untitled h1
untitled h2

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| 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  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  |                      |           |
t a b l e
1. 0 i n t

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  
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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

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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  
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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


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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  
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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


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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
t a b l e
1 1. 0 s t

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  
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  
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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


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1 4. 0 S T A TI S TI C A L C O N SI D E R A TI O N S
t a b l e
r e f e r

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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


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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
t a b l e
1. 0 i n t

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 om 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 r e 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 08 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.
t a b l e
1. 2 g v h

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 ta cr 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 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 k a 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 n efits 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 pitaliz ati 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 glear 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].
t a b l e
1. 3 cli n ic

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/ m 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 h e 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 effic ac 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 n ce 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/ m 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 yla ctic re gi me ns.
t a b l e
2. 0 o b j

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  
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
t a b l e
3 . 0 s t

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 da y + 1, 1 0 m g/ m 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 o n da y + 1, + 3, + 6) a n d M M F.
t a b l e
3. 2 n u m

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 .
t a b l e
3. 3 re pl ace

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.
t a b l e
3. 4 e x pecte

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.  
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  
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 a b l e
3. 4. 2 d ur

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.  
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.  
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 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.
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4. 1 i ncl usi

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 (s ee 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.
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4. 2 e xcl usi

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).  
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.
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5. 0 r e gi

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 D ata 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.
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5. 1 r a 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).
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6. 0 t r e

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 dic ati 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

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 p ere 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:
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gr o u p a

M T X will be gi ve n at 1 5 m g/ m I V o n d a y + 1. T h e n M T X will be gi ve n at 1 0 m g/ m 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 d a 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.
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gr o u p b

M T X will be gi ve n at 5 m g/ m I V o n d a 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.
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6. 2 ge ner al

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 u cralf 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 x ce 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 yla ctic 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 )
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.  
.
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6. 2. 2 a ne

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.
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6. 2. 3 t hr

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.
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6. 2. 4 a nti

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.
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6. 2. 5 f e

A g gressi ve dia g n ostic a n d t hera pe utic ma n a 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 d e d g ui deli nes f or t he ma n a 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).
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6. 2. 6 m o

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

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.
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6. 2. 8 n utr

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
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6. 2. 9 a ntie

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.
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6. 2. 1 0 m

If ac ute graft- v ers us- h ost disease d e vel o ps, t he pri mar y te a 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 p e n di x I f or A c 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 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 w ee 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:  
| 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 w ee 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:  
| 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                              |                  |             |     |             |             |  
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 w ell, wit h eit her aer os oliz e 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.
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6. 3 d ur ati

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.
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7. 0 d o si

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.
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7. 1. 1 t acr

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.
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7. 1. 2 m yc

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.
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7. 1. 3 m et

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.
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8. 0 a d v

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. 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.
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8. 1 a d verse

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 vers e 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 pitaliz ati 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 vers e 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).
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8. 1. 1 t acr

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.
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8. 1. 2 m yc

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.
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8. 1. 3 met h

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 vers e effects are malaise, fati g u e, c hills a n d fe ver, a n d diz zi 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.
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8. 2 dr u g

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. 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 pr essi 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.
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8. 2. 2 m yc

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. A c 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.
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8. 2. 3 t acr

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.
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8. 2 defi niti o

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 nic al 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 ni 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 gic al 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 plic ate d b y ac ute, lifet 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 gic al pr oce d ure, t hera p e utic e n d osc o p y or o perati o n). Gr a des 5 are fatal a d v ers e e ve nt r es ulti n g i n de at h.
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8. 2. 3 seri o

