Bone Marrow Transplant From Partially Matched Donors and Nonmyeloablative Conditioning for Blood Cancers (BMT CTN 0603)

A Multi-Center, Phase II Trial of Nonmyeloablative Conditioning (NST) and Transplantation of Partially HLA-Mismatched Bone Marrow From Related Donors for Patients With Hematologic Malignancies (BMT CTN #0603)

Bone marrow transplants are one treatment option for people with leukemia or lymphoma. Family members or unrelated donors with a similar type of bone marrow usually donate their bone marrow to the transplant patients. This study will evaluate the effectiveness of a new type of bone marrow transplant-one that uses lower doses of chemotherapy and bone marrow donated from family members with only partially matched bone marrow-in people with leukemia or lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma, Follicular; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia, Myeloid, Acute; Burkitt Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
• Intervention / Treatment: Biological: Haploidentical Bone Marrow Transplantation; Biological: GVHD prophylaxis

Detailed Description

Leukemia and lymphoma are types of blood cancers. Chemotherapy is a common treatment option for people with these types of cancers, but if the cancer does not respond well to chemotherapy, or if the cancer returns, a bone marrow transplant is another treatment option. In a bone marrow transplant procedure, healthy bone marrow is taken from a donor and transplanted into the patient. Bone marrow can be donated by a family member or an unrelated donor who has a similar type of bone marrow. Most bone marrow transplants are performed using a donor who is a perfect or close-to-perfect tissue match. However, for participants in this study, researchers have determined that a completely matched donor is unavailable within participants' families, and an unrelated donor match has not been found either. Participants do, however, have a family member who is a partial tissue match. Typically, people who are undergoing a bone marrow transplant receive high doses of chemotherapy before the transplant to prepare their bodies to accept the donor bone marrow. In this study, participants will undergo a new type of bone marrow transplant called a nonmyeloablative transplant, which is a reduced intensity method of transplantation that does not require high doses of chemotherapy. The purpose of the study is to examine the safety and effectiveness of a nonmyeloablative bone marrow transplant that uses partially matched bone marrow donated by a family member as a treatment option for people with leukemia or lymphoma.

This study will enroll people with leukemia or lymphoma who have a family member with a partial tissue match. Participants will be admitted to the hospital and will first receive a type of chemotherapy called fludarabine, which will be given intravenously for 5 days. In addition, another type of chemotherapy, cyclophosphamide, will be given intravenously on the first and second day. After 5 days, participants will receive a small dose of radiation. The next day, participants will undergo the bone marrow transplant. The third and fourth day after the transplant, participants will receive high doses of cyclophosphamide to help prevent two complications, graft rejection, which occurs when the body's immune system rejects the donor bone marrow, and graft-versus-host disease (GVHD), which is an attack by the donor cells on the body's normal tissues. On the fifth day after the transplant, participants will receive two additional medications, tacrolimus and mycophenolate mofetil (MMF), to help prevent GVHD; some participants may receive cyclosporine instead of tacrolimus. Participants will receive MMF for about 5 weeks and tacrolimus for about 6 months. Also beginning on the fifth day after the transplant, participants will receive daily injections of a growth factor called granulocyte-colony stimulating factor (G-CSF), which is a natural protein that increases the white blood cell count; G-CSF will be continued until a participant's white blood cell count is normal again.

Participants will remain in the hospital for approximately 2 to 3 months, but possibly longer if there are complications. While participants are in the hospital, blood samples will be collected regularly to evaluate the response and possible side effects to treatment, including GVHD. If necessary, participants will receive platelet and red blood cell transfusions. Follow-up study visits will occur 6 months and 1 year after the transplant. At Months 1, 2, 6, and 12 after the transplant, blood or bone marrow samples will be obtained. Study researchers will keep track of participants' medical condition through phone calls or mailings to participants and their doctors once a year for the rest of the participants' lives.

