve 
( 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 pa ble of self -
care, > 5 0 % of 
wa ki n g h o urs o ut 
of be 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 nical Feat ures:  
 Mac ul o pa p ular 
ras h 
 Lic he n pla n us -li ke 
feat ures 
 P a p ul os q ua m o us 
lesi o ns or ic ht h ys 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 he ma  
 Er yt h r o der ma 
 P oi kil o der ma  
 Pr urit us  
 Scler otic feat ures  
 Hair i n v ol ve me nt  
 Nail i n v ol ve me nt  
% B S A i n v ol ve d:  
 
 
 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 ve me nt 
wit h s u perficial 
scler otic feat ures 
“ n ot hi d e b o u n d” 
(a ble t o pi nc h) 
 > 5 0 % B S A O R dee p 
scler otic feat ures “ hi de-
b o u n d” ( u na ble t o 
pi nc h) O R  i m paire d 
m o bilit y, ulcerati o n or 
se vere pr urit us 
M O U T H  
 
 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 ke 
si g nifica ntl y 
 M o derate  
s y m pt o ms wit h 
disease si g ns 
WI T H  partial 
li mitati o n of oral 
i nta ke 
 Se vere s y m pt o ms 
wit h disease si g ns o n 
e xa mi nati o n WI T H  
maj or li mitati o n of oral 
i nta ke 
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 ye 
s y m pt o ms n ot 
affecti n g A D L 
(re q uiri n g e ye-
dr o ps <  3 x/ da y) 
O R  
as y m pt o matic 
si g ns of kerat o-
c o nj u ncti vitis 
sicca 
 M o derate dr y 
e ye s y m pt o ms 
partiall y affecti n g 
A D L (re q uiri n g 
e ye-dr o ps > 3 
x/ da y or p u nct ual 
pl u gs), 
WI T H O U T  
visi o n 
i m pair me nt 
 Se vere dr y e ye 
s y m pt o ms si g nifica ntl y 
affecti n g A D L (s pecial 
e ye ware t o relie ve pai n) 
O R  u na ble t o w or k 
beca use of oc ular 
s y m pt o ms O R  l oss of 
visi o n ca use d b y 
kerat oc o nj u ncti vitis 
sicca 
GI T R A C T  
 N o s y m pt o ms  
 S y m pt o ms 
s uc h as 
 S y m pt o ms 
ass ociate d wit h 
 S y m pt o ms ass ociate d 
wit h si g nifica nt wei g ht 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
4 0  
d ys p ha gia, 
a n ore xia, na usea, 
v o miti n g, 
a b d o mi nal pa i n 
or diarr hea 
wit h o ut 
si g nifica nt wei g ht 
l oss ( < 5 %) 
mil d t o 
m o derate d wei g ht 
l oss ( 5-1 5 %)  
l oss > 1 5 %, re q uires 
n utriti o nal s u p ple me nt f or 
m ost cal orie nee ds O R  
es o p ha geal dilati o n  
L I V E R 
A S T _ _ _ _  
A L T _ _ _ _  
A P _ _ _ _  
T bili 
 
 N or mal L F T  
 Ele vate 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 nz y mes 2 -5 x 
U L N  
 Bilir u bi n or e nz y mes 
> 5 x U L N  
L U N G S  
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  
 M il d 
s y m pt o ms ( S O B 
cli m bi n g o ne 
fli g ht of stairs) 
 
 
 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 O B 
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 ver s y m pt o ms 
( S O B at rest; re q uiri n g 
O 2)  
 
 
 F E V 1 4 0 -5 9 % O R  
L F S 6 -9  
J OI N T S A N D 
F A S CI A  
 N o 
s y mpt o ms  
 
 Mil d ti g ht ness 
of ar ms or le gs, 
n or mal or mil d 
decrease d ra n ge 
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 he ma t h o u g ht 
d ue t o fasciitis, 
m o derate d 
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 decrease 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 oes, 
b utt o n s hirts, dress self, 
etc.)  
 
G E NI T A L T R A C T  
 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 nec ol o gic 
e xa m 
 
 S y m pt o matic 
wit h m o derate 
si g ns o n e xa m 
A N D  wit h mil d 
d ys pare u nia or 
disc o mf ort wit h 
g y nec ol o gic 
e xa 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 vere 
ulcerati o n)  A N D  se vere 
pai n wit h c oit us or 
i na bility t o i nsert 
va gi nal s pec ul u m  
 
Ot h er i n di c at or s, cli ni c al m a nif e st ati o n s or c o m pli c ati o n s r el at e d t o c hr o ni c G V H D. 
  
