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

NCT02793544 | Completed Phase 2 Results DMC

• 1 other identifier: 15-MMUD
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 11

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.

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)

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  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 overall survival probability and 90% CI will be calculated by the Kaplan Meier product limit estimator.

  365 days post transplant

Secondary Outcomes (31)

• Progression-free Survival

  180 days and 365 days post-transplant

• Transplant-related Mortality

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

• Cumulative Incidence of Neutrophil Recovery

  100 days and 365 days post transplant

• Cumulative Incidence of Platelet Recovery

  100 days and 365 days post transplant

• Cumulative Incidence of Acute GVHD

  100 days post-transplant

Study Arms (4)

Regimen A (RIC: Flu/Cy/TBI)

ACTIVE COMPARATOR

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.

Drug: Fludarabine; Drug: Cyclophosphamide 14.5 mg/kg/day IV on Days -6, -5; Radiation: Total Body Irradiation (TBI) 200cGy on Day -1; Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Drug: Sirolimus; Drug: Mycophenolate mofetil; Drug: G-CSF; Drug: Pre-HCT Mesna on Days -6 and -5; Drug: Post-HCT Mesna

Regimen B 2a (FIC: Bu/Cy)

ACTIVE COMPARATOR

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.

Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; Drug: Busulfan; Drug: Cyclophosphamide 50mg/kg/day IV on Days -2,-1; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Drug: Sirolimus; Drug: Mycophenolate mofetil; Drug: G-CSF; Drug: Pre-HCT Mesna on Days -2 and -1; Drug: Post-HCT Mesna

Regimen B 2b (FIC: Bu/Flu)

ACTIVE COMPARATOR

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.

Drug: Fludarabine; Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; Drug: Busulfan; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Drug: Sirolimus; Drug: Mycophenolate mofetil; Drug: G-CSF; Drug: Post-HCT Mesna

Regimen C (FIC: Cy/TBI)

ACTIVE COMPARATOR

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.

Procedure: Infusion of non-T-cell depleted bone marrow on Day 0; Drug: Cyclophosphamide 50mg/kg/day IV on Days -5,-4; Radiation: Total Body Irradiation (TBI) 200cGy twice a day on Days -3, -2, -1; Drug: Post-HCT Cyclophosphamide 50mg/kg IV on Day+3, +4; Drug: Sirolimus; Drug: Mycophenolate mofetil; Drug: G-CSF; Drug: Pre-HCT Mesna on Days -5 and -4; Drug: Post-HCT Mesna

Interventions

Fludarabine DRUG

* 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.

Also known as: Fludara®

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2b (FIC: Bu/Flu)

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

* 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.

Also known as: Cytoxan®

Regimen A (RIC: Flu/Cy/TBI)

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

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

Regimen A (RIC: Flu/Cy/TBI)

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

* 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.

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu); Regimen C (FIC: Cy/TBI)

Busulfan DRUG

* 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)

Also known as: Busulfex®

Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu)

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

* 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.

Also known as: Cytoxan®

Regimen B 2a (FIC: Bu/Cy)

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

* 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.

Also known as: Cytoxan®

Regimen C (FIC: Cy/TBI)

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

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

Regimen C (FIC: Cy/TBI)

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

* 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.

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu); Regimen C (FIC: Cy/TBI)

Sirolimus DRUG

* 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.

Also known as: rapamycin, Rapamune®

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu); Regimen C (FIC: Cy/TBI)

Mycophenolate mofetil DRUG

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.

Also known as: MMF, Cellcept®

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu); Regimen C (FIC: Cy/TBI)

G-CSF DRUG

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.

Also known as: filgrastim

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu); Regimen C (FIC: Cy/TBI)

Pre-HCT Mesna on Days -6 and -5 DRUG

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.

Regimen A (RIC: Flu/Cy/TBI)

Pre-HCT Mesna on Days -2 and -1 DRUG

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.

Regimen B 2a (FIC: Bu/Cy)

Pre-HCT Mesna on Days -5 and -4 DRUG

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.

Regimen C (FIC: Cy/TBI)

Post-HCT Mesna DRUG

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.

Regimen A (RIC: Flu/Cy/TBI); Regimen B 2a (FIC: Bu/Cy); Regimen B 2b (FIC: Bu/Flu); Regimen C (FIC: Cy/TBI)

Eligibility Criteria

• Age: 15 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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))

You may not qualify if:

• 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

Sponsors & Collaborators

• Center for International Blood and Marrow Transplant Research: lead
• National Marrow Donor Program: collaborator

Study Sites (11)

Shands HealthCare & University of Florida

Gainesville, Florida, 32610, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

University of Maryland Greenebaum Cancer Center

Baltimore, Maryland, 21201, United States

Location

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21287, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center - Adults

New York, New York, 10065, United States

Location

University of North Carolina Hospitals

Chapel Hill, North Carolina, 27599, United States

Location

Ohio State Medical Center, James Cancer Center

Columbus, Ohio, 43210, United States

Location

Virginia Commonwealth University Massey Cancer Center Bone Marrow Transplant Program

Richmond, Virginia, 23298, United States

Location

Froedtert Memorial Lutheran Hospital

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (1)

• 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.

  PMID: 33905264 DERIVED

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Lymphocytic, Chronic, B-Cell; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Leukemia, Biphenotypic, Acute

Interventions

fludarabine; fludarabine phosphate; Cyclophosphamide; Whole-Body Irradiation; Busulfan; Sirolimus; Mycophenolic Acid; Granulocyte Colony-Stimulating Factor; Filgrastim

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myeloid

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Radiotherapy; Therapeutics; Investigative Techniques; Butylene Glycols; Glycols; Alcohols; Mesylates; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfonic Acids; Sulfur Acids; Sulfur Compounds; Macrolides; Lactones; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Steve Spellman
• Organization: National Marrow Donor Program/BeTheMatch

sspellma@nmdp.org

763-406-8334

Study Officials

• Javier Bolaños Meade, MD

  Sidney Kimmel Comprehensive Cancer Centre at Johns Hopkins

  STUDY CHAIR

• Bronwen E. Shaw, MD, PhD

  CIBMTR/Medical College of Wisconsin

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2016
• First Posted: June 8, 2016
• Study Start: December 1, 2016
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: August 6, 2025
• Results First Posted: August 6, 2025

Record last verified: 2025-07

Locations

US (11)