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 pitaliz ati 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 ers e 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 pitaliz ati 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 gic al 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.


```
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8. 2. 4 e x

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 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.
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8. 2. 5 at tri

Attri b uti o n is t he relati o ns hi p bet wee n a n a d v ers e 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.
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8. 3 re p orti

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 h e 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 oc al 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 vers e 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 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.
t a b l e
8. 4 seri o us

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 vers e e v e nts.
t a b l e
8. 5 d at a

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.
t a b l e
9. 0 p h a

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  
| 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 hiliz e 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 diz zi 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, diz zi 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, sele cti 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 h ereas 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).  
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 de crease 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.
t a b l e
1 0. 0 c o

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.
t a b l e
1 0. 1. 1 b

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 o cc 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 ges 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.
t a b l e
1 0. 1. 2 p

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.
t a b l e
1 0. 1. 3 res

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 s a 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 niz e 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.
t a b l e
1 0. 1. 4 s

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 C 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 ostpr 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. 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 C 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.
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1 0. 1. 5 pri

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 b ase.  
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.
t a b l e
1 0. 1. 6 t

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 95 9 1 All o ge n La b orat ori es Re gistr y/ Data b ase. 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 ur e 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 te c 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.  
Meas uri n g i m m u nit y t o mali g na nt c ells, n or mal c ells, 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.
t a b l e
1 0. 1. 7 ris

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.
t a b l e
1 1. 0 s t

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 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
t a b l e
1 1. 1. 3 p

Sa me assess me nts as a b o ve ( d uri n g h os pitaliz ati 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  
| 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)             | 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         | D uri n g I nitial                                               |                                                                                     |                                                                        |          |                        |
| H os pitalizati o n f or  All o -H S C T                        |                                                                  |                                                                                     |                                                                        |          |                        |
| 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
t a b l e
e n gr aft me

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 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.
t a b l e
ac ute gr aft- v

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 p e 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.
t a b l e
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.
t a b l e
le n gt h of

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.
t a b l e
or g a n t

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. 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 n cti 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 n e- 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.
t a b l e
e v al u ati

D o n or c hi meris m will be assesse d b y a n al ysis of si n gle-ta n d e 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.
t a b l e
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.
t a b l e
1 2 . 0 m

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.
t a b l e
1 2. 2 r ate

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.
t a b l e
1 2. 3 i nci

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
t a b l e
1 3. 0 r e

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).
t a b l e
1 3. 1 d at

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 or e 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. A ccess 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 ur ce 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  
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  
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.
t a b l e
1 3. 2 re g

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.
t a b l e
1 3. 2. 1 wr

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.
t a b l e
1 3. 2. 2 s

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.
t a b l e
1 3. 2. 3 rete

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.
t a b l e
1 3. 2. 4 a

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 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.
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1 3. 2. 5 d

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.
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1 4. 0 s t

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 esi 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 T ac, 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 plic ati 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.
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r e f e r

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 dsi 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 wd 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 graftve 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 graftvers 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 di 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.


```  
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 be cl 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.

```
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| 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                                    | > 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 2 -3  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 3. 1 -6  m g/ dl  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 |  
| 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).
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0 n o ne or diarr h ea < 2 8 0 ml/ m / da y  
  
1 2 8 0 -5 5 5 ml/ m / day  
  
2 5 5 6- 8 3 3 ml/ m / day 3 > 8 3 3 ml/ m / day 4 se vere a b d o mi nal pai n, w/ or w/ o ut ili us  
| Sc ore 0                                                                                                                                                                                                                                                                                                                                                                                                              | Sc ore 1                                                                                                                                                                                                                                             | Sc ore 2                                                                                                                                                                                                              | Sc ore 3                                                                                                                                               |                                                                                                                           |                                                                                                                     |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------|
| Perf or m a nce Sc ore:                                                                                                                                                                                                                                                                                                                                                                                               |  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 %) |                                                                                                                     |
| K P S                                                                                                                                                                                                                                                                                                                                                                                                                 | E C O G L P S                                                                                                                                                                                                                                        |                                                                                                                                                                                                                       |                                                                                                                                                        |                                                                                                                           |                                                                                                                     |
| 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 deb 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                                                                                                                                                                                                                                                                                                                                                                                 |  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                                                                                                                                                                                            |                                                                                                                                                        |                                                                                                                           |                                                                                                                     |
|  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 yedr o ps 3 x/ da y)  O R  as y m pt o matic  si g ns of kerat oc 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   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                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                       |                                                                                                                                                        |                                                                                                                           |                                                                                                                     |
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| 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                                                                                                                                                                |  N o s y m pt o ms                                  |  M il d  s y m pt o ms ( S O B  cli m bi n g o ne  fli g ht of stairs)                                                                            |  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)                                                                                                                         |  Se ver s y m pt o ms  ( S O B at rest; re q uiri n g  O 2) |        |
| D L C O                                                                                                                                                                           |  F E V 1 > 8 0 %  O R L F S = 2                     |  F E V 1 4 0 -5 9 %  O R L F S 6 -9                                                                                                               |  F E V 1 4 0 -5 9 % O R  L F S 6 -9                                                                                                                                                                |                                                              |        |
|  F E V 1 6 0 -7 9 %  O R L F S 3 -5                                                                                                                                              |                                                      |                                                                                                                                                    |                                                                                                                                                                                                     |                                                              |        |
| 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 d ecrease of  R O M A N D si g nifica nt  li mitati o n of A D L  ( u na ble t o tie s h 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  
| 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) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ |                                                     |                                             |
t a b l e
c h r o ni

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 nic all 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.  
| 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 u ccal 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.
a p p e n
c h r o ni

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 nat 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 le ast 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 ele ctr 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.