C h e c k all t h at a p pl y 
  
A s si g n a s c or e t o it s s e v erit y ( 0- #) b a s e d o n it s f u n cti o n al i m p a ct w h er e a p pli c a bl e 
  
○     n o n e = 0 
  
○     mil d  = 1 
  
○     m o d er at e = 2 
  
○     s e v er e = 3 
 
 
 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
4 1  
E s o p h a g e al stri ct ur e/ w e b _ _ _ _ _    P eri c ar di al Eff u si o n _ _ _ _ _         Pl e ur al Eff u si o n( s) _ _ _ _ _ 
A s cit e s ( s er o siti s) _ _ _ _ _ 
          N e p hr oti c s y n dr o m e _ _ _ _ _        P eri p h er al N e ur o p at h y _ _ _ _ _ 
M y a st h e ni a Gr a vi s _ _ _ _ _              C ar di o m y o p at h y _ _ _ _ _              E o si n o p hili a > 5 0 0 ul _ _ _ _ _ 
P ol y m y o siti s _ _ _ _ _                       C ar di a c c o n d u cti o n                     C or o n ar y art er y i n v ol v e m e nt                                       
 
                                                d ef e ct s _ _ _ _ _                             i n v ol v e m e nt _ _ _ _ _ 
Pl at el et s < 1 0 0, 0 0 0/ ul _ _ _ _ _        Pr o gr e s si v e o n s et _ _ _ _ _ _ _ _ _ _ _ _      
Ot h er s: ( s p e cif y) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
C H R O NI C G V H D G R A DI N G  
 
MI L D : i n v ol ves o nl y 1 or 2 or ga ns or sites (e x ce pt t he l u n g), wit h n o cli nicall y si g nifica nt 
f u ncti o nal i m pair me nt ( ma xi m u m of sc ore 1 i n all affect e d or ga ns or sites).  
 
M O D E R A T E : i n v ol ves: ( 1) at least 1 or ga n or sit e wit h cli nicall y si g nifica nt b ut n o maj or 
disa bilit y ( ma xi m u m sc ore of 2 i n a n y affecte d or ga n or site) or ( 2) 3 or m ore or ga ns or sites 
wit h n o cli nicall y si g nifica nt f u ncti o nal i m pair me nt ( ma xi m u m sc ore of 1 i n all affecte d or ga ns 
or sites). Or a l u n g sc ore of 1 will als o be c o nsi dere d m o derate c hr o nic G V H D.  
 
S E V E R E : i n dicates maj or disa bilit y ca us e d b y c hr o nic G V H D (sc ore of 3 i n a n y or ga n or 
site). Or a l u n g sc ore of 2 or great er will als o be c o nsi dere d se vere c hr o nic G V H D. 
 
 
A P P E N DI X III 
 
W O R L D H E A L T H O R G A NI Z A TI O N ( W H O) M U C O SI TI S G R A DI N G S C A L E 
 
Gra de 0  
Gra de 1  
Gra de 2  
Gra de 3  
Gra de 4  
N o 
m uc ositis  
S ore ness +/ - 
Er yt h e ma  
Er yt h e ma, 
ulcers; a bilit y 
t o eat s oli ds 
Ulcers , 
re q uires li q ui d 
diet   
A li me ntati o n 
n ot p ossi ble.  
 
T he f oll o wi n g a d diti o nal g ui deli nes ma y b e use d i n t he assess me nt of oral m uc ositis  
 G r a de 1 ma y i n cl u de b uccal m uc osal s call o pi n g wit h or wit h o ut er yt h e ma. 
N o ulcers.  Patie nt c a n s wall o w a s olid diet. 
 G r a de 2 ma y i n cl u de ulcers wit h or wit h o ut er yt h e ma.  Patie nt ca n s w all o w a 
s oli d diet. 
 Gr a de 3 ma y i n cl u de ulcers wit h or wit h o ut (e xte nsi ve) er yt he ma.  Patie nt is 
a ble t o s wall o w a li q ui d, b ut n ot s oli d diet. 
 G r a de 4 refers t o m uc ositis t o t he e xte nt t hat ali me ntati o n is n ot p ossi ble.  If 
t otal pare nteral n utriti o n was starte d f or reas o ns ot her t ha n m uc ositis, a 
deter mi nati o n of t he s u bj ect’s a bilit y t o s w all o w m ust be ma de usi n g t he 
a b o ve criteria. 


C A S E  6 Z 1 3   
Pr ot oc ol Versi o n 6/ 2 8/ 2 0 2 2 
4 2  
 
A P P E N DI X I V 
 
T BI A D MI NI S T R A TI O N  
 
Patie nts ma y be tr eate d eit her i n t he A P/ P A p ositi o n a n d/ or i n t he ri g ht a n d left lateral 
p ositi o n.  C o m pe nsat ors or bl oc ks ma y be use d t o c o m pe nsate f or t he t hi n ner parts of t h e 
anat o m y ( nec k, h ea d, l o wer le gs, a n d feet). 
 
T otal d ose will be 1 2 0 0- 1 3 2 0 c G y i n 6- 8 fracti o ns o ver 3- 4 da ys wit h at least si x h o urs 
be t wee n fracti o ns de pe n di n g o n i nstit uti o nal g ui deli nes.  D ose will be prescri be d at t he le vel 
of t he  u m bilic us at mi d pla ne. 
 
