Double Cord Versus Haploidentical (BMT CTN 1101)

Phase 3

Completed

Conditions: Acute Myelogenous Leukemia
Burkitt's Lymphoma
Acute Lymphocytic Leukemia
Mantle Cell Lymphoma
Follicular Lymphoma
Hodgkin Lymphoma
Non-Hodgkin Lymphoma

Interventions: Biological: Haploidentical Bone Marrow Transplant
Biological: Double Umbilical Cord Blood Transplant

Registration Number: NCT01597778

Lead Sponsor: Medical College of Wisconsin

Brief Summary: Hematopoietic cell transplants (HCT)are one treatment option for people with leukemia or lymphoma. Family members,unrelated donors or banked umbilical cordblood units with similar tissue type can be used for HCT. This study will compare the effectiveness of two new types of bone marrow transplants in people with leukemia or lymphoma: one that uses bone marrow donated from family members with only partially matched bone marrow; and, one that uses two partially matched cord blood units.

Detailed Description: Reduced intensity conditioning (RIC) blood or marrow transplantation (BMT) has allowed older and less clinically fit patients to receive potentially curative treatment with allogeneic HCT for high risk or advanced hematological malignancies. Patients lacking an HLA-matched sibling may receive a graft from a suitably HLA-matched unrelated donor. However, up to a third of patients will not have an HLA-matched sibling or a suitably matched adult unrelated donor (i.e., no more than a mismatch at a single locus). Even when a suitably matched unrelated donor is identified, data from the National Marrow Donor Program (NMDP) indicate that a median of four months is required to complete searches that result in transplantation; thus, some number of patients succumb to their disease while awaiting identification and evaluation of a suitably matched adult unrelated donor.

Single or dual center studies have shown that partially HLA-mismatched related bone marrow (haplo-BM) and unrelated double umbilical cord blood (dUCB) are valuable sources of donor cells for RIC HCT, thus extending this treatment modality to patients who lack other donors. In order to study the reproducibility, and thus, the wider applicability of these two alternative donor strategies, The Blood and Marrow Transplantation Clinical Trials Network (BMT CTN) conducted two parallel multicenter prospective Phase II clinical trials. These two studies evaluated the safety and efficacy of related haplo-BM (BMT CTN 0603) and dUCB (BMT CTN 0604) transplantation after RIC. Both of these alternative donor approaches produced early results similar to that reported with unrelated donor, and even HLA-matched sibling, HCT. These data demonstrate not only the efficacy of both of these approaches, but also that both can be safely exported from the single center setting. Both haplo-BM and dUCB grafts can be obtained rapidly for greater than 90% of patients lacking an HLA-matched donor. This study will test the hypothesis that progression free survival at two years after RIC haplo-BM transplantation is similar to the progression free survival after RIC dUCB transplantation.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 368

Inclusion Criteria

Patients 18 to 70 years old
Patients must have available both: a)One or more potential related mismatched donors (biologic parent(s) or siblings (full or half) or children). At least low resolution DNA based human leukocyte antigen (HLA) typing at HLA-A, -B, and -DRB1 for potential haploidentical sibling donors is required. b)At least two potential umbilical cord blood units identified. Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x 10^7/kg. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA-A, HLA-B (at low resolution using DNA based typing) and HLA-DRB1 (at high resolution using DNA based typing). Confirmatory typing is not required for randomization.
Acute Lymphoblastic Leukemia (ALL) in first complete remission (CR1) that is NOT considered favorable-risk as defined by the presence of at least one of the following: Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), other Mixed Lineage Leukemia (MLL) rearrangements; White blood cell counts of greater than 30,000/mcL (B-ALL) or greater than 100,000/mcL (T-ALL)at diagnosis; Recipient age older than 30 years at diagnosis; Time to CR greater than 4 weeks
Acute Myelogeneous Leukemia (AML) in CR1 that is NOT considered as favorable-risk. Favorable risk is defined as having one of the following: t(8.21) without CKIT mutation, inv(16) without CKIT mutation or t(16;16), normal karyotype with mutated NPM1 and not FLT-ITD, normal karyotype with double mutated CEBPA, Acute promyelocytic leukemia (APL) in first molecular remission at end of consolidation
Acute Leukemias in 2nd or subsequent CR
Biphenotypic/Undifferentiated/Prolymphocytic Leukemias in first or subsequent CR, adult T-cell leukemia/lymphoma in first or subsequent CR
Burkitt's lymphoma: second or subsequent CR
Lymphoma fulfilling the following criteria: Chemotherapy-sensitive (at least stable disease lymphomas that have failed at least 1 prior regimen of multi-agent chemotherapy and are INELIGIBLE for an autologous transplant. Patients with chronic lymphocytic leukemia (CLL) are not eligible regardless of disease status.
Performance status: Karnofsky score greater than or equal to 70%.

