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HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

Primary Purpose

Myelodysplastic Syndrome (MDS), Chronic Lymphocytic Leukemia (CLL), Chemotherapy-sensitive Lymphoma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Fludarabine

Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5

Total Body Irradiation (TBI) 200cGy on Day -1

Infusion of non-T-cell depleted bone marrow on Day 0

Busulfan

Cyclophosphamide 50mg/kg/day IV on Days -2,-1

Cyclophosphamide 50mg/kg/day IV on Days -5,-4

Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1

Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4

Sirolimus

Mycophenolate mofetil

G-CSF

Pre-HCT Mesna on Days -6 and -5

Pre-HCT Mesna on Days -2 and -1

Pre-HCT Mesna on Days -5 and -4

Post-HCT Mesna

About this trial

This is an interventional treatment trial for Myelodysplastic Syndrome (MDS)

Eligibility Criteria

15 Years - 70 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age ≥ 15 years and < 71 years at the time of signing the informed consent form
Partially HLA-mismatched unrelated donor: 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
Product planned for infusion is bone marrow
Disease and disease status:
1. Acute Leukemias or T lymphoblastic lymphoma in 1st or subsequent complete remission (CR): Acute lymphoblastic leukemia (ALL)/T lymphoblastic lymphoma; acute myelogenous leukemia (AML); acute biphenotypic leukemia (ABL); acute undifferentiated leukemia (AUL)
2. Myelodysplastic Syndrome (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 International Prognostic Scoring System (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
3. Chronic Lymphocytic Leukemia (CLL) in CR if RIC is to be used; in CR or partial response (PR) if 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
Performance status: Karnofsky or Lansky score ≥ 60% (Appendix A)
Adequate organ function defined as:
1. Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), or left ventricular shortening fraction (LVFS) ≥ 25%
2. Pulmonary: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital capacity (FVC) ≥ 50% predicted by pulmonary function tests (PFTs)
3. Hepatic: total bilirubin ≤ 2.5 mg/dL, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 5 x upper limit of (ULN) (unless disease related)
4. Renal: serum creatinine (SCr) within normal range for age (see table 2.3). If SCr is outside normal range for age, creatinine clearance (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))
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.
Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive), and a hematologic malignancy who meets all other eligibility requirements must:
1. Receive only RIC regimen (i.e. Regimen A)
2. Be willing to comply with effective antiretroviral therapy (ARV)
3. Have achieved a sustained virologic response for 12 weeks after cessation of hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C)

Exclusion Criteria:

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.
Autologous HCT < 3 months prior to the time of signing the informed consent form
Females who are breast-feeding or pregnant
HIV-positive subjects:
1. 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).
2. 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).
3. May not be currently prescribed ritonavir, cobacistat and/or zidovudine
Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
Prior allogeneic HCT
History of primary idiopathic myelofibrosis
MDS subjects may not receive RIC and must be < 50 years of age at the time of signing the informed consent form

Sites / Locations

Shands HealthCare & University of Florida
University of Miami
H. Lee Moffitt Cancer Center and Research Institute
University of Maryland Greenebaum Cancer Center
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Karmanos Cancer Institute
Memorial Sloan Kettering Cancer Center - Adults
University of North Carolina Hospitals
Ohio State Medical Center, James Cancer Center
Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program
Froedtert Memorial Lutheran Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Arm Label

Regimen A (RIC: Flu/Cy/TBI)

Regimen B 2a (FIC: Bu/Cy)

Regimen B 2b (FIC: Bu/Flu)

Regimen C (FIC: Cy/TBI)

Arm Description

Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5 Total Body Irradiation (TBI) 200cGy on Day -1 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.

Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) Cyclophosphamide 50mg/kg/day IV on Days -2,-1 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.

Busulfan ≥ 9mg/kg total dose on Days -6, -5, -4, -3 (IV or PO) Fludarabine 30 mg/m2/day IV on Days -6, -5, -4, -3, -2 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.

Cyclophosphamide 50mg/kg/day IV on Days -5,-4 Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1 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.

Outcomes

Primary Outcome Measures

Overall Survival

Secondary Outcome Measures

Progression-free survival

Transplant-related mortality

Cumulative incidence of neutrophil recovery

Cumulative incidence of platelet recovery

Cumulative incidence of primary graft failure

Donor Chimerism

Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted)

Peripheral blood chimerism

The percentage of subjects with peripheral blood (unsorted) chimerism>95%

Cumulative incidence of acute GVHD

Cumulative incidence of chronic GVHD

Cumulative incidences of viral reactivations and infections

Cumulative incidence of relapse/progression

Cumulative incidences of thrombotic microangiopathy (TMA) and hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS)

Proportion of subjects proceeding to transplant

Donor Selection Characteristics

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

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

Full Information

NCT ID

NCT02793544

First Posted

May 31, 2016

Last Updated

November 30, 2020

Sponsor

Center for International Blood and Marrow Transplant Research

Collaborators

National Marrow Donor Program

1. Study Identification

Unique Protocol Identification Number

NCT02793544

Brief Title

HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

Official Title

A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide for Patients With Hematologic Malignancies

