Clinical trial NCT02793544
Conditions: Myelodysplastic Syndrome (MDS) Chronic Lymphocytic Leukemia (CLL) Chemotherapy-sensitive Lymphoma Acute Lymphoblastic Leukemia (ALL)/T Lymphoblastic Lymphoma Acute Myelogenous Leukemia (AML) Acute Biphenotypic Leukemia (ABL) Acute Undifferentiated Leukemia (AUL)
Sponsor: Center for International Blood and Marrow Transplant Research
Start date: 2016-12-01; Completion date: 2020-03-01
Enrollment: 80 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center, single arm Phase II study of hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated bone marrow transplantation donors and post-transplantation cyclophosphamide (PTCy), sirolimus and mycophenolate mofetil (MMF) for graft versus host disease (GVHD) prophylaxis in patients with hematologic malignancies.

Detailed description:

Arms: arm 1: 1. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2
2. Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5
3. Total Body Irradiation (TBI) 200cGy on Day -1
4. Infusion of non-T-cell depleted bone marrow on Day 0

Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above. arm 2: 1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO)
2. Cyclophosphamide 50mg/kg/day IV on Days -2,-1
3. Infusion of non-T-cell depleted bone marrow on Day 0

Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above. arm 3: 1. Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO)
2. Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2
3. Infusion of non-T-cell depleted bone marrow on Day 0

Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above. arm 4: 1. Cyclophosphamide 50mg/kg/day IV on Days -5,-4
2. Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1
3. Infusion of non-T-cell depleted bone marrow on Day 0

Although a schedule is proposed above, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the recommended regimen above.
Interventions: intervention 1: Fludarabine intervention 2: Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 intervention 3: Total Body Irradiation (TBI) 200cGy on Day -1 intervention 4: Infusion of non-T-cell depleted bone marrow on Day 0 intervention 5: Busulfan intervention 6: Cyclophosphamide 50mg/kg/day IV on Days -2,-1 intervention 7: Cyclophosphamide 50mg/kg/day IV on Days -5,-4 intervention 8: Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 intervention 9: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4 intervention 10: Sirolimus intervention 11: Mycophenolate mofetil intervention 12: G-CSF intervention 13: Pre-HCT Mesna on Days -6 and -5 intervention 14: Pre-HCT Mesna on Days -2 and -1 intervention 15: Pre-HCT Mesna on Days -5 and -4 intervention 16: Post-HCT Mesna
Intervention descriptions: intervention 1: * Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-60 minute IV infusion on Days -6 through -2 (maximum cumulative dose, 150 mg/m2).
* The body surface area (BSA) for fludarabine dosing is based on adjusted ideal body weight (IBW) (Appendix K).
* creatinine clearance may change during the days fludarabine is given. Adjustment in fludarabine dose due to creatinine changes during conditioning is permitted. intervention 2: * Cy 14.5 mg/kg/day is administered as a 1-2 hour IV infusion on Days -6 and -5 after hydration.
* Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.
* Hydration prior to Cy may be given according to institutional guideline.
* Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight. intervention 3: * 200 cGy TBI is administered in a single fraction on Day -1.
* Radiation sources, dose rates, and shielding follow institutional practice. intervention 4: * On Day 0, the harvested bone marrow is infused.
* Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated cells/kg recipient weight.
* The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight. intervention 5: * Busulfan ≥ 9mg/kg total dose (IV or PO) on Days -6, -5, -4, -3 (PK monitoring required to achieve a daily area under the curve (AUC) target of 4800-5300 μM\*min (Perkins et al., 2012))
* Busulfan dosing is based on adjusted IBW (Appendix K) intervention 6: * Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days -2 and -1 after hydration.
* Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.
* Hydration prior to Cy may be given according to institutional guideline.
* Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight. intervention 7: * Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days -5 and -4 after hydration.
* Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.
* Hydration prior to Cy may be given according to institutional guideline.
* Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual weight. intervention 8: * 200cGy TBI is administered in twice daily on Days -3, -2, and -1.
* Radiation sources, dose rates, and shielding follow institutional practice. intervention 9: * Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 (ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 (approximately 24 hours after Day+3 Cy).
* Hydration with Cy, management of volume status, and monitoring for hemorrhagic cystitis will follow institutional standards.
* Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.
* Cy is dosed according to IBW, unless the subject weighs less than IBW, in which case these drugs will be dosed according to actual body weight. intervention 10: * Sirolimus dosing is based on adjusted IBW (Appendix K).
* Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be continued if there is GVHD.

For subjects ≥ 18 years old:

* A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours after Cy completion.
* Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by high performance liquid chromatography (HPLC) or immunoassay.

For subjects \< 18 years old:

* A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, is given on Day+5, at least 24 hours after Cy completion.
* Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 - 15 ng/mL as measured by HPLC or immunoassay. intervention 11: MMF begins on Day+5, at least 24 hours after completion of PTCy. MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose not to exceed 3 grams (i.e. maximum 1 g PO TID).

An equivalent IV dose (1:1 conversion) may instead be given. MMF prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is GVHD. intervention 12: Granulocyte-colony stimulating factor (G-CSF): filgrastim or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial dose is allowed), until the absolute neutrophil count (ANC) is ≥ 1,000/mm3 over the course of 3 consecutive days.

Additional G-CSF may be administered as warranted. intervention 13: Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.

Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight. intervention 14: Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.

Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight. intervention 15: Use of Mesna and dosing will be done according to institutional standards. A recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy.

Mesna is dosed according to adjusted IBW (Appendix K), unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual weight. intervention 16: Mesna is required. Mesna IV dose must be ≥ 80% of the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy on Day+3 and Day+4.

Mesna is dosed according to IBW, unless the subject weighs less than IBW, in which case Mesna will be dosed according to actual body weight.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 A Multi-Center, Phase II Trial of HLA-
Mismatched Unrelated Donor Bone 
Marrow Transplantation with Post-
Transplantation Cyclophosphamide 
for Patients with Hematologic 
Malignancies  
NCT02793544 
Document Date: 14Mar2018 
 
 
 


1 
NMDP IRB-2016-0365 
NMDP IRB Approved 
 
 
A Multi-Center, Phase II Trial of HLA-Mismatched 
Unrelated Donor Bone Marrow Transplantation with Post-
Transplantation Cyclophosphamide for Patients with 
Hematologic Malignancies 
 
Resource for Clinical Investigation in Blood and Marrow 
Transplantation (RCI BMT) PROTOCOL 15-MMUD 
Version 4.0 
 March 14, 2018 
 
Protocol Chairperson(s) 
Javier Bolaños Meade, MD1 
Bronwen E. Shaw, MD, PhD2 
 
Protocol Team  
Richard Ambinder, MD, PhD1 
Brent Logan, PhD2 
Claudio Anasetti, MD3 
Leo Luznik, MD1 
Linda Burns, MD4 
John McCarty, MD6 
Dennis Confer, MD4 
Maxim Norkin, MD, PhD7 
Steven Devine, MD4 
Miguel-Angel Perales, MD8 
Mary Horowitz, MD, MS2 
Joseph Pidala, MD, PhD3 
Alan Howard, PhD4 
Voravit Ratanatharathorn, MD9 
Farhad Khimani, MD3 
Thomas Shea, MD10 
Krishna Komanduri, MD5 
Hannah Choe, MD11 
Sponsored by the National Marrow Donor Program® (NMDP) 
 
 
     1 
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
     2 
Center for International Blood and Marrow Transplant Research (CIBMTR)/Medical College of 
Wisconsin 
     3 
H. Lee Moffitt Cancer Center and Research Institute 
     4 
CIBMTR/NMDP 
     5 
University of Miami, Sylvester Comprehensive Cancer Center 
     6 
Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program 
     7 
Shands HealthCare & University of Florida 
     8 
Memorial Sloan Kettering Cancer Center 
     9 
Karmanos Cancer Institute  
     10 
University of North Carolina Hospitals - Chapel Hill 
     11 
Ohio State Medical Center, James Cancer Center


RCI BMT Protocol #15-MMUD 
 
 
Version 4.0 March 14, 2018 
 
2 
NMDP IRB-2016-0365 
NMDP IRB Approved 
 
General Information 
 
 
Sponsor Contact Information 
NMDP 
500 N 5th St  
  
Minneapolis, MN 55401 
 
CIBMTR Medical Monitor 
Name: Linda Burns, MD 
Email: lburns2@nmdp.org 
Phone: 763-406-4273 
 
CIBMTR Protocol Officer 
Name: Dennis Confer, MD 
Email: dconfer@nmdp.org 
Phone: 763-406-3425 
 
CIBMTR Protocol Coordinators 
Name: Lexi Adams, MPH, CCRP 
Email: aadams@nmdp.org 
Phone: 763-406-8735 
Name: Michael Tierney 
Email: mtierney@nmdp.org 
Phone: 763-406-8245 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RCI BMT Protocol #15-MMUD 
 
 
Version 4.0 March 14, 2018 
 
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NMDP IRB-2016-0365 
NMDP IRB Approved 
PROTOCOL SYNOPSIS – RCI BMT PROTOCOL 15-MMUD 
 
A Multi-Center, Phase II Trial of Transplantation of HLA-Mismatched Unrelated Donor 
Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide for Patients 
with Hematologic Malignancies 
 
Sponsor:  National Marrow Donor Program® 
 
Principal Investigator(s): Javier Bolaños Meade, MD and Bronwen Shaw, MD, PhD 
 
Study Design:  This  is a multi-center, single arm Phase II study of hematopoietic cell 
transplantation (HCT) using human leukocyte antigen (HLA)-mismatched unrelated bone 
marrow transplantation donors and post-transplantation cyclophosphamide (PTCy), sirolimus 
and mycophenolate mofetil (MMF) for graft versus host disease (GVHD) prophylaxis in patients 
with:  
1. Acute lymphoblastic leukemia (ALL)/T lymphoblastic lymphoma (T-LBL), acute 
myelogenous leukemia (AML), acute biphenotypic leukemia (ABL), or acute 
undifferentiated leukemia (AUL) in 1st or subsequent complete remission (CR) 
2. Myelodysplastic syndrome (MDS), fulfilling the following criteria: 
a. Subjects with de novo MDS who have or have previously had Intermediate-2 or 
High risk disease as determined by the International Prognostic Scoring System 
(IPSS). Current Intermediate-2 or High risk disease is not a requirement. 
b. Subjects must have < 20% bone marrow blasts, assessed within 60 days of 
informed consent. 
c. Subjects may have received prior therapy for the treatment of MDS prior to 
enrollment. 
3. Chronic lymphocytic leukemia (CLL) in complete response (CR) (if reduced intensity 
conditioning [RIC] is to be used), or complete or partial response (PR) (if full intensity 
conditioning [FIC] is to be used). 
4. Chronic myeloid leukemia (CML) in 1st or subsequent chronic phase characterized by 
<10% blasts in the blood or bone marrow. 
5. Chemotherapy-sensitive lymphoma in status other than 1st CR. 
 
Primary Objective:  The primary objective is to determine overall survival (OS) 1-year after 
HLA-mismatched unrelated donor (MMUD) bone marrow transplantation using PTCy, sirolimus 
and MMF to prevent GVHD. 
 
Secondary Objectives: Subjects enrolled in this study will also be followed for the following 
endpoints: progression-free survival (PFS) at Day+180 and 1-year post-HCT, cumulative 
incidence of neutrophil recovery, cumulative incidence of platelet recovery, cumulative 
incidence of primary graft failure, donor chimerism, cumulative incidences of acute GVHD 
(aGVHD) and chronic GVHD (cGVHD), cumulative incidences of viral reactivations and 
infections, transplant-related mortality (TRM) at Day+100, Day+180, and 1-year post-HCT, 
cumulative incidence of relapse/progression, cumulative incidences of thrombotic 
microangiopathy (TMA) and hepatic veno-occlusive disease (VOD)/ sinusoidal obstruction 
syndrome (SOS), and incidence of donor clonal hematopoiesis. The proportion of subjects 


RCI BMT Protocol #15-MMUD 
 
 
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proceeding to HCT after informed consent will be described. The donor selection characteristics 
will also be described. Time to donor identification from the search request will be described.  
Analysis of long-term survivors will be performed for subjects who consent to the CIBMTR 
Research Database protocol using routine data collection forms and time points per CIBMTR 
requirements. 
 
Eligibility Criteria: Subjects must be between the ages of 15 and 70 years with the diagnosis of 
a hematologic malignancy as described above and with a partially (4/8 – 7/8) HLA-MMUD 
defined by high resolution typing at HLA-A, -B, -C and –DRB1. Subjects must have adequate 
organ function defined as: 1) left ventricular ejection fraction (LVEF) at rest ≥ 35% (RIC cohort) 
or LVEF at rest ≥ 40% (FIC cohort), or shortening fraction (LVFS) ≥ 25%; 2) diffusing capacity 
of the lungs for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital 
capacity (FVC) ≥ 50% predicted; 3) total bilirubin ≤ 2.5 mg/dL, and alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 5 x upper limit of 
normal (ULN) (unless ALT, AST, and/or ALP are disease related); 4) serum creatinine (SCr) 
within normal range for age, or creatinine clearance (CrCl) > 40 mL/min/1.73m2 if SCr outside 
normal range for age; 5) Karnofsky or Lansky performance score ≥ 60%; and 6) if applicable, > 
3 months since a previous autologous HCT. 
 
Treatment Descriptions:  
 
The conditioning regimen will consist of one of the following: 
 
     Regimen A (RIC). Recommended schedule as below:    
1. Fludarabine 30 mg/m2/day intravenously (IV) on Days –6, –5, –4, –3, –2 
2. Cy 14.5 mg/kg/day IV on Days –6, –5 
3. Total body irradiation (TBI) 200 centigray (cGy) on Day –1 
4. Day 0 will be the day of infusion of non-T-cell depleted bone marrow 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards as long as the prescribed doses are the same as in the recommended regimen 
above. 
 
     Regimen B (FIC). Recommended schedule as below:    
1. Busulfan ≥ 9mg/kg total dose (IV or oral (PO)) on Days -6, -5, -4, -3            
(Pharmacokinetic (PK) monitoring required to achieve a daily area under the 
curve (AUC) target of 4800-5300 μM*min (see section 2.6.1)) 
2a. Cy 50mg/kg/day IV on Days -2, -1  
OR 
1. Busulfan ≥ 9mg/kg total dose (IV or oral (PO)) on Days -6, -5, -4, -3 
(Pharmacokinetic (PK) monitoring required to achieve a daily area under the 
curve (AUC) target of 4800-5300 μM*min (see section 2.6.1)) 
2b. Fludarabine 30 mg/m2/day IV on Days –6, –5, –4, –3, –2 
3. Day 0 will be the day of infusion of non-T-cell depleted bone marrow 
 


RCI BMT Protocol #15-MMUD 
 
 
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Although a schedule is proposed above, the regimen can be given according to institutional 
standards as long as the prescribed doses, and busulfan monitoring, are the same as in the 
recommended regimen above. 
 
     Regimen C (FIC). Recommended schedule as below:          
1. Cy 50mg/kg/day IV on Days -5, -4 
2. TBI 200cGy twice a day on Days -3, -2, -1 
3. Day 0 will be the day of infusion of non-T-cell depleted bone marrow 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards as long as the prescribed doses are the same as in the recommended regimen 
above. 
 
Post-Transplant Treatments 
 
The GVHD prophylaxis regimen will consist of: 
1. Cy 50 mg/kg/day IV on Days+3, +4 
2. Mesna recommendation: Mesna IV dose ≥ 80% of the total daily dose of Cy, given in 
divided doses 30 minutes before and at 3, 6, and 8-9 hours after completion of Cy 
Institutional standards for mesna use and dosing may be used when necessary. 
3. Sirolimus (PO) beginning on Day+5 with dose adjusted to maintain a level of 5-15 
ng/mL through Day+180 
4. MMF 15 mg/kg PO TID beginning on Day+5, maximum dose 1g PO TID (maximum 
daily dose 3g/day) through Day+35 
 
The Hematopoietic Growth Factor regimen will consist of: 
1. Granulocyte-colony stimulating factor (G-CSF) or a biosimilar given at a dose of 5 
mcg/kg/day (actual body weight) IV or subcutaneously (SC) (rounding to the nearest vial 
dose is allowed) beginning Day+5 until absolute neutrophil count (ANC)  1,000/mm3 
for 3 consecutive days 
 
Accrual Objective: The target sample size is 80 subjects accrued into two strata: 40 subjects 
receiving FIC and 40 subjects receiving RIC. 
 
Accrual Period: 
The estimated accrual period is 2 years. 
 
Study Duration: 
Subjects will be followed for 1-year post-HCT. 
 
Interim Analysis: 
There will be no formal interim analyses for efficacy.  Monitoring of two 
key safety endpoints (overall mortality and grade III-IV aGVHD by Day+100) will be conducted 
weekly. If a stopping rule as described in table 5.4 is triggered, enrollment will be paused while 
the Data and Safety Monitoring Board (DSMB) conducts a review of the safety data.  
 
Stopping Guidelines: See table 5.4. 
 


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STUDY SCHEMA 
Aim: To determine OS at 1-year after HLA-MMUD bone marrow HCT using PTCy, sirolimus 
and MMF to prevent GVHD. 
Recipient Inclusion Criteria: 
1. Age ≥ 15 years and < 71 years at the time of signing the informed consent form. Note: 
HIV-negative subjects with MDS must be < 50 years of age at time of signing the 
informed consent form.  
2. Partially HLA-MMUD: HLA typing will be performed at high resolution (allele level) for 
the HLA-A, -B, -C, and –DRB1 loci; a minimum match of 4/8 at HLA-A, -B, -C, and –
DRB1 is required 
3. Product planned for infusion is bone marrow 
4. Disease and disease status: 
a. ALL/T-LBL; AML; ABL; AUL in 1st or subsequent CR 
b. MDS, fulfilling the following criteria: 
i. Subjects with de novo MDS who have or have previously had 
Intermediate-2 or High risk disease as determined by the IPSS. Current 
Intermediate-2 or High risk disease is not a requirement. 
ii. Subjects must have < 20% bone marrow blasts, assessed within 60 days of 
informed consent. 
iii. Subjects may have received prior therapy for the treatment of MDS prior 
to enrollment 
c. CLL in: 
i. CR if RIC is to be used OR 
ii. CR or PR if FIC is to be used 
d. CML in 1st or subsequent chronic phase characterized by <10% blasts in the blood 
or bone marrow 
e. Chemotherapy-sensitive lymphoma in status other than 1st CR 
5. Performance status: Karnofsky or Lansky score ≥ 60% (Appendix A) 
6. Adequate organ function defined as: 
a. Cardiac: LVEF at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), or 
LVFS ≥ 25%  
b. Pulmonary: DLCO, FEV1, FVC ≥ 50% predicted by pulmonary function tests 
(PFTs). DLCO value may be corrected or uncorrected for hemoglobin. 
c. Hepatic: total bilirubin ≤ 2.5 mg/dL, and ALT, AST, and ALP < 5 x ULN (unless 
ALT, AST, and/or ALP are disease related) 
d. Renal: SCr within normal range for age (see table 2.3A). If SCr is outside normal 
range for age, CrCl > 40 mL/min/1.73m2 must be obtained (measured by 24-hour 
(hr) urine specimen or nuclear glomerular filtration rate (GFR), or calculated GFR 
(by Cockcroft-Gault formula for those aged ≥ 18 years; by Original Schwartz 
estimate for those < 18 years) (see table 2.3B)) 
7. Subjects ≥ 18 years of age must have the ability to give informed consent according to 
applicable regulatory and local institutional requirements. Legal guardian permission must 
be obtained for subjects < 18 years of age. Pediatric subjects will be included in age 
appropriate discussion in order to obtain assent. 
8. Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive), and a 
hematologic malignancy who meets all other eligibility requirements must: 


RCI BMT Protocol #15-MMUD 
 
 
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a. Receive only RIC regimen (i.e. Regimen A) 
b. Be willing to comply with effective antiretroviral therapy (ARV) 
c. Have achieved a sustained virologic response for 12 weeks after cessation of 
hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C) 
 
Recipient Exclusion Criteria: 
1. Suitable HLA-matched related or 8/8 allele matched (HLA-A, -B, -C, -DRB1) unrelated 
donor available. This exclusion does not apply to HIV-positive subjects who have a 
CCR5delta32 homozygous donor. 
2. Autologous HCT < 3 months prior to the time of signing the informed consent form 
3. Females who are breast-feeding or pregnant 
4. HIV-positive subjects: 
a. Acquired immunodeficiency syndrome (AIDS) related syndromes or symptoms 
that may pose an excessive risk for transplantation-related morbidity as determined 
by the Treatment Review Committee (see Appendix D).  
b. Untreatable HIV infection due to multidrug ARV resistance. Subjects with a 
detectable or standard viral load > 750 copies/mL should be evaluated with an HIV 
drug resistance test (HIV-1 genotype). The results should be included as part of the 
ARV review (described in Appendix D). 
c.  May not be currently prescribed ritonavir, cobacistat and/or zidovudine 
5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication with 
evidence of progression of clinical symptoms or radiologic findings) 
6. Prior allogeneic HCT 
7. Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia or 
polycythemia vera 
8. HIV-negative subjects with MDS may not receive RIC and must be < 50 years of age at 
the time of signing the informed consent form.  
 
Donor Inclusion Criteria: 
1. Must be unrelated to the subject and 
matched at between 4/8 and 7/8 HLA 
alleles for HLA-A, -B, -C, and –DRB1 
2. Donors must meet NMDP medical 
suitability requirements for bone marrow 
donation.  
3. Donors must undergo eligibility 
screening according to current FDA 
requirements. Donors who do not meet 
one or more of the donor screening 
requirements may donate under urgent 
medical need. 
4. Must have the ability to give informed 
consent according to applicable NMDP 
donor regulatory requirements 
5. Must agree to donate bone marrow 
Donor Exclusion Criteria: 
1. Recipient positive anti-donor HLA 
antibodies against a mismatched allele in the 
selected donor determined by either: 
a. a positive crossmatch test of any titer 
(by complement-dependent 
cytotoxicity or flow cytometric 
testing) or  
b. the presence of anti-donor HLA 
antibody to any HLA locus (HLA-A, 
-B, -C, –DRB1, -DQB1, -DQA1, -
DPB1, -DPA1) with mean 
fluorescence intensity (MFI) >1000 
by solid phase immunoassay 
 


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Primary Endpoint: 
OS is defined as the time from HCT to death 
from any cause, loss to follow up or end of 
study, whichever comes first (through 1-
year).  
Secondary Endpoints: 
• PFS at Day+180 and 1-year post-HCT 
• TRM at Day+100, day+180 and 1-year post-
HCT 
• Cumulative incidence of neutrophil recovery 
• Cumulative incidence of platelet recovery 
• Cumulative incidence of primary graft 
failure 
• Donor chimerism 
• Cumulative incidences of aGVHD and 
cGVHD 
• Cumulative incidences of viral reactivations 
and infections (Cytomegalovirus (CMV), 
Epstein–Barr virus (EBV), BK virus, 
Adenovirus (ADV), human herpesvirus 6 
(HHV-6)) 
• Cumulative incidence of relapse/progression 
• Cumulative incidences of TMA and 
VOD/SOS 
• Incidence of development of donor clonal 
hematopoiesis 
• Proportion of subjects proceeding to HCT 
after informed consent  
• Donor selection characteristics  
• Time to donor identification from search 
request 
• Analysis of long-term survivors 
 
Conditioning Regimens: 
 
Regimen A (RIC). Recommended 
schedule as below:    
1. Fludarabine 30 mg/m2/day 
intravenously (IV) on Days –6, –5, –4, –
3, –2 
2. Cy 14.5 mg/kg/day IV on Days –6, –5 
3. Total body irradiation (TBI) 200 
centigray (cGy) on Day –1 
4. Day 0 will be the day of infusion of 
non-T-cell depleted bone marrow 
Although a schedule is proposed above, 
the regimen can be given according to 
institutional standards as long as the 
prescribed doses are the same as in the 
recommended regimen above. 
Post-Transplant Treatments: 
 
GVHD Prophylaxis regimen: 
• Cy 50 mg/kg/day IV on Days+3, +4 
• Mesna recommendation: Mesna IV dose ≥ 
80% of the total daily dose of Cy, given in 
divided doses 30 minutes before and at 3, 6, 
and 8-9 hours after completion of Cy. 
Institutional standards for mesna use and 
dosing may be used when necessary. 
• Sirolimus (PO) beginning on Day+5 with 
dose adjusted to maintain a level of 5-15 
ng/mL through Day+180 
• MMF 15 mg/kg PO TID beginning on 
Day+5, maximum dose 1g PO TID 
(maximum daily dose 3g/day) through 
Day+35 


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Regimen B (FIC). Recommended schedule 
as below:    
1. Busulfan ≥ 9mg/kg total dose (IV or oral 
(PO)) on Days -6, -5, -4, -3            
(Pharmacokinetic (PK) monitoring 
required to achieve a daily area under 
the curve (AUC) target of 4800-5300 
μM*min (see section 2.6.1)) 
2a. Cy 50mg/kg/day IV on Days -2,-1 
  
OR 
 
1. Busulfan ≥ 9mg/kg total dose (IV or oral 
(PO)) on Days -6, -5, -4, -3 
(Pharmacokinetic (PK) monitoring 
required to achieve a daily area under 
the curve (AUC) target of 4800-5300 
μM*min (see section 2.6.1)) 
2b. Fludarabine 30 mg/m2/day IV on  
      Days –6, –5, –4, –3, –2 
 
3.  Day 0 will be the day of infusion of non 
T-cell depleted bone marrow 
 
Although a schedule is proposed above, 
the regimen can be given according to 
institutional standards as long as the 
prescribed doses, and Busulfan 
monitoring, are the same as in the 
recommended regimen above. 
 