T BI will be deli vere d fr o m eit her a li near accelerat or or c o balt s o urce at a d ose rate of 
bet wee n 4 a n d 2 6 c G y/ mi n ute usi n g e ner gies of b et wee n 1 a n d 2 5 M V. 
 
T he s ki n d ose s h o ul d be at least 9 0 % of t he prescri be d d ose.  If a hi g h er e n er g y bea m ( > 4 
M V)is use d f or t he T BI treat me nts, a b ea m s p oiler s h o ul d be use d t o acc o m plis h t his or 
t her m ol u mi nesce nt d osi metr y d ata s u b mitte d s h o wi n g t hat t he s ki n d ose is at least 9 0 % of t he 
pre scri be d d os e. 
 
Testic ular b o osts c o ul d b e use d f or all males wit h A L L (a n d acc or di n g t o i nstit uti o nal 
practices f or ot her dis eas es) de pe n di n g o n i nstit uti o nal g ui deli nes.  T h e testic ular b o ost 
rec o m me n dati o n is si n gl e 4 0 0 c G y fracti o n wit h eit her electr o ns pres cri be d t o D ma x  or 
p h ot o ns  prescri be d t o t he mi d pla ne of t he scr ot u m.  If electr o ns are use d, t h e e ner g y f or t he 
testic ular b o ost de pe n ds o n t he t hic k ness of t he testicles a n d is c h ose n s o t hat t he D 9 0 
c orres p o n ds t o t he p osteri or s urface of t he s cr ot u m. 

ICF_003.pdf: 
CASE6Z13 Informed Consent 5/4/2022 
Page 1 of 13 
CONSENT FOR CANCER RESEARCH  
 
Project Title: Tacrolimus, mini-dose Methotrexate and Mycophenolate Mofetil versus 
Tacrolimus and Methotrexate for the Prevention of Acute Graft-versus-Host-Disease 
(NCT01951885) 
 
Principal Investigator: Betty Hamilton, M.D. (CC) 216-445-7580  
 
Cancer research studies are coordinated by physicians and scientists from Cleveland Clinic, 
University Hospitals and Case Western Reserve University (CWRU) through the NIH National 
Cancer Institute (NCI) designated Case Comprehensive Cancer Center (Case CCC).  The goal 
of this collaboration is to enhance cancer treatment and research in Northeast Ohio.  This study 
is being offered at Cleveland Clinic. 
 
INTRODUCTION 
We are asking you to participate in a clinical research study. The purpose of this document is 
to summarize your discussion with the research team and provide you with written information 
to help you decide whether you want to participate in research.  Your decision is completely 
voluntary.  
 
Your treating doctor may also be an investigator on this research study. If so, your doctor will 
have an interest in both your welfare and in the research study. You are not required to take 
part in this research study offered by your doctor. You may ask for a second opinion from 
another doctor who is not linked to this study. If you choose not to be in this study, the quality 
of your regular medical care will not be affected.  
 
Please ask any questions you may have about the study or this consent form before signing it. 
Please take your time to make your decision. You will be given a copy of this form to keep. 
 
PURPOSE 
You are being asked to participate in this research study because you have a medical disease 
called a hematological or lymphoproliferative malignancy (cancer of the blood) and have 
agreed to undergo an allogeneic hematopoietic cell transplant.  This means the stem cells you 
receive for your transplant will come from a donor.  The details of the transplant procedure are 
explained in a separate consent form.  When you have an allogeneic transplant, you may get 
another disease called graft-versus-host disease (GVHD).  GVHD is a reaction that occurs 
when donor bone marrow or peripheral blood stem cells are infused into your body and sees 
your body as foreign.  As a result, this damages many tissues and affects your immune system.  
Many organs of the body (skin, (including hair), eyes, mouth, liver, joints, muscles and bowel) 
can be damaged by this immune disorder.  GVHD can cause skin rashes, feeling sick to your 
stomach, throwing up, abdominal pain, diarrhea and/or yellowing of the skin or eyes.  In severe 
cases, it can cause death.  You will be given drugs that have been shown to help prevent you 
from getting GVHD or to lessen the severity of it.  You will start GVHD prevention around the 
time you get your donor cells and it can last many months after the transplant. 
 


CASE6Z13 Informed Consent 5/4/2022 
Page 2 of 13 
The purpose of this study is to compare the effectiveness two different combinations of GVHD 
medications to prevent or lessen the severity of GVHD.  One is using a standard of treatment 
regimen consisting of Methotrexate and Tacrolimus. The other treatment plan uses a lower 
dose of Methotrexate with Tacrolimus and Mycophenolate. 
 