Study Type

Interventional

2. Study Status

Record Verification Date

November 2020

Overall Recruitment Status

Completed

Study Start Date

December 2016 (Actual)

Primary Completion Date

March 2020 (Actual)

Study Completion Date

March 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Center for International Blood and Marrow Transplant Research

Collaborators

National Marrow Donor Program

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

80 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Regimen A (RIC: Flu/Cy/TBI)

Arm Type

Active Comparator

Arm Description

Arm Title

Regimen B 2a (FIC: Bu/Cy)

Arm Type

Active Comparator

Arm Description

Arm Title

Regimen B 2b (FIC: Bu/Flu)

Arm Type

Active Comparator

Arm Description

Arm Title

Regimen C (FIC: Cy/TBI)

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Fludarabine

Other Intervention Name(s)

Fludara®

Intervention Description

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 Type

Drug

Intervention Name(s)

Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5

Other Intervention Name(s)

Cytoxan®

Intervention Description

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 Type

Radiation

Intervention Name(s)

Total Body Irradiation (TBI) 200cGy on Day -1

Intervention Description

200 cGy TBI is administered in a single fraction on Day -1. Radiation sources, dose rates, and shielding follow institutional practice.

Intervention Type

Procedure

Intervention Name(s)

Infusion of non-T-cell depleted bone marrow on Day 0

Intervention Description

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 Type

Drug

Intervention Name(s)

Busulfan

Other Intervention Name(s)

Busulfex®

Intervention Description

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 Type

Drug

Intervention Name(s)

Cyclophosphamide 50mg/kg/day IV on Days -2,-1

Other Intervention Name(s)

Cytoxan®

Intervention Description

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 Type

Drug

Intervention Name(s)

Cyclophosphamide 50mg/kg/day IV on Days -5,-4

Other Intervention Name(s)

Cytoxan®

Intervention Description

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 Type

Radiation

Intervention Name(s)

Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1

Intervention Description

200cGy TBI is administered in twice daily on Days -3, -2, and -1. Radiation sources, dose rates, and shielding follow institutional practice.

Intervention Type

Drug

Intervention Name(s)

Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4

Intervention Description

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 Type

Drug

Intervention Name(s)

Sirolimus

Other Intervention Name(s)

rapamycin, Rapamune®

Intervention Description

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 Type

Drug

Intervention Name(s)

Mycophenolate mofetil

Other Intervention Name(s)

MMF, Cellcept®

Intervention Description

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 Type

Drug

Intervention Name(s)

G-CSF

Other Intervention Name(s)

filgrastim

Intervention Description

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 Type

Drug

Intervention Name(s)

Pre-HCT Mesna on Days -6 and -5

Intervention Description

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 Type

Drug

Intervention Name(s)

Pre-HCT Mesna on Days -2 and -1

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Pre-HCT Mesna on Days -5 and -4

Intervention Description

Intervention Type

Drug

Intervention Name(s)

Post-HCT Mesna

Intervention Description

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.

Primary Outcome Measure Information:

Title

Overall Survival

Time Frame

1 year post transplant

Secondary Outcome Measure Information:

Title

Progression-free survival

Time Frame

180 days and 365 days post-transplant

Title

Transplant-related mortality

Time Frame

100 days, 180 days, and 365 days post-transplant

Title

Cumulative incidence of neutrophil recovery

Time Frame

1 year post transplant

Title

Cumulative incidence of platelet recovery

Time Frame

1 year post transplant

Title

Cumulative incidence of primary graft failure

Time Frame

56 days post-transplant

Title

Donor Chimerism

Description

Peripheral blood chimerism (% of donor chimerism) in whole blood (unsorted)

Time Frame

28 days, 56 days, 100 days, 180 days, and 365 days post-transplant

Title

Peripheral blood chimerism

Description

The percentage of subjects with peripheral blood (unsorted) chimerism>95%

Time Frame

56 days post-transplant

Title

Cumulative incidence of acute GVHD

Time Frame

100 days post-transplant

Title

Cumulative incidence of chronic GVHD

Time Frame

180 days and 365 days post-transplant

Title

Cumulative incidences of viral reactivations and infections

Time Frame

100 days, 180 days and 365 days post-transplant

Title

Cumulative incidence of relapse/progression

Time Frame

180 days and 365 days post-transplant

Title

Cumulative incidences of thrombotic microangiopathy (TMA) and hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS)