Regimen C (FIC). Recommended schedule 
as below: 
         
1. Cy 50mg/kg/day IV on Days -5, -4 
2. TBI 200cGy twice a day on Days -3, -2, -
1 
3. Day 0 will be the day of infusion of non-
T-cell depleted bone marrow 
 
Although a schedule is proposed above, 
the regimen can be given according to 
institutional standards as long as the 
prescribed doses are the same as in the 
recommended regimen above. 
Hematopoietic Growth Factor regimen: 
• G-CSF or a biosimilar given at a dose of 5 
mcg/kg/day IV or SC beginning on Day+5 
until ANC  1,000/mm3 for 3 consecutive 
days 
 


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TABLE OF CONTENTS 
 
1 
BACKGROUND AND RATIONALE .................................................................................. 12 
1.1 
Background .................................................................................................................................. 12 
1.2 
Rationale for Study ....................................................................................................................... 16 
2              STUDY DESIGN ........................................................................................................................ 16 
2.1         Study Overview ............................................................................................................................. 16 
2.2         Hypothesis and Objectives ............................................................................................................. 16 
2.2.1 
Primary Hypothesis .................................................................................................................. 16 
2.2.2 
Secondary Hypotheses  ............................................................................................................. 16 
2.2.3 
Study Objectives ....................................................................................................................... 17 
2.3 
Subject Eligibility ......................................................................................................................... 17 
2.3.1 
Inclusion Criteria ...................................................................................................................... 17 
2.3.2 
Exclusion Criteria  .................................................................................................................... 19 
2.4 
Donor Eligibility ........................................................................................................................... 20 
2.4.1 
Inclusion Criteria ...................................................................................................................... 20 
2.4.2 
Exclusion Criteria  .................................................................................................................... 20 
2.5         Donor Prioritization Schema ......................................................................................................... 20 
2.6         Treatment Plan .............................................................................................................................. 21 
2.6.1 
Protocol-specific treatment information ................................................................................... 21 
2.6.2 
Supportive Care ........................................................................................................................ 26 
2.6.3 
Tests, Procedures, Observations ............................................................................................... 26 
2.6.3.1 
    Treatment Schemas ............................................................................................................... 32 
2.6.4 
Risks and Toxicities .................................................................................................................. 41 
3 
SUBJECT ENROLLMENT .................................................................................................. 47 
3.1 
Screening and Enrollment Procedures .......................................................................................... 47 
3.1.1 
Screening Procedures ................................................................................................................ 47 
3.1.2 
Enrollment Procedures.............................................................................................................. 47 
3.2 
Withdrawal Procedures ................................................................................................................ 48 
4 
STUDY ENDPOINTS ............................................................................................................ 48 
4.1 
Primary Endpoint ......................................................................................................................... 48 
4.2 
Secondary Endpoints .................................................................................................................... 48 
4.3 
Definition of CR by Disease Type ............................................................................................... 53 
5 
STATISTICAL CONSIDERATIONS .................................................................................. 54 
5.1 
General Considerations ................................................................................................................ 54
 
Study Design ................................................................................................................................ 54 
5.2.1 
 Accrual ...................................................................................................................................... 54 
5.3 
Sample Size and Power Considerations ....................................................................................... 54 
5.4 
Interim Analysis and Stopping Guidelines ................................................................................... 55 
5.5 
Analysis of Study Endpoints ........................................................................................................ 56 
5.6 
Demographic and Baseline Characteristics .................................................................................. 58 
5.7 
Disposition of Subjects ................................................................................................................. 58 
6 
DATA REPORTING .............................................................................................................. 59 
6.1 
Data Capture Methods .................................................................................................................. 59 


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6.2 
Adverse Event and Unanticipated Problem Reporting ................................................................. 60 
6.2.1 
Event Defintions ....................................................................................................................... 60 
6.2.1.1 
Adverse Event Reporting .......................................................................................................... 62 
7 
PROTOCOL DEVIATIONS ................................................................................................. 64 
7.1  
Investigator Reporting Responsibilities ....................................................................................... 64 
7.2 
Study Monitoring ......................................................................................................................... 64 
7.2.1 
Data Safety Monitoring ............................................................................................................ 64 
7.2.2 
Study Site Monitoring Plan ...................................................................................................... 64 
8 
REGULATORY CONSIDERATIONS ................................................................................ 64 
8.1 
Institutional Review Board/Ethics Committee approval .............................................................. 64 
8.2 
Informed Consent ......................................................................................................................... 65 
 
LIST OF APPENDICES        ............................................................................................................ 66 
APPENDIX A    Performance Status  ......................................................................................................... 67 
APPENDIX B 
List of Abbreviations ...................................................................................................... 68 
APPENDIX C 
NMDP Procedure for Identification of CCR5delta32 Mutation Homozygous Donors 
Related to this Protocol ............................................................................................................................... 72 
APPENDIX D    Treatment Review Committee for HIV-Positive Subjects  ............................................. 73 
APPENDIX E 
Suggested Prophylaxis for HIV-Positive Subjects .......................................................... 74 
APPENDIX F 
PK Drug-Drug Interactions with ARVs .......................................................................... 75 
APPENDIX G    Additional Evaluations for HIV-Postive Subjects  .......................................................... 78 
APPENDIX H 
Diagnosis and Severity Scoring for Acute and Chronic GVHD ..................................... 79 
APPENDIX I 
Correlative Study Procedures .......................................................................................... 87 
APPENDIX J 
MMUD Selection Algorithm .......................................................................................... 92 
APPENDIX K 
Recommended Formulas for Calculation for Adjusted and Ideal Body Weight ............ 94 
APPENDIX L 
Guidance on Reviewing and Reporting Unanticipated Problems ................................... 95 
APPENDIX M References ....................................................................................................................... 97 
 
 
 
 
 
 


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1 
BACKGROUND AND RATIONALE 
1.1 Background 
Allogeneic HCT is a potentially curative therapy for a variety of hematologic diseases, including 
the acute and chronic leukemias, myelodysplasia, lymphoma, and multiple myeloma.  Clinical 
data now confirm that T-cells contained within the donor graft are capable of exerting a “graft-
versus-malignancy” effect (Horowitz et al., 1990).  However, successful application of 
allogeneic HCT to patients with hematologic diseases is limited by the toxicity related to the 
allogeneic donor cells which result in GVHD, a life threatening complication. Development of 
GVHD is associated with lower OS and thus the prevention of GVHD is a cornerstone of 
allogeneic HCT therapy (Choi & Reddy, 2014).  
 
Transplantation using cells from HLA-identical sibling donors results in the lowest incidence of 
GVHD, and such donors are prioritized; however, only approximately 30% of patients have an 
HLA-identical sibling donor. Alternative sources of stem cells for those without an HLA-
identical sibling include unrelated donors, umbilical cord blood and HLA-mismatched 
(haploidentical) related donors (Kekre & Antin, 2014). When using these donor sources, more 
intensive strategies are required to reduce the incidence of rejection and/or GVHD resulting from 
greater differences in both major and minor histocompatibility antigens. 
 
Several methods may overcome the drawbacks associated with HLA-mismatched 
transplantation. In vivo T-cell depletion using alemtuzumab or anti-thymocyte globulin (ATG) is 
well recognized to reduce the incidence of both acute and chronic GVHD and graft rejection but 
is associated with delayed immune reconstitution and subsequent problems with infection, 
particularly reactivation of viruses (Potter et al., 2014; Chakraverty et al., 2010; Walker et al., 
2016; Bacigalupo et al., 2006).  
 
Several studies indicate that administering high dose, PTCy decreases the incidence of acute and 
chronic GVHD after HLA-mismatched transplantation without an adverse effect on immune 
reconstitution.  The immunobiologic rationale for administering Cy after HCT is that recently 
activated, alloreactive T-cells (the cells most responsible for GVHD) are selectively sensitive to 
the toxic effects of this drug (Mayumi, Umesue, & Nomoto, 1996).  
 
This strategy was initially tested in HCT using cells from partially HLA-mismatched (HLA-
haploidentical) relatives in two independent single center clinical trials with favorable results 
(Luznik et al., 2008). Eighty-eight consecutive patients of all ages with high-risk hematologic 
malignancies were accrued to these trials between 1999 and 2006. Transplantation conditioning 
consisted of Cy 14.5 mg/kg/day IV on Days –6 and –5, fludarabine 30 mg/m2/day IV on Days –6 
to –2, and 200 cGy of TBI on Day –1.  On Day 0, patients received donor bone marrow, which 
was obtained in a targeted collection of 4 x 108 nucleated cells/kg recipient weight and depleted 
of red blood cells by processing on a Gambro Spectra apheresis instrument. On Day+3, 50 mg/kg 
Cy was administered. A subset of patients received an additional dose of Cy on Day+4.  
Pharmacologic prophylaxis of GVHD was initiated on the day following completion of PTCy.  
All patients received tacrolimus and MMF.  Patients received filgrastim 5 mcg/kg daily starting 
at Day+5 and continuing until recovery of neutrophils to >1000/L for three days. The outcomes 
of these studies showed: graft failure in 18% (73% of whom had measurable disease); complete 
donor chimerism (>95%) in patients with sustained engraftment by 2 months after HCT; 


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cumulative incidences of grades II-IV and III-IV aGVHD by Day+200 of 35% and 10%, 
respectively; cumulative incidences of overall and extensive cGVHD in the first year after HCT 
of 22% and 14%, respectively. The cumulative incidences of non-relapse mortality (NRM) at 
180 days and 1-year after HCT were 13% and 19%, respectively.  The cumulative incidences of 
relapse at 1 and 2 years after HCT were 50% and 57%, respectively. At a median follow-up of 
survivors of 817 days (range, 112-1808 days), the actuarial OS of the entire group at 1 and 2 
years were 45% and 35%, respectively.   
 
Based on these encouraging results, the BMT CTN initiated a Phase II study to test this approach 
in a multi-center setting (Brunstein, et al., 2011). Fifty patients (<70 years) with high-risk 
leukemia or lymphoma were included. Only one patient had primary graft failure and all 
engrafting patients had 100% donor chimerism at Day+56. The 100-day cumulative incidence of 
grade II-IV aGVHD was 32%.The 1-year cumulative incidences of NRM and relapse were 7% 
and 45%, respectively, with 1-year probabilities of OS and PFS of 62% and 48%, respectively. 
 
Some disease states continue to have a higher non-engraftment rate in this setting. Unpublished 
data from Johns Hopkins University reveals that in the haploidentical non-myeloablative setting, 
patients with active CLL have a 7-fold increase risk of graft-failure. Other groups have found 
higher rates of graft failure in patients with CLL in the non-myeloablative setting (Delgado et al., 
2006). 
 
These studies, and others, show that use of PTCy with additional post-HCT immune suppression 
allows successful outcomes using very mismatched donors. Clinical practice has now evolved to 
include PTCy as standard of care GVHD prophylaxis for patients receiving cells from 
haploidentical donors (Bashey & Solomon, 2014). However, there are several drawbacks to use 
of haploidentical related donors. Related donors often fall outside the norms used for accepting 
unrelated donors (i.e. >60 or <18, or presence of comorbidities) with several important 
consequences for both the patient and the donor.  
 
The use of older donors is associated with worse clinical outcomes for recipients.  Kollman et al. 
(2001) showed, in a retrospective analysis of 6978 unrelated bone marrow transplants,  that 
patients receiving cells from an unrelated donor under the age of 30 had significantly better 
survival than those with older donors  (p = 0.0002). Younger donors were associated with a 
significantly lower risk of severe aGVHD among HLA-mismatched pairs. Incidences at 
Day+100 were 30%, 41%, and 40%, respectively, with donors aged 18 to 30 years, 31 to 45 
years, and more than 45 years (p < 0.0001). A significantly lower risk of cGVHD was also found 
with younger donors (p = 0.02). These data were confirmed in a later study (Kollman et al., 
2015) including 6349 unrelated donor transplant recipients, which again showed that using 
donors under the age of 32 conferred a significant survival advantage (p <0.001). As in the 
previous study, the incidence of GVHD was lower with a younger donor. This publication 
included a recent validation subset of 4690 HLA-matched (8/8 HLA-A, -B, -C, and –DRB1 loci) 
donor-recipient pairs which showed a linear impact of donor age on patient survival, with 
younger donor ages associated with higher survival (p = .006). Importantly, all three of these 
studies showed that the effect of donor age was present irrespective of the degree of HLA 
matching between the pair, suggesting that it is an independent risk factor for survival and 
GVHD.  


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Finally, a European Blood and Marrow Transplant group study (Kroger et al., 2012) of 719 MDS 
patients over the age of 50 years showed that patients transplanted from a younger unrelated 
donor (<30 years) had significantly higher 5-year OS in comparison with those transplanted from 
a related donor or an older unrelated donor (>30 years): 40% vs 33% vs 24% (p = 0.04). Other 
data do not confirm this finding of better outcomes with an unrelated compared to a related 
donor (Alousi et al., 2013). 
 
Additionally, other non-HLA donor selection factors (such as ABO status, sex and parity), which 
are variably associated with differences in HCT outcomes, can often not be prioritized in the 
related donor setting (Kollman et al., 2015). Although there is controversy about the impact of 
ABO matching on HCT outcome, large recent CIBMTR studies suggest a survival advantage 
with ABO matching (Pidala, et al., 2014). Although the impact of ABO matching has not been 
studied in the haploidentical setting, it is an important logistical issue when transplanting bone 
marrow, as mismatching requires red cell depleting procedures, which may result in a loss of 
stem cells, potentially increasing the risk of poor engraftment. The ability to select amongst 
donors to avoid ABO mismatching is an attractive option, seldom available when choosing 
among related donors. Use of female donors is also associated with reduced engraftment and 
parous donors are associated with increased cGVHD (Shaw et al., 2005; Kollman et al., 2001). In 
the haploidentical PTCy setting, transplanting female donor bone marrow into a male recipient is 
associated with an increase in the probability of graft failure (Kongtim, Cao, & Ciurea, 2016). 
 
There are also potential ethical and logistic considerations when using related donors. While any 
potential coercion and conflicts of interest are removed in the unrelated donor setting due to 
anonymity between patients and donor and the separation of patient and donor care, this is not 
always the case in the related donor setting. Additionally, older donors are much more likely to 
have co-existent health issues, which may increase the risks of adverse events (AEs) post 
donation or require peripheral blood rather than bone marrow harvest (Anthias, et al., 2015a), 
though most of the experience with PTCy is with HCT using bone marrow grafts. Recently, 
concerns have been raised about the psychologic impact of donation in pediatric donors (Bitan et 
al., 2015). Conflicts of interest may arise where the donor and recipient are both managed by the 
same team. Although health assessment and consent are not separated in many centers, this is 
almost always not the case with the bone marrow harvest, since only transplant teams are trained 
in this intervention (Anthias et al., 2015b). There is evidence that donor AEs are increased in 
centers where harvest numbers are low (Shaw et al., 2015) which may be an issue in centers 
performing only infrequent bone marrow harvest on related donors. In this protocol utilizing 
unrelated donors, bone marrow collection will be centralized using facilities performing large 
numbers of procedures for the NMDP. Operators are likely to have appropriate levels of 
expertise thus minimizing donor AEs. 
 
A perceived restriction in the use of unrelated donors is the time necessary to find a donor, a 
delay which is thought to be associated with inferior patient outcomes. The ability to select a 
MMUD would remove this barrier by greatly increasing the appropriate donor pool for each 
patient, thereby increasing the likelihood of finding a donor available to donate in a timely 
manner. The ability to select a MMUD would also benefit patients from ethnic minorities who 
are also more likely to find a mismatched than a matched unrelated donor on international donor 


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registries. With currently over 20 million unrelated donors listed on the international donor 
registries, multiple mismatched donors are expected to be available for each patient; thus, donor 
selection can be optimized and expedited. 
 
A recent single center feasibility study at Johns Hopkins University is evaluating the use of 
MMUD bone marrow transplantation using PTCy, sirolimus and MMF to prevent GVHD 
(Kasamon et al., 2015). The conditioning regimen used is non-myeloablative and includes 
fludarabine, Cy and low dose TBI with two doses of PTCy (Day+4 and +5). Sirolimus and MMF 
are started on Day+5. The primary objectives include estimating that 6 month probability of 
survival without grade III-IV GVHD or graft failure. The disease and age inclusion criteria are 
broad. Patients are eligible if they lack a first degree related donor or haploidentical donor. 
Potential donors in this protocol could be unrelated donors, first cousins and second-degree 
relatives. HLA matching at 6 HLA loci is considered. Patients with donor specific antibodies are 
excluded. 
 
Thus far 16 patients have been enrolled onto the protocol with a MMUD. Most (N=9) received 
the HCT for AML. The unrelated grafts had a median of 2 HLA mismatches and included three 
7/10 matches, one 6/10 match, and one 5/10 match. HLA-C mismatch was present in 10 grafts 
(63%) and complete -DP mismatch in 6 (38%). By revised Disease Risk Index, 25% of patients 
were high risk, 69% intermediate risk, and 6% low risk; 69% were in CR at time of transplant. 
The median graft doses were 3.36 x 108 total nucleated cells/kg and 3.87 x 107 CD3+ cells/kg. 
All patients engrafted, and there were no non-relapse deaths or prohibitive toxicities. By 
competing-risk analysis, the estimated cumulative incidence of neutrophil recovery was 100% by 
Day+29, with a median of 20 (range 14-29) days. Platelet recovery ≥ 20,000/µL was 100% by 
Day+46, with a median of 32 (range 12-46) days. By Day+60, 14/15 (93%) evaluable patients 
achieved full donor chimerism in either CD3+ or unsorted cells. Notably, there were no cases of  
grade III-IV aGVHD. Grade ≥ II aGVHD was limited to 2 cases of skin-only grade II aGVHD 
and 1 case of grade II skin and ungradable visceral aGVHD. By competing-risk analysis, the 
estimated cumulative incidence of grade II aGVHD was 12% at Day+100 (90% confidence 
interval (CI), 0-27%) and 19% at Day+180 (90% CI, 2-37%). The cumulative incidence of any 
cGVHD at 1 and 2 years was 7% (90% CI, 0-18%). Critical illness prior to relapse was limited to 
1 case of sepsis which resolved. With a 3-year median follow-up, the probability of PFS was 
56% at 1-year and 50% at 3 years. The cumulative incidence of relapse was 44% at 1-year. 
Median OS has not been reached, with an estimated 1-year and 3-year OS of 68%.  
 
In order to broaden the expanded access which this protocol will provide to patients without a 
matched donor to additional patients, we have included the option of myeloablative conditioning 
(Shabbir-Moosajee, Lombardi, & Ciurea, 2015). Although this PTCy approach has not been 
tested using mismatched unrelated donors, there is evidence for its efficacy in the haploidentical 
setting. Data published in abstract (Symons et al., 2015) from Johns Hopkins University is 
presented here (personal communication: Heather Symons). 96 patients have been transplanted 
using the PTCy, CNI and MMF approach using unmanipulated BM from haploidentical donors. 
73 patients received Busulfan (Day -6, -5, -4 and -3, adjusted to AUC) and Cytoxan (day -2 and -
1, 50mg/kg/day) (Symons et al., 2015); 23 received standard CyTBI conditioning (Thomas et al., 
1977). Median patient age was 42 (range: 1-65), and transplants were done for diverse 
hematological malignancies. 80/88 patients were eligible for assessment of chimerism at day 60, 


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with 91% having >95% donor chimerism at that time. Rates of grade II-IV and III-IV acute 
GVHD were 17% and &% respectively. Chronic GVHD occurred in 15% of patients (5% 
moderate/severe). The TRM at 100 days and 1-year was 6% and 11%, and relapse at the 1-year 
and 3 years was 36% and 44%. Overall survival at 1-year is 72%. Based on these encouraging 
results we include the option of a myeloablative approach in this study. 
 
Given that this is the only current experience with PTCy in the unrelated donor setting, and the 
lack of increased toxicity with PTCy and sirolimus as described above, we will use a harmonized 
approach to GVHD prophylaxis for all patients in this study irrespective of conditioning 
regimen. This approach is also supported by in vitro data showing synergism between PTCy and 
sirolimus (Fitzhugh et al., 2013). Additionally, sirolimus promotes Treg expansion, and may 
inhibit graft rejection and GVHD by promoting T-cell tolerance (Cutler & Antin, 2004). There 
may also be positive antiviral and graft versus leukemia effects (Kasamon et al., 2012). 
 
Based upon the encouraging safety and efficacy data from the Johns Hopkins University study and 
the potential advantages of using HLA-mismatched unrelated versus related donors, we wish to 
test the safety and anti-tumor efficacy of HLA MMUD bone marrow transplantation with PTCy, 
sirolimus and MMF in a national, multi-center Phase II trial. 
 
1.2 
Rationale for Study  
The proposed study will evaluate outcomes in MMUD bone marrow transplant recipients using 
either FIC or RIC regimens with PTCy, sirolimus and MMF for GVHD prophylaxis, where 
patients do not have an HLA-identical sibling or 8/8 matched unrelated donor available. This 
study will extend the single center approach used at Johns Hopkins University in the non-
myeloablative setting to a multi-center setting. In addition, it will test the encouraging results of 
myeloablative conditioning in the haploidentical setting to that of MMUD. 
  
2 
STUDY DESIGN 
2.1 
 Study Overview 
This is a multi-center, single arm Phase II study to assess the safety and efficacy of MMUD bone 
marrow transplantation using PTCy, sirolimus and MMF for GVHD prophylaxis.  The purpose is 
to determine whether results in a single center setting can be duplicated in a multi-center setting 
with survival outcomes similar to those achieved with haploidentical bone marrow HCT using a 
similar approach.   
 
2.2 
Hypotheses and Objectives 
2.2.1 Primary Hypothesis 
Our primary hypothesis is that 1-year survival after HLA MMUD bone marrow 
transplantation is 65% or higher, similar to the 1-year survival observed after 
haploidentical (related) donor bone marrow transplantation. 
 
2.2.2 Secondary Hypotheses 
1. Greater than 90% of subjects will engraft and more than 80% of engrafting subjects 
will achieve  95% donor chimerism by Day+56. 


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2. The incidence of grades III-IV GVHD will be less than 15% at Day+100. 
 
2.2.3 Study Objectives 
The primary objective is to determine OS through 1-year after HLA MMUD bone 
marrow HCT using PTCy.  
 
Secondary objectives include estimating the following: PFS at Day+180 and 1-year post-
HCT; TRM at Day+100, Day+180, and 1-year post-HCT; cumulative incidence of 
neutrophil recovery; cumulative incidence of platelet recovery; cumulative incidence of 
primary graft failure; donor chimerism; cumulative incidences of aGVHD and cGVHD; 
cumulative incidences of viral reactivations and infections; cumulative incidence of 
relapse/progression; and cumulative incidences of TMA and VOD/SOS. The proportion 
of subjects proceeding to HCT after informed consent will be described.  The donor 
selection characteristics will also be described.  Time to donor identification from the 
search request will be described. Incidence of development of donor clonal hematopoiesis 
will be described.  Analysis of long-term survivors will be performed for subjects who 
consent to the CIBMTR Research Database protocol using routine data collection forms 
and time points per CIBMTR requirements. 
 
2.3 
Subject Eligibility 
2.3.1 Inclusion Criteria 
1. Age ≥ 15 years and < 71 years at the time of signing the informed consent form. 
Note: HIV-negative subjects with MDS must be <50 years of age at time of signing 
the informed consent form. 
2. Partially HLA-MMUD: HLA typing will be performed at high resolution (allele level) 
for the HLA-A, -B, -C, and –DRB1 loci; a minimum match of 4/8 at HLA-A, -B, -C, 
and –DRB1 is required 
3. Product planned for infusion is bone marrow 
4. Disease and disease status: 
a. Acute leukemias or T-LBL in 1st or subsequent CR  
i. ALL or T-LBL defined by the following:  
• < 5% blasts in the bone marrow 
• Normal maturation of all cellular components in the bone marrow 
• No currently active extramedullary disease (EMD) (e.g., central 
nervous system (CNS), soft tissue disease) 
• ANC ≥ 1,000/mm3 
ii. AML defined by the following:  
• < 5% blasts in the bone marrow 
• No blasts with Auer rods 
• Normal maturation of all cellular components in the bone marrow 
• No currently active EMD (e.g., CNS, soft tissue disease) 
• 
ANC ≥ 1,000/mm3 
iii. ABL/AUL defined by the following: 
• < 5% blasts in the bone marrow 


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• Normal maturation of all cellular components in the bone marrow 
• No currently active EMD (e.g., CNS, soft tissue disease) 
• ANC ≥ 1,000/mm3 
b. MDS fulfilling the following criteria: 
• Subjects with de novo MDS who have or have previously had 
Intermediate-2 or High risk disease as determined by the IPSS. Current 
Intermediate-2 or High risk disease is not a requirement. 
• Subjects must have < 20% bone marrow blasts, assessed within 60 days 
of informed consent. 
• Subjects may have received prior therapy for the treatment of MDS prior 
to enrollment 
c. CLL in CR (if RIC is to be used), or CR or PR (if FIC is to be used)  
CR is defined by the following: 
• No evidence of lymphadenopathy 
• No organomegaly 
• Neutrophils ≥ 1.5 × 109/L 
• Hemoglobin > 11 g/dL 
• Lymphocytes < 4 × 109/L 
• Bone marrow < 30% lymphocytes 
• Absence of constitutional symptoms (including weight loss, fever, and 
night sweats) 
PR is defined by the following: 
• ≥ 50% decrease in peripheral blood lymphocyte count from 
pretreatment value 
• ≥ 50% reduction in lymphadenopathy if present pretreatment 
• ≥ 50% reduction in liver and/or spleen size if enlarged pretreatment 
One or more of the following: 
• Neutrophils ≥ 1.5 ×109/L or 50% improvement over baseline 
• Platelets > 100 ×109/L or 50% improvement over baseline 
• Hemoglobin > 11 g/dL or 50% improvement over baseline 
d. CML in 1st or subsequent chronic phase characterized by <10% blasts in the 
blood or bone marrow 
e. Chemotherapy-sensitive lymphoma in status other than 1st CR 
5. Performance status: Karnofsky or Lansky score ≥ 60% (Appendix A) 
6. Adequate organ function defined as: 
a. Cardiac: LVEF at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), 
or LVFS ≥ 25% 
b. Pulmonary: DLCO, FEV1, FVC ≥ 50% predicted by PFTs. DLCO value may be 
corrected or uncorrected for hemoglobin. 
c. Hepatic: total bilirubin ≤ 2.5 mg/dL, and ALT, AST, and ALP < 5 x ULN (unless 
ALT, AST, and/or ALP are disease related)  
d. Renal: SCr within normal range for age (see table 2.3A). If SCr is outside normal 
range for age, CrCl > 40 mL/min/1.73m2 must be obtained (measured by 24-hr 
urine specimen or nuclear GFR, or calculated GFR (by Cockcroft-Gault formula 


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for those aged ≥ 18 years; by Original Schwartz estimate for those < 18 years) 
(see table 2.3B)) 
 
TABLE 2.3A: SCr WITHIN NORMAL RANGE FOR AGE 
 
 
 
 
TABLE 2.3B: CALCULATED GFR CrCl ESTIMATION METHOD BY AGE 
Age 
Calculated GFR CrCl estimation method 
Formula  
≥ 18 years  Cockcroft-Gault formula (based on IBW) 
 
IBW(men)=50kg+2.3kg∗(heightover60inches) 
IBW(women)=45.5kg+2.3kg∗(heightover60inches) 
Cockcroft-Gault formula: CrCl (mL/min) = [(140 – Age) 
x (Weight in kg)] / (SCr x 72)  (x 0.85 for females) 
 
<18 years  
Original Schwartz estimate 
CrCl (mL/min/1.73m2)= [length (cm) x k] / SCr 
k = 0.55 for adolescent females <18 years  
k = 0.7 for adolescent males <18 years  
 
7. Subjects ≥ 18 years of age must have the ability to give informed consent according 
to applicable regulatory and local institutional requirements. Legal guardian 
permission must be obtained for subjects < 18 years of age. Pediatric subjects will be 
included in age appropriate discussion in order to obtain assent. 
8. Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive) and a 
hematologic malignancy who meets all other eligibility requirements must: 
a. Receive only RIC regimen (i.e. Regimen A)  
b. Be willing to comply with effective ARV 
c. Have achieved a sustained virologic response for 12 weeks after cessation of 
hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C) 
 
2.3.2 Exclusion Criteria 
1. Suitable HLA-matched related or 8/8 allele matched (HLA-A, -B, -C, -DRB1) 
unrelated donor available. This exclusion does not apply to HIV-positive subjects 
who have a CCR5delta32 homozygous donor. 
2. Autologous HCT < 3 months prior to the time of signing the informed consent form 
3. Females who are breast-feeding or pregnant 
4. HIV-positive subjects: 
a. AIDS related syndromes or symptoms that may pose an excessive risk for 
transplantation-related morbidity as determined by the Treatment Review 
Committee (see Appendix D).  
b. Untreatable HIV infection due to multidrug ARV resistance. Subjects with a 
detectable or standard viral load > 750 copies/mL should be evaluated with an 
HIV drug resistance test (HIV-1 genotype). The results should be included as part 
of the ARV review (described in Appendix D). 
Age (Years) 
Maximum SCr (mg/dL) 
15 
1.2 
> 15 
1.5 


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c. Not currently prescribed ritonavir, cobacistat and/or zidovudine 
5. Current uncontrolled bacterial, viral or fungal infection (currently taking medication 
with evidence of progression of clinical symptoms or radiologic findings) 
6. Prior allogeneic HCT 
7. Primary myelofibrosis or myelofibrosis secondary to essential thrombocythemia or 
polycythemia vera 
8. HIV-negative subjects with MDS may not receive RIC and must be < 50 years of age 
at the time of signing the informed consent form  
 
2.4 
Donor Eligibility 
2.4.1 Inclusion Criteria 
1. Must be unrelated to the subject and matched at between 4/8 and 7/8 HLA alleles for 
HLA-A, -B, -C, and –DRB1 
2. Must meet NMDP medical suitability requirements for bone marrow donation.  
3. Must undergo eligibility screening according to current FDA requirements. Donors 
who do not meet one or more of the donor screening requirements may donate under 
urgent medical need.  
4. Must have the ability to give informed consent according to applicable NMDP donor 
regulatory requirements 
5. Must agree to donate bone marrow 
 
2.4.2 Exclusion Criteria 
1. Recipient positive anti-donor HLA antibodies against a mismatched allele in the 
selected donor determined by either: 
a. a positive crossmatch test of any titer (by complement-dependent 
cytotoxicity or flow cytometric testing) or  
b. the presence of anti-donor HLA antibody to any HLA locus (HLA-A, -B, -C, 
–DRB1, -DQB1, -DQA1, -DPB1, -DPA1) with MFI >1000 by solid phase 
immunoassay 
 
2.5 
Donor Prioritization Schema 
The donor search will be coordinated centrally by the NMDP but the final donor selection will be 
made by the study site. The following donor selection characteristics must be considered to 
perform the selection: number of mismatches at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, donor 
age, donor-recipient CMV serostatus match, donor weight, donor-recipient sex match, and 
donor-recipient ABO group match. In addition, CCR5delta32 genotype should be assessed in 
donors being considered for HIV-positive patients. 
 
The MMUD selection algorithm (Appendix J) is the proposed search strategy that prioritizes 
donor age, CMV serostatus, and ABO match over HLA match. This strategy should not be 
considered the prescribed search strategy for potential study subjects. Study sites may instead 
utilize institutional donor selection practices.  
 