All of the drugs being used in this study are approved by the U.S. Food and Drug 
Administration (FDA) for helping to prevent (or lessen the severity of) graft versus host 
disease.  This study consists of two study groups.  Group A will receive the standard dose of 
Methotrexate with Tacrolimus.  Group B will receive a “mini-dose” of Methotrexate with 
Tacrolimus and Mycophenolate.  If you decide to join the study, you will be randomly assigned 
to Group A or B.  If you choose not to join the study, you will receive standard treatment for 
GVHD. 
 
About 100 people will take part in this research study at Cleveland Clinic 
  
Conflict of Interest Disclosure 
One or more of the Investigators conducting this study serve as paid speakers, consultants or 
advisory committee members for a company that makes products used in this study.  These 
financial interests are within permissible limits established by the Cleveland Clinic Conflict of 
Interest Policy.  If you have any questions, please ask your study doctor or call the Institutional 
Review Board at 216-444-2924. 
 
STUDY PROCEDURES 
Your participation in this study will last for one year after your hematopoietic cell transplant.  
You will take the GVHD drugs in Group A or B for at least 100 days and then your doctor will 
begin to taper the medications if you do not show any signs of GVHD.  The taper is usually 
done by approximately 180 days, but may be longer if there are signs or symptoms of GVHD.   
 
Your doctor may decide to stop or adjust the dose of the GVHD drugs you are receiving before 
100 days for many reasons including if: 
 It is considered to be in your best interest 
 Pregnancy occurs during the course of therapy 
 The study is temporarily or prematurely suspended 
 You experience excessive toxicity to one of the drugs 
 
If you are removed from the research study, your doctor will explain to you why you were 
removed.  Your doctor will decide with you, what further treatment is needed or available for 
GVHD treatment. 
 
In addition, you can choose to stop participating in the research study at any time.  However, if 
you decide to end your participation in this study, we encourage you to talk to your doctor first. 
 
It is standard of care to be followed closely after your hematopoietic cell transplant.  These 
details are discussed in the treatment consent for your transplant.  All of the assessments, tests, 
hospital stays and follow up appointments for this study are part of the standard of care for 
your hematopoietic cell transplant. 


CASE6Z13 Informed Consent 5/4/2022 
Page 3 of 13 
 
Screening 
The evaluations to determine if you are eligible for this study will take place during your 
staging appointments for your hematopoietic cell transplant.  All of these test and assessments 
are done as part of your transplant evaluation. These include the following:  
 Age, gender, race 
 Medical history 
 Complete physical exam 
 Disease assessment of tumor or site involved 
 Weight 
 Performance status (ECOG or Lansky scores).  These scores represent how a 
person’s disease affects the daily living activities and abilities of the person. 
 Laboratory test results including complete blood count and differential, liver enzyme 
tests, coagulation tests, and tests to see if you have been exposed to viruses such as 
cytomegalovirus (CMV) and the AIDS virus. 
 Pregnancy test for female of childbearing age 
 Pulmonary function testing 
 
Randomization/Study Intervention 
If these evaluations show that you are eligible to participate in this research study and you 
choose to participate in this study, you will be assigned to Group A or Group B by chance 
using a process similar to the flip of a coin.  This process is called randomization.  Neither you 
nor the study staff will select the group to which you will be assigned. 
 
You will receive Tacrolimus starting the day before (day -1) you receive your donor cells (day 
0) regardless of which group you are assigned to. Tacrolimus is given once a day and will 
continue for 100 days after your transplant.  Tacrolimus will be given intravenously but will be 
changed to oral medication when you can tolerate it. 
 
If you are in Group B, you will also receive Mycophenolate starting the day after (day +1) your 
transplant and continuing for 45. Mycophenolate is given two times a day.  Mycophenolate 
will be given intravenously but will be changed to oral medication when you can tolerate it. 
 
Both Tacrolimus and Mycophenolate can be tapered after day 100 and day 45 respectively if 
there is not any evidence of GVHD.  This will be decided by your doctor.   
 
If you are in Group A, you will receive one Methotrexate dose of 15 mg/m2 on the day after 
your transplant (day +1) and one Methotrexate dose of 10 mg/m2 on day +3, day +6, and day + 
11.  Methotrexate is given intravenously.  This is considered the standard dose of 
Methotrexate. 
 
If you are in Group B, you will receive a “mini-dose” of Methotrexate on day +1, day +3 and 
day +6.  This “mini-dose” will be 5 mg/m2 of Methotrexate. 
 