Time Frame

1 year post transplant

Title

Proportion of subjects proceeding to transplant

Time Frame

1 year post transplant

Title

Donor Selection Characteristics

Description

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 Frame

1 year post transplant

Title

Time from search to donor identification

Time Frame

1 year post transplant

Title

Subgroup analysis of HIV-positive subjects

Description

Time Frame

1 year post transplant

Title

Donor clonal hematopoiesis

Description

The proportion of subjects developing donor clonal hematopoiesis

Time Frame

100 days and 365 days post-transplant

10. Eligibility

Sex

All

Minimum Age & Unit of Time

15 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥ 15 years and < 71 years at the time of signing the informed consent form Partially HLA-mismatched unrelated donor: 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 Product planned for infusion is bone marrow Disease and disease status: Acute Leukemias or T lymphoblastic lymphoma in 1st or subsequent complete remission (CR): Acute lymphoblastic leukemia (ALL)/T lymphoblastic lymphoma; acute myelogenous leukemia (AML); acute biphenotypic leukemia (ABL); acute undifferentiated leukemia (AUL) Myelodysplastic Syndrome (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 International Prognostic Scoring System (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 Chronic Lymphocytic Leukemia (CLL) in CR if RIC is to be used; in CR or partial response (PR) if FIC is to be used Chronic myeloid leukemia (CML) in 1st or subsequent chronic phase characterized by <10% blasts in the blood or bone marrow. Chemotherapy-sensitive lymphoma in status other than 1st CR Performance status: Karnofsky or Lansky score ≥ 60% (Appendix A) Adequate organ function defined as: Cardiac: left ventricular ejection fraction (LVEF) at rest ≥ 35% (RIC cohort) or LVEF at rest ≥ 40% (FIC cohort), or left ventricular shortening fraction (LVFS) ≥ 25% Pulmonary: diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume (FEV1), forced vital capacity (FVC) ≥ 50% predicted by pulmonary function tests (PFTs) Hepatic: total bilirubin ≤ 2.5 mg/dL, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) < 5 x upper limit of (ULN) (unless disease related) Renal: serum creatinine (SCr) within normal range for age (see table 2.3). If SCr is outside normal range for age, creatinine clearance (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)) 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. Subjects with documentation of confirmed HIV-1 infection (i.e. HIV-positive), and a hematologic malignancy who meets all other eligibility requirements must: Receive only RIC regimen (i.e. Regimen A) Be willing to comply with effective antiretroviral therapy (ARV) Have achieved a sustained virologic response for 12 weeks after cessation of hepatitis C antiviral treatment (in HIV-positive subjects with hepatitis C) Exclusion Criteria: 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. Autologous HCT < 3 months prior to the time of signing the informed consent form Females who are breast-feeding or pregnant HIV-positive subjects: 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). 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). May not be currently prescribed ritonavir, cobacistat and/or zidovudine Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings) Prior allogeneic HCT History of primary idiopathic myelofibrosis MDS subjects may not receive RIC and must be < 50 years of age at the time of signing the informed consent form

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Javier Bolaños Meade, MD

Organizational Affiliation

Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins

Official's Role

Study Chair

First Name & Middle Initial & Last Name & Degree

Bronwen E. Shaw, MD, PhD

Organizational Affiliation

CIBMTR/Medical College of Wisconsin

Official's Role

Study Chair

Facility Information:

Facility Name

Shands HealthCare & University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Facility Name

University of Miami

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

H. Lee Moffitt Cancer Center and Research Institute

City

Tampa

State/Province

Florida

ZIP/Postal Code

33612

Country

United States

Facility Name

University of Maryland Greenebaum Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21201

Country

United States

Facility Name

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Karmanos Cancer Institute

City

Detroit

State/Province

Michigan

ZIP/Postal Code

48201

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center - Adults

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

University of North Carolina Hospitals

City

Chapel Hill

State/Province

North Carolina

ZIP/Postal Code

27599

Country

United States

Facility Name

Ohio State Medical Center, James Cancer Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43210

Country

United States

Facility Name

Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program

City

Richmond

State/Province

Virginia

ZIP/Postal Code

23298

Country

United States

Facility Name

Froedtert Memorial Lutheran Hospital

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

33905264

Citation

Shaw BE, Jimenez-Jimenez AM, Burns LJ, Logan BR, Khimani F, Shaffer BC, Shah NN, Mussetter A, Tang XY, McCarty JM, Alavi A, Farhadfar N, Jamieson K, Hardy NM, Choe H, Ambinder RF, Anasetti C, Perales MA, Spellman SR, Howard A, Komanduri KV, Luznik L, Norkin M, Pidala JA, Ratanatharathorn V, Confer DL, Devine SM, Horowitz MM, Bolanos-Meade J. National Marrow Donor Program-Sponsored Multicenter, Phase II Trial of HLA-Mismatched Unrelated Donor Bone Marrow Transplantation Using Post-Transplant Cyclophosphamide. J Clin Oncol. 2021 Jun 20;39(18):1971-1982. doi: 10.1200/JCO.20.03502. Epub 2021 Apr 27.

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HLA-Mismatched Unrelated Donor Bone Marrow Transplantation With Post-Transplantation Cyclophosphamide

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