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2.6 
Treatment Plan 
2.6.1 Protocol-specific treatment information 
Regimen A (RIC). Recommended schedule as below: 
1. Fludarabine 
• Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-
60 minute IV infusion on Days –6 through –2 (maximum cumulative dose, 150 
mg/m2). 
• The body surface area (BSA) dosing is based on adjusted ideal body weight 
(IBW) (Appendix K), unless the subject weighs less than IBW, in which case 
dosing is based on actual body weight. 
• CrCl may change during the days fludarabine is given. Adjustment in dose due to 
creatinine changes during conditioning is permitted. Please see table 2.3B for 
calculated GFR CrCl estimation method by age. 
o For decreased CrCl, fludarabine dosage is reduced as follows: 
▪ CrCl 46-60 mL/min, fludarabine = 24 mg/m2 
▪ CrCl 31-45 mL/min, fludarabine = 22.5 mg/m2 
▪ CrCl 21-30 mL/min, fludarabine = 19.5 mg/m2 
▪ 
CrCl < 20 mL/min, fludarabine = 15 mg/m2 
2. Pre-HCT Cy 
• Cy 14.5 mg/kg/day is administered as a 1-2 hour IV infusion on Days –6 and –5 
after hydration. 
• Use of Mesna and dosing will be done according to institutional standards. A 
recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily 
dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 
hours after completion of Cy. 
• Hydration prior to Cy may be given according to institutional guideline. 
• Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the 
subject weighs less than IBW, in which case these drugs will be dosed according 
to actual weight. 
3. TBI 
• 200 cGy TBI is administered in a single fraction on Day –1.  
• Radiation sources, dose rates, and shielding follow institutional practice. 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards as long as the prescribed doses are the same as in the recommended regimen 
above. 
Regimen B (FIC). Recommended schedule as below:  
1. Busulfan 
• Busulfan ≥ 9mg/kg total dose (IV or PO) on Days -6, -5, -4, -3 (PK monitoring 
required  to achieve a daily AUC target of 4800-5300 μM*min (Perkins et al., 
2012)) 
• Busulfan dosing is based on adjusted IBW (Appendix K), unless the subject 
weighs less than IBW, in which case dosing is based on actual body weight. 


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2a. Pre-HCT Cy 
• Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days –2 and –1 
after hydration. 
• Use of Mesna and dosing will be done according to institutional standards. A 
recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily 
dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 
hours after completion of Cy. 
• Hydration prior to Cy may be given according to institutional guideline. 
• Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the 
subject weighs less than IBW, in which case these drugs will be dosed according 
to actual weight. 
OR 
 
2b. Fludarabine 
 
• Fludarabine 30 mg/m2/day (adjusted for renal function) is administered over a 30-
60 minute IV infusion on Days –6 through –2 (maximum cumulative dose, 150 
mg/m2). 
• The BSA dosing is based on adjusted IBW (Appendix K), unless the subject 
weighs less than IBW, in which case dosing is based on actual body weight. 
• CrCl may change during the days fludarabine is given. Adjustment in fludarabine 
dose due to creatinine changes during conditioning is permitted. Please see table 
2.3B for calculated GFR CrCl estimation method by age. 
o For decreased CrCl, fludarabine dosage is reduced as follows: 
▪ CrCl 46-60 mL/min, fludarabine = 24 mg/m2 
▪ CrCl 31-45 mL/min, fludarabine = 22.5 mg/m2 
▪ CrCl 21-30 mL/min, fludarabine = 19.5 mg/m2 
▪ CrCl < 20 mL/min, fludarabine = 15 mg/m2 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards as long as the prescribed doses, and Busulfan monitoring, are the same as in the 
recommended regimen above. 
 
Regimen C (FIC). Recommended schedule as below: 
1. Pre-HCT Cy 
• Cy 50mg/kg/day is administered as a 1-2 hour IV infusion on Days –5 and –4 
after hydration. 
• Use of Mesna and dosing will be done according to institutional standards. A 
recommended approach is as follows: Mesna IV dose of ≥ 80% of the total daily 
dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-9 
hours after completion of Cy. 
• Hydration prior to Cy may be given according to institutional guideline.  
• Cy and mesna are dosed according to adjusted IBW (Appendix K), unless the 
subject weighs less than IBW, in which case these drugs will be dosed according 
to actual weight. 


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2. TBI 
• 200cGy TBI is administered in twice daily on Days –3, -2, and -1.  
• Radiation sources, dose rates, and shielding follow institutional practice. 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards as long as the prescribed doses are the same as in the recommended regimen 
above. 
Bone marrow transplantation 
• On Day 0, the harvested bone marrow is infused.  
• Donor bone marrow will be harvested with a target yield of 4 x 108 nucleated 
cells/kg recipient weight (actual, ideal, or adjusted ideal per institutional practice). 
• The lowest acceptable nucleated cells yield is 1.5 x 108 cells/kg recipient weight 
(actual or adjusted per institutional practice).  
o Study sites should notify the 15-MMUD CIBMTR Protocol Coordinators 
if they are aware of a collection that yields lower total nucleated cells 
(TNC) than expected. 
• TNC/kg (and CD34+ cells/kg if available) infused will be recorded. 
• The graft will not be manipulated to deplete T-cells.  
• Processing for ABO incompatibility follows institutional practices.  
• Peripheral stem cell harvest is not permitted.  
• Use of a cryopreserved graft is not permitted. 
 
Post-Transplant Treatments 
PTCy 
• Cy 50mg/kg IV, over 1-2 hours (depending on volume), is given on Day+3 
(ideally between 60 and 72 hours after bone marrow infusion) and on Day+4 
(approximately 24 hours after Day+3 Cy). 
• Hydration with Cy, management of volume status, and monitoring for 
hemorrhagic cystitis will follow institutional standards. 
• Mesna recommendation: Mesna IV dose ≥ 80% of the total daily dose of Cy and 
given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after 
completion of Cy. Institutional standards for mesna use and dosing may be used 
when necessary. 
• Cy and mesna are dosed according to IBW, unless the subject weighs less than 
IBW, in which case these drugs will be dosed according to actual body weight. 
 
It is crucial that no systemic immunosuppressive agents are given until at least 24 
hours after the completion of the PTCy. This includes corticosteroids as anti-
emetics. 
 
Sirolimus 
For subjects ≥ 18 years:  
• Sirolimus dosing is based on adjusted IBW (Appendix K).  


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• A one-time sirolimus loading dose, 6 mg PO, is given on Day+5, at least 24 hours 
after Cy completion.  
• Sirolimus is then continued at a maintenance dose (starting dose 2 mg PO QD), 
with dose adjustments to maintain a trough of 5 – 15 ng/mL as measured by high 
performance liquid chromatography (HPLC) or immunoassay.  
 
For subjects < 18 years:  
• Sirolimus dosing is based on adjusted IBW (Appendix K).   
• A one-time sirolimus loading dose, 3 mg/m2 PO with the dose not to exceed 6 mg, 
is given on Day+5, at least 24 hours after Cy completion.  
• Sirolimus is then continued at a maintenance dose (starting dose 1 mg/m2 PO QD, 
maximum 2 mg PO QD), with dose adjustments to maintain a trough of 5 – 15 
ng/mL as measured by HPLC or immunoassay.  
 
All subjects: 
• Sirolimus prophylaxis is discontinued after the last dose on Day+180, or may be 
continued if there is GVHD.  
• There is no planned taper. If subject experiences toxicity potentially attributable 
to sirolimus requiring dose adjustment or omission of 4 or more doses prior to 
Day+180, study site Principal Investigator must contact protocol chairs for 
guidance regarding sirolimus dosing.  
• Study site Principal Investigator must contact protocol chairs for guidance 
regarding sirolimus dosing if considering stopping sirolimus before Day+56 (in 
the presence of suspected graft failure or for other clinical reasons) 
• Sirolimus troughs should be checked at minimum weekly through Day+100 and 
then monitoring thereafter per institutional practices.  
• More frequent monitoring is required if a new medication is initiated or if the 
subject develops renal insufficiency or hepatic dysfunction. 
 
Drugs that may increase sirolimus blood concentrations include:  
• Calcium channel blockers: diltiazem, nicardipine, verapamil.  
• Calcineurin inhibitors (CNI): cyclosporine.  
• Antifungal agents: ketoconazole, clotrimazole, fluconazole, itraconazole, 
voriconazole, posaconazole, isavuconazole. 
• Macrolide antibiotics: clarithromycin, erythromycin, troleandomycin.  
• Gastrointestinal prokinetic agents: cisapride, metoclopramide.  
• Other drugs: bromocriptine, cimetidine, danazol, HIV protease inhibitors.  
 
Drugs that may decrease sirolimus concentrations include:  
• Anticonvulsants: carbamazepine, phenobarbital, phenytoin.  
• Antibiotics: rifabutin, rifapentine, rifampin 
• Herbal preparations: St. John’s Wort (Hypericum perforatum)  
 
 


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Guidelines for HIV-positive subjects continuing ARV with various prophylaxis regimens 
are detailed below in Table 2.6A (Alvarnas & Ambinder, 2012). 
 
TABLE 2.6A CONTINUATION OF ARV BASED ON  
GVHD PROPHYLAXIS REGIMEN1 
 
GVHD 
Prophylaxis Agent  
Raltegravir 
Based Regimen  
NNRTI2 Based 
Regimen  
Other  
 
Sirolimus  
Continue ARV as 
tolerated  
 
Continue ARV. 
Sirolimus dose 
adjustments will be 
required (Appendix F)  
Consultation 
recommended, reviewed 
on a case by case basis  
 
Cy  
Continue ARV as 
tolerated  
 
Continue ARV as 
tolerated with caution 
and frequent monitoring 
(Appendix F)  
Consultation 
recommended, reviewed 
on a case by case basis3  
 
1Subjects should be switched to raltegravir-based regimens whenever possible  
2Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)  
3Restart ARV after Cy prophylaxis (Day+5) as soon as subject can tolerate oral medications 
 
MMF 
MMF begins on Day+5, at least 24 hours after completion of PTCy. The MMF dose is 15 
mg/kg PO TID (according to adjusted IBW (Appendix K)) with total daily dose not to 
exceed 3 g (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) may 
instead be given. Dose modification guidelines are provided in section 2.6.4. MMF 
prophylaxis is discontinued after the last dose on Day+35, or may be continued if there is 
GVHD. 
 
Growth factors 
G-CSF (filgrastim) or a biosimilar begins on Day+5 at a dose of 5 mcg/kg/day (according 
to actual body weight) IV or SC (rounding to the nearest vial dose is allowed), until the 
ANC is ≥ 1,000/mm3 over the course of 3 consecutive days. Additional G-CSF may be 
administered as warranted. Pegfilgrastim (Neulasta®) and granulocyte-macrophage 
colony-stimulating factor (GM-CSF) or their biosimilars are not permitted. 
 
Post-HCT donor cellular infusion (DCI) 
Prophylactic post-HCT DCI (for persistent detectable malignancy, prophylaxis in the 
absence of detectable malignancy, or mixed donor chimerism) is not permitted before 
Day+100. Any use of DCI, and the indication for DCI must be recorded. 
 
Other post-HCT therapy 
Preemptive systemic cancer therapy is permitted post-HCT (e.g., deoxyribonucleic acid 
(DNA)-methyltransferase inhibitor, tyrosine kinase inhibitor, rituximab for CD20+ 
malignancy). Intrathecal chemotherapy and consolidative radiation therapy are permitted. 
The use of such post-HCT therapies will be recorded. 
 


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2.6.2 Supportive Care 
Subjects should receive supportive care including transfusions, antiemetics, infection 
prophylaxis and nutritional support according to institutional guidelines. Infection 
prophylaxis should include, but is not limited to, agents or strategies to prevent herpes 
simplex, CMV, Pneumocystis jirovecii, and fungal infections.  
Seizure prophylaxis must be given with busulfan containing regimens per institutional 
guidelines. 
Herbal supplements and nutraceuticals are contraindicated. 
HIV-positive subjects: ARV is only effective when administered in combination and with 
consistency. Single agent therapy or repeated interruptions in therapy lead to drug 
resistance. The ARV guidelines (Appendices D and E) are designed to minimize the 
possibility of drug interactions with high dose chemotherapy. ARV should be 
administered only when it is anticipated that the ARV regimen can be taken on a 
consistent basis (i.e., conditioning regimen toxicities such as nausea and mucositis will 
not interfere with dosing schedules). In cases where the subject receives an HCT using a 
CCR5delta32 homozygous donor, ARV should be continued through at least Day+100.  
• Subjects on RIC Regimens: Subjects will continue on ARV therapy.  
 
Table 2.6B (Alvarnas & Ambinder, 2012) outlines continuation guidelines for ARV 
regimens based on the conditioning regimen used. 
 
TABLE 2.6B: CONTINUATION OF ARV BASED ON CONDITIONING REGIMEN 
 
 
Raltegravir 
Based Regimen  
NNRTI Based 
Regimen  
Other  
 
RIC 
Regimen A: 
Fludarabine 
Cy  
Continue 
throughout 
conditioning as 
tolerated  
Continue 
throughout 
conditioning as 
tolerated  
Consultation 
recommended, 
reviewed on a case 
by case basis  
See Appendix F (Table F-1) for detailed information on each interaction. 
 
2.6.3 Tests, Procedures, Observations 
Pre-conditioning evaluations (must be completed within 4 weeks prior to start of 
conditioning)*: 
• Complete history and physical (H&P) with height and weight 
• HCT-Specific Co-Morbidity Index (HCT-CI) score 
• Complete blood count (CBC) with differential  
• HLA typing (recipient and donor)† 
• Disease evaluation:  
o Acute leukemias, MDS, CLL, CML, and lymphomas with bone marrow 
involvement pre-HCT: Bone marrow aspiration with or without biopsy for 


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morphology, flow cytometry and cytogenetic analysis (fluorescence in situ 
hybridization (FISH) as indicated). 
o For lymphoma and CLL subjects: pre-HCT imaging required; computed 
tomography (CT)/positron emission tomography (PET)/ magnetic 
resonance imaging (MRI) scans of neck, chest, abdomen and pelvis as 
appropriate per center policy 
• Performance status (Karnofsky if > 16 years, Lansky score if < 16 years) 
• Echocardiogram (echo) or multiple-gated acquisition scan (MUGA) with 
measurement of LVEF or LVFS 
• PFT with measurements of FEV1, FVC and DLCO. DLCO value may be corrected 
or uncorrected for hemoglobin. 
• Serum chemistries including creatinine, total bilirubin, ALT, AST, and ALP. If 
SCr is outside normal range for age, CrCl (measured by 24-hr urine specimen or 
nuclear GFR, or calculated GFR (by Cockcroft-Gault formula for those aged ≥ 18 
years; by Original Schwartz estimate for those < 18 years)) must be obtained 
• β-HCG serum pregnancy test for females of childbearing potential (FCBP) 
o FCBP is defined as a female with evidence of menarche who has not been 
surgically sterilized, and is not post-menopausal (menopausal: > 45 years 
of age with no menstrual period for ≥ 12 months) 
• Patient and donor CIBMTR Biorepository sample collection† 
 
*HIV-positive subjects: See Appendix D for the Treatment Review Committee 
approval process for HIV-positive subject conditioning regimen; Appendix G for 
additional evaluations for HIV-positive subjects; and Appendix I for additional 
research laboratory samples. 
†Pre-conditioning evaluations that do not need to be completed within 4 weeks 
prior to the start of conditioning. 
 
Conditioning evaluations (Days -6 through -1): 
• Busulfan PK monitoring for subjects receiving Regimen B (AUC target of 4800-
5300 μM*min per day). Timing of sample collection for Busulfan PK 
determination may be done according to institutional standards. 
 
Post-HCT evaluations: 
• Day+7 (+/- 5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+14 (+/- 5 days) 
o H&P  


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o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+21 (+/-5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o Peripheral blood collection 
▪ Research: gene expression profile 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+28 (+/- 5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
o Peripheral blood collection 
▪ Routine: chimerism in whole blood (unsorted); CD3 and CD33 
subsets if available 
• Day+35 (+/- 5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+42 (+/- 5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+49 (+/- 5 days) 


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o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+56 (+/- 5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
o Peripheral blood collection 
▪ Routine: chimerism in whole blood (unsorted); CD3 and CD33 
subsets if available  
• Day+63 (+/- 5 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+100 (+/- 7 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
o Peripheral blood collection 
▪ Routine: chimerism in whole blood (unsorted); CD3 and CD33 
subsets if available  
▪ Research: gene expression profile; immune reconstitution 
o Bone marrow collection  
▪ Routine: disease evaluation (see below) 
▪ Research: donor clonal hematopoiesis assessment (all subjects – 
regardless of disease) 
o Disease evaluation  
▪ Acute leukemias, MDS, CLL, CML, lymphomas with bone 
marrow involvement pre-HCT: Bone marrow aspiration with or 


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without biopsy for morphology, flow cytometry and cytogenetic 
analysis (FISH as indicated) 
▪ Lymphoma/CLL: Imaging studies as indicated (e.g. CT, PET, 
MRI) 
o See Appendix G for additional Day+100 evaluations for HIV-positive 
subjects 
• Day+150 (+/- 7 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
• Day+180 (+/- 28 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
o Peripheral blood collection 
▪ Routine: chimerism in whole blood (unsorted); CD3 and CD33 
subsets if available  
▪ Research: gene expression profile 
o Bone marrow collection  
▪ Routine: disease evaluation (see below) 
o Disease evaluation  
▪ Acute leukemias, MDS, CLL, CML, lymphomas with bone 
marrow involvement pre-HCT: Bone marrow aspiration with or 
without biopsy for morphology, flow cytometry and cytogenetic 
analysis (FISH as indicated). 
▪ Lymphoma/CLL: Imaging studies as indicated (e.g. CT, PET, 
MRI) 
o Survival status 
o See Appendices G and I for additional Day+180 evaluations for HIV-
positive subjects 
• Day+270 (+/- 28 days) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 


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o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
o See Appendix G for additional Day+270 evaluations for HIV-positive 
subjects 
• 1-year (Day+365 (+/- 28 days)) 
o H&P  
o CBC with differential 
o Serum chemistries 
o GVHD assessment 
o Toxicity assessment 
o Viral infections/reactivations assessment of CMV, EBV, BK, ADV, and 
HHV-6  
o Peripheral blood collection 
▪ Routine: chimerism in whole blood (unsorted); CD3 and CD33 
subsets if available  
▪ Research: immune reconstitution 
o Bone marrow collection  
▪ Routine: disease evaluation (see below) 
▪ Research: donor clonal hematopoiesis assessment (all subjects – 
regardless of disease)  
o Disease evaluation  
▪ Acute leukemias, MDS, CLL, CML, lymphomas with bone 
marrow involvement pre-HCT: Bone marrow aspiration with or 
without biopsy for morphology, flow cytometry and cytogenetic 
analysis (FISH as indicated). 
▪ Lymphoma/CLL: Imaging studies as indicated (e.g. CT, PET, 
MRI) 
o Survival status 
o See Appendices G and I for additional Day+365 evaluations for HIV-
positive subjects 


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2.6.3.1 Treatment Schemas 
Regimen A (RIC): Flu/Cy/TBI 
 
 
Days pre-HCT 
Day 0 
Days post-HCT 
Evaluation/Event 
Eligibility 
assessments* 
 –6 → 
–5 
 –4 → 
–2 
–1 
3→ 
4 
5 
7 
14 
21 
28 
35 
42 
49 
56 
63 
100 
150 
180 
270 
365 
Informed Consent and 
Study Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete H&P 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCT-CI score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing (recipient and 
donor) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow collection: 
disease evaluation1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
CBC w/differential 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging2,3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echo or MUGA (LVEF or 
LVFS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT (FEV1, FVC & DLCO) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistries4 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
β-HCG serum pregnancy 
test (FCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 30 mg/m2/day 
IV5 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cy 14.5 mg/kg/day IV5 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna6 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin antibiotic 
prophylaxis7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TBI 200cGy5 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infuse non-T-cell-depleted 
bone marrow 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RCI BMT Protocol #15-MMUD 
 
 
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Cy 50 mg/kg/day IV8 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin sirolimus (PO) dose 
adjusted to maintain a level 
of 5-15 ng/mL 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMF 15 mg/kg PO TID 
(maximum dose 1g PO TID, 
maximum dose 3g/day) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin G-CSF 5 mcg/kg/day 
SC or IV, continue until 
ANC  1000/mm3 x 3 
consecutive days 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess chimerism in 
peripheral blood9 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Discontinue MMF (optional 
if GVHD is active) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Discontinue sirolimus 
(optional if GVHD is 
active) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
GVHD assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral 
infections/reactivations 
assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Research sample collection 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 


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NMDP IRB-2016-0365 
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Regimen B – 2a (FIC): Bu/Cy  
 
 
Days pre-HCT 
Day 0 
Days post-HCT 
Evaluation/Event 
Eligibility 
assessments* 
 –6 → 
–3 
–2 → 
–1 
3→ 
4 
5 
7 
14 
21 
28  35 
42 
49 
56 
63 
100  
150 
180  270 
365  
Informed Consent and 
Study Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete H&P 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCT-CI score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing (recipient and 
donor) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow collection: 
disease evaluation1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
CBC w/differential 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging 2,3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echo or MUGA (LVEF or 
LVFS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT (FEV1, FVC & DLCO) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistries4 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
β-HCG serum pregnancy 
test (FCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan ≥ 9mg/kg total 
dose (IV or PO)11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan PK monitoring12 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin antibiotic 
prophylaxis7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna6  
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cy 50mg/kg/day IV11  
 
 
X 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infuse non-T-cell-depleted 
bone marrow 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RCI BMT Protocol #15-MMUD 
 
 
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NMDP IRB-2016-0365 
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Begin sirolimus (PO) dose 
adjusted to maintain a level 
of 5-15 ng/mL   
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMF 15 mg/kg PO TID 
(maximum dose 1g PO TID, 
maximum dose 3 g/day) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin G-CSF 5 mcg/kg/day 
SC or IV, continue until 
ANC  1000/mm3 x 3 
consecutive days 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess chimerism in 
peripheral blood9 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Discontinue MMF (optional 
if GVHD is active) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Discontinue sirolimus 
(optional if GVHD is active) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
GVHD assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral 
infections/reactivations 
assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Research sample collection 
X10 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 


RCI BMT Protocol #15-MMUD 
 
 
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NMDP IRB-2016-0365 
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Regimen B – 2b (FIC): Bu/Flu 
 
 
Days pre-HCT 
Day 0 
Days post-HCT 
Evaluation/Event 
Eligibility 
assessments* 
–6 → 
–3 
–2 
-1 
3→ 
4 
5 
7 
14 
21 
28 
35 
42 
49 
56 
63 
100 
150 
180 
270 
365 
Informed Consent and Study 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete H&P 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCT-CI score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing (recipient and 
donor) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow collection: 
disease evaluation1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
CBC w/differential 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging 2,3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echo or MUGA (LVEF or 
LVFS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT (FEV1, FVC & DLCO) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistries4 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
β-HCG serum pregnancy test 
(FCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan ≥ 9mg/kg total dose 
(IV or PO)11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Busulfan PK monitoring12 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fludarabine 30 mg/m2/day 
IV11 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin antibiotic prophylaxis7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infuse non-T-cell-depleted 
bone marrow 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna6  
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cy 50 mg/kg/day IV8 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RCI BMT Protocol #15-MMUD 
 
 
Version 4.0 March 14, 2018 
 
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NMDP IRB-2016-0365 
NMDP IRB Approved 
 
Begin sirolimus (PO) dose 
adjusted to maintain a level 
of 5-15 ng/mL   
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMF 15 mg/kg PO TID 
(maximum dose 1g PO TID, 
maximum dose 3 g/day) 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin G-CSF 5 mcg/kg/day 
SC or IV, continue until 
ANC  1000/mm3 x 3 
consecutive days 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess chimerism in 
peripheral blood9 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Discontinue MMF (optional 
if GVHD is active) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Discontinue sirolimus 
(optional if GVHD is active) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
GVHD assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral infections/reactivations 
assessment 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Research sample collection 
X10 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 


RCI BMT Protocol #15-MMUD 
 
 
Version 4.0 March 14, 2018 
 
38 
NMDP IRB-2016-0365 
NMDP IRB Approved 
Regimen C (FIC): Cy/TBI 
 
 
Days pre-HCT 
Day 
0 
Days post-HCT 
Evaluation/Event 
Eligibility 
assessments* 
–5 → 
–4 
–3 → 
–1 
3→ 
4 
5 
7 
14 
21 
28 
35 
42 
49 
56 
63 
100 
150 
180 
270 
365 
Informed Consent and Study 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete H&P 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HCT-CI score 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing (recipient and 
donor) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow collection: 
disease evaluation1  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
CBC w/differential 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging 2,3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Performance Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echo or MUGA (LVEF or 
LVFS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PFT (FEV1, FVC & DLCO) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum chemistries4 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
β-HCG serum pregnancy test 
(FCBP) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin antibiotic prophylaxis7 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mesna6  
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cy 50mg/kg/day IV 5 
 
X 
 
 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TBI 200cGy twice a day 5 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infuse non-T-cell-depleted 
bone marrow 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin sirolimus (PO) dose 
adjusted to maintain a level of 
5-15 ng/mL   
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


RCI BMT Protocol #15-MMUD 
 
 
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39 
NMDP IRB-2016-0365 
NMDP IRB Approved 
1 Acute leukemias, MDS, CLL, CML, and lymphomas with bone marrow involvement pre-HCT: Bone marrow aspiration with or without biopsy for 
morphology, flow cytometry and cytogenetic analysis (FISH as indicated). 
2 Lymphoma/CLL subjects: Pre-HCT imaging required. CT/PET/MRI scans of neck, chest, abdomen and pelvis as appropriate per center policy. 
3 Lymphoma/CLL subjects: Post-HCT imaging studies as indicated (e.g. CT, PET, MRI).  
4 Serum chemistries include creatinine, total bilirubin, ALT, AST, and ALP. If SCr is outside normal range for age, CrCl (measured by 24-hr urine specimen or 
nuclear GFR, or calculated GFR (by Cockcroft-Gault formula for those aged ≥ 18 years; by Original Schwartz estimate for those < 18 years)) must be obtained. 
5 Although a schedule is proposed, the regimen can be given according to institutional standards as long as the prescribed doses are the same as in the 
recommended regimen. 
6 Mesna recommendation: Mesna IV dose ≥ 80% of the total daily dose of Cy, given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after 
completion of Cy. Institutional standards for mesna use and dosing may be used when necessary. 
7 Start of antibiotic prophylaxis may be altered based on institutional standard 
8 First dose of PTCy must be administered 60-72 hrs after infusion of bone marrow 
9 Peripheral blood chimerism in whole blood (unsorted); CD3 and CD33 subsets if available 
10 HIV-positive patients only: pre-conditioning sample collection for Latent HIV Cellular Reservoir Analysis 
11 Although a schedule is proposed, the regimen can be given according to institutional standards as long as the prescribed doses, and Busulfan monitoring, are 
the same as in the recommended regimen. 
12 Timing of sample collection for Busulfan PK determination may be done according to institutional standards. 
MMF 15 mg/kg PO TID 
(maximum dose 1g PO TID, 
maximum dose 3 g/day) 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Begin G-CSF 5 mcg/kg/day 
SC or IV, continue until ANC 
 1000/mm3 x 3 consecutive 
days 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assess chimerism in 
peripheral blood9 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
Discontinue MMF (optional if 
GVHD is active) 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Discontinue sirolimus 
(optional if GVHD is active) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
GVHD assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Viral infections/reactivations 
assessment 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Research sample collection 
X10 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
 
X 


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NMDP IRB-2016-0365 
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* HIV-positive subjects: See Appendix D for the Treatment Review Committee approval process for HIV-positive subject conditioning regimen; Appendix G for 
additional evaluations for HIV-positive subjects; and Appendix I for additional research laboratory samples.  


 
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2.6.4 Risks and Toxicities 
Below is a list of the most common toxicities for therapies used in this study. See the 
U.S. Food and Drug Administration (FDA)-approved package insert for each drug for a 
comprehensive list of AEs. 
 
Busulfan (Busulfex®) 
 
Busulfan (1, 4-dimethanesulfonoxybutane) is an alkylating agent. The drug is extensively 
metabolized by the liver and its metabolites are eventually excreted in the urine. 
 
Busulfan toxicities include: 
• Gastrointestinal: nausea, vomiting, constipation, diarrhea, abdominal discomfort, 
anorexia, dyspepsia, mucositis, stomatitis 
• Hepatobiliary: VOD/SOS 
• Neurologic: headache, insomnia, seizures, dizziness 
• Cardiovascular: hypertension, hypotension and tachycardia 
• Pulmonary: dyspnea, lung fibrosis, cough 
• Endocrine and metabolic: electrolyte imbalance 
• Genitourinary: amenorrhea, dysmenorrhea, infertility 
• Dermatologic: rash, urticarial 
• Miscellaneous: rhinorrhea, cataracts, fluid retention 
 
PK monitoring of Busulfan is required to achieve a daily AUC target of 4800-5300 
μM*min (Perkins et al., 2012). Busulfan dosing is based on adjusted IBW (Appendix K), 
unless the subject weighs less than IBW, in which case dosing is based on actual body 
weight. 
 