 
 


CASE6Z13 Informed Consent 5/4/2022 
Page 4 of 13 
Study Assessments 
After your hematopoietic cell transplant, data will be collected.  All of the test and assessments 
are standard of care for patients undergoing a hematopoietic cell transplant. The following is a 
list of parameters that will be followed in this study after your transplant:  
 Performance status (ECOG or Lansky). These scores represent how a person’s 
disease affects the daily living activities and abilities of the person. 
 Disease/tumor assessments 
 Weight 
 Laboratory test including complete blood count and differential, liver enzymes and 
coagulation studies 
 Laboratory tests to monitor for infection with the Cytomegaolvirus (CMV), a 
common virus which can cause infection when you are immunosuppressed. 
 Degree of inflammation and sores (mucositis) in your oral cavity from chemotherapy 
and medications.  
 GVHD monitoring 
 Laboratory tests to determine the percent of donor white cells compared to your own 
white cells in your blood (chimerism studies) to monitor how well your donor cells 
are growing in your bone marrow.  
 Tacrolimus serum levels 
 Organ (liver, kidney and pulmonary) toxicity assessments 
 Infection 
 Need for parenteral nutrition, which is nutrition given intravenously through a 
catheter if you are unable to eat.  
 Use of intravenous medicine to control your pain. 
 
The above parameters will be followed for one year after your transplant. 
 
RISKS 
GVHD is caused by an immune attack on your tissues from the transplanted donor cells and 
there for all treatments for GVHD include drugs to suppress (turn off) this immune attack.  All 
of the drugs in this study can increase your chance of infection including the standard treatment 
for GVHD.  There for you will take several protective antibiotics and be watched carefully for 
an infections while you are being treated for GVHD.  Tell your doctors immediately if you get 
a fever, chills, a cough or any other symptoms that might be part of an infection. 
 
All of the drugs in this study can have risk and side effects, including the standard treatment 
for GVHD.  Your doctors will watch you carefully for any side effects and will modify your 
treatment if they develop.  The drugs used in this study may cause all, some or none of the side 
effects listed below.  In addition, there is always the risk that you might experience side effects 
or other adverse reactions which other patients before you have not experienced 
 
Side effects that we know about are described in the tables below.  Side effects are categorized 
into either: 
 Likely – This type of side effect is expected to occur in more than 20% of patients.  
This means that 21 or more patients out of 100 might get this side effect 


CASE6Z13 Informed Consent 5/4/2022 
Page 5 of 13 
 Unlikely – This type of side effect is expected to occur in 20% of patients or fewer.  
This means that 20 patients or fewer out of 100 might get this side effect 
 Rare, but Serious – This type of side effect does not occur very often, in fewer than 
2% of patients, but is serious when it occurs.  This means that 1 or 2 patients (or 
fewer) out of 100 might get this side effect. 
 
Risk and Side Effects of Tacrolimus 
 
Likely 
Less Likely 
Rare but Serious 
 Reversible, but 
sometimes irreversible 
damage to the kidneys 
 Loss of magnesium, 
calcium and potassium 
 High blood pressure 
 Tremors (shaking of 
the hands) 
 Increases in blood 
lipids/fats (cholesterol 
and triglycerides) 
 Nausea 
 Vomiting 
 Liver problems 
 Changes to the brain 
that may cause 
confusion 
 Insomnia 
 Unwanted hair 
growth 
 
 Seizures 
 Changes in vision 
 Dizziness 
 Red blood cell destruction 
 Progressive multifocal 
leukoencephalopathy, a rare 
disease caused by a virus 
which causes progressive 
damage to the white matter of 
the brain.   
 Posterior reversible 
encephalopathy syndrome 
(PRES), a rare neurologic 
syndrome typically including 
symptoms of elevated blood 
pressure, headache, confusion 
and possibly seizure 
It is very important that you do not eat grapefruit or drink grapefruit juice while taking 
Tacrolimus.  It is very important that you do not drink soft drinks containing bergamottin.  
Common soft drinks that have bergamottin are Fresca, Squirt and Sunny Delight. 
 
Risk and Side Effects of Mycophenolate Mofetil 
 
Likely 
Less Likely 
Rare but Serious 
 Miscarriage 
 Birth defects 
 Diarrhea 
 Damage to unborn baby 
 Limited effectiveness of 
birth control 
 Stomach pain 
 Upset stomach 
 Vomiting  
  Headache 
 Tremors (shaking of the 
hands) 
 Low white blood cell 
 Low red blood cell count 
(anemia) 
 Rash 
 Difficulty falling asleep or 
staying asleep 
 Dizziness 
 Uncontrollable hand 
shakes  
 Difficulty breathing 
 Unusual bruising 
 Fast heartbeat 
 Excessive tiredness 
 Weakness 
 Blood in stool 
 Bloody vomit 
 Change in vision 
 Progressive multifocal 
leukoencephalopathy, a 
rare disease caused by a 
virus which causes 
progressive damage to the 


CASE6Z13 Informed Consent 5/4/2022 
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count with increased risk 
of infection 
 Increased blood lipids/fats 
(cholesterols) 
 Swelling of the hands, 
feet, ankles, or lower legs 
white matter of the brain.   
 
 
Additional Information about Mycophenolate Mofetil (MMF) 
 MMF could be damaging to an unborn baby if you are pregnant or become pregnant 
while receiving the drug. 
 MMF can make birth control pills less effective and increase your chances of 
becoming pregnant while taking it. 
 If you could become pregnant, you must use 2 effective forms of birth control for 4 
weeks before starting MMF, during treatment, and for 6 weeks after stopping MMF. 
 