• Study Type: Interventional
• Enrollment (Actual): 55
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92093
      • University of California San Diego Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0277
      • University of Florida College of Medicine (Shands)
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Bone Marrow Transplant Group of Georgia, Northside Hospital
  • Hawaii
    • Honolulu, Hawaii, United States, 96826
      • Kapi'olani Medical Center for Women and Children, University of Hawaii
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, Greenbaum Cancer Center
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University/Sidney Kimmel Comprehensive Cancer Center (SKCCC)
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • DFCI, Massachusetts General Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute, Children's Hospital of Michigan
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University, Barnes Jewish Hospital
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Oregon Health & Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111-2442
      • Fox Chase, Temple University
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37232-8210
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Washington
    • Seattle, Washington, United States, 98109-1024
      • Fred Hutchinson Cancer Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Participants must be 21 to 70 years old; participants 1 to 21 years old are also eligible if they are ineligible for BMT CTN #0501 (NCT00412360)
• Donor must be at least 18 years of age
• Human leucocyte antigen (HLA) typing will be performed at high resolution (allele level) for the HLA-A, -B, Cw, DRB1, and -DQB1 loci. A minimum match of 5/10 is required. An unrelated donor search is not required for a person to be eligible for this study if the clinical situation dictates an urgent transplant. Clinical urgency is defined as 6 to 8 weeks from referral to transplant center or low likelihood of finding a matched, unrelated donor. The donor and recipient must be identical, as determined by high resolution typing, on at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DRB1, and HLA-DQB1. Fulfillment of this criterion shall be considered sufficient evidence that the donor and recipient share one HLA haplotype, and typing of additional family members is not required.
• Must have received cytotoxic chemotherapy within 3 months of the consent date (measured from the start date of chemotherapy)
• Acute leukemias (includes T lymphoblastic lymphoma) in the second or subsequent complete remission (CR)
• Burkitt's lymphoma in the second or subsequent CR
• Lymphoma

• Patients with adequate physical function as measured by the following:

  1. Heart: left ventricular ejection fraction at rest must be greater than or equal to 35%, or shortening fraction greater than 25%
  2. Liver: bilirubin less than or equal to 2.5 mg/dL and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase less than five times the upper limit of normal
  3. Kidney: serum creatinine within normal range for age, or if serum creatinine is outside the normal range for age, then kidney function (creatinine clearance or glomerular filtration rate (GFR) is greater than 40 mL/min/1.73m^2
  4. Pulmonary: forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and carbon monoxide diffusing capacity (DLCO) greater than 50% predicted (corrected for hemoglobin). If unable to perform pulmonary function tests, then oxygen (O2) saturation must be greater than 92% on room air.
  5. Performance status: Karnofsky/Lansky score greater than or equal to 60%

Exclusion Criteria:

• Have an HLA-matched, related, or 7 or 8/8 allele matched (HLA-A, -B, -Cw, -DRB1) related donor able to donate
• Had an autologous hematopoietic stem cell transplant in the 3 months before study entry
• Pregnant or breastfeeding
• Evidence of HIV infection or known HIV positive serology
• Current uncontrolled bacterial, viral, or fungal infection (i.e., currently taking medication with evidence of progression of clinical symptoms or radiologic findings)
• Prior allogeneic hematopoietic stem cell transplant
• History of primary idiopathic myelofibrosis

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Haploidentical Bone Marrow Transplant; Participants will receive a human leucocyte antigen (HLA) haploidentical bone marrow transplantation using a non-myeloablative preparative regimen, GVHD prophylaxis.

Biological: Haploidentical Bone Marrow Transplantation; The transplant preparative regimen is listed below. The - sign is the number of days before the transplant.; Fludarabine: 30 mg/m2 intravenously (IV) on Days -6, -5, -4, -3, and -2; Cyclophosphamide (Cy): 14.5 mg/kg IV on Days -6 and -5; Total body irradiation (TBI): 200 centigray (cGy) on Day -1 Day 0 is the day of the infusion of non-T-cell depleted bone marrow. The bone marrow will be obtained from haploidentical related donor.; Biological: GVHD prophylaxis; The GVHD prophylaxis regimen will consist of the following: Cy: 50 mg/kg IV on Days 3 and 4; Tacrolimus: (IV or orally) beginning on Day 5 with dose adjusted to maintain a level of 5 to 15 mg/mL; Mycophenolate mofetil (MMF): 15 mg/kg orally three times a day (TID) beginning on Day 5; maximum dose will be 1 g orally TID; Granulocyte-colony stimulating factor (G-CSF) 5 mcg/kg/day beginning on Day 5 until absolute neutrophil count (ANC) is greater than or equal to 1,000/mm^3 for 3 consecutive days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Overall Survival at 180 Days From the Time of Transplant	Measured at Month 6 and Year 1