Fludarabine (Fludara®) 
Fludarabine is a fluorinated nucleoside analog. After phosphorylation to fluoro-ara-
adenosine triphosphate (ATP) the drug appears to incorporate into DNA and inhibit DNA 
polymerase alpha, ribonucleotide reductase and DNA primase, thus inhibiting DNA 
synthesis. Excretion of fludarabine is impaired in subjects with impaired renal function. 
 
Fludarabine toxicities include: 
• Hematologic: hematopoietic suppression including neutropenia with increased 
risk of infection and immunosuppression 
• Neurologic: peripheral neuropathy and encephalopathy manifested by fatigue, 
weakness, paresthesia, visual disturbances, somnolence and coma 
• Gastrointestinal: nausea, vomiting, diarrhea and stomatitis 
• Dermatologic: rash, urticarial 
• Pulmonary: cough, idiopathic pneumonitis, dyspnea 
• Miscellaneous: fever  


 
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Dose adjustments of fludarabine are required for renal insufficiency if the estimated CrCl 
is < 60 mL/min (per section 2.6.1). Fludarabine BSA dosing is based on adjusted ideal 
body weight (IBW) (Appendix K), unless the subject weighs less than IBW, in which 
case dosing is based on actual body weight. 
 
Cyclophosphamide (Cytoxan®) 
Cyclophosphamide (Cy) is an alkylating agent. It is activated by the liver cytochrome 
P450 system to cytotoxic metabolites, which form cross-links with DNA. It is cell cycle-
nonspecific. 
 
Cy toxicities include: 
• 
Gastrointestinal: nausea, vomiting, anorexia, stomatitis, diarrhea, abdominal pain 
• 
Hematologic: myelosuppression, thrombocytopenia, carcinogenesis, anemia 
• 
Cardiovascular: severe chronic heart failure characterized by cardiomegaly, 
pericardial effusions, diffuse voltage decrease on ECG and decreased LVEF 
• 
Genitourinary: hemorrhagic cystitis (prevented by hydration and mesna therapy or 
bladder irrigation) and gonadal function impairment, amenorrhea, dysmenorrhea, 
infertility, damage to unborn baby 
• 
Pulmonary: rare pulmonary toxicity, lung fibrosis 
• 
Dermatologic: alopecia, rash, urticarial 
• 
Miscellaneous: fluid retention, allergic reaction 
 
Dose adjustments for Cy will not be made.  
 
Pre-HCT Cy: dosed according to adjusted IBW (Appendix K), unless the subject weighs 
less than IBW, in which case Pre-HCT Cy will be dosed according to actual weight. 
 
PTCy: dosed according to IBW, unless the subject weighs less than IBW, in which case 
PTCy will be dosed according to actual body weight. 
 
 
Mesna (Mesnex®) 
Mesna (sodium-2-mercaptoethanesulphonate) is a prophylactic agent used to prevent 
hemorrhagic cystitis induced by the oxazophosphorines (Cy and ifosfamide). It has no 
intrinsic cytotoxicity and no antagonistic effects on chemotherapy. Mesna binds with 
acrolein, the urotoxic metabolite produced by the oxazophosphorines, to produce a non-
toxic thioether and slows the rate of acrolein formation by combining with 4-hydroxy 
metabolites of oxazophosphorines. 
 
Mesna toxicities include:  
• Cardiovascular: hypotension 
• Dermatologic: rash, urticarial 
• Gastrointestinal: nausea and vomiting, diarrhea, abdominal pain, altered taste 
• Neurologic: headache, joint or limb pain  
• Miscellaneous: fatigue 


 
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Pre-HCT Mesna: pre-transplant use of mesna and dosing will be done according to 
institutional standards. A recommended approach is as follows: mesna IV dose ≥ 80% of 
the total daily dose of Cy and given in divided doses 30 minutes before and at 3, 6, and 8-
9 hours after completion of Cy. Mesna is dosed according to adjusted IBW (Appendix 
K), unless the subject weighs less than IBW, in which case mesna will be dosed 
according to actual weight. 
 
Post-HCT Mesna: the recommended approach is mesna IV dose ≥ 80% of the total daily 
dose of Cy, given in divided doses 30 minutes before and at 3, 6, and 8-9 hours after 
completion of Cy. Institutional standards for mesna use and dosing may be used when 
necessary. Mesna is dosed according to IBW, unless the subject weighs less than IBW, in 
which case mesna will be dosed according to actual body weight.  
 
 
MMF (Cellcept®) 
MMF is an ester prodrug of the active immunosuppressant mycophenolic acid (MPA). 
 
MMF toxicities include: 
• Hematologic: pancytopenia with increased risk of infection and 
immunosuppression, anemia 
• Cardiovascular: hypertension, hypotension, tachycardia 
• Dermatologic: rash, urticarial 
• Gastrointestinal: nausea and vomiting, diarrhea, abdominal pain, altered taste, 
hematemesis, hematochezia 
• Neurologic: headache, joint or limb pain, dizziness, insomnia, Progressive 
Multifocal Leukoencephalopathy (PML), tremors 
• Genitourinary: miscarriage, birth defects, damage to unborn baby, limited 
effectiveness of birth control 
• Endocrine and metabolic: hyperlipidemia, hyperglycemia, electrolyte imbalances 
• Pulmonary: dyspnea 
• Miscellaneous: fatigue, changes in vision, edema, unusual contusions, allergic 
reaction, leg cramps 
 
Drug interactions: MMF activity is decreased with oral antacids and cholestyramine. 
There are no pharmacokinetic interactions with cotrimoxazole, oral contraceptives, or 
cyclosporine. Acyclovir or ganciclovir blood levels may increase due to competition for 
tubular secretion. High doses of salicylates or other highly protein-bound drugs may 
increase the free fraction of MPA and exaggerate the potential for myelosuppression. 
 
Dose adjustments: No dose adjustments are required for liver dysfunction. For renal 
insufficiency, MMF dosing should not be modified unless dialysis is needed, in which 
case MMF can be reduced to 25-50% of the starting dose. 
 


 
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The MMF dose is 15 mg/kg PO TID (adjusted IBW (Appendix K)) with total daily dose 
not to exceed 3 g (i.e. maximum 1 g PO TID). An equivalent IV dose (1:1 conversion) 
may instead be given. 
 
 
Sirolimus (rapamycin, Rapamune®) 
Sirolimus is an immunosuppressant that inhibits cytokine-stimulated T-cell activation and 
proliferation, and also inhibits antibody formation. 
 
Drug formulations: The mean bioavailability of sirolimus after administration of the 
tablet is ~27% higher than the oral solution. Sirolimus oral tablets are not bioequivalent 
to the oral solution. Clinical equivalence has been demonstrated at the 2-mg dose level; 
however, it is not known if higher doses are clinically equivalent on a mg to mg basis. 
a. Sirolimus oral solution: sirolimus oral solution (1 mg/mL) should be stored 
protected from light and refrigerated at 2°C to 8°C (36°F to 46°F). For dilution, 
the appropriate dose should be measured using an amber oral syringe, then added 
to a glass or plastic container that holds at least 60 mL. Before taking the dose, it 
should be diluted with water or orange juice then taken immediately; it should not 
be diluted with grapefruit juice. The syringe should be discarded after one use. 
Sirolimus oral solution provided in bottles may develop a slight haze when 
refrigerated, which does not affect product quality; allow the product to stand at 
room temperature and shake gently until the haze disappears. 
b. Sirolimus tablets: sirolimus tablets are available in 1 mg and 2 mg tablets that 
cannot be crushed or broken. Sirolimus tablets should be stored at 20° to 25° C 
(68°–77°F), protected from light. 
 
Sirolimus toxicities include:  
• 
Gastrointestinal: constipation, abdominal pain, nausea, diarrhea, dyspepsia, 
vomiting, anorexia, stomatitis, ascites 
• 
Pulmonary: dyspnea, asthma, cough, upper respiratory infection (URI), pleural 
effusion 
• 
Dermatologic: acne, rash, urticarial, pruritus, delayed wound healing 
• 
Hematologic: thrombocytopenia, anemia, thrombotic thrombocytopenic purpura 
(TTP), hemolytic uremic syndrome (HUS), TMA, immunosuppression, 
leukopenia, lymphoproliferative disorders 
• 
Cardiovascular:  hypertension, hypotension, chest pain, tachycardia, congestive 
heart failure, pericardial effusion 
• 
Genitourinary: urinary tract infection (UTI), renal dysfunction, proteinuria, 
kidney disease 
• 
Neurologic: headache, arthralgia, back pain, tremors, insomnia 
• 
Endocrine and metabolic: hypertriglyceridemia, hypercholesterolemia, 
hyperglycemia, electrolyte imbalance 
• 
Musculoskeletal: arthrosis, bone necrosis, osteoporosis, myalgias 
• 
Miscellaneous: peripheral edema, fever, flu-like syndrome 
 


 
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Sirolimus toxicities are summarized in Table 2.6C (Pidala, Alousi, & MacMillan, 2015) 
below. 
TABLE 2.6C: SIROLIMUS TOXICITIES 
 
Common (>20%) 
Occasional (5-20%) 
Rare (<5%) 
Immediate  
(within 1-2 days) 
Headache (L), 
hypertension (L), 
immunosuppression (L), 
fever, nausea, diarrhea, 
constipation 
Chest pain, insomnia, 
dyspepsia, vomiting, 
dyspnea 
Hypotension, asthma, 
cough, flu-like 
syndrome, tachycardia, 
anorexia, 
hypersensitivity 
reactions 
Prompt  
(within 2-3 weeks) 
Tremor (L), renal 
dysfunction, pain 
(abdominal, back, 
arthralgias), 
hyperlipidemia c 
(hypercholesterolemia, 
hypertriglyceridemia), 
hyperglycemia, edema 
including peripheral 
edema, anemia 
Elevated liver function 
tests (with 
elevated sirolimus 
levels), stomatitis, 
infections 
(including UTI, URI), 
mild thrombocytopenia, 
leukopenia, electrolyte 
disturbances 
(hyper/hypokalemia [L], 
hypophosphatemia, 
hypomagnesemia [L]), 
rash, hives, pruritus, 
delayed wound healing 
or dehiscence (L), 
proteinuria, 
TTP/ HUS/TMA  
especially with 
concurrent CNIs  
Pleural and pericardial 
effusions, pulmonary 
toxicity (non-infectious 
pneumonitis, 
bronchiolitis obliterans 
organizing pneumonia 
(BOOP), 
pulmonary fibrosis)), 
myalgias 
Delayed (any time later 
during therapy, 
excluding above 
conditions) 
Acne 
 
Kidney disease, 
congestive heart failure, 
ascites, arthrosis, bone 
necrosis, osteoporosis 
Late (any time after 
completion of treatment) 
 
 
Lymphoproliferative 
disorders, skin 
malignancies 
Unknown frequency and 
timing 
Embryo/fetotoxic; unknown whether excreted in human milk 
(L): Toxicity may also occur later. 
a Significant transaminitis, generally without sequellae, may occur. Sirolimus has been associated with higher rates 
of VOD after FIC. 
b Incidence 3% to < 20% in a trial of kidney transplantation. In allogeneic HCT, increase in TMA from 4.2% with 
tacrolimus or cyclosporine alone, versus 10.8% with tacrolimus/sirolimus combination was noted. 
c Lipid-lowering agent may be required; consider if fasting serum triglycerides are > 2.5 x ULN, and recommend 
starting if > 800 mg/dL. 
 
Drug interactions:  
• Sirolimus is known to be a substrate for both cytochrome CYP3A4 and 
Pglycoprotein. 


 
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• Agents that may increase sirolimus levels include tri-azole drugs (especially 
voriconazole and posaconazole*), amiodarone, calcium channel blockers, 
macrolide antibiotics (but not azithromycin), micafungin, gastrointestinal 
prokinetic agents (cisapride, metoclopramide), cimetidine, cyclosporine, 
grapefruit juice, and HIV protease inhibitors. 
• Agents that may decrease sirolimus levels include anticonvulsants 
(carbamazepine, phenobarbital, phenytoin), rifamycins, St. John’s Wort. 
Dose adjustments:  
• The sirolimus dose is adjusted to maintain a serum trough level of 5-15 ng/mL.  
• Changes in levels due to altered bioavailability should be apparent within 24-48 
hours. 
• For sirolimus without CNI as in this study, a 20-25% reduction of sirolimus dose 
is recommended for trough levels >12 – 18 ng/mL, and a 20-25% increase is 
recommended for trough levels < 5 ng/mL. 
• Renal failure does not affect the excretion of sirolimus.  
• Excretion is reduced in liver failure; impaired hepatic function should prompt 
consideration of reduction in sirolimus maintenance doses but no dose adjustment 
of the loading dose is necessary. 
 
Due to extreme interactions with triazole antifungal agents (fluconazole, itraconazole, 
clotrimazole, posaconazole, voriconazole, ketoconazole) sirolimus should be 
administered cautiously together with fluconazole, itraconazole, or posaconazole, 
and with extreme caution if administered together with voriconazole.  If co-
administration is unavoidable, then the dose of sirolimus should be greatly reduced when 
used in combination with an azole antifungal medication as recommended in Table 2.6D 
(Pidala, Alousi, & MacMillan, 2015) and that there should be very frequent monitoring of 
trough concentrations of sirolimus in whole blood.  Sirolimus concentrations should be 
measured upon initiation, during co-administration, and at discontinuation of antifungal 
treatment, with sirolimus doses adjusted accordingly. 
 
TABLE 2.6D: PRE-EMPTIVE DOSE REDUCTION OF SIROLIMUS WHEN 
USED IN COMBINATION WITH AZOLE 
Antifungal 
Sirolimus 
 
Dose  
Voriconazole 
90% 
Posaconazole 
90% 
Isavuconazole 
90% 
Itraconazole 
90% 
Fluconazole 
50% 
 
 
 


 
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TBI 
TBI toxicities include: 
• Gastrointestinal: nausea, vomiting, diarrhea, anorexia 
• Hematologic: hematopoietic suppression including neutropenia with increased risk 
of infection, bleeding and immunosuppression, carcinogenesis, anemia  
• Dermatologic: reversible skin pigmentation and alopecia 
• Genitourinary: infertility 
• Pulmonary: lung fibrosis 
• Miscellaneous: fever, parotiditis, fatigue, growth retardation, cataract formation 
 
3 
SUBJECT ENROLLMENT 
3.1 
Screening and Enrollment Procedures  
3.1.1  Screening Procedures 
Eligibility assessments must be performed within 4 weeks prior to the start of conditioning*:  
• H&P 
• HCT-CI score 
• CBC with differential 
• HLA typing (recipient and donor)† 
• Performance status 
• Echo or MUGA with measurement of LVEF or LVFS 
• PFTs with measurements of FEV1, FVC and DLCO. DLCO value may be 
corrected or uncorrected for hemoglobin. 
• Serum chemistries (AST, ALT, ALP, total bilirubin, SCr (with CrCl measured by 
24-hr urine specimen or nuclear GFR, or calculated GFR (by Cockcroft-Gault 
formula for those aged ≥ 18 years; by Original Schwartz estimate for those < 18 
years) for subjects where SCr is outside normal range for age)) 
• β-HCG pregnancy test for FCBP 
• Acute leukemias, MDS, CLL, CML, and lymphomas with bone marrow 
involvement pre-HCT: Bone marrow aspiration with or without biopsy for 
morphology, flow cytometry and cytogenetic analysis (fluorescence in situ 
hybridization (FISH) as indicated). 
• Patient and donor CIBMTR Biorepository sample collection† 
• Lymphoma/CLL subjects: pre-HCT imaging required. CT/PET/MRI scans of 
neck, chest, abdomen and pelvis as appropriate per center policy. 
 
*See Appendix G for additional evaluations for HIV-positive subjects; Appendix 
D for the Treatment Review Committee approval process for the HIV-positive 
subject’s conditioning regimen; and Appendix I for additional research laboratory 
samples. 
†Pre-conditioning evaluations that do not need to be completed within 4 weeks 
prior to the start of conditioning. 
 


 
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3.1.2 Enrollment Procedures 
Subjects must be consented prior to study-specific 
evaluations/procedures/tests/interventions (i.e. evaluations/procedures/tests/interventions 
that are beyond standard of care and directly required per protocol).  Subjects having 
documented informed consent and meeting all eligibility criteria for the study should be 
enrolled at least 7 days prior to the start of conditioning.  
• Note: HIV-positive subjects must be enrolled prior to collection of the pre-
conditioning Latent HIV Reservoir sample (sample collection to take place within 
8 weeks prior to the start of conditioning). 
 
Subjects are to be registered using the following procedures:  
• If not yet established, generate a CIBMTR Research Identification Number 
(CRID) using the tool in the FormsNet3 data entry system.  
• An authorized user at the center completes the 15-MMUD Demographics and 
Inclusion/Exclusion forms in the Rave module.  
 
3.2 
Withdrawal Procedures  
Subjects have the right to withdraw consent for study participation at any time and for any 
reason.  If a subject withdraws prematurely after HCT, all data normally collected at the 1-year 
study time point should be gathered at the time of premature discontinuation and reported  in the  
forms in the Rave module.   
An explanation of why the subject is withdrawing from the study must be documented in the 
medical record and the Study Exit form in the Rave module.  All subjects who withdraw from 
the study with an ongoing AE must be followed until resolution of the event, death, or until the 
investigator concludes that the event is stable with no further improvement anticipated. 
Subjects lost to follow-up must be reported on the Study Exit form in the Rave module. 
In the case that the subject decides to prematurely discontinue study treatment (“refuses 
treatment”), the subject must be asked if he or she can be contacted for further information. The 
outcome of that discussion must be documented in the medical record. 
 
4 
STUDY ENDPOINTS 
4.1 
Primary Endpoint 
The primary endpoint for the study is OS at 1-year post-HCT.  Subjects who are lost to follow-up 
prior to 1-year will be censored at the time of the last observation, and the OS proportion will be 
estimated using the Kaplan-Meier method.   
 
4.2 
Secondary Endpoints 
Secondary endpoints include:  
Progression-free survival 
PFS is defined as the time from HCT until the documentation of disease progression/relapse or 
death due to any cause, whichever occurs first. PFS will be evaluated at Day+180 and +365.  
 
Transplant-related mortality 


 
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TRM is defined as death without evidence of disease progression or recurrence. TRM will be 
evaluated at Day+100, +180, and +365. 
 
Cumulative incidence of neutrophil recovery  
Neutrophil recovery is defined as achieving a donor derived ANC ≥ 500/mm3 for 3 consecutive 
laboratory values on different days. The first day of the 3 laboratory values will be designated as 
the day of neutrophil engraftment. Death prior to neutrophil recovery will be considered a 
competing risk. 
 
Cumulative incidence of platelet recovery 
Platelet recovery is defined as achieving a platelet count ≥ 20,000/μL for 3 consecutive 
laboratory values on different days (with no platelet transfusions in the preceding seven days). 
The first day of the 3 laboratory values will be designated as the day of platelet recovery. Death 
prior to platelet recovery will be considered a competing risk. 
 
Cumulative incidence of primary graft failure 
Primary graft failure is defined as lack of donor-derived neutrophil engraftment (i.e. <5% donor 
chimerism on all laboratory values) by Day+56 in subjects surviving a minimum of 14 days post-
HCT.  Death prior to primary graft failure will be considered a competing risk. 
 
Donor Chimerism 
Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted) will be described 
on Day +28, +56, +100, +180, and +365.  
 
Peripheral blood chimerism at Day+56 
The percentage of subjects with peripheral blood chimerism in whole blood (unsorted) >95% by 
Day+56. 
 
Cumulative incidences of aGVHD and cGVHD 
aGVHD is defined as any skin, gastrointestinal or liver abnormalities fulfilling the BMT CTN 
Manual of Operations (MOP) criteria of grades II-IV or grades III-IV (Appendix H). 
cGVHD is defined per National Institutes of Health (NIH) Consensus Criteria and includes organ 
involvement and severity, and overall global composite score (mild/moderate/severe) (Appendix 
H). 
 
Cumulative incidences of viral reactivations and infections 
We will assess the incidence of CMV, EBV, BK, ADV, and HHV-6 viral activations and 
infections at Day+100, +180 and +365. Severity grading of infections is defined in table 4.2 
(BMT CTN MOP, 2013). 
 
 
 
 
 
 
 


 
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TABLE 4.2: INCIDENCE OF VIRAL REACTIVATIONS AND INFECTIONS 
 
Type of 
Infection/ 
Severity Grade 
Grade 1 
Grade 2 
Grade 3 
CMV 
Asymptomatic CMV viremia 
untreated or a CMV viremia 
with viral load decline by at 
least 2/3 of the baseline 
value  after 2 weeks of 
therapy 
Clinically active CMV 
infection (e.g. symptoms, 
cytopenias) 
or CMV Viremia not 
decreasing by at least 2/3 of 
the baseline value after 2 
weeks of therapy 
CMV end-organ involvement 
(pneumonitis, enteritis, 
retinitis) 
 
 
 
 
 
EBV 
EBV reactivation not treated 
with rituximab 
 
EBV reactivation requiring 
institution of therapy with 
rituximab 
 
EBV post-transplant 
lymphoproliferative disorder 
(PTLD) 
 
ADV 
Adenoviral conjunctivitis 
asymptomatic viruria, 
asymptomatic stool shedding 
and viremia not requiring 
treatment   
Adenoviral URI, viremia, or 
symptomatic viruria requiring 
treatment 
ADV with end-organ 
involvement (except 
conjunctivitis and upper 
respiratory tract) 
HHV-6 
Asymptomatic HHV-6 
viremia untreated or an 
HHV-6 viremia with a viral 
load decline by at least 0.5 
log after 2 weeks of therapy 
 
Clinically active HHV-6 
infection (e.g. symptoms, 
cytopenias) or HHV-6 
viremia without viral load 
decline 0.5 log after 2 weeks 
of therapy 
 
BK 
BK viremia or viruria with 
cystitis not requiring 
intervention 
BK viremia or viruria with 
clinical consequence  
requiring prolonged therapy 
and/or surgical intervention 
 
 
Cumulative incidence of relapse/progression 
Testing for recurrent malignancy in the blood, bone marrow or other sites will be used to assess 
relapse and progression post-HCT. For the purpose of this study, relapse is defined by either 
morphological, cytogenetic/molecular or radiological evidence of disease consistent with pre-
HCT features. The event for this endpoint is the time interval from HCT to relapse/recurrence of 
disease or to last follow-up through 1-year post-HCT.  Death in remission is considered a 
competing risk.  
 
Acute leukemias (including ABL and AUL) and T-LBL relapse is defined as the 
recurrence of disease after CR, meeting the following criteria:  
• ≥ 5% blasts in the bone marrow or peripheral blood 
• EMD 
 
MDS relapse/progression is defined by at least one of the following:  
• 
Satisfying criteria for evolution into acute leukemia; or, 


 
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• 
Reappearance of pre-transplant morphologic abnormalities, detected in 
bone marrow specimens; or, 
• 
Reappearance of pre-transplant cytogenetic abnormality in at least one 
metaphase on each of two separate consecutive examinations at least one 
month apart, regardless of the number of metaphases analyzed.  
• 
Institution of any therapy to treat relapsed disease (institution of any 
therapy not meant for maintenance or prevention), including withdrawal of 
immunosuppressive therapy or DCI, will be considered evidence of 
relapse regardless of whether the criteria described above are met. 
 
CLL disease relapse or progression is defined by at least one of the following: 
• Reappearance of any manifestation of disease after achieving CR 
• ≥ 50% increase in the sum of the products of ≥ 2 lymph nodes (≥ 1 lymph node 
must be ≥ 2 cm) or new nodes 
• ≥ 50% increase in liver or spleen size, or new hepatomegaly or splenomegaly 
• ≥ 50% increase in absolute lymphocyte count to ≥ 5 ×109/L 
• Transformation to a more aggressive histology 
 
CML disease relapse is defined as recurrence of disease after complete hematologic 
remission. Disease progression is defined as any of the following changes in disease 
status: 
• Advancement from chronic phase to accelerated phase. 
• Advancement from chronic phase to blast phase. 
 
Accelerated phase 
One or more of the following must be present: 
o 10%-19% blasts in blood or marrow 
o ≥ 20% basophils in peripheral blood 
o Clonal marrow cytogenetic abnormalities in addition to the single 
Philadelphia chromosome (clonal evolution) 
o Increasing spleen size, unresponsive to therapy 
o Increasing WBC, unresponsive to therapy 
o Thrombocytopenia (platelets < 100,000), unrelated to therapy 
o Thrombocytosis (platelets > 1,000,000), unresponsive to therapy  
Blast phase 
Characterized by having ≥ 20% blasts in the peripheral blood or bone marrow. 
Having extramedullary blastic infiltrates (i.e., myeloid sarcoma, granulocytic 
sarcoma, or chloroma) also qualifies as blast phase. 
 
Lymphoma disease relapse or progression is defined as any new lesion and/or > 50% 
increase in the least diameter of previously involved sites: 
• Spleen/Liver 
> 50% increase from nadir of any previous lesions 
• Bone Marrow 
New or recurrent involvement 
 


 
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Cumulative incidences of TMA and VOD/SOS 
The cumulative incidences of TMA and VOD/SOS will be described in transplanted 
subjects, treating death as a competing risk. 
VOD/SOS is defined as: 
Modified Seattle Criteria 
In the first 20 days after HCT, the presence of ≥2 
of the following: 
• 
Bilirubin >2 mg/dL  
• 
Hepatomegaly or pain in right upper quadrant 
• 
Weight gain (>2% basal weight) 
 
(Dalle, J.H., & Giralt, S., 2015) 
 
TMA is defined as (Ho et al., 2005): 
• RBC fragmentation and >2 schistocytes per high-power field on peripheral smear 
• Concurrent increased serum LDH above institutional baseline 
• Concurrent renal and/or neurologic dysfunction without other explanation 
o Renal dysfunction defined as either:  
▪ Doubling of SCr from baseline (baseline = creatinine before hydration 
and just before conditioning initiation) OR  
▪ 50% decrease in CrCl from baseline 
• Negative direct and indirect Coombs test results  
 
BMT CTN Consensus for TMA severity scoring: 
Grade I 
Evidence of RBC destruction (schistocytosis) without clinical consequences 
Grade II 
Evidence of RBC destruction with increased creatinine ≤ 3 x ULN  
Grade III 
Evidence of RBC destruction with creatinine > 3 x ULN not requiring dialysis 
Grade IV 
Evidence of RBC destruction with renal failure requiring dialysis, and/or 
encephalopathy 
 
Proportion of subjects proceeding to transplant  
The proportion of subjects proceeding to HCT will be described, along with a breakdown of 
the reasons for not proceeding to HCT and their frequencies. 
 
Donor Selection Characteristics 
The donor selection characteristics will be described. Donor selection characteristics include: 
number of mismatches at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, donor age, donor-
recipient CMV serostatus match, donor weight, donor-recipient sex match and donor-
recipient ABO group match. 
 
Time from search to donor identification 
Time from preliminary search and time from formal search to donor identification (i.e. the 
day the donor is selected by the study site) will be described. 
 
 


 
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Donor clonal hematopoiesis 
The proportion of subjects developing donor clonal hematopoiesis will be described at Day+ 
100 and +365. 
 