 
 
Risk and Side Effects of Methotrexate 
 
Likely 
Less Likely 
Rare but Serious 
 High levels of liver 
enzymes in the blood 
which may mean liver 
irritation or damage 
 
 Nausea 
 Vomiting 
 Loss of appetite 
 Diarrhea 
 Chills and/or fever 
 Inflammation and/or sores 
in the mouth, gums, throat 
and/or esophagus 
 Inflammation of the 
intestines which may 
cause bleeding 
 Sensitivity to sunlight and 
increased risk of sunburn 
 Fewer white blood cells, 
red blood cells and 
platelets in the blood. 
 A low number of red 
blood cells can make 
you feel tired and 
weak. 
 A low number of white 
blood cells can make it 
easier to get infections. 
 A low number of 
platelets causes you to 
 Severe allergic reaction 
which can be life 
threatening with shortness 
of breath, low blood 
pressure and a rapid heart 
rate 
 The rapid death of large 
numbers of tumor cells 
which can cause the 
potassium and phosphate 
salts and the uric acid in 
the blood to rise quickly 
and this could lead to a 
life-threatening irregular 
heart beat or damage to 
the kidneys.  
 Severe rashes which can 
cause loss of skin or 
damage to mucous 
membranes or which can 
cause peeling, redness and 
pain on the palms of the 
hands and soles of the feet  
 Damage, inflammation 
and/or scarring of lung 


CASE6Z13 Informed Consent 5/4/2022 
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bruise and bleed 
 Learning disability 
 Dizziness 
 Sense of not feeling well 
or tiredness 
 Drowsiness 
 Blurred vision 
 Rashes with itching and 
hives 
 Hair loss, inflammation of 
the hair follicles 
 Acne 
 Tearing and inflammation 
of the eyes 
 Darkening of the 
fingernails 
tissue which may make 
you short of breath and 
cough 
 Seizures 
 Temporary damage to the 
brain such that you may 
experience headaches, 
drowsiness, difficulty 
speaking or forming 
words, blurred vision or 
temporary blindness, and 
decreased reflexes 
 Temporary loss of 
function or feeling in the 
lower part of the body 
(partial paralysis) 
 Severe damage to brain 
tissue which over time 
could lead to difficulty 
carrying out normal daily 
tasks or could lead to a 
coma. 
 Inflammation and scarring 
of the liver 
 Damage to the bone 
which could lead to 
arthritis pain and 
weakness of the bone 
 Inflammation of the heart 
 Fluid buildup around the 
heart 
 Damage to the kidney 
 
 
Reproductive Health/Sexual Activity 
Because the risk to an unborn child (human embryo, fetus) or pregnant/lactating woman is 
unknown, you can NOT participate in this study if you are a female of childbearing potential 
unless you have a current negative pregnancy test.  In addition, whether you are male or 
female, you must agree to either complete abstinence from heterosexual intercourse or use 
(two) medically approved forms of birth control for the duration of the study. You will agree to 
inform your doctor immediately if:   
 
1) you have any reason to think you may be pregnant  
 
2) you find that there is now a risk of you becoming pregnant  
 
3) you have stopped using a medically approved form of birth control Acceptable 
methods of birth control include: birth control pills, birth control implants (depo-provera), 
diaphragm, intrauterine device (IUD), cervical cap and condoms with spermicide. 


CASE6Z13 Informed Consent 5/4/2022 
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BENEFITS  
Although this study cannot be guaranteed to be of benefit to you, it is hoped that your taking 
part may help in the treatment of your GVHD. A possible advantage of this study is that one of 
the treatment regimens may lessen the severity of GVHD and also lessen the toxicity of side 
effects of the drugs used in the treatment of GVHD.  However, you may not benefit from this 
treatment.  It is also hoped that the information learned from this study will help your doctors 
better treat GVHD in patients having hematopoietic cell transplants in the future. 
 
ALTERNATIVE PROCEDURES OF TREATMENT 
If you do not wish to participate in this study, you will be treated with standard GVHD therapy 
according to the type of preparative regimen and type of donor being used for your allogeneic 
hematopoietic cell transplant. 
 
COSTS AND COMPENSATION 
Cleveland Clinic will pay for the costs of procedures, tests, visits, hospitalization or drugs in 
connection with this treatment.  You or your insurance company will be responsible for all cost 
because GVHD treatment is standard of care for allogeneic hematopoietic cell transplants 
 
For more information on clinical trial and insurance coverage, you can visit the National 
Cancer Institute’s (NCI) website at  
http://cancer.gov/clinicaltrials/understanding/insurance-coverage   
You can print a copy of the ‘Clinical Trials and Insurance Coverage’ information from this 
website.  Another way to get information is to call 1-800-4-CANCER (1-800-422-6237) and 
ask NCI for a free copy.  
 