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Donor Cell Engraftment	Marrow or Blood Sample. Donor cell engraftment is defined as donor chimerism ≥ 5% on Day ≥ 56 after transplantation. Chimerism should be evaluated on Days ~28, ~56, ~180, and ~365 after transplantation. Chimerism may be evaluated in whole blood or mononuclear fraction.	Measured at Day 56
Acute Graft-versus-host Disease (GVHD)		Measured at Day 100
Chronic GVHD		Measured at Year 1
Treatment-related Mortality (TRM)		Measured at 6 months and 1 year
Neutrophil Recovery	Cumulative incidence of neutrophil recovery >500/μL at day +56	Measured at Days 28, 56, 90, and 100
Primary Graft Failure	Primary graft failure is defined as < 5% donor chimerism on all measurements.	Measured at Day 67
Secondary Graft Failure	Secondary graft failure is defined as initial recovery followed by neutropenia with < 5% donor chimerism. If no chimerism assays were performed and absolute neutrophil count is < 500/mm3, then it will be counted as a secondary graft failure.	Measured at Day 100
Platelet Recovery	Platelet Recovery to 20K	Measured at Days 56, 90, and 100
Platelet Recovery	Platelet Recovery to 50K	Measured at Days 56, 90, and 100
Progression-free Survival	Progression-free survival is defined as the minimum time interval of the times to relapse/recurrence, to death or to last follow-up.	Measured at Year 1
Infections	Number of infections; infections will be reported by anatomic site, date of onset, organism and resolution, if any. Patients will be followed for infection for 1 year post-transplant.	Measured at Year 1

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: National Cancer Institute (NCI); National Heart, Lung, and Blood Institute (NHLBI); National Marrow Donor Program; Blood and Marrow Transplant Clinical Trials Network

Publications and helpful links

General Publications

• Brunstein CG, Fuchs EJ, Carter SL, Karanes C, Costa LJ, Wu J, Devine SM, Wingard JR, Aljitawi OS, Cutler CS, Jagasia MH, Ballen KK, Eapen M, O'Donnell PV; Blood and Marrow Transplant Clinical Trials Network. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011 Jul 14;118(2):282-8. doi: 10.1182/blood-2011-03-344853. Epub 2011 Apr 28.
• Eapen M, O'Donnell P, Brunstein CG, Wu J, Barowski K, Mendizabal A, Fuchs EJ. Mismatched related and unrelated donors for allogeneic hematopoietic cell transplantation for adults with hematologic malignancies. Biol Blood Marrow Transplant. 2014 Oct;20(10):1485-92. doi: 10.1016/j.bbmt.2014.05.015. Epub 2014 May 23.

Helpful Links

• National Marrow Donor Program
• Click here for the Blood and Marrow Transplant (BMT) Clinical Trials Network (CTN) Web site

Study record dates

Study Major Dates

• Study Start: October 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: February 20, 2009
• First Submitted That Met QC Criteria: February 20, 2009
• First Posted (Estimate): February 23, 2009

Study Record Updates

• Last Update Posted (Actual): January 4, 2023
• Last Update Submitted That Met QC Criteria: December 7, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Acute Myelogenous Leukemia; Acute Lymphoblastic Leukemia/Lymphoma; Mantel-Cell Lymphoma; Hematopoietic Transplant; Non-Myeloablative Transplant; Haplo-Identical Transplant
• Additional Relevant MeSH Terms: Virus Diseases; Infections; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; DNA Virus Infections; Tumor Virus Infections; Epstein-Barr Virus Infections; Herpesviridae Infections; Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Burkitt Lymphoma; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
• Other Study ID Numbers: BMTCTN0603; U01HL069294 (U.S. NIH Grant/Contract); 5U24CA076518 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Results will be published in a manuscript
• IPD Sharing Time Frame: Within 6 months of official study closure at participating sites.
• IPD Sharing Access Criteria: Available to the public.
• IPD Sharing Supporting Information Type: Study Protocol; Informed Consent Form (ICF)