4.3 
Definition of CR by Disease Type 
4.3.1 Acute Leukemias/T-LBL  
4.3.1.1 ALL/T-LBL:  
• < 5% blasts in the bone marrow 
• Normal maturation of all cellular components in the bone marrow 
• No currently active EMD (e.g., CNS, soft tissue disease) 
• ANC ≥ 1,000/mm3 
4.3.1.2 AML:  
• < 5% blasts in the bone marrow 
• No blasts with Auer rods 
• Normal maturation of all cellular components in the bone marrow 
• No currently active EMD (e.g., CNS, soft tissue disease) 
• Neutrophils ANC ≥ 1,000/mm3 
4.3.1.3 ABL/AUL: 
• < 5% blasts in the bone marrow 
• Normal maturation of all cellular components in the bone marrow 
• No currently active EMD (e.g., CNS, soft tissue disease) 
• Neutrophils ANC ≥ 1,000/mm3 
 
4.3.2 MDS (maintained for a minimum of 4 weeks): 
• Bone marrow evaluation: < 5% myeloblasts with normal maturation of all 
cell lines 
• Peripheral blood evaluation:  
o Hemoglobin ≥ 11 g/dL untransfused without erythropoietic support 
o ANC ≥ 1000/mm3 without myeloid growth factor support 
o Platelets ≥ 100,000/mm3 without thrombopoietic support 
o 0% blasts in blood 
4.3.3 CLL:  
• No evidence of lymphadenopathy 
• No organomegaly 
• Neutrophils ≥ 1.5 × 109/L 
• Hemoglobin > 11 g/dL 
• Lymphocytes < 4 × 109/L 
• Bone marrow < 30% lymphocytes 
• Absence of constitutional symptoms (including weight loss, fever, and night 
sweats) 
 
4.3.4 CML (a treatment response where all of the following criteria are met): 
• 
White blood count is < 10 × 109/L, without immature granulocytes and 
with < 5% basophils 
• 
Platelet count < 450 × 109/L 


 
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• 
Non-palpable spleen 
 
4.3.5 Lymphoma: 
• Complete disappearance of all known disease.  
• For typically PET-avid lymphoma, a post-treatment residual mass of any 
size is permitted as long as it is PET negative.  
• For variably, PET-avid lymphoma, all lymph nodes and nodal masses 
must have regressed as measured by CT to < 1.5 cm (for nodes > 1.5 cm 
before therapy) or < 1 cm (for nodes 1.1 cm to 1.5 cm before therapy) 
• Spleen/Liver: Not palpable; nodules disappeared 
• 
Bone Marrow: Infiltrate cleared on repeat biopsy. If indeterminate by 
morphology, immunohistochemistry should be negative 
      
 
5 
STATISTICAL CONSIDERATIONS 
5.1 
General Considerations 
All available data will be used and missing data will not be estimated or carried forward in any 
statistical summary or analyses. Descriptive summary statistics include the number of subjects, 
mean, median, percent coefficient of variation (if required), standard deviation, and minimum 
and maximum values (quantitative variables) or the number of subjects and percentages by 
category (qualitative variables). Baseline is defined as the last non-missing value prior to the 
receipt of study regimen.  
 
5.2 
Study Design 
This study is a single arm Phase II, multi-center trial. It is designed to assess OS 1-year after 
HLA-MMUD bone marrow HCT and PTCy.  The sample size is 80 subjects split into two strata 
of 40 subjects each for separate analysis.  One stratum will include subjects receiving FIC, and 
the other will include subjects receiving RIC.   
 
5.2.1 Accrual 
The target sample size is 80 subjects accrued into two strata: 40 subjects receiving FIC 
and 40 subjects receiving RIC. It is estimated that two years of accrual will be necessary 
to enroll the targeted sample size. Accrual will be reported by race, ethnicity, sex, and 
age.  If accrual to one of the strata occurs faster than for the other stratum, we will 
conduct the analysis for the stratum which is accrued faster without waiting for the other 
stratum to close and complete follow up. 
 
 
5.3 
Sample Size and Power Considerations  
The sample size is 80 subjects for this trial, split into two strata of 40 subjects each (subjects 
receiving FIC and subjects receiving RIC will be analyzed separately).  Ninety percent CIs were 
calculated for varying probabilities based on the sample size.  Table 5.3A provides CIs for a 
variety of true underlying proportions.  Of particular interest is where the OS probability is 65%, 
which is the targeted 1-year survival probability.  For this setting, the CI length is 27%.  The 
percentages above and below this range are meant to represent other plausible PFS percentages.   
 


 
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The precision of the estimates alternatively could be viewed as a lower bound on the probability 
of OS.  The probability to rule out OS percentages of a certain size is known as “power.”  Table 
5.3B provides the probability (or power) that the lower bound of a 90% two-sided CI for the OS 
probability will be greater than various OS thresholds between 40% and 55%.  In particular, 
when the true OS percentage is 65%, there is 80% power to rule out an OS percentage of ≤ 45%.  
This can equivalently be viewed as testing the following hypothesis: Ho: p = 0.45 versus H1: p ≠ 
0.45.  Based on table 5.3B below, there is 80% power at = .10 (two-sided) to reject the null 
hypothesis if the true OS percentage is 65%. 
 
TABLE 5.3A:  CI LENGTHS AND POSSIBLE CIs FOR VARIOUS UNDERLYING 
OVERALL SURVIVAL PROBABILITIES 
 
N/stratum 
OS% 
Length of 90% CI 
Possible CIs 
40 
80 
22.8 
66.8 
89.6 
40 
70 
25.7 
56.0 
81.7 
40 
65 
26.6 
50.8 
77.4 
40 
60 
27.3 
45.8 
73.1 
40 
50 
27.8 
36.1 
63.9 
 
The OS probability estimate will be based on the Kaplan-Meier product limit estimator using 
Greenwood’s formula as the variance estimate.  In the absence of censoring, the Kaplan-Meier 
estimate reduces to the simple binomial proportion. 
 
TABLE 5.3B:  PROBABILITY OF RULING OUT A THRESHOLD OF SIZE  
T OR LARGER FOR VARIOUS TRUE UNDERLYING OVERALL 
SURVIVAL PERCENTAGES, WITH N=40 PER STRATUM 
 
 
Probability of ruling out OS 
Percentages of size T or smaller 
True OS 
T=0.55 
0.50 
0.45 
0.40 
0.70 
0.58 
0.81 
0.94 
0.99 
0.68 
0.47 
0.72 
0.89 
0.97 
0.65 
0.31 
0.57 
0.80 
0.93 
0.60 
0.13 
0.32 
0.57 
0.79 
 
5.4 
Interim Analysis and Stopping Guidelines  
There will be no formal interim analyses for efficacy.  Monitoring of two key safety endpoints 
(overall mortality and grade III-IV aGVHD by Day+100) will be conducted weekly. If a 
stopping rule as described below is triggered, enrollment will be paused while the DSMB 
conducts a review of the safety data.  Both grade III-IV aGVHD and overall mortality within 100 
days are expected to occur no more than 15% of the time; therefore, the same stopping rules will 
be applied to each safety endpoint.  The detailed stopping rule is shown in the table below. 
 


 
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The DSMB has regularly scheduled meetings at least annually and as frequently as quarterly. 
Emergency meetings may be called at any time by either Monitoring Board Chairperson, Vice-
Chairperson or appropriate CIBMTR representative.  
 
TABLE 5.4: SAFETY STOPPING RULE (APPLIES TO BOTH GRADE III-IV AGVHD 
AND OVERALL MORTALITY WITHIN 100 DAYS).  STOP IF ≥X EVENTS IN N 
SUBJECTS EVALUABLE. 
 
N 
5 
9 
13 
17 
21 
26 
31 
35 
40 
# of events, x 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
This toxicity pausing rule has a 10% chance of being triggered if the true toxicity rate is 15%, and 
a 92% chance of being triggered if the true toxicity rate is 35%.  If the true toxicity rate is 35%, 
the stopping rule will be triggered on average after approximately 16 subjects are evaluable for the 
safety endpoint.  Note that the pausing guidelines serve as a trigger for consultation with the DSMB 
for additional review, and are not formal “stopping rules” that would mandate automatic closure 
of study enrollment.  
 
5.5 
Analysis of Study Endpoints 
5.5.1 Analysis of Primary Endpoint 
The primary analysis will consist of estimating the 1-year OS probability based on the Kaplan-
Meier product limit estimator, separately in the two strata (subjects receiving FIC; subjects 
receiving RIC).  The event is death from any cause.  The time to this event is the time from 
HCT to death, loss to follow-up, or end of study (whichever comes first). The 1-year OS 
probability and 90% CI will be calculated.  All transplanted subjects will be included in this 
analysis.   
 
5.5.2 Analysis of Secondary Endpoints 
Progression-free survival 
Death or relapse/progression will be considered events, and the PFS distribution will be 
estimated by the Kaplan-Meier curve, starting from the time of HCT.  A 90% CI will be 
constructed at Day+180 and +365.   
 
Transplant-related mortality 
TRM is death occurring in subjects in the absence of disease progression or relapse.  A 
cumulative incidence curve will be computed along with a 90% CI at Day+100, +180, 
and +365.  Progression/relapse will be considered as a competing risk.   
 
Cumulative incidence of neutrophil recovery 
To assess the incidence of neutrophil recovery from day of HCT, a cumulative incidence 
curve will be computed along with a 90% CI.  Death prior to neutrophil recovery will be 
considered a competing risk. 
Cumulative incidence of platelet recovery 


 
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To assess the incidence of platelet recovery from day of HCT, a cumulative incidence 
curve will be computed along with a 90% CI.  Death prior to platelet recovery will be 
considered a competing risk. 
 
Cumulative incidence of primary graft failure 
The frequency and proportion of subjects experiencing primary graft failure by Day+56 
will be described with a 90% CI.  Death prior to primary graft failure will be considered a 
competing risk. 
Donor Chimerism 
Peripheral blood donor chimerism will be measured at Day+28, +56, +100, +180, and 
+365.  The degree of donor chimerism will be summarized at each time point using 
descriptive statistics.   
Peripheral blood chimerism at Day+56 
The percentage of patients with peripheral blood chimerism >95% by Day+56 will be 
summarized. 
 
Cumulative incidence of aGVHD 
We will assess the incidence of grades II-IV and grades III-IV aGVHD from day of HCT.  
The first day of aGVHD onset at a certain grade will be used to calculate a cumulative 
incidence curve for that aGVHD grade.  An overall cumulative incidence curve will be 
computed along with a 90% CI at Day+100 with death and relapse considered as 
competing risks. 
 
Cumulative incidence of cGVHD 
To assess the incidence and severity of cGVHD from day of HCT, a cumulative 
incidence curve will be computed along with a 90% CI at Day+180 and 365.  Death and 
relapse prior to occurrence of cGVHD will be considered as competing risks. 
 
Cumulative incidences of viral reactivations and infections 
To assess the incidence of CMV, EBV, BK, ADV, and HHV-6 viral activations and 
infections, a cumulative incidence curve will be computed along with a 90% CI at 
Day+100, +180 and +365. 
 
Cumulative incidence of relapse/progression 
To assess the incidence of progression/relapse from day of HCT, a cumulative incidence 
curve will be computed along with a 90% CI at Day+180 and +365.  Death prior to 
progression/relapse will be considered as a competing risk.   
 
Cumulative incidences of TMA and VOD/SOS 
The cumulative incidence of TMA and VOD/SOS will be described in transplanted 
subjects, treating death as a competing risk. 
 
Proportion of subjects proceeding to transplant  
The proportion of subjects proceeding to HCT will be described, along with a breakdown 
of the reasons for not proceeding to HCT and their frequencies. 


 
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Donor Selection Characteristics 
The donor selection characteristics will be described. Donor selection characteristics 
include: number of mismatches at HLA-A, -B, -C, -DRB1, -DQB1, -DPB1, donor age, 
donor-recipient CMV serostatus match, donor weight, donor-recipient sex-match and 
donor-recipient ABO group match. 
 
Time from search to donor identification 
Time from preliminary search to and time from formal search to donor identification (i.e. 
the day the donor is selected by the study site) will be described. 
 
Subgroup analysis of HIV-positive subjects 
If CCR5delta32 homozygous donors are successfully found and used for one or more 
HIV-positive subjects, a descriptive analysis of baseline characteristics and outcomes for 
those HIV-positive subjects will be conducted, including the viral load detected over time 
obtained from collected samples. 
 
Donor clonal hematopoiesis 
The proportion of subjects developing donor clonal hematopoiesis will be described at 
Day+100 and +365. 
 
5.6 
Demographic and Baseline Characteristics  
Demographic and baseline characteristics will be summarized for all subjects. Characteristics to 
be described are: recipient age, recipient race/ethnicity, recipient performance status, pre-HCT 
comorbidity index (HCT-CI), HLA match, recipient disease type and stage, recipient remission 
status, number of prior treatments, time from diagnosis to HCT, and conditioning regimen. 
Donor/recipient sex match, donor/recipient CMV serostatus, donor/recipient ABO group, donor 
weight and donor age will also be described. 
 
5.7 
Disposition of Subjects 
The number of subjects enrolled in the study and the disposition of all subjects will be 
summarized.  Subjects who discontinue study participation will be listed according to the off-
study criteria that applies.  
Off-Study Criteria 
All subjects who have received their HCT will be followed on-study through 1-year post-HCT.  
Subjects will be removed from the study for the following reasons: 
1. Withdrawal of consent  
2. Subject determined ineligible by the study team after initial enrollment 
3. Discontinued per medical discretion of the P.I. or Medical Monitor 
4. Donor cannot provide bone marrow as planned 
5. Transplant canceled, insufficient dose of bone marrow obtained 
6. Transplant canceled, donor reason 
7. Transplant canceled, subject (recipient) reason 
8. Lost to Follow-Up 


 
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9. Death 
Study sites must complete the Study Exit form in Rave for any subjects meeting one of these 
criteria. The Study Exit form is also completed to indicate that a subject has completed the study 
per protocol.  
 
 
6 
DATA REPORTING 
 
 
6.1 
Data Capture Methods 
The data collection forms for the subjects enrolled on this study include the standard CIBMTR 
data collection forms in the FormsNet3 Recipient module, and study-specific CIBMTR data 
collection forms in Rave.  
 
CIBMTR data reporting time points used in this study:  
• 
Baseline  
• 
Infusion data  
• 
100 days post-HCT  
• 
6 months post-HCT  
• 
1-year post-HCT 
• 
Subject death (if applicable)  
 
Many important data elements for the study are collected on the standard reporting forms and 
therefore timely and accurate completion of these forms is essential. Centers must continue to do 
standard CIBMTR follow-up reporting on these subjects beyond the study time point of 1-year 
post-HCT, per CIBMTR reporting requirements. 
 
The following forms will be completed by study site personnel within the timeframes specified: 
 
Study-specific forms in Rave module  
Submission timeframes 
Demographics 
At least 7 days prior to the start of conditioning 
Inclusion/Exclusion 
At least 7 days prior to the start of conditioning 
Medical history 
At least 7 days prior to the start of conditioning 
Conditioning regimen 
(with regimen-specific form completion) 
Within 7 days of HCT date 
Infusion 
Within 7 days of HCT date 
Follow-up 
Within 7 days of evaluation date for study time point 
Post-transplant treatments 
Within 7 days of evaluation date for study time point 
Sirolimus 
Within 7 days of evaluation date for study time point 
MMF 
Within 7 days of evaluation date for study time point 
Hematopoietic recovery 
Within 7 days of evaluation date for study time point 
Protocol-specified sample collections 
Within 7 days of evaluation date for study time point 
Peripheral blood chimerism 
Within 7 days of evaluation date for study time point 
DCI 
Within 7 days of evaluation date on corresponding Follow-up form 
(when DCI is indicated on the Follow-up form completed for the 
study time point) 


 
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Disease evaluation 
Within 7 days of evaluation date for study time point (Day+100; 
Day+180; Day+365; or when relapse is reported) 
Acute GVHD assessment 
Within 7 days of evaluation date on corresponding Follow-up form 
(when aGVHD is indicated on the Follow-up form completed for 
the study time point) 
Chronic or Overlap GVHD 
• 
Assessment 
• 
Organ involvement at diagnosis 
• 
Status 
• 
Therapy 
Within 7 days of evaluation date on corresponding Follow-up form 
(when chronic or overlap GVHD is indicated on Follow-up form 
for time point) 
Viral reactivations or infections 
Within 7 days of evaluation date on corresponding Follow-up form 
(when viral reactivations or infections is indicated on Follow-up 
form for time point) 
TMA assessment 
Within 7 days of evaluation date on corresponding Follow-up form 
(when TMA is indicated on Follow-up form for time point) 
VOD/SOS  
• 
Assessment 
• 
Evaluations at diagnosis 
• 
Therapy 
• 
Maximum severity 
• 
Current status 
Within 7 days of evaluation date on corresponding Follow-up form 
(when VOD/SOS is indicated on Follow-up form for time point) 
HIV-positive pre-conditioning  
At least 7 days prior to the start of conditioning (for HIV-positive 
subjects only) 
HIV-positive post-transplant 
Within 7 days of evaluation date for study time point (for HIV-
positive subjects only) 
Adverse Event 
• 
Assessment 
• 
Summary 
• 
Meds 
• 
Laboratory values 
• 
Tests 
• 
Grade 3 unexpected AEs: within 3 business days of knowledge 
of the event  
• 
Grade 4-5 unexpected AEs: within 24 hours of knowledge of 
the event 
• 
Grade 5 expected AEs: within 24 hours of knowledge of the 
event 
Unanticipated Problem (UPIRSO/UP) 
Within 3 business days of the investigator becoming aware of the 
issue 
Study Exit 
Within 7 days of study exit event date 
 
6.2 
Adverse Event and Unanticipated Problem Reporting 
6.2.1 Event Definitions  
Adverse Event – Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the medical 
treatment or procedure (attribution of definite, probable, possible, unlikely, or unrelated).  
 
Expected Adverse Event – Any AE listed in the informed consent, product inserts, or 
study materials. 
 
Life-Threatening Adverse Event – Any AE that places the participant, in view of the 
investigator, at immediate risk of death from the reaction. 
 
Serious Adverse Event (SAE) – Any AE that results in any of the following outcomes: 
death, a life threatening AE, in-patient hospitalization or prolongation of existing 


 
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hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. 
 
Unexpected Adverse Event – Any AE, the specificity or severity of which is NOT listed 
in the study protocol, product inserts or informed consent document. 
 
Unanticipated Problem – any incident, experience, or outcome that meets all of the 
following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
Institutional Review Board (IRB)-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population being 
studied; 
2. related or possibly related to participation in the research; and 
3. suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
See Appendix L for further details and examples. 
 
Attribution – The determination of whether an AE is related to a medical treatment or 
procedure.  Attribution categories: 
• Definite – The AE is clearly related to the study procedure/treatment(s).  
• Probable – The AE is likely related to the study procedure/treatment. 
o The AE is not likely to be caused by the subject’s underlying medical 
condition or other concomitant therapy, and the nature of the AE or the 
temporal relationship between the onset of the AE and study 
procedure/treatment administration lead the investigator to believe that 
there is a reasonable chance of causal relationship.  
• Possible – The AE may be related to the study procedure/treatment(s). 
o The AE could be attributed to the subject’s underlying medical 
condition or other concomitant therapy, but the nature of the AE or the 
temporal relationship between the onset of the AE and study 
procedure/treatment administration lead the investigator to believe that 
there could be a causal relationship. 
• Unlikely – The AE is doubtfully related to the study procedure/treatment(s). 
• Unrelated – The AE is clearly NOT related to the study 
procedure/treatment(s). 
o The AE is most plausibly explained by the subject’s underlying medical 
condition or other concomitant therapy, or the AE has no plausible 
biological relationship to study procedure/treatment.  
 
Grade – Severity of the AE.  All toxicities will be graded using the Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03.  The CTCAE includes 
a grading (severity) scale for each AE term:   
 


 
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Grade 0 – No AE or within normal limits 
 
 
 
1 – Mild AE 
2 – Moderate AE 
3– Severe AE 
4– Life-threatening or disabling AE 
5– Fatal AE 
 
6.2.1.1 Reporting Requirements 
 
Unexpected Adverse Events: Grades 3-5 unexpected AEs will be reported on the 
Adverse Event form in the Rave module. The CIBMTR Protocol Coordinator will 
review all submitted unexpected AEs and forward the information to the Medical 
Monitor for review.  
▪ Grade 3 unexpected AEs, irrespective of the attribution of the event to the 
study procedure/treatment, must be reported within three business days of 
knowledge of the event.   
▪ Grade 4-5 unexpected AEs, irrespective of the attribution of the event to 
the study procedure/treatment, must be reported within 24 hrs of 
knowledge of the event.   
 
All unexpected AEs will be reviewed by the Medical Monitor within two business 
days of receiving the summary of the AE from the study site.  If the Medical Monitor 
requires additional information to make his/her assessment, study sites will have 4 
business days to respond to the request for additional information. The Medical 
Monitor will provide expedited notification with event assessment and any 
modification recommendation to the CIBMTR within seven days of the AE. 
 
TABLE 6.2.1: REPORTING UNEXPECTED ADVERSE EVENTS 
 
SEVERITY GRADE  
ATTRIBUTION  
STUDY SITE REPORTING REQUIREMENTS  
5 – Fatal– 
4 – Life-threatening  
or Disabling  
All attributions  
Submit the Adverse Event form to CIBMTR within 24 hours of 
learning of the event.  
• 
Grade 5 AEs: 
o 
AE form should include potential contributing 
causes of death 
o 
Study site must also complete all follow up forms 
through date of death, and study exit form 
3 – Severe  
All attributions  
Submit the Adverse Event form to CIBMTR within 3 business 
days of the AE.    
 
Note: For any AE that is ongoing at the time of death, the date of death should be reported as the resolution date. 
 
Expected Adverse Events:  
All Grade 5 expected AEs must be reported via the Adverse Event form within 24 
hours of learning of the death. Expected AEs < Grade 5 need not be reported via the 
Adverse Event form, as they will be captured on other event-driven case report forms. 
The CIBMTR Protocol Coordinator will review Grade 5 expected AEs reported, and 
forward the information to the Medical Monitor for review.  


 
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The CIBMTR will prepare semi-annual summary reports of all Grade 5 expected AEs 
for the DSMB.  See Table 6.2.2. for expected event reporting expectations.  
 
The CIBMTR Protocol Coordinator and Medical Monitor will review the AEs monitored 
for stopping guidelines on a weekly basis.  
 
Additionally, the CIBMTR Protocol Coordinator and Medical Monitor will review 
reported toxicity, GVHD, infection, and primary graft failure events on a weekly basis to 
assess whether there are safety concerns that should be referred to the DSMB.   
 
Any concern regarding the type or frequency of an AE will be reported to the DSMB 
when warranted. The DSMB will determine if additional review is required and make 
recommendations to the study team concerning continuation of the study. If the DSMB 
recommends modification of protocol documents and/or determines that the event affects 
the conduct of the overall trial, the event will be reported to the NMDP IRB. The 
Principal Investigators and the Protocol Team will meet to determine protocol 
modifications based on DSMB recommendations. 
 
The NMDP IRB will report events to regulatory agencies following NMDP IRB 
processes and procedures. CIBMTR will distribute reports of such events and any 
protocol modifications to study sites and study site Principal Investigators will be 
responsible for local IRB submission. 
 
 
TABLE 6.2.2: REPORTING EXPECTED ADVERSE EVENTS  
 
SEVERITY GRADE 
ATTRIBUTION 
STUDY SITE REPORTING REQUIREMENT 
5 – Fatal  
 
All attributions 
Submit Adverse Event form within 24 hours of learning of the death. 
Submit death summaries and/or autopsy reports of the expected AE to 
CIBMTR as requested. 
The summaries should include potential contributing causes of death. 
 
 
 
Adverse Event Updates:  AEs should be followed until resolution of the event, death, or 
until the investigator concludes that the event is stable with no further improvement 
anticipated. Updates are reported by revising the Adverse Event form in the Rave 
module. 
 
Unanticipated Problems: Unanticipated problems should be reported within three 
business days of the investigator becoming aware of the issue, via the Unanticipated 
Problem form in the Rave module.   
 
All Unanticipated Problems will be reviewed by the Medical Monitor within three 
business days of receiving the summary of the Unanticipated Problem from the study site. 
The Medical Monitor will provide expedited notification with event assessment and any 
modification recommendation to the CIBMTR within seven days of the Unanticipated 
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7 
PROTOCOL DEVIATIONS 
7.1 
Investigator Reporting Responsibilities  
Circumstances may arise when it is necessary for subject safety to deviate from the study 
protocol. When feasible, Investigators should contact the protocol chairs and CIBMTR 
Protocol Coordinator beforehand to discuss the intended deviation(s). All deviations, whether 
approved beforehand or not, are required to be documented and explained by the 
Investigator, and reported to the study sponsor within 7 business days.  
All protocol deviations will be documented in the Rave module by the study sponsor. 
Study sites are also required to note deviations in patient medical records and report them to 
their local IRB in accordance with local policies. All protocol deviations will be compiled 
centrally by the CIBMTR Protocol Coordinator and reported to the NMDP DSMB. 
Non-emergency minor deviations from the protocol will be permitted with approval from the 
CIBMTR Protocol Coordinator. 
 
7.2 
Study Monitoring 
7.2.1 Data Safety Monitoring 
The NMDP DSMB will review a summary of AEs at least twice yearly.  
The report will be made available to study sites. If the DSMB recommends protocol 
or informed consent changes, they will be distributed to the participating Principal 
Investigators. It is the responsibility of each Principal Investigators to forward the 
distributed communication to their local IRB. 
 
7.2.2 Study Site Monitoring Plan 
The Principal Investigator [or his/her deputy] will permit study-related onsite and/or 
centralized monitoring visits by representatives of the CIBMTR or designees, and 
regulatory inspection(s) (e.g., FDA) to ensure proper conduct of the study and 
compliance with all FDA safety reporting requirements. Access must be provided to 
source documents, data collection forms, informed consent and assent forms, and any 
other study documents.  
The Principal Investigator [or his/her deputy] agrees to cooperate with the monitor to 
ensure that any problems detected in the course of these monitoring visits are 
resolved. 
 
Details about monitoring can be found in the Study Monitoring Plan. 
 
8 
 REGULATORY CONSIDERATIONS 
8.1 
Institutional Review Board/Ethics Committee approval 
The protocol for this study has been designed in accordance with the general ethical 
principles outlined in the Declaration of Helsinki and the Belmont Report.  The review of this 
protocol by the IRB and the performance of all aspects of the study, including the methods 
used for obtaining informed consent, must also be in accordance with principles enunciated 


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in the Belmont Report, as well as International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Guidelines, Title 21 of the Code of 
Federal Regulations (CFR), Part 50 Protection of Human Subjects and Part 56 Institutional 
Review Boards. 
The NMDP IRB serves as the Coordinating Center IRB for the protocol. The study site 
Principal Investigators will be responsible for preparing documents for submission to the 
institutional IRB of their study sites and obtaining written approval for this study.  The 
approval will be obtained prior to the initiation of the study at the study site. 
The approval for both the protocol and informed consent must specify the date of approval, 
protocol number and version, or amendment number. 
Any approved amendments to the protocol must be submitted by the study site Principal 
Investigator to the local IRB for approval.  The study site Principal Investigator is also 
responsible for notifying the institutional IRB of any serious deviations from the protocol, or 
anything else that may involve added risk to subjects. 
 
8.2 
Informed Consent 
All subjects in this study must provide informed consent prior to any study related 
procedures as per Good Clinical Practices as set forth in the CFR and ICH guidelines. Legal 
guardian permission must be obtained for subjects < 18 years of age. Pediatric subjects will 
be included in age appropriate discussion in order to obtain assent. 
Documentation that informed consent (or minor assent with parental permission) occurred 
prior to the subject’s entry into the study and the informed consent process must be recorded 
in the subject’s source documents.  The original informed consent form signed and dated by 
the subject and by the person obtaining the subject’s informed consent prior to the subject’s 
entry into the study, must be maintained in the transplant center’s study files. 
 