RESEARCH-RELATED INJURY  
If injury occurs as a result of your involvement in this research, medical treatment is available 
from Cleveland Clinic or another medical facility but you/your medical insurance will be 
responsible for the cost of this treatment.  A research injury is an injury that happens as a result 
of taking part in this research study.  If you are injured by a medical treatment or procedure 
that you would have received even if you weren’t in the study, that is not considered a 
“research injury”. There are no plans for payment of medical expenses or other payments, 
including lost wages, for any research-related injury.  To help avoid injury, it is very important 
to follow all study directions. 
 
Further information about research-related injuries is available by contacting the Cleveland 
Clinic Institutional Review Board at (216) 444-2924  
 
 
PRIVACY AND CONFIDENTIALITY 
Authorization to Use or Disclose (Release) Health Information that Identifies You for a 
Research Study  
 
If you volunteer to participate in this research, your protected health information (PHI) that 
identifies you will be used or disclosed to Dr. Betty Hamilton and the research staff at 


CASE6Z13 Informed Consent 5/4/2022 
Page 9 of 13 
Cleveland Clinic for the purposes of this research and to Case Western Reserve University for 
administration. 
 
The PHI that we may use or disclose (release) for this research may include your name, 
address, phone number, date of birth, Social Security number, information from your medical 
record, lab tests, or certain information relating to your health or condition. 
 
Some of the tests and procedures done solely for this research study may also be placed in your 
medical record so other doctors know you are in this study.  Upon completion of the study, you 
may have access to the research information that is contained in your medical record.   
In addition to the investigators and research staff listed above, your PHI may be looked at by 
other groups involved with the study such as the Cleveland Clinic Institutional Review Board, 
and the Case Comprehensive Cancer Center Protocol Review and Monitoring Committee.  
Your PHI may also be used by and/or disclosed (released) to: 
 
 The Food and Drug Administration; 
 The Department of Health and Human Services; 
 The National Cancer Institute (NCI); 
 Other Institutional Review Boards;  
 Data Safety and Monitoring Boards;  
 
Once your personal health information is released it may be re-disclosed and no longer 
protected by privacy laws. 
 
Your research information may be used and disclosed indefinitely, but you may stop these uses 
and disclosures at any time by writing to Dr. Betty Hamilton, Cleveland Clinic R35, 9500 
Euclid Avenue, Cleveland, OH 44195 or calling 216/445-7580. .  Your participation in the 
research will stop, but any information previously recorded about you cannot be removed from 
the records and will continue to be used as part of this research.  Also, information already 
disclosed outside the Cleveland Clinic cannot be retrieved.  This will not affect your rights to 
treatment or benefits outside the research study.    
 
The Cleveland Clinic will not use your information collected in this study for another research 
purpose without your written permission; unless the Cleveland Clinic Institutional Review 
Board (IRB) assures your privacy and confidentiality is protected.  The IRB is a committee 
whose job it is to protect the safety and welfare of research subjects. 
 
By signing this informed consent form, you are authorizing such access to your research and 
medical record information.  If you choose not to sign this consent form, you will not be able 
to participate in this research study.  This Authorization does not have an expiration date. 
 
Voluntary Participation 
Your participation in this research study is voluntary.  Choosing not to participate will not alter 
your usual health care or involve any penalty or loss of benefits to which you are otherwise 
entitled.  If you decide to join the study, you may withdraw at any time and for any reason 


CASE6Z13 Informed Consent 5/4/2022 
Page 10 of 13 
without penalty or loss of benefits.  If information generated from this study is published or 
presented, your identity will not be revealed.   
 
In the event new information becomes available that may affect the risks or benefits associated 
with this study or your willingness to participate in it, you will be notified so that you can 
decide whether or not to continue participating.   
 
Termination of Participation 
Your participation in this study may be discontinued by your doctor or the investigator in 
charge of the study without your consent for any reason, including but not limited to: 
 His/her judgment that any condition or circumstance may jeopardize your welfare or the 
integrity of the study 
 Your failure to follow instructions of your doctor or the investigator 
 If the study is stopped by the investigator and/or your doctor before completion of the 
study. 
 
Questions About the Research 
If you have any questions, you can ask the Principal Investigator and/or research staff.  Dr. 
Betty Hamilton can be reached at 216/445-7580. 
 
Emergency and After-hours Contact Information   
As a Cleveland Clinic patient, you should contact the page operator at (216) 444-2200 or toll 
free at (800) 223-2273, and ask for the oncologist (cancer doctor) that is on call. 
 
If you have questions about your rights as a research subject, you may contact the Institutional 
Review Board (IRB) at Cleveland Clinic IRB 216-444-2924  
 
Where Can I Get More Information? 
You may call the National Cancer Institute’s Cancer Information Services at: 
 
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615 
 
You may also visit the NCI website at http://cancer.gov 
 
For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials 
 
For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo 
You will get a copy of this form.  If you want more information about this study, ask your 
study doctor.   
 