 


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LIST OF APPENDICES: 
 
APPENDIX A 
PERFORMANCE STATUS 
 
APPENDIX B            LIST OF ABBREVIATIONS 
 
 
APPENDIX C 
NMDP PROCEDURE FOR IDENTIFIACTION OF 
CCR5DELTA32 MUTATION HOMOZYGOUS DONORS 
RELATED TO THIS PROTOCOL 
 
APPENDIX D 
TREATMENT REVIEW COMMITTEE FOR HIV-POSITIVE 
SUBJECTS 
 
 
APPENDIX E  
SUGGESTED PROPHYLAXIS FOR HIV-POSITIVE 
SUBJECTS 
 
 
  
APPENDIX F 
PK DRUG-DRUG INTERACTIONS WITH ARVs 
 
 
APPENDIX G 
ADDITIONAL EVALUATIONS FOR HIV-POSITIVE 
SUBJECTS 
  
APPENDIX H 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE AND 
CHRONIC GVHD  
 
APPENDIX I 
CORRELATIVE STUDY PROCEDURES  
 
APPENDIX J 
MMUD SELECTION ALGORITHM 
  
 
APPENDIX K 
RECOMMENDED FORMULAS FOR CALCULATION OF 
ADJUSTED AND IBW 
  
 
APPENDIX L 
GUIDANCE ON REVIEWING AND REPORTING 
UNANTICIPATED PROBLEMS 
 
APPENDIX M 
REFERENCES 
 
 
 
 
 
 
 
 


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APPENDIX A 
PERFORMANCE STATUS 
 
KARNOFSKY SCALE, ≥ 16 YEARS 
 
100% – normal, no complaints, no signs of disease 
90% – capable of normal activity, few symptoms or signs of disease 
80% – normal activity with some difficulty, some symptoms or signs 
70% – caring for self, not capable of normal activity or work 
60% – requiring some help, can take care of most personal requirements 
50% – requires help often, requires frequent medical care 
40% – disabled, requires special care and help 
30% – severely disabled, hospital admission indicated but no risk of death 
20% – very ill, urgently requiring admission, requires supportive measures or treatment 
10% – moribund, rapidly progressive fatal disease processes 
 
LANSKY PLAY-PERFORMANCE SCALE, < 16 YEARS 
 
100 %– fully active, normal 
90% – minor restrictions in strenuous physical activity 
80% – active, but tired more quickly 
70 %– greater restriction of play and less time spent in play activity 
60 %– up and around, but active play minimal; keeps busy by being involved in quieter   activities 
50 %– lying around much of the day, but gets dressed; no active playing participates in all quiet   
        play and activities 
40% – mainly in bed; participates in quiet activities 
30% – bedbound; needing assistance even for quiet play 
20% – sleeping often; play entirely limited to very passive activities 
10% – doesn’t play; does not get out of bed 
 
 
 
 


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APPENDIX B 
LIST OF ABBREVIATIONS 
µL 
microliter 
μM 
micrometer 
ABL 
acute biphenotypic leukemia 
ADV 
adenovirus 
AE 
adverse event 
aGVHD 
acute graft versus host disease 
AIDS 
acquired immunodeficiency syndrome 
ALL 
acute lymphoblastic leukemia 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myelogenous leukemia 
ANC 
absolute neutrophil count 
ARV 
antiretroviral therapy 
AST 
aspartate aminotransferase 
ATG 
anti-thymocyte globulin 
ATP 
adenosine triphosphate 
AUC 
area under the curve 
AUL 
acute undifferentiated leukemia 
AZT 
zidovudine 
BID 
two times a day (bis in die) 
BMT CTN 
Blood and Marrow Transplant Clinical Trials Network 
BOOP 
bronchiolitis obliterans organizing pneumonia 
BSA 
body surface area 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
cGVHD 
chronic graft versus host disease 
cGy 
centigray 
CI 
confidence interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CLL 
chronic lymphocytic leukemia 
cm 
centimeter 
CML 
Chronic myelogenous leukemia 
CMV 
Cytomegalovirus 
CNI 
calcineurin inhibitors 
CNS 
central nervous system 


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CR 
complete remission/complete response 
CrCl 
creatinine clearance 
CRID 
CIBMTR Research Identification Number 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Cy 
cyclophosphamide 
dL 
deciliter 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DCI 
donor cellular infusion 
DNA 
deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein–Barr virus 
EDTA 
ethylenediaminetetraacetic acid 
FCBP 
females of childbearing potential 
EMD 
extramedullary disease 
FDA 
U.S. Food and Drug Administration 
FEV1 
forced expiratory volume 
FIC 
full intensity conditioning 
FISH 
fluorescence in situ hybridization 
FVC 
forced vital capacity 
g 
gram 
G-CSF 
granulocyte-colony stimulating factor 
GFR 
glomerular filtration rate 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GVHD 
graft versus host disease 
H&P 
history and physical 
HAART 
highly active antiretroviral therapy 
HCT 
hematopoietic cell transplantation 
HCT-CI 
hematopoietic cell transplantation comorbidity index 
HHS 
U.S. Department of Health & Human Services 
HHV-6 
human herpesvirus 6 
HI 
Hematologic Improvement 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HPLC 
high performance liquid chromatography 
hr 
hour 
HSV 
herpes simplex virus 


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HUS 
hemolytic uremic syndrome 
IBW 
ideal body weight 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
INSTI 
integrase strand transfer inhibitor 
INR 
international normalized ratio 
IPSS 
International Prognostic Scoring System  
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram 
L 
liter 
LVEF 
left ventricular ejection fraction 
LVFS 
left ventricular shortening fraction 
m2 
square meter 
mm3 
cubic millimeter 
MAC 
M. Avium Complex 
mcg 
microgram 
MDS 
myelodysplastic syndrome 
MFI 
mean fluorescence intensity 
mg 
milligram 
min 
minute 
mL 
milliliter 
MMF 
mycophenolate mofetil 
MMUD 
mismatched unrelated donor 
MOP 
manual of procedures 
MPA 
mycophenolic acid 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated acquisition scan  
ng 
nanogram 
NIH 
National Institutes of Health 
NMDP 
National Marrow Donor Program 
NNRTI 
Non-nucleoside Reverse Transcriptase Inhibitors 
NRM 
non-relapse mortality 
NRTI 
Nucleoside Reverse Transcriptase Inhibitors 
OHRP 
Office for Human Research Protections 
OS 
overall survival 
PCR 
polymerase chain reaction 


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PET 
positron emission tomography 
PFS 
progression-free survival 
PFTs 
pulmonary function tests 
PK 
pharmacokinetic 
PML 
progressive multifocal leukoencephalopathy 
PO 
by mouth (per os) 
PR 
partial response 
PTCy 
post-transplantation cyclophosphamide 
PTLD 
post-transplant lymphoproliferative disorder 
QD 
one day (quaque die) 
RCI BMT 
Resource for Clinical Investigation in Blood and Marrow Transplantation 
RIC 
reduced intensity conditioning 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SC 
subcutaneous 
SCr 
serum creatinine 
SOS 
sinusoidal obstruction syndrome 
TBI 
total body irradiation 
TID 
three times a day (ter in die) 
T-LBL 
T lymphoblastic lymphoma 
TMA 
thrombotic microangiopathy 
TMP/SMX 
trimethoprim/sulfamethoxazole 
TRM 
transplant-related mortality 
TTP 
thrombotic thrombocytopenic purpura 
ULN 
upper limit of normal 
URI 
upper respiratory infection 
UTI 
urinary tract infection 
VOD 
hepatic veno-occlusive disease 
VZV 
varicella–zoster virus 
 


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APPENDIX C 
NMDP PROCEDURE FOR IDENTIFICATION OF CCR5DELTA32 MUTATION 
HOMOZYGOUS DONORS RELATED TO THIS PROTOCOL 
 
Background  
A recent case report by Hütter et al. (NEJM, 2009) documented the outcome of an allogeneic 
HCT performed for the treatment of AML in which the well-matched donor was selected for 
homozygosity for the CCR5delta32 mutation. The recipient had been known to be HIV-
infected prior to developing AML and the German transplant team hypothesized that 
hematopoietic cells from such a donor could confer natural resistance to HIV infection in the 
transplanted hematopoietic and immune cells. A single HLA-matched donor homozygous for 
the CCR5delta32 mutation was identified among approximately 80 well-matched donors and 
an allogeneic HCT for the treatment of the patient’s AML was performed using that donor. 
Following HCT, the recipient’s ARV medications were discontinued and viral titers were 
monitored. No subsequent recrudescence of HIV replication was detected. The recipient 
relapsed with AML approximately one year later but a second HCT using the same donor 
was successfully performed with continued primary disease remission and HIV control with 
undetectable HIV viral loads two years following the second HCT (Hütter, personal 
communication). 
 
The 15-MMUD Protocol Team would like to replicate these findings in the context of 
allogeneic HCT as proposed under this protocol. It is known that the incidence of 
CCR5delta32 homozygosity is essentially limited to European populations, with highest 
incidence in Northern Europeans (Galvani and Novembre, 2005); from these data, it is 
apparent that non-European populations manifest homozygosity too rarely to warrant 
evaluation. Additionally, it is also known that donor ethnicity strongly correlates with 
recipient ethnicity.  
 
In view of that fact that this protocol allows the use of HLA MMUDs there is a statistically 
higher chance of finding a CCR5delta32 mutation homozygous donor for the patient. 
 
Assessment of donor CCR5delta32 homozygosity should be considered for any HIV-positive 
patient who meets the criteria for inclusion in the 15-MMUD protocol. 
 
CCR5delta32 homozygosity status will be considered for donors who have been previously 
typed for this polymorphism and have the information available at the time of the search. No 
additional sample collection or informed consent is required for these donors. 
 
 
References  
Hütter G, Nowak D, Mossner M, Ganepola S, ßig A, Allers K, Schneider T, Hofmann J, 
Kücherer K, Blau O, Blau IW, Hofmann WK, Thiel E. Long-Term Control of HIV by CCR5 
Delta32/Delta32 Stem-Cell Transplantation. New Engl J Med. 2009; 360:692-8.  
Galvani A, Novembre J. The evolutionary history of the CCR5-D32 HIV-resistance 
mutation. Microbes Infect. 2005; 7: 302–309. 


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APPENDIX D 
TREATMENT REVIEW COMMITTEE FOR HIV-POSITIVE SUBJECTS 
 
Due to the complex nature of the patient population and the potential for numerous drug-drug 
interactions between the ARV regimen and the allogeneic HCT conditioning regimen, each 
subject’s conditioning regimen must be reviewed with the Treatment Review Committee. 
This review should typically occur at least 4 weeks prior to the planned conditioning regimen 
start date in order to allow sufficient time for any necessary adjustments to the subject’s 
medication regimen.  
 
The treating institution will review subjects with the Treatment Review Committee prior to 
the initiation of HCT therapy by a review panel composed of experts in HIV drug resistance, 
HIV care, pharmacology, HCT infectious diseases and oncology. Recommendations for HCT 
are based on the following supporting documentation:  
 
− Current diagnosis  
− Past medical history  
− Prior ARV history  
− Documented ARV drug toxicities  
− Drug allergies  
− History of HLA B57 antigen testing, if available  
− Current creatinine and liver function tests  
− Past and recent HIV drug resistance test results 
− Current ARV drug regimen  
− Current concomitant medications  
 
The Committee will review available past and current HIV-1 genotype results for subjects 
with detectable viremia so as to exclude subjects with multi-drug resistant HIV-1 who are 
unlikely to achieve viral suppression on alternate ARV regimens. The Committee will also 
advise with regard to various drug interactions anticipated during the course of HCT. The 
Treatment Review Committee will include well-qualified investigators from the Johns 
Hopkins University. Review materials will be sent to the panel 4 weeks prior to initiation of 
HCT therapy to allow sufficient time for implementation of recommendations for the ARV 
regimen. The Treatment Review form and de-identified copies of the supporting 
documentation (noted above) must be submitted to the CIBMTR Protocol Coordinator. The 
CIBMTR Protocol Coordinator will then provide these materials to the Treatment Review 
Committee to conduct their review. 
 
 
 
 


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APPENDIX E 
SUGGESTED PROPHYLAXIS FOR HIV-POSITIVE SUBJECTS 
 
Infectious prophylaxis for HIV-positive subjects undergoing HCT will include prophylaxis 
for:  
1. Bacteria: In keeping with the BMT CTN MOP and local institutional standards.  
2. Pneumocystis Jiroveci Pneumonia: Prophylaxis will be administered until CD4 counts are 
>200 and for a minimum of 6 months. Several effective regimens are available. Subject 
tolerance (nausea, allergic reaction, G6PD or other considerations) may contraindicate a 
particular regimen. Choices in order of preference are: 1) TMP/SMX 1 double-strength 
daily; 2) TMP/SMX 1 single strength daily; 3) dapsone 100 mg daily (may be decreased 
to 50 mg daily if given in combination with pyrimethamine as described below for 
toxoplasmosis prophylaxis; 4) atovaquone 1500 mg daily; and, 5) aerosolized or IV 
pentamidine monthly, or per institutional standard.  
3. Toxoplasmosis: Subjects on TMP/SMX do not require additional prophylaxis. If 
toxoplasma IgG is positive and TMP/SMX cannot be used subjects should be 
prophylaxed for at least 3 months after HCT and until CD4>100. This prophylaxis may 
be either: 1) dapsone 50 mg PO daily and pyrimethamine 50 mg/week and leucovorin 25 
mg/week or 2) atovaquone 1500 mg daily plus pyrimethamine 25 mg/day plus leucovorin 
10 mg/day. Since all medications for toxoplasmosis prophylaxis are oral, and some 
subjects may be unable to take PO medications in the peri-HCT period, polymerase chain 
reaction (PCR) for toxoplasmosis should be checked at least weekly whenever 
prophylaxis must be held in toxoplasma IgG positive subjects for more than a week and 
the CD4 is < 100.  
4. Fungi: Anti-fungal prophylaxis will be per local institutional practice. It is noted that in 
histoplasma endemic areas (Midwest and Puerto Rico) antifungal prophylaxis is standard 
for CD4 <150 and would be appropriate for at least 3 months after HCT and until 
CD4>150 (see Appendix F for detailed interactions with ARVs).  
5. Herpes simplex virus (HSV)/varicella–zoster virus (VZV): One of the following 
regimens should be used for 1-year after HCT, or per institutional standard, unless the 
subject remains on immunosuppressive acyclovir 400 - 800 mg PO BID, valaciclovir 500 
mg PO BID, or famciclovir 500 mg PO BID.  
6. M. Avium Complex (MAC): If CD4 < 50, azithromycin suggested at 1200 mg q week or 
600 mg twice weekly.  
7. Hepatitis:  
a. Subjects with positive hepatitis B surface antigen should be evaluated for viral DNA 
replication (viral load) by a quantitative PCR method before enrolling the subject on 
the study.  
b. Lamivudine or newer generation of anti-hepatitis B agents, like tenofovir, should be 
started in those with detectable hepatitis B viral load according to institutional 
preferences. The goal of the treatment should be achieving undetectable (<500 
copies/ml) viral load status.  
c. Subjects should be maintained on anti-hepatitis B treatment throughout 
chemotherapy, throughout the HCT, and at least 1-year post-HCT.  
d. Subjects with hepatitis C must have achieved a sustained virologic response for 12 
weeks after cessation of antiviral treatment to be eligible for the study. 


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APPENDIX F 
PK DRUG-DRUG INTERACTIONS WITH ARVs 
 
Preferred ARV Regimens for Subjects Undergoing Allogeneic HCT  
Tier 1: Raltegravir (INSTI) based therapy (no interruption of therapy is required)  
Tier 2: NNRTI based therapy (interruption of therapy may be required, see Table F-1)  
 
Summary of ARV Agents and Drug-Drug Interactions  
1. NNRTIs (efavirenz, nevirapine, etravirine)  
a. Dosing: Efavirenz is the preferred agent in this class, nevirapine should be used 
with caution due to toxicity 
b. Toxicity: Class adverse effects include, rash, hepatotoxicity and gastrointestinal 
intolerance  
c. Metabolism: NNRTIs are metabolized hepatically via cytochrome P450 co-
enzymes  
d. Drug Interactions  
i. 
All NNRTIs induce CYP3A4 (etravirine > efavirenz > nevirapine)  
ii. 
Efavirenz  
1. Substrate for CYP3A4 (major), 2B6 (major)  
2. Inhibits CYP2C9 (moderate), 2C19 (moderate), 3A4 (moderate)  
3. Induces CYP2B6 (weak), 3A4 (strong)  
 
2. Nucleoside Reverse Transcriptase Inhibitors (NRTI) (abacavir, didanosine, 
emtricitabine, lamivudine, stavudine, tenofovir)  
a. Dosing: Zidovudine (AZT) must not be used in subjects receiving HCT  
b. Toxicity: Adverse effects of the class include lactic acidosis, peripheral 
neuropathy and hepatic steatosis  
c. Metabolism: Not extensively metabolized, eliminated renally (except abacavir)  
d. Drug Interactions  
i. 
None of the NRTIs are metabolized via CYP450 co-enzymes  
ii. 
Avoid additive toxicities  
 
3. Other Agents  
a. Raltegravir (INSTI): Preferred agent due to excellent tolerability and lack of drug-
drug interactions  
b. Maraviroc: Substrate of CYP3A4, but does not induce or inhibit the metabolism 
of other agents  
c. Enfuviritide: No clinically relevant drug interactions, reserved for salvage therapy 
only 
d. Ritonavir: must not be used in subjects receiving HCT 
e. Cobicistat: must not be used in subjects receiving HCT 
 
 
 


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TABLE F-1: SUMMARY OF ARV DRUG-DRUG INTERACTIONS  
Conditioning Regimen  
 
Metabolism 
(Primary Site)  
Interaction Potential* 
(Predicted Effect)  
Recommendation/Evidence  
 
Regimen A: 
Flu/Cy/TBI 
 
Fludarabine:  
• Rapid 
dephosphorylation to 
2-fluoro-ara-A, then 
phosphorylated to 2-
fluoro-ara-ATP 
intracellularly  
 
Cy (Liver):  
• Prodrug is 
converted by hepatic 
microsomal enzymes 
to the active form. 
The activation 
pathway involves 
CYP2B6, CYP2C9 
and CYP3A4 
isoenzymes.  
• Substrate for 
CYP2A6 (minor), 
2B6 (major), 2C8/9 
(minor), 2C19 
(minor), 3A4 (major)  
• Inhibits CYP3A4 
(weak)  
• Induces CYP2B6 
(weak), 2C8/9 (weak)  
• Active metabolites 
include acrolein  
Low  
• Efavirenz has been 
given in combination 
with fludarabine.  
High 
• NNRTIs may increase 
levels of acrolein 
through CYP 
induction. Other CYP 
inducers like phenytoin 
have been shown to 
increase the AUC of 
active metabolites by 
50%.   
Raltegravir-Based: May 
continue highly active 
antiretroviral therapy 
(HAART) as tolerated  
 
NNRTI-Based: May 
continue HAART as tolerated  
 
ARV should not be resumed 
until, at least, 72 hours after 
the last dose of Cy and once 
the subject is able to 
consistently tolerate oral 
medications.  
 
 
*Combinations have not been studied and the interaction potential has been predicted based on the metabolic 
pathways of each agent. 
 
TABLE F-2: PK INTERACTIONS FOR GVHD PROPHYLAXIS AND ARVs 
Concomitant Medication 
Effect on sirolimus  
Mechanism  
Recommendation  
Integrase Inhibitor  
• Raltegravir (RLV)  
 
None 
N/A 
No adjustments necessary.  
Monitor sirolimus trough 
levels 2-3 times/week.  
Raltegravir based regimens 
may be preferred over 
NNRTI- based regimens as it 
is primarily metabolized via 
glucuronidation and not by 
CYP3A4.  
Fusion Inhibitor  
• Enfuviritide (ENF, T20)  
 
None  
N/A 
No adjustments necessary.  
Monitor sirolimus trough 
levels 2-3 times/week.  
CCR5 Antagonist  
• Maraviroc (MVC)  
 
None 
N/A 
No adjustments necessary.  
Monitor sirolimus trough 
levels 2-3 times/week. 


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 NNRTIs  
• Efavirenz (EFV)  
• Nevirapine (NVP)  
 
↓ Sirolimus Levels  
 
Strong induction of 
CYP3A4  
 
Continue sirolimus at the 
same dose and monitor 
trough levels daily.  
Based on level:  
• < 3 ng/mL: Increase 
sirolimus daily dose by 25%  
• 3 - 12 ng/mL: No 
adjustment  
• >12 ng/mL: Decrease 
sirolimus daily dose by 25%  
 
Full induction effects may 
take up to two weeks. Daily 
sirolimus doses are 
substantially increased for 
most patients with co-
administration of NNRTIs. 
Efavirenz is a more potent 
inducer of CYP3A4 than is 
nevirapine. 
NNRTIs  
• Etravirine (ETV)  
 
↓↓ Sirolimus Levels  
(Thoeretical)  
Potent induction of 
CYP3A4  
 
Concomitant use of etravirine 
and sirolimus should be 
discouraged.  
NRTIs  
• Abacavir (ABC)  
• Didanosine (ddI)  
• Emtricitabine (FTC)  
• Lamivudine (3TC)  
• Stavudine (d4T)  
• Tenofovir (TDF)  
 
None 
N/A 
No adjustments necessary.  
Monitor sirolimus trough 
levels 2-3 times/week.  
Frequent monitoring of renal 
function is required for those 
patients on tenofovir due to 
the increased risk of 
nephrotoxicity.  
For patients with renal 
impairment, adjust NRTI 
doses according to local 
guidelines.  
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX G 
ADDITIONAL EVALUATIONS FOR HIV-POSITIVE SUBJECTS 
 
PRE-CONDITIONING 
In addition to the Pre-Conditioning evaluations stated in section 2.6.3, the following Pre-
Conditioning evaluations must be completed for subjects who are HIV-positive: 
 
Within 6 months prior to start of conditioning: 
1. Obtain hepatitis B core and hepatitis C antibody test results. If hepatitis B core and/or 
hepatitis C antibodies are positive, hepatitis B DNA PCR and/or hepatitis C RNA PCR 
must be tested and results provided. 
a. HIV-positive subjects with hepatitis C must have achieved a sustained virologic 
response for 12 weeks after cessation of antiviral treatment to be eligible for the 
study. 
 
Within 8 weeks prior to start of conditioning:  
1. CMV PCR or antigenemia assay results 
2. HIV-1 RNA level (HIV viral load by standard assay) results 
3. CD4 count results 
4. Duration of HIV/AIDS diagnosis, history of prior opportunistic illnesses 
5. Medication list to include all current antiviral, antibiotics and opportunistic infection 
prophylaxis 
6. Peripheral blood collected for Latent HIV Cellular Reservoir Analysis (see Appendix I) 
7. Tropism assay results 
 
Within 4 weeks prior to start of conditioning:  
1. Treatment Review Committee approval (see Appendix D) 
 
POST-HCT 
In addition to the Post-HCT evaluations stated in section 2.6.3, the following Post-HCT 
evaluations must be completed for subjects who are HIV-positive: 
1. Day+100 (+/- 7 days) 
• CD4 count results 
2. Day+180 (+/- 28 days) 
• CD4 count results 
• Peripheral blood collected for Latent HIV Cellular Reservoir Analysis (see 
Appendix I) 
3. Day+270 (+/- 28 days)  
• CD4 count results 
4. 1-year (Day+365 (+/- 28 days)) 
• CD4 count results 
• Peripheral blood collected for Latent HIV Cellular Reservoir Analysis (see 
Appendix I) 


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APPENDIX H 
DIAGNOSIS AND SEVERITY SCORING FOR ACUTE AND CHRONIC GVHD 
 
1. Acute GVHD organ staging 
 
 
2. Consensus Acute GVHD Grading (PRZEPIORKA, ET. AL., 1995) 
 
 
 
 
 
 
 
 


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3. Grading of Chronic GVHD (NIH Criteria) 
 
 


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4. Categories of Acute and Chronic GVHD 
 
Categories of Acute and Chronic GVHD 
Category 
Time of 
Symptoms 
after HCT  
Presence 
of Acute 
GVHD 
Features 
Presence of 
Chronic 
GVHD 
Features* 
Acute GVHD 
Classic acute GVHD 
≤100 d 
Yes 
No 
Late-onset acute GVHD 
>100 d 
Yes 
No 
Chronic GVHD 
Classic chronic GVHD 
No time 
limit 
No 
Yes 
Overlap syndrome 
No time 
limit 
Yes 
Yes 
*As defined in section 5 (below) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. Signs and Symptoms of Chronic GVHD 
Organ or Site 
Diagnostic (Sufficient 
to Establish the 
Diagnosis of Chronic 
GVHD) 
Distinctive (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis 
of Chronic GVHD) 
Other Features* 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
Skin 
Poikiloderma 
Depigmentation 
Sweat impairment 
Erythema 
Lichen planus-like 
features 
Ichthyosis 
Maculopapular 
rash 
Sclerotic features 
Keratosis pilaris 
Pruritus 
Morphea-like features 
Hypopigmentation 
Lichen sclerosis-like 
features 
Hyperpigmentation 
Nails 
 
Dystrophy 
 
 
Longitudinal ridging, 
splitting, or brittle 
features 
Onycholysis 
Pterygium unguis 
Nail loss (usually 
symmetric; affects 
most nails)† 
Scalp and body 
hair 
New onset of scarring 
or nonscarring scalp 
alopecia (after 
recovery from 
chemoradiotherapy) 
Scaling, 
papulosquamous 
lesions 
Thinning scalp hair, typically 
patchy, coarse, or dull (not 
explained by endocrine or 
other causes) 
Premature gray hair 
Mouth 
Lichen-type features 
Xerostomia 
Gingivitis 
Hyperkeratotic plaques 
Mucocele 
Mucositis 
Restriction of mouth 
opening from sclerosis 
Mucosal atrophy 
Pseudomembranes† 
Ulcers† 
Erythema 
Pain 
Eyes 
New onset dry, gritty, 
or painful eyes‡ 
Photophobia 
Cicatricial 
conjunctivitis 
Keratoconjunctivitis 
sicca‡ 
Confluent areas of 
punctate keratopathy 
Periorbital hyperpigmentation 


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Organ or Site 
Diagnostic (Sufficient 
to Establish the 
Diagnosis of Chronic 
GVHD) 
Distinctive (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis 
of Chronic GVHD) 
Other Features* 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
Blepharitis (erythema of the 
eyelids with edema) 
Genitalia 
Lichen planus-like 
features 
Erosions† 
Vaginal scarring or 
stenosis 
Fissures† 
Ulcers† 
GI tract  
Esophageal web 
Strictures or stenosis in 
the upper to mid third 
of the esophagus† 
Exocrine pancreatic 
insufficiency 
Anorexia 
Nausea 
Vomiting 
Diarrhea 
Weight loss 
Failure to thrive 
(infants and 
children) 
Liver 
Total bilirubin, 
ALP >2 × ULN 
ALT or AST >2 × 
ULN† 
Lung 
Bronchiolitis obliterans 
diagnosed with lung 
biopsy 
Bronchiolitis 
obliterans diagnosed 
with PFTs and 
radiology‡ 
 
BOOP 
Muscles, fascia, 
joints 
Fasciitis 
Joint stiffness or 
contractures secondary 
to sclerosis 
Myositis or 
polymyositis‡ 
Edema 
Muscle cramps 
Arthralgia or arthritis 
Hematopoietic and 
immune 
 
 
Thrombocytopenia 
 
Eosinophilia 
Lymphopenia 
Hypo- or 
hypergammaglobulinemia 
Autoantibodies (AIHA and 
ITP) 
Other 
 
 
Pericardial or pleural 
effusions 
 
Ascites 


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Organ or Site 
Diagnostic (Sufficient 
to Establish the 
Diagnosis of Chronic 
GVHD) 
Distinctive (Seen in 
Chronic GVHD, but 
Insufficient Alone to 
Establish a Diagnosis 
of Chronic GVHD) 
Other Features* 
Common (Seen 
with Both Acute 
and Chronic 
GVHD) 
Peripheral neuropathy 
Nephrotic syndrome 
Myasthenia gravis 
Cardiac conduction 
abnormality or 
cardiomyopathy 
* Can be acknowledged as part of the cGVHD symptomatology if the diagnosis is confirmed. 
† In all cases, infection, drug effects, malignancy, or other causes must be excluded. 
‡ Diagnosis of cGVHD requires biopsy or radiology confirmation (or Schirmer test for eyes). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX I 
CORRELATIVE STUDY PROCEDURES 
 
The research samples supporting the correlative laboratory studies described below in 
sections A, B, and C will be required of all subjects enrolled on this trial.  The laboratory 
study described in section D below applies only to HIV-positive subjects. All correlative 
studies were designed to address very specific questions relevant to this HCT trial. Detailed 
instructions regarding sample collection, packaging and shipping can be found in the 15-
MMUD Clinical Trial Laboratory Manual provided to study sites.  
 
A. Gene Expression Profile Based Model to Predict Donor Cell Immune Tolerance 
In a previous investigation, Pidala and colleagues examined peripheral blood 
transcriptional markers in tolerant and non-tolerant HCT recipients with the goals of 
developing an accurate phenotypic classifier and dissecting biologic mechanisms of 
immune tolerance following HCT with promising results. We will use this approach in 
this correlative study to prospectively investigate tolerance development following 
PTCy/sirolimus/MMF therapy among MMUD HCT. 
 
Aim 1: Identify and verify transcriptional markers predictive of immune tolerance 
development  
(a) Day+100 and/or Day+180 samples will be used for prediction of immune tolerance, 
defined by complete discontinuation of immunosuppression and absence of GVHD. 
 
Aim 2:  Investigate longitudinal change in transcriptional markers for prediction of 
immune tolerance development   
(a) Change in gene expression from Day+21 to Day+180 will be examined for prediction 
of immune tolerance development. 
 
Research blood samples will be collected from recipients on Day+21, Day+100, and 
Day+180. Two PAXgene 2.5 mL-fill Blood RNA (IVD) tubes will be drawn at each time 
point. This whole blood collection system stabilizes RNA, and thus is ideal for collection 
and shipment from multiple study sites to H. Lee Moffitt Cancer Center and Research 
Institute for analysis. Based on expected yield of 0.5-1ug RNA/mL whole blood, total 
RNA isolated (~ 2.5-5ug) will be more than sufficient for planned mRNA profiling 
platforms (Affymetrix gene array, Nanostring nCounter technology). RNA will be 
isolated from whole blood (total RNA, inclusive of small RNA to permit microRNA 
analysis), and RNA integrity confirmed. 
 
The collection of these samples should be scheduled for Monday-Thursday of any given 
week. Samples must be stored at room temperature and shipped on the day of collection 
in an ambient sample shipping kit for next morning receipt at the H. Lee Moffitt Cancer 
Center and Research Institute.  
In rare cases where samples must be collected on Friday, Saturday, or Sunday, samples 
must be stored in the refrigerator at 2 – 8°C until shipped in a validated insulated cooled 


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sample shipping kit to the H. Lee Moffitt Cancer Center and Research Institute on 
Monday or the next business day in the case of a holiday. 
 
B. Clonal Hematopoiesis Assessments 
Age-related clonal hematopoiesis has recently been found to affect significant proportion 
of otherwise asymptomatic older individuals. In order to examine the incidence of HCT 
recipients developing donor clonal hematopoiesis and potential functional and clinical 
consequences we will study post-HCT DNA obtained from HCT recipients in the current 
study. Post-HCT DNA will be obtained from recipient bone marrow research samples 
collected at the time of standard of care bone marrow aspirates performed on Day+100 
and Day+365. A custom panel (TBD) designed as a clinical leukemia panel of genes 
important in oncogenesis will be evaluated by targeted next-generation sequencing. To 
investigate the propensity of donor clones for expansion and malignant transformation we 
will analyze the clonal architecture of donor-derived hematopoiesis in the recipients over 
time. We will apply targeted next-generation sequencing (as described above) to better 
understand the clonal dynamics in the recipients. We will analyze the changes in variant 
allele frequency of previously identified premalignant clones as well as the occurrence of 
additional cooperating mutations. 
 
Aim 1: To define the population of bone marrow recipients who develop donor clonal 
hematopoiesis 
 
Aim 2:  To determine the clinical and functional consequences of the hematopoietic 
clones marked by somatic mutations in donor-derived hematopoiesis post-HCT 
 
A 4 mL research bone marrow aspirate aliquot will be collected at the time of standard of 
care bone marrow aspirates performed at Day+100 and Day+365. The 4 mL aliquot of 
bone marrow will be added to two 2 mL-fill PAXgene Blood DNA tubes (IVD) and 
shipped priority overnight to the CIBMTR Biorepository.  Samples will be frozen for 
later use for this correlative study, which will be conducted by a qualified investigator 
(TBD).  
 
The collection of these samples should be scheduled for Monday-Friday of a given week.  
Samples must be stored at room temperature and shipped on the day of collection in an 
ambient sample shipping kit for next morning receipt at the CIBMTR Biorepository. If 
shipped on a Friday for Saturday delivery, the shipment must be designated for Saturday 
delivery. 
In rare cases where samples must be collected on Saturday or Sunday, samples must be 
stored upright in the refrigerator at 2 – 8°C until ambient temperature shipment to the 
CIBMTR Biorepository on Monday or the next business day in the case of a holiday. 
 
C. Immune Reconstitution Studies  
Immune system reconstitution dynamics will be assessed by measuring absolute number 
of leukocytes and the percentage of T, B, NK, monocyte, and dendritic cell subsets as 
defined by multiparameter flow cytometry.  Post-HCT peripheral blood samples will be 


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collected to explore the relationships of immune cell populations with the development of 
acute and/or chronic GVHD, and with outcomes including PFS, TRM and OS. 
 
A peripheral blood research sample (10 mL) will be collected from recipients on 
Day+100 and Day+365. The 10 mL blood sample will be added to one 10 mL (or two 
6mL) sodium heparin blood tube and shipped priority overnight to Roswell Park Cancer 
Institute. 
 
The collection of these samples must be scheduled for Monday-Friday of a given week.  
Samples must be stored at room temperature and shipped on the day of collection in an 
insulated ambient sample shipping kit for next morning receipt at Roswell Park Cancer 
Institute. If shipped on a Friday for Saturday delivery, the shipment must be designated 
for Saturday delivery. 
 
D. Latent HIV Cellular Reservoir Analysis (HIV-positive patients only) 
In patients with undetectable viral load as measured in conventional assays, there is 
persistent viremia that can be measured at single copy/mL by specialized PCR analysis.  
This viremia may reflect virus being released by the decay of latently infected cells or 
possibly ongoing viral replication.  Therapies that impact on the latently infected 
reservoir might be expected to change the viremia if it mainly reflected the decay of 
latently infected cells. Pre-HCT conditioning therapies may kill cells that constitute the 
latency reservoir and thus might thus be expected to impact on the reservoir and the very 
low level viremia that can be assessed by this assay. 
 
Required Latent HIV Research Sample Collections on HIV-positive Patients 
Once an HIV-positive patient with one or more available MMUDs that are homozygous 
for the CCR5delta32 mutation is consented and enrolled on the trial, a required peripheral 
blood research sample will be collected at approximately 8 weeks prior to initiation of 
ablative therapy.  The peripheral blood research sample (180 mL) will be collected and 
placed into eighteen (18) 10 mL EDTA containing, lavender-top Vacutainer tubes. 
Additional scheduled required Latent HIV research samples will be collected at Day+180 
and Day+365.   
HIV-positive patients may be contacted by researchers at the Sidney Kimmel 
Comprehensive Cancer Centre at Johns Hopkins regarding additional research requests 
after study completion. A separate informed consent would be required to participate in 
that research. 
The collection of these samples should be scheduled on only a Monday, Tuesday or 
Wednesday of a given week. Samples must be stored at room temperature and shipped on 
the day of collection in an insulated ambient shipping kit for next morning receipt at the 
Johns Hopkins Laboratory. In all cases, this large volume peripheral blood sample 
collection should be scheduled with consideration of other standard of care and required 
research sample collections so that the collection of the entire sample volume might be 
possible. Study sites must notify the CIBMTR Protocol Coordinator prior to sample 
collection at each time point to advise of the planned collection date.


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Required Research Samples Associated with Protocol Associated Correlative Studies  
Purpose 
 Sample Type 
Sample Collection Summary 
Collection 
Time Points 
Shipping Specifications 
Shipping Location 
Gene Expression 
Profile Testing 
5 mL 
Peripheral Blood 
• 
Collect 5 mL peripheral blood sample and 
place 2.5 mL into each of two PAXgene 
Blood RNA (IVD) tubes. Gently mix 
sample by inversion 8-10 times to mix 
sample well with RNA stabilization 
solution.  
• 
Store at room temperature while preparing 
to ship to project laboratory. 
• 
Samples are to be collected Monday -
Thursday only 
Day+21; 
Day+100; 
Day+180 
 
PAXgene tubes will be shipped 
at ambient temperature on the 
day of collection by priority 
overnight FedEx delivery to H. 
Lee Moffitt Cancer Laboratory.  
H. Lee Moffitt 
Cancer Laboratory 
Clonal 
Hematopoiesis 
Assessment 
4 mL 
Bone Marrow 
Aspirate 
• 
Collect 4 mL bone marrow aspirated 
sample and place a 2 mL volume into each 
of two PAXgene Blood DNA (IVD) tubes. 
• 
Store at room temperature while preparing 
to ship to project laboratory. 
• 
Samples may be collected Monday -Friday  
Day+100 and 
Day+365 
 
PAXgene tubes will be shipped 
at ambient temperature on the 
day of collection by priority 
overnight FedEx delivery to the 
CIBMTR Biorepository for 
storage for future clonal 
hematopoiesis assessment. 
 
CIBMTR 
Biorepository  
Immune 
Reconstitution 
Studies 
10 mL 
Peripheral Blood 
• 
Collect 10 mL peripheral blood sample and 
place into one 10 mL (or two 6mL) green 
top plastic BD Vacutainer® tubes, 
containing Sodium-Heparin anticoagulant. 
Gently mix sample by inversion 8-10 times 
to mix sample well with heparin 
anticoagulant.  
• 
Store at room temperature while preparing 
to ship to project laboratory.  
• 
Samples may be collected Monday -Friday 
Day+100 and 
Day+365 
 
Blood sample tubes will be 
shipped on the day of collection 
at ambient temperature by 
priority overnight FedEx 
delivery to Roswell Park Cancer 
Institute Laboratory.  
Roswell Park Cancer 
Institute Laboratory 
 
 
 
 
 


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Additional Required Research Samples for HIV-positive subjects only 
 
Purpose 
Sample Type 
Sample Collection Summary 
Collection  
Time Points 
Shipping Specifications 
Shipping 
Location 
Latent HIV Cellular 
Reservoir Analysis 
180 mL 
Peripheral Blood 
• 
Collect 180 mL peripheral blood sample 
and place into 18, 10 mL-fill lavender top 
plastic BD Vacutainer® tubes, containing 
EDTA anticoagulant. Gently mix sample 
by inversion 8-10 times to mix sample well 
with heparin anticoagulant.  
• 
Store at room temperature while preparing 
to ship to project laboratory.  
• 
Samples are to be collected Monday -
Wednesday only 
Pre-Conditioning; 
Day+180 and 
Day+365 
 
Blood sample tubes will be 
shipped on the day of collection 
at ambient temperature by 
priority overnight FedEx 
delivery to Johns Hopkins 
Laboratory. 
Johns Hopkins 
Laboratory 
 
 


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APPENDIX J 
MMUD SELECTION ALGORITHM 
  
Given no available suitable 8/8 matched related or unrelated donor, study sites may utilize 
the proposed MMUD search strategy process noted below. This selection algorithm 
prioritizes donor age, CMV serostatus, and ABO match over HLA. 
 
1. Among donors who are at least 4/8 allele matched (HLA-A, -B, -C, -DRB1), exclude 
any donor with HLA alleles against which the patient has specific antibodies.   
2. Attempt to find a donor that meets all following criteria: 
a. Young donor <30 years over 31-40 years over 41-50 years over 51-60 years 
b. ABO matched to patient over minor ABO mismatch over major ABO mismatch 
c. CMV serostatus matched to patient CMV (i.e. CMV positive donor for CMV 
positive patient) over CMV mismatch 
3. If donor meeting all criteria in #2 above is not available, the transplant team may 
choose among donors using institutional practices regarding prioritizing among these 
characteristics. 
4. Once donor age, ABO match and CMV status have been optimized, the following 
characteristics should be pursued (if possible): 
a. Male over nulliparous female over parous female  
b. Donor having body weight sufficient for adequate cell collection per patient size, 
if data available 
c. Donor availability information (last donor contact date with NMDP) 
5. After optimizing non-HLA criteria, the transplant team may select the donor based on 
HLA factors: 
a. Best allele match out of 8 alleles (HLA-A, -B, -C, -DRB1; 7>6>5>4) 
b. Consideration of -DPB1 allele matching (allele matching or T-cell-epitope  
permissive)  
c. Consideration of -DQB1 matching 
d. Consideration of other HLA-loci or genetic markers (e.g. -DRB3/4/5, Killer 
Immunoglobulin-like Receptor) 
 
Selection for any HIV-positive patient will prioritize donors homozygous for CCR5delta32 
mutation as the primary selection criteria.  Additional donor selection criteria with 
consideration of age, gender, donor weight, ABO matching, CMV matching and donor 
availability will be made by the transplant team. 
 
Multiple NMDP resources are available to assist study sites with donor selection assistance:  
• Traxis application: may be used by study sites to search for donors. Please note the 
following limitations: 
o Traxis results do not include donors <5/6 HLA-A, -B, -DRB1 antigen level match 
to the recipient.  
o This protocol allows for lower overall matching; many potential donors will not 
be available in the default NMDP HapLogic listing in Traxis.  


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• NMDP Immunogenetic Operations group: may use additional methods to identify 
donors.  
• 
NMDP Case Management group: may use the MMUD selection algorithm with 
specific search factor(s) at the request of the study site. NMDP Case Management then 
provides a Search Strategy Advice (SSA) report to the study site within 5 business days 
of the request. The results included in the SSA balance the MMUD algorithm with the 
study site’s specifications. 
 
During donor selection, study sites may consider other factors that may impact the product 
and/or the infusion:     
• Plans for cell processing/manipulation may increase the potential for a reduction in TNC 
yield. 
• Product travel time may delay the planned infusion date (and conditioning regimen 
schedule in relation to the infusion date). 
o Late product pick-up time: some collection centers do not allow product pick-up 
until later in the day, which may result in product delivery delay. 
• In instances where the product requires processing prior to infusion, it may be beneficial 
to delay Day 0 by one day (especially if the product requires transcontinental travel). 


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APPENDIX K 
RECOMMENDED FORMULAS FOR CALCULATION OF ADJUSTED AND IDEAL 
BODY WEIGHT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adjusted IBW = IBW + 0.25 (Actual weight – IBW)  
 
The following formulas for pediatric and adult IBW calculations are 
recommended, but IBW may be calculated according to institutional SOPs.  
 
• Recommended IBW Calculation for Age 15 - 17 years (Traub-Johnson 
Equation for Children): 
 
IBW = [(Height in cm)2 x 1.65]/1000 
 
• Recommended IBW Calculation for Age > 18 years:  
 
IBW(men)=50kg+2.3kg∗(heightover60inches) 
 
IBW(women)=45.5kg+2.3kg∗(heightover60inches) 


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APPENDIX L 
GUIDANCE ON REVIEWING AND REPORTING  
UNANTICIPATED PROBLEMS 
 
For more information, see http://www.hhs.gov/ohrp/policy/advevntguid.html#Q1. 
 
Below are pertinent excerpts from the Office for Human Research Protections (OHRP) Guidance on 
Reviewing and Reporting Unanticipated Problems Involving Risks to Subjects. 
 
I. What are unanticipated problems? 
The phrase “unanticipated problems involving risks to subjects or others” is found but not defined in 
the U.S. Department of Health & Human Services (HHS) regulations at 45 CFR part 46.  OHRP 
considers unanticipated problems, in general, to include any incident, experience, or outcome that 
meets all of the following criteria: 
1. unexpected (in terms of nature, severity, or frequency) given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the subject population being studied; 
2. related or possibly related to participation in the research (in this guidance document, possibly 
related means there is a reasonable possibility that the incident, experience, or outcome may 
have been caused by the procedures involved in the research); and 
3. suggests that the research places subjects or others at a greater risk of harm (including physical, 
psychological, economic, or social harm) than was previously known or recognized. 
OHRP recognizes that it may be difficult to determine whether a particular incident, experience, or 
outcome is unexpected and whether it is related or possibly related to participation in the research.  
 
II. How to determine which AEs are unanticipated problems? 
In OHRP’s experience, most IRB members, investigators, and institutional officials understand the 
scope and meaning of the term AE in the research context, but lack a clear understanding of OHRP’s 
expectations for what, when, and to whom AEs need to be reported as unanticipated problems, given 
the requirements of the HHS regulations at 45 CFR part 46.  
The following Venn diagram summarizes the general relationship between AEs and unanticipated 
problems:  
 
 
 
 


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To determine whether an AE is an unanticipated problem, the following questions should be asked:  
• 
Is the AE unexpected? 
• 
Is the AE related or possibly related to participation in the research? 
• 
Does the AE suggest that the research places subjects or others at a greater risk of harm than 
was previously known or recognized? 
If the answer to all three questions is yes, then the AE is an unanticipated problem. 
 
 
 
 
 
III. Some examples of unanticipated problems: 
 
• 
A series of related AEs that individually may not be unexpected but indicate a trend that 
places research participants or others at a greater risk of harm than was previously known or 
recognized.  
• 
A breach of confidentiality.  
• 
Incarceration of a participant in a protocol not approved to enroll prisoners.  
• 
Complaint of a participant when the complaint indicates unexpected risks.         
• 
A paper published from another study that shows that the risks or potential benefits of the 
research may be different than initially presented to the IRB.  
 
 


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APPENDIX M 
REFERENCES 
 
Alousi, A.M., Le-Rademacher, J., Saliba, R.M., Appelbaum, F.R., Artz, A., Benjamin, 
J., …Champlin, R.E. (2013). Who is the better donor for older hematopoietic transplant 
recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood, 121, 2567-
2573. 
 
Alvarnas, J., & Ambinder, R. (2012). Allogeneic Hematopoietic Cell Transplant for 
Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals. BMT 
CTN Clinical Trials Network.  
 
Anthias, C., van Walraven, S.M., Sørensen, B.S., de Faveri, G.N., Fechter, M., Cornish, J., 
… Shaw, B.E. (2015). Related hematopoietic cell donor care: is there a role for unrelated 
donor registries? Bone Marrow Transplant, 50, 637-641.  
 
Anthias, C., Shaw, B.E., Kiefer, D.M., Liesveld, J.L., Yared, J., Kamble, R.T., … O'Donnell, 
P.V. (2016). Significant Improvements in the Practice Patterns of Adult Related Donor Care 
in US Transplantation Centers. Biology of Blood and Marrow Transplantation, 22, 520-527. 
 
Bacigalupo, A., Lamparelli, T., Barisione, G., Bruzzi, P., Guidi, S., Alessandrino, 
P.E., …Gruppo Italiano Trapianti Midollo Osseo (GITMO). (2006). Thymoglobulin prevents 
chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related 
mortality: long-term follow-up of a randomized trial in patients undergoing unrelated donor 
transplantation. Biology of Blood and Marrow Transplantation, 12, 560-565. 
 
Bashey, A., & Solomon, S.R. (2014). T-cell replete haploidentical donor transplantation 
using post-transplant CY: an emerging standard-of-care option for patients who lack an 
HLA-identical sibling donor. Bone Marrow Transplantation, 49, 999-1008.  
 
Bitan, M., van Walraven, S.M., Worel, N., Ball, L.M., Styczynski, J., Torrabadella, M., … 
Pulsipher, M.A. (2016). Determination of Eligibility in Related Pediatric Hematopoietic Cell 
Donors: Ethical and Clinical Considerations. Recommendations from a Working Group of 
the Worldwide Network for Blood and Marrow Transplantation Association. Biology of 
Blood and Marrow Transplant, 22, 96-103. 
 
Blood and Marrow Transplant Clinical Trials Network (2013). Technical Manual of 
Procedures, v3.0. 
 
Brunstein, C.G., Fuchs, E.J., Carter, S.L., Karanes, C., Costa, L.J., Wu, J., … Blood and 
Marrow Transplant Clinical Trials Network. (2011). Alternative donor transplantation after 
reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-


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mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood, 
118, 282-288.  
 
Chakraverty, R., Orti, G., Roughton, M., Shen, J., Fielding, A., Kottaridis, P., …Mackinnon, 
S. (2010). Impact of in vivo alemtuzumab dose before reduced intensity conditioning and 
HLA-identical sibling stem cell transplantation: pharmacokinetics, GVHD, and immune 
reconstitution. Blood, 116, 3080-3088.  
 
Choi S.W., & Reddy, P. (2014). Current and emerging strategies for the prevention of graft-
versus-host disease. Nature Reviews Clinical Oncology, 11, 536-547.  
 
Cutler, C., & Antin, J.H. (2004). Sirolimus for GVHD prophylaxis in allogeneic stem cell 
transplantation. Bone Marrow Transplantation, 34, 471-476. 
 
Dalle, J.H., & Giralt, S.A. (2016). Hepatic Veno-Occlusive Disease after Hematopoietic 
Stem Cell Transplantation: Risk Factors and Stratification, Prophylaxis, and Treatment. 
Biology of Blood Marrow Transplantation, 22, 400-409. 
 
Delgado, J., Thomson, K., Russell, N., Ewing, J., Stewart, W., Cook, G., …Milligan, D.W. 
(2006). Results of alemtuzumab-based reduced-intensity allogeneic transplantation for 
chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation 
Study. Blood, 107, 1724–1730. 
 
Fitzhugh, C.D., Weitzel, R.P., Hsieh, M.M., Phang, O.A., Madison, C., Luznik, L., … 
Tisdale, J. F. (2013). Sirolimus and post transplant Cy synergistically maintain mixed 
chimerism in a mismatched murine model. Bone Marrow Transplantation, 48, 1335–1341. 
 
Ho, V.T., Cutler, C., Carter, S., Martin, P., Adams, R., Horowitz, M., … Giralt, S. (2005). 
Blood and Marrow Transplant Clinical Trials Network Toxicity Committee Consensus 
Summary: Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplantation. 
Biology of Blood and Marrow Transplantation, 11, 571-575. 
 
Horowitz, M.M., Gale, R.P., Sondel, P.M., Goldman, J.M., Kersey, J., Kolb, H.J.,...Bortin, 
M.M. (1990). Graft-versus-leukemia reactions after bone marrow transplantation. Blood, 75, 
555-562.  
 
Kasamon, Y., Luznik, L., Bolanos-Meade, J., Fuchs, E., Jones, R., Leffell, M., …Gamper, C. 
(2012). Reduced intensity, partially HLA mismatched allogeneic BMT for hematologic 
malignancies using donors other than first-degree relatives. Sidney Kimmel Comprehensive 
Cancer Center. 
 
Kasamon, Y.L., Fuchs, E.J., Bolanos-Meade, J., Leffell, M.S., Zahurak, M., Rosner, G.L., … 
Luznik, L. (2015).  Nonmyeloablative (NMA), HLA-Mismatched Unrelated Donor (mMUD) 
BMT with High-Dose Posttransplantation Cyclophosphamide (PTCy) Has Outcomes Similar 
to Matched BMT. Blood, 126, 2002. 
 


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Kekre, N., & Antin, J.H. (2014). Hematopoietic stem cell transplantation donor sources in the 
21st century: choosing the ideal donor when a perfect match does not exist. Blood, 124, 334-
343. 
 
Kollman, C., Howe, C.W., Anasetti, C., Antin, J.H., Davies, S.M., Filipovich, A.H., … 
Confer, D.L. (2001). Donor characteristics as risk factors in recipients after transplantation of 
bone marrow from unrelated donors: the effect of donor age. Blood, 98, 2043-2051. 
 
Kollman, C., Spellman, S.R., Zhang, M.J., Hassebroek, A., Anasetti, C., Antin, J.H., … 
Eapen, M. (2016). The effect of donor characteristics on survival after unrelated donor 
transplantation for hematologic malignancy. Blood, 127, 260-267. 
 
Kongtim, P., Cao, K., & Ciurea, S.O. (2016). Donor Specific Anti-HLA Antibody and Risk 
of Graft Failure in Haploidentical Stem Cell Transplantation. Advances in Hematology, 2016, 
1-10. 
 
Kröger, N., Zabelina, T., de Wreede, L.,  Berger, J., Alchalby, H., van Biezen, A.,  … de 
Witte, T. on behalf of the MDS subcommittee of the Chronic Leukemia Working Party of the 
European Group for Blood and Marrow Transplantation (EBMT). (2013). Allogeneic stem 
cell transplantation for older advanced MDS patients: improved survival with young 
unrelated donor in comparison with HLA-identical siblings. Leukemia, 27, 604–609. 
 
Luznik, L., O'Donnell, P.V., Symons, H.J., Chen, A.R., Leffell, M.S., Zahurak, M., …Fuchs, 
E.J. (2008). HLA-haploidentical bone marrow transplantation for hematologic malignancies 
using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. 
Biology of Blood and Marrow Transplantation, 14, 641-650.  
 
Mayumi, H., Umesue, M., & Nomoto, K. (1996). Cyclophosphamide-induced immunological 
tolerance: an overview. Immunobiology, 195, 129-139. 
 
Perkins, J., Kim, J., Anasetti, C., Fernandez, H., Perez, L.E., Ayala, E., … Field, T.L. (2012). 
Maximally Tolerated Busulfan Systemic Exposure in Combination with Fludarabine as 
Conditioning before Allogeneic Hematopoietic Cell Transplantation. Biology of Blood and 
Marrow Transplantation, 18, 1099-1107. 
 
Pidala J., Lee S.J., Ahn, K.W., Spellman, S., Wang, H.L., Aljurf, M., … Anasetti, C. (2014). 
Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated 
allogeneic hematopoietic cell transplantation. Blood, 124, 2596-2606.  
 
Pidala, J., Alousi, A., & MacMillan, M. (2015). A Randomized, Phase II, Multi-Center, Open 
Label, Study Comparing Sirolimus to Prednisone in Patients with Minnesota Standard Risk, 
Ann Arbor 1/2 Confirmed Acute Graft-Versus-Host Disease. BMT CTN Clinical Trials 
Network. 
 


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Potter, V.T., Krishnamurthy, P., Barber, L.D., Lim, Z., Kenyon, M., Ireland, R.M., …Mufti, 
G.J. (2014).  Long-term outcomes of alemtuzumab-based reduced-intensity conditioned 
hematopoietic stem cell transplantation for myelodysplastic syndrome and acute 
myelogenous leukemia secondary to myelodysplastic syndrome. Biology of Blood and 
Marrow Transplantation, 20, 111-117. 
 
Shabbir-Moosajee, M., Lombardi, L., & Ciurea, S.O. (2015). An overview of conditioning 
regimens for haploidentical stem cell transplantation with post-transplantation 
cyclophosphamide. American Journal of Hematology, 90, 541-548.  
 
Shaw, B.E., Russell, N.H., Devereux, S., Das-Gupta, E., Mackinnon, S., Madrigal, J.A., … 
Byrne, J.L. (2005). The impact of donor factors on primary non-engraftment in recipients of 
reduced intensity conditioned transplants from unrelated donors. Haematologica, 90, 1562-
1569. 
 
Shaw, B.E., Logan, B.R., Kiefer, D.M., Chitphakdithai, P., Pedersen, T.L., Abdel-Azim, H., 
… Pulsipher, M.A. (2015). Analysis of the Effect of Race, Socioeconomic Status, and Center 
Size on Unrelated National Marrow Donor Program Donor Outcomes: Donor Toxicities Are 
More Common at Low-Volume Bone Marrow Collection Centers. Biology of Blood and 
Marrow Transplantation, 21, 1830-1838. 
 
Symons, H.J., Chen, A., Gamper, C., Cooke, K.R., Showel, M., Bolanos-Meade, J., … 
Fuchs, E.J. (2015). Haploidentical BMT using fully myeloablative conditioning, T cell 
replete bone marrow grafts, and post-transplant cyclophosphamide (PT/Cy) has limited 
toxicity and promising efficacy in largest reported experience with high risk hematologic 
malignancies. Biology of Blood and Marrow Transplantation, 21, S29. 
 
Thomas, E.D., Buckner, C.D., Banaji, M., Clift, R.A., Fefer, A., Flournoy, N., …Weiden, 
P.L. (1977). One hundred patients with acute leukemia treated by chemotherapy, total body 
irradiation, and allogeneic marrow transplantation. Blood, 49, 511-533. 
 
Walker, I., Panzarella, T., Couban, S., Couture, F., Devins, G., Elemary, M., …Canadian 
Blood and Marrow Transplant Group. (2016). Pretreatment with anti-thymocyte globulin 
versus no anti-thymocyte globulin in patients with haematological malignancies undergoing 
haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-
label, phase 3, multicentre trial. The Lancet Oncology, 17, 164-173. 
 
 
 
 
 
 
 

ICF_001.pdf: 
 
15-MMUD study consent v2.1                                      NMDP IRB Approved August 16, 2018 through August 15, 2019 
IRB-2016-0365 
Page 0 of 14 
 
 
A Multi-Center, Phase II Trial of HLA-
Mismatched Unrelated Donor Bone 
Marrow Transplantation with Post-
Transplantation Cyclophosphamide 
for Patients with Hematologic 
Malignancies 
NCT02793544 
Document date: 16Aug2018 
 


15-MMUD study consent v2.1                                     NMDP IRB Approved August 16, 2018 through August 15, 2019 
IRB-2016-0365 
Page 1 of 14 
 
 
 
 
Informed Consent to Participate in a Research Study 
Throughout this document, references to “You” may stand for either the study subject or the 
parent/legally authorized representative of the study subject if the subject is younger than the 
legal age of majority under applicable law of the jurisdiction in which the research study will be 
conducted, or otherwise unable to legally give informed consent to participate in the research 
study.  
The signature(s) at the end will clarify whether the study subject is signing this consent form on 
their own behalf or via a parent/legally authorized representative. 
 
1. Title of Research Study 
A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow 
Transplantation with Post-Transplantation Cyclophosphamide for Patients with Hematologic 
Malignancies 
 
 
2. Principal Investigator  
[Enter name of Transplant Center Principal Investigator] 
 
3. Contact Information for Emergencies After Hours or on Weekends or Holidays: 
[Enter name(s) and phone number(s) for emergency contact person(s) at Transplant Center] 
 
4. Sponsors and Source of Funding or Other Material Support 
Be The Match® operated by the National Marrow Donor Program® (NMDP) 
 
5. Introduction 
This is a clinical trial, a type of research study.  Clinical trials include only people who 
choose to take part. A clinical trial is a research study to answer specific medical questions. 
The information from this study may help future patients. This form tells you about the study. 
In addition, the study doctor (the person in charge of the research) will explain the study to 
you. 
 
 
You are being asked to take part in this study because you have been found to have a 
cancer of the blood or lymph glands that may be treatable with stem cell transplantation 
(transplant) from a relative or unrelated donor. We and other transplant centers have the 
most experience using a donor who is a “perfect” or “close to perfect” tissue match to you. 
Tissue typing shows that you do not have a “perfect” or “close to perfect” relative or 
unrelated donor; however, you do have a mismatched unrelated donor (MMUD) who is a 
“partial match” to you. 
 