US National Institutes of Health (NIH) Clinical Trial Database 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This Web site will not include information that can identify you. At 
most, the Web site will include a summary of the results. You can search this Web site at any 
time. 


CASE6Z13 Informed Consent 5/4/2022 
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OPTIONAL SAMPLE RESEARCH 
Collection, Testing, and Storage of Human Subject Material 
The purpose of this portion of the consent document is to provide you with information to help 
you decide whether you wish to donate extra tissue samples for research during a planned 
clinical evaluation in which samples would be obtained for clinical purposes also.  Your 
decision is completely voluntary and will not affect your medical care or your eligibility to 
participate in a clinical study if you choose not to donate your tissue.  You are being asked to 
donate tissue samples to the Research Sample Repository because you have consented to a 
graft versus host disease (GVHD) study.  A repository is a place where tissue samples are 
frozen and stored to be used for research in the future.  Research in GVHD depends on the 
availability of blood, tissue (skin, GI tract and liver biopsies) and bone marrow of transplant 
recipients and donors for laboratory studies. The exact studies are not known at this time but 
they will be studies to improve our understanding of GVHD.  Samples will be stored 
indefinitely. 
 
In addition to laboratory studies, correlation of clinical data such as age, sex, disease, 
treatment, progression may be used.   
 
Your tissue will be used for research only.  It will not be sold.  You do not have to donate your 
tissue for research.  You are free to say yes or no.  Your regular medical care will not change.   
 
Risks of Stored Material and Genetic Testing 
There may be unknown risks associated with the storage of samples.  The samples contain 
genetic information (i.e. DNA) therefore can potentially be used to determine paternity or for the 
release of private health information.  However, there are no plans to test for specific genetic 
diseases with your samples. We will make every attempt to insure that your personal information 
will be confidential, but complete confidentiality cannot be guaranteed. 
 
A new federal law, called the Genetic Information Nondiscrimination Act (GINA), effective 
May 21, 2010, generally makes it illegal for health insurance companies, group health plans, 
and most employers to discriminate against you based on genetic information.  This law 
generally will protect you in the following ways: (1) Health insurance companies and group 
health plans may not request your genetic information that we get from this research and may 
not use your genetic information when making decisions regarding your eligibility or 
premiums; and (2) Employers with 15 or more employees may not use your genetic 
information from this research when making a decision to hire, promote, or fire you or when 
setting terms of your employment.  This new federal law does not apply to companies that sell 
life insurance, disability insurance, or long-term care insurance and does not protect you 
against discrimination based on an already diagnosed genetic condition or disease. 
 
Benefits of Stored Materials and Genetic Testing 
There are no direct benefits to you from the collection and storage of these samples.  You will not 
receive any financial gain from studies done using your stored samples. 
 
No matter what you decide, it will not affect the care you receive as part of the study.   
 


CASE6Z13 Informed Consent 5/4/2022 
Page 12 of 13 
SIGNATURE FOR SAMPLE RESEARCH 
 
1. Check one box: Please indicate whether you agree to permit the study investigators to 
request and do research on your biopsy tissue and the blood that is collected for clinical care. 
Testing may be conducted at any time in the future if investigators obtain Institutional Review 
Board approval from your transplant center.   
 
 
   Yes       
  No   _________Initials of Research Subject or Legal Guardian 
 
 
SIGNATURE  
 
Statement of Participant 
I have read and have had verbally explained to me the above information and have had all my 
questions answered to my satisfaction.  I understand that my participation is voluntary and that 
I may stop my participation in the treatment at any time.  Signing this form does not waive any 
of my legal rights.   I understand that a copy of this consent will be provided to me. By signing 
below, I agree to take part in this treatment.   
 
_______________________________________________ 
Printed name of Participant 
 
_______________________________________________            _____________ 
Participant Signature (if 18 years or older) 
 
 
 
Date 
 
 
 
 
 
Statement of Person Conducting Informed Consent Discussion 
I have discussed the information contained in this document with the participant and it is my 
opinion that the participant understands the risks, benefits, alternatives and procedures 
involved with this treatment. 
 
_______________________________________________ 
Printed name of person obtaining consent 
 
_______________________________________________            ________ 
Signature of person obtaining consent 
 
 
 
 
Date 
 
 
 
 
 
 
 
 
 
 


CASE6Z13 Informed Consent 5/4/2022 
Page 13 of 13 
Permission of Parent/Legal Guardian 
You and your child have had the above treatment explained to you and your child, in language 
that you and your child can understand, and you give permission for your child’s participation. 
 
_______________________________________________           ________   
Parent/Guardian Signature (if child is less than 18 years) 
 
Date 
 
 
Child Assent Statement  
I have had the above treatment explained to me in language I understand and I agree to 
participate. 
  
________________________________________________ 
          ___________ 
Child Signature (Children above age 7) 
 
 
 
          Date