You are being invited to participate in this study because your doctor has determined that 
the best option for treating your disease is a bone marrow transplant using a MMUD. 
 
 
 


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Page 2 of 14 
 
 
Please take your time to make your decision about taking part in this study. You may 
discuss your decision with your friends and family.  You can also discuss it with the medical 
staff at the transplant center.  
 
6. Purpose of the study 
The purpose of this study is to see if using a MMUD is safe and effective in patients 
undergoing bone marrow transplant. 
 
It is your choice whether or not you want to participate in this study. You and the medical 
staff at your transplant center will discuss other options before you make your decision 
about participating in this study. 
 
As many as 80 patients will participate in this research study from medical centers 
throughout the United States. 
 
7. Study Procedures 
If you choose to participate in this study, your study doctor will check your general health to 
assure that you are eligible.  Many of the tests and procedures listed below are part of your 
regular care.  You may have had some of them done already.  Your study doctor will 
determine if any of these tests or procedures will need to be repeated for you to participate 
in the study. Your participation in this study will end at approximately one year after your 
transplant. 
Prior to transplant 
A complete medical history and physical exam will be done before transplant.  Other tests 
may include:  
• 
blood tests (for both standard of care and research tests) 
• 
urine tests 
• 
breathing tests 
• 
heart function test  
• 
bone marrow tests 
• 
CT/PET/MRI scans (only patients with lymphoma or Chronic Lymphocytic Leukemia) 
• 
pregnancy test (for females of childbearing potential) 
 
You will have a thin plastic tube (catheter) placed into a large vein in your chest (called a 
Hickman or central line).  This will require surgery, and you will be asked to sign a separate 
consent form for this procedure.  The catheter will be used for many of the drugs given in 
this study and for the required blood draws. 
 
HIV-positive patients may have additional tests and evaluations performed prior to 
transplant. Some of the blood samples collected will be used for research. 
 
Preparing for your transplant 
 
The nurses and doctors count backwards from 6 to 0 when talking about the days before 
your transplant.  Day -6 (minus 6) is the first day of the preparative regimen and Day 0 is the 
day of your transplant. 
 
On this study, you will receive one of the three following treatments (as determined by your 
physician for your particular case): 
 


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Treatment A 
• 
Fludarabine will be given by an intravenous infusion (through your vein) on Days -6 
through -2. 
• 
Cyclophosphamide (Cy) will be given by an intravenous infusion on Days -6 and -5.  
• 
Mesna will be given by intravenous infusion before and after Cy on Days -6 and -5. 
• 
Total body irradiation (TBI) will be given on Day -1. 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards. 
 
Treatment B 
• 
Busulfan will be given by either an intravenous infusion or by mouth on Days -6 
through -3. 
• 
You will also be given one of the two following treatments: 
o Cy will be given by an intravenous infusion on Days -2 and -1.  
▪ 
Mesna will be given by intravenous infusion before and after Cy on 
Days -2 and -1. 
o Fludarabine will be given by an intravenous infusion on Days -6 through -2.  
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards. 
 
Treatment C 
• 
Cy will be given by an intravenous infusion on Days -5 and -4.  
• 
Mesna will be given by intravenous infusion before and after Cy on Days -5 and -4. 
• 
TBI will be given on Days -3 through -1. 
 
Although a schedule is proposed above, the regimen can be given according to institutional 
standards. 
 
 
During your transplant 
 
On your transplant day (Day 0), the bone marrow will be given to you through your catheter, 
like a blood transfusion. The cells will travel to your bone marrow where they will start to 
make healthy, new blood cells after several weeks. 
 
Treatment after transplant 
The nurses and doctors count forwards from Day 0 when talking about the days after your 
transplant.  Since Day 0 is the day of your transplant, days after your transplant are called 
Day+ (plus). For example, 3 days after your transplant would be called Day+3. 
 
After your transplant, you will receive the following treatments: 
• 
Cy will be given by an intravenous infusion on Days+3 and +4 
• 
Mesna will be given by intravenous infusion before and after Cy on Days+3 and +4. 
• 
Sirolimus will be given by mouth from Day+5 through Day+180 
• 
Mycophenolate mofetil (MMF) will be given by mouth from Day+5 through Day+35 
• 
Granulocyte-colony stimulating factor (G-CSF) (filgrastim) will be given by an 
intravenous infusion, or as an injection from Day+5 until a type of white blood cell 
(neutrophil) has achieved a certain level for 3 consecutive days 
 
Evaluations after transplant 


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The following tests will be done weekly after your transplant: 
• 
complete medical history and physical exam 
• 
blood tests (some of these samples will be used for research) 
• 
GVHD assessment 
• 
toxicity assessment 
• 
infection assessment 
 
A chimerism test of your blood (to determine how well your new cells are growing) will be 
done at 28 days, 56 days, 100 days, 180 days, and 1 year after transplant. 
 
Bone marrow tests will be done at 100 days, 180 days, and 1 year after transplant. Some of 
these samples will be used for research. 
 
Patients with lymphoma or Chronic Lymphocytic Leukemia will have imaging studies (e.g. 
CT, PET, MRI) done at 100 days, 180 days, and 1 year after transplant. 
 
HIV-positive patients may have additional tests and evaluations performed after transplant. 
Some of the blood samples collected will be used for research. While your participation in 
this study will end at approximately one year after your transplant, HIV-positive patients 
may be contacted by researchers at the Sidney Kimmel Comprehensive Cancer Centre at 
Johns Hopkins regarding additional research requests after study completion. A separate 
consent would be required to participate in that research. 
 
 
8. Possible Discomforts and Risks 
There are risks involved in this study.  There may be side effects from the drugs or study 
procedures.  The side effects we know about are described below.  They may vary from 
person to person.  Many of the side effects will go away.  However, sometimes side effects 
can be very severe and long lasting.  Everything possible will be done to lessen the side 
effects.  Your doctor may suggest that you take certain drugs to reduce some of the side 
effects.  You should know that some complications can be fatal.  
 
Table 1: Risks and Side Effects 
Likely 
What it means: This type of side effect is expected in more than 20% of patients. 
This means that 21 or more patients out of 100 might get this side effect. 
Less Likely 
What it means: This type of side effect is expected in 20% of patients or fewer. 
This means that 20 or fewer patients out of 100 might get this side effect. 
Rare, but 
Serious 
What it means: This type of side effect is expected in fewer than 10% of patients. 
This means that 10 or fewer patients out of 100 might get this side effect. It 
doesn’t happen very often, but is serious when it does. 
 
BUSULFAN 
Likely (>20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Abdominal discomfort 
• 
Constipation 
• 
Diarrhea 
• 
Dizziness 
• 
Fluid retention 
• Cough 
• Liver disease 
• High blood pressure 
• Imbalance in 
electrolytes (necessary 
• Cataracts (clouding of the 
lens of the eye) 
• Lung fibrosis (scarring of lung 
tissue with cough and 
shortness of breath) 


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FLUDARABINE 
Likely (> 20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Decreased white blood cell 
count with risk of infection 
• 
Suppression of the immune 
system 
• 
Tiredness 
• 
Nausea and vomiting 
• 
Mouth sores 
• 
Fever 
• 
Skin rash/hives 
• Diarrhea 
• Numbness and tingling 
in hands and/or feet 
related to irritation of 
nerves of the hand 
and/or feet 
• Changes in vision 
• Pneumonia (inflammation in 
lungs, often from infection) 
• Agitation or nervousness 
• Confusion 
• Cough 
• Difficulty breathing and 
shortness of breath 
• Weakness 
• Severe brain injury and death 
• Coma 
 
CYCLOPHOSPHAMIDE (Cy) 
Likely (>20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Diarrhea 
• 
Damage to male (testes) and 
female (ovaries) sex glands 
• 
Fluid retention 
• 
Hair loss 
• 
Infertility (unable to become 
pregnant (women) or get a 
female partner pregnant 
(men)) 
• 
Irregular or no menstrual 
cycles 
• 
Loss of appetite 
• 
Nausea and vomiting 
• 
Suppression of the immune 
system 
• 
Decreased platelet count 
and increased risk of 
bleeding 
• 
Bleeding in the bladder 
• 
Low red blood cell 
count 
• 
Damage to the fetus if 
you become pregnant 
while taking the drug 
• 
Abdominal pain 
• 
Skin rash/hives 
• 
Allergic reaction 
• 
Lung fibrosis (scarring of lung 
tissue with cough and 
shortness of breath) 
• 
Severe heart muscle injury 
and death  
• 
Secondary (new) cancers 
• 
Headache 
• 
Heartburn 
• 
Difficulty falling asleep and 
staying asleep 
• 
Lack of appetite 
• 
Mouth sores 
• 
Nausea and vomiting 
• 
Runny nose 
• 
Skin rashes/hives 
• 
Irregular or no menstrual 
cycles 
• 
Fast heartbeat 
blood salts) 
• High sugar levels in the 
blood 
• Infertility (unable to 
become pregnant 
(women) or get a 
female partner 
pregnant (men)) 
• Low blood pressure 
• Seizures 
• Difficulty breathing and 
shortness of breath 
 


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MESNA 
Likely (>20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Diarrhea 
• 
Nausea and vomiting 
• 
Headache 
• 
Weakness 
 
• 
Abdominal pain 
• 
Skin rash/hives 
• 
Low blood pressure 
• 
Joint and/or limb pain 
• 
Altered taste 
 
 
 
MYCOPHENOLATE MOFETIL (MMF) 
 
Likely (>20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Diarrhea 
• 
Limited effectiveness of birth 
control 
• 
Abdominal pain 
• 
Nausea and vomiting 
• 
Headache 
• 
Tremors 
• 
Decreased white blood cell 
count, red blood cell count, 
and platelets with increased 
risk of infection 
• 
Suppression of the immune 
system 
• 
Increased blood cholesterols 
• 
High sugar levels in the 
blood 
• 
Imbalance in electrolytes  
(necessary blood salts) 
• 
Swelling of the hands, feet, 
ankles, or lower legs 
• 
Leg cramps 
• 
Low red blood cell 
count 
• 
Skin rash/hives 
• 
Difficulty falling asleep 
or staying asleep 
• 
Dizziness 
• 
Altered taste 
• 
Joint and/or limb pain 
• 
Low blood pressure 
• 
High blood pressure 
• 
Damage/birth defects 
to the fetus if you 
become pregnant while 
taking the drug 
• 
Miscarriage 
 
• 
Difficulty breathing and 
shortness of breath 
• 
Unusual bruising 
• 
Fast heartbeat 
• 
Weakness 
• 
Blood in stool 
• 
Bloody vomit 
• 
Change in vision 
• 
Allergic reaction 
• 
Progressive Multifocal 
Leukoencephalopathy (a rare 
disorder caused by a virus 
that damages the material 
that covers and protects 
nerves in the white matter of 
the brain (myelin))  
 
 
SIROLIMUS 
 
Likely (>20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Headache 
• 
High blood pressure 
• 
Suppression of the immune 
system 
• 
Fever 
• 
Nausea 
• 
Diarrhea 
• 
Constipation 
• 
Tremors 
• 
Kidney dysfunction 
• 
Chest pain 
• 
Difficulty falling asleep 
or staying asleep 
• 
Vomiting 
• 
Skin rash/hives 
• 
Decreased platelet 
count and increased 
risk of bleeding 
• 
Low white blood cell 
count with increased 
• 
Low blood pressure 
• 
Asthma 
• 
Cough 
• 
Fast heartbeat 
• 
Lack of appetite  
• 
Lung fibrosis (scarring of lung 
tissue with cough and 
shortness of breath) 
• 
Pneumonia (inflammation in 
lungs, often from infection) 


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• 
Back pain 
• 
Abdominal pain 
• 
High cholesterol 
• 
High triglycerides (type of fat 
found in blood) 
• 
High sugar levels in the 
blood 
• 
Swelling of the hands, feet, 
ankles, or lower legs 
• 
Low red blood cell count 
• 
Acne 
• 
Joint and/or limb pain 
risk of infection 
• 
Itchiness 
• 
Difficulty breathing and 
shortness of breath 
• 
Heartburn 
• 
Mouth sores 
• 
Imbalance in 
electrolytes (necessary 
blood salts) 
• 
Abnormal liver tests 
• 
Urinary tract infection 
• 
Upper respiratory 
infection 
• 
Delayed wound healing 
• 
Abnormal amount of 
protein in urine 
• 
Increased blood 
clotting in small blood 
vessels throughout the 
body (called TTP) 
• 
Abnormal premature 
destruction of red blood 
cells (called HUS and 
TMA) 
 
• 
Kidney disease 
• 
Congestive heart failure 
• 
Skin cancer 
• 
Weakened bones 
• 
Bone tissue death 
• 
Flu-like syndrome 
• 
Fluid around abdomen 
• 
Excessive growth of lymphatic 
cells 
• 
Muscle pain 
• 
Fluid around lungs 
• 
Fluid around heart 
 
TOTAL BODY IRRADIATION (TBI) 
Likely (>20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Weakness 
• 
Hair loss 
• 
Infertility (unable to become 
pregnant (women) or get a 
female partner pregnant 
(men)) 
• 
Loss of appetite 
• 
Nausea and vomiting 
• 
Fever  
• 
Cataracts (clouding of 
the lens of the eye) 
• 
Inflammation of the 
salivary gland 
• 
Skin pigmentation 
(reversible) 
• 
Stunted growth 
• 
Low white blood cell 
count with increased 
risk of infection 
• 
Low red blood cell 
count 
• 
Suppression of the 
immune system 
• 
Diarrhea 
• 
Lung fibrosis (scarring of lung 
tissue with cough and 
shortness of breath) 
• 
Secondary (new) cancers 
 
 
 
 


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FILGRASTIM (G-CSF) 
 
 
RISKS OF BONE MARROW TRANSPLANTATION IN GENERAL: 
Graft vs. Host Disease (GVHD): This occurs when the donor’s white blood cells recognize 
your body as “foreign.”  The donor’s cells then attack the cells of your body.  GVHD can be 
mild or severe.  In the most severe cases, it can cause death.  You will be watched closely 
for this complication and given specific treatment to prevent and treat it.  GVHD is treated 
with drugs that weaken the immune system.  This makes you more likely to get infections.  
Treatment of GVHD may last from months to years.  One of the most common treatments 
for GVHD is prednisone.  Prolonged treatment with prednisone may result in cataracts, bone 
loss, diabetes, high blood pressure, bone fracture, and muscle loss.  
There are 2 forms of GVHD: acute (early) and chronic (late) GVHD.  Chronic GVHD occurs 
most commonly in patients who have had acute GVHD, but may occur in patients who did 
not have any acute GVHD.  
Symptoms of Early or Acute GVHD (seen in 60-70% of subjects) 
• 
Skin rash 
• 
Diarrhea 
• 
Nausea and vomiting 
• 
Abdominal pain or cramping 
• 
Increased risk of infection 
• 
Liver disease (inflammation of the liver and yellowing of the skin) 
 
Symptoms of Late or Chronic GVHD (seen in 30-40% of subjects) 
• 
Skin rash 
• 
Hair loss 
• 
Thickened skin 
• 
Dry mouth 
• 
Dry eyes 
• Diarrhea 
• Increased risk of infection 
• Liver disease or inflammation 
• Lung disease (scarring of the lungs) 
Graft Failure:  This occurs when your body does not accept the transplanted cells.  Graft 
failure may occur in 5-10% of subjects.  We do not know how likely graft failure is in a 
protocol like this one that does not completely kill the marrow before transplant.  It is also 
possible that the blood stem cells will grow, but not work normally.  This will result in low 
blood counts for a long period of time.  If graft failure occurs, you may be able to have a 
second transplant with cells from the same donor or from another donor, if another donor is 
available.  Graft failure may result in death from infections, low red blood cell count or 
bleeding.  
Likely (> 20%) 
Less Likely (≤ 20%) 
Rare, but Serious (<10%) 
• 
Ache or pain inside the 
bones 
• 
Headache 
• 
Tiredness 
• 
Difficulty falling asleep or 
staying asleep 
• 
Local irritation (skin) at 
the injection site 
• 
Nausea and vomiting  
• 
Low number of 
platelets in the blood 
• 
Allergic reaction 
• 
Low fever 
• 
Enlargement or rupture of the 
spleen 
• 
Worsening of pre-existing skin 
rashes 


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Damage to the vital organs in your body: This could affect any organ in your body such 
as heart, lungs, liver, gut, kidneys and bladder, brain, etc.  Some subjects will experience 
severe lung problems due to infections and/or due to a reaction of the lungs to the 
chemotherapy and/or radiation. Some subjects can suffer veno-occlusive disease of the liver 
(VOD).  VOD is damage to the liver that can occur as a result of transplant.  Symptoms and 
signs include yellowing of the skin (jaundice), a swollen and painful liver, fluid retention, 
weight gain and abnormal liver tests.  In severe cases, VOD can lead to liver failure or even 
cause death. 
Serious Infections:  Your immune system will be not be normal for many months after the 
transplant, and the white blood cells that fight infection will be very low or not functioning 
well. During this time, there is an increased risk of viral, fungal or bacterial infections.  You 
will be prescribed certain medications to reduce the chance of those infections.  However, 
preventive treatments are not always effective.  If you develop an infection you may have to 
stay in the hospital longer or be re-hospitalized after transplant.  Infections can be very 
serious or cause death.  
Recurrence of cancer: There is a chance that the transplant will not cure your disease or 
that it returns even if the transplant is initially successful.   
 
REPRODUCTIVE RISKS  
 
 
For pregnancy/risk to fetus (For Women): The treatments in this study have not been 
proven to be safe at any stage of pregnancy. You should not become pregnant or nurse 
your baby while on this study. If you are sexually active you and your male partner(s) 
must use a combination of two methods of birth control or you must not have sexual 
intercourse. Effective birth control methods include: 1) refraining from all acts of vaginal 
intercourse (abstinence); 2) consistent use of birth control pills; 3) injectable birth control 
methods (Depo-Provera); 4) tubal sterilization or male partner who has undergone a 
vasectomy; and 5) use of a diaphragm with contraceptive jelly and/or condoms with 
contraceptive foam, with every act of intercourse. You will have to use birth control or 
abstain from having sexual intercourse the whole time you are in this study. If you become 
pregnant during the research study, please tell the investigator and your doctor immediately.  
 
For pregnancy/risk to fetus (For Men): Causing a pregnancy while receiving treatment on 
this study can affect a fetus. If you are sexually active you and your female partner(s) must 
use a combination of two methods of birth control or you must not have sexual intercourse. 
Effective birth control methods include: 1) refraining from all acts of vaginal intercourse 
(abstinence); 2) consistent use of birth control pills; 3) injectable birth control methods 
(Depo-Provera); 4) tubal sterilization or male partner who has undergone a vasectomy; and 
5) use of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam, with 
every act of intercourse. You will have to use birth control or abstain from having sexual 
intercourse the whole time you are on therapy on this study. If a sexual partner becomes 
pregnant during the research study, please tell the investigator and ask your partner to tell 
her doctor immediately. 


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Sterility and future childbearing potential for males and females: Chemotherapy and/or 
radiation may affect fertility.  Male subjects may become sterile (unable to produce sperm).  
Female subjects may find that their menstrual cycle becomes irregular or stops 
permanently.  However, this does not mean that you cannot become pregnant, and you 
must use some effective method of birth control.  Damage to reproductive tissue may result 
in birth defects or permanent inability to father a child or become pregnant.  You should 
discuss these risks and options in detail with your doctor and the investigator before 
entering this study. 
 
OTHER RISKS 
 
There is small risk that an unauthorized person could find out which data are yours. Your 
transplant center and the Center for International Blood & Marrow Transplant Research 
(CIBMTR) will take every precaution to make sure that this does not happen. Your data will 
only be labeled with a number code. 
 
As with any research study, there might be side effects that are unknown at this time.  You 
will be monitored for the occurrence of side effects and should report any unusual events to 
the study staff.   
 
9. Possible Benefits to Being in the Study 
It is not known if you will benefit from participating in this study.  The knowledge gained from 
this study may help future patients who have a stem cell transplant using a mismatched 
unrelated donor (MMUD). 
 
10.  Alternatives to Participation 
Participation in this study is voluntary. You do not have to be in this study.  Your choice will 
not affect current or future health care you receive at this institution.  Before you decide to 
be in this study, you and the medical staff will discuss other options available to you. Your 
other choices may include: 
• 
Treatment with other drugs, radiation, or a combination of drugs and radiation 
without a transplant. 
• 
A bone marrow, blood stem cell, or cord blood transplant that is not part of this study. 
• 
Participation in another study. 
• 
No treatment at this time.  
 
Talk to your study doctor about your choices before you decide if you will take part in this 
study. 
 
11.  Cost of Participating in the Study 
You will not be responsible for any additional costs related to study procedures. Your 
participation in this study should not result in any costs other than those associated with the 
treatment of your disease. Some tests and procedures that are provided as part of regular 
care will not be paid for by the study sponsor. You or your insurance carrier will be charged 
or held responsible for the costs of that care. Some insurance companies or government 
health care programs may limit what they will pay for certain routine services that are 
performed in a research study, in which case, you may be responsible. For questions about 
your costs, financial responsibilities, and/or medical insurance coverage for your transplant 
and this study, please contact [Enter Transplant Center financial counselor name] at [Enter 
Transplant Center financial counselor].   


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For more information on clinical trials and insurance coverage, you can visit the National 
Cancer Institute’s Web site at http://www.cancer.gov/clinicaltrials/learningabout.  You can 
print a copy of the “Clinical Trials and Insurance Coverage” information from this web site.  
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask 
them to send you a free copy. 
 
12.  Reimbursement for Participating in the Study 
You will not be paid for your participation in this research study. You will not receive 
compensation or reimbursement for any extra expenses (travel, meals, etc.) you may incur 
through your participation on this trial. 
 
13.  In the Event of Injury While Participating in the Study 
If you are injured or become ill while taking part in this study, medical care will be provided 
at this center. If you think you may have experienced a research-related injury please 
contact your doctor, or one of the people listed at the top of this form. No funds have been 
set aside to pay you if you are injured. You or your insurance company will be charged for 
ongoing medical care and/or hospitalization. 
 
You do not give up any legal rights by signing this form. 
 
14.  Protection of Your Privacy and Confidentiality of Your Research Records 
Your participation in this research study will be kept private and confidential. Your medical 
information including demographic information (such as race and ethnicity, gender and 
household income) will be kept private and confidential. [Enter Transplant Center name] and 
the organizations listed below will not disclose your participation by any means of 
communication to any person or organization, except by your written request, or permission, 
or unless required by federal, state or local laws, or by a regulatory agency. 
 
Individuals authorized by the organizations below may request access to your research and 
medical records for inspections or audits.  In agreeing to participate, you consent to such 
inspections and to copying of excerpts from these records, if required by their authorized 
representatives. 
 
a. [Enter Transplant Center name] 
b. Institutional Review Boards (IRBs) responsible for this study 
c. National Marrow Donor Program (NMDP) 
d. Center for International Blood and Marrow Transplant Research (CIBMTR) 
e. CIBMTR Data and Safety Monitoring Board (DSMB), not part of [Enter Transplant 
Center name] 
f. 
Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins (HIV-positive patients 
only) 
 
Scientific and medical findings resulting from a study may be presented at meetings and 
published so that the information can be useful to others. You will not be identified in these 
presentations or publications. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most, the 
Web site will include a summary of the results.  You can search this Web site at any time. 
 
15.  Voluntary Participation in and Withdrawal from the Study 


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It is up to you if you want to participate in this study.  If you choose not to participate in this 
study, this decision will not affect your right or access to health care or any other services 
that you are entitled to receive.   
 
If you decide to participate, you may withdraw at any time. There will be no penalties if you 
withdraw from the study.  You will not lose any benefits to which you are entitled, and you 
will continue to receive medical care.    
 
If you choose to withdraw from the study, please tell [Enter Transplant Center PI name] at 
[Enter Transplant Center PI phone number].   
 
 
[Enter name of Transplant Center Principal Investigator, the Sponsor, the Institutional 
Review Board may stop the study at any time. The investigator(s), your doctor, or the 
Sponsor may remove you from the study at any time without your permission.   
 
It may be necessary to stop taking part in this study if: 
• 
Your condition does not change or gets worse. 
• 
You are not able to follow the study requirements. 
• 
The research study is no longer safe for you. 
• 
Another treatment may be more helpful. 
• 
The study stops for safety reasons. 
• 
[Enter Transplant Center name] is no longer taking part in the study 
 
If you withdraw or you are removed from the study for any reason, the study doctor may ask 
to continue to follow you in order to monitor your safety. 
 
Even if you leave the study, the information collected from your participation will be included in 
the study results, unless you specifically ask that it not be included. 
You will be informed of any new findings which may affect your health, welfare, or 
willingness to stay on the study.   
 
16.  Questions or Concerns about the study 
If you have questions, concerns or complaints about this study, please contact:  
[Enter Transplant Center study contact name] at [Enter Transplant Center study contact phone 
number]. 
 
If you have questions or concerns about your rights as a research subject or about potential 
risks and injuries, please contact: [Enter Transplant Center Research Subjects Protection Office 
contact name] at [Enter Transplant Center Research Subjects Protection Office contact phone 
number]. 
 
If you wish to contact an independent third party not connected with this study about problems, 
concerns, questions, information, or input, please contact a Patient Services Coordinator with 
the Be the Match Patient Services at 1-888-999-6743 or patientinfo@nmdp.org.   
[Enter Transplant Center office of research subject advocacy contact information]. 
 
You will be given a copy of this consent form for your records. 
 
 
 


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Subject’s Statement of Consent 
I have been informed about this research study’s purpose, procedures, possible benefits and 
risks. I have been given a chance to ask questions and have had them answered to my 
satisfaction. I understand that I can ask more questions at any time. 
 
I voluntarily agree to participate in this study. 
 
By signing this consent form as a subject in a research study, I have not given up any of the 
legal rights which I otherwise would have. 
 
 _____________________________________  _____________________________  
Signature of Subject 
Date 
 
 
 _____________________________________  
Print Name of Subject 
 
 
Parent/Legally Authorized Representative Consent 
 
 
 
 _____________________________________________   _____________________________  
 Signature of Parent/Legally Authorized Representative 
Date 
 
 
 _____________________________________________  
 Print Name of Parent/Legally Authorized Representative    
 
 
 
 
 
 
 
 
 
Certification of Counseling Healthcare Professional 
 
I certify that the nature and purpose, the potential benefits, and possible risks associated with 
participation in this research study have been explained to the above individual and that any 
questions about this information have been answered. 
 
 _____________________________________________   _____________________________  
 Signature of Counseling Healthcare Professional               Date 
 
 
 _____________________________________________   
 
 Print Name of Counseling Healthcare Professional 
 
 
 
 
 
 
 
 
 
NATIONAL MARROW DONOR 
PROGRAM® 
INSTITUTIONAL REVIEW BOARD 
CONSENT FORM APPROVAL DATE: 
AUGUST 16, 2018 
Do not sign this form after the 
Expiration date of: August 15, 2019 
 


15-MMUD study consent v2.1                                     NMDP IRB Approved August 16, 2018 through August 15, 2019 
IRB-2016-0365 
Page 14 of 14 
 
 
Use of an Interpreter: Complete if an interpreter was used to obtain consent from the 
subject/parent/legally authorized representative 
Subject/parent/legally authorized representative who is not fluent in English:  
 An oral translation of this document was administered to the subject/parent/legally 
authorized representative in ____________________ [language understood by 
subject/parent/legally authorized representative] by an individual proficient in English and 
____________________ [language understood by subject/parent/legally authorized 
representative].  See attached short form for documentation. 
Subject/parent/legally authorized representative who is deaf or hard-of-hearing requiring sign 
language communication:  
 A sign language interpretation of this document was administered to the 
subject/parent/legally authorized representative by an individual proficient in sign language. 
Print name of Interpreter:  ________________________  Date: ____________ 
 
Signature of Interpreter: ________________________________ 
 
English-speaking subject/parent/legally authorized representative who is illiterate 
and/or legally blind 
I attest to the following: 
 Consent document was read to the subject/parent/legally authorized representative.  
 Subject/parent/legally authorized representative can understand and comprehend spoken 
English, but is physically unable to talk or write. 
 Subject/parent/legally authorized representative is competent (i.e. able to understand the 
concepts of the study and evaluate the risk and benefit of being in the study when it is 
explained verbally) and able to indicate approval or disapproval for study participation by 
other means. 
Method used for communication with subject/parent/legally authorized representative:  
______________________________________________________ 
Specific means by which the subject/parent/legally authorized representative communicated 
agreement to participate in the study: _________________________________________ 
Print name of Witness*:  __________________________________   Date: ____________ 
Signature of Witness: ___________________________________     Time: ____________ 
*A witness is a person who is independent from the trial or a member of staff who not involved in obtaining consent.