Additional Patient Inclusion Criteria for Conditioning:

Patients with Adequate Physical Function as Measured by: a. Cardiac: Left ventricular ejection fraction at rest must be greater than or equal to 40%, or shortening fraction less than 25%; b. Hepatic: Bilirubin less than or equal to 2.5 mg/dL, except for patients with Gilbert's syndrome or hemolysis. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and Alkaline Phosphatase less than 5 x upper limit of normal; c. Renal: Serum creatinine within normal range, or if serum creatinine outside normal range, then renal function (measured or estimated creatinine clearance or GFR)greater than 40 mL/min/1.73m^; d. Pulmonary: Diffusing capacity of the lung for carbon monoxide (DLCO) (corrected for hemoglobin), forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) greater than 50% predicted;
Additional Patient Inclusion Criteria for Patients Assigned to Haploidentical BM Arm: Patients must be HLA typed at high resolution using DNA based typing at the following HLA-loci: HLA-A, -B, -C and DRB1 and have available a related haploidentical BM donor with 2, 3, or 4 HLA-mismatches. A unidirectional mismatch in either the graft versus host or host versus graft direction is considered a mismatch. The donor and recipient must be HLA identical for at least one antigen (using high resolution DNA based typing) at the following genetic loci: HLA-A, HLA-B, HLA-C, and HLA-DRB1. 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.
Additional Patient Inclusion Criteria for Patients Assigned to Double Umbilical Cord Blood Arm:
1. Patients must have available two UCB units fulfilling the following criteria:
  1. Each unit must have a minimum of 1.5 x 10^7/kg pre-cryopreserved total nucleated cell dose. For non-red blood cell depleted units, the minimum pre-cryopreserved total nucleated cell dose of each unit must be at least 2.0 x10^7/kg.
  2. Units must be HLA matched at a minimum of 4/6 to the recipient at HLA -A, HLA-B (at low resolution using DNA based typing), and HLA -DRB1 (at high resolution using DNA based typing).
  3. Additional graft selection criteria specified in section 2.5
2. Patients must have received at least one cycle of the cytotoxic chemotherapy regimens (or regimen of similar intensity) listed in Appendix D within 3 months of enrollment (measured from the start date of chemotherapy) OR have had an autologous transplant within 24 months of enrollment OR receive 300 cGy as part of the preparative regimen

Exclusion Criteria

Patients with suitably matched related or unrelated donor, as defined per institutional practice.
Recipients of prior autologous hematopoietic stem cell transplantation are ineligible if disease recurrence occurred less than 6 months from their autologous stem cell transplant.
Current uncontrolled bacterial, viral or fungal infection (currently taking medication with evidence of progression of clinical symptoms or radiologic findings).
Prior allogeneic HCT.
Patients with history of primary idiopathic myelofibrosis or any severe marrow fibrosis.
Planned use of prophylactic donor lymphocyte infusion (DLI) therapy.
Anti-donor HLA antibodies.

Additional exclusion criteria:

Pregnancy or breast-feeding.
Evidence of HIV infection or known HIV positive serology.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Haploidentical Bone Marrow Transplant	Haploidentical Bone Marrow Transplant	Participants will receive haploidentical bone marrow transplant using a reduced intensity conditioning regimen.
Double Umbilical Cord Blood Transplant	Double Umbilical Cord Blood Transplant	Participants will receive a double umbilical cord blood transplant using a reduced intensity conditioning regimen.

Primary Outcome Measures

Name	Time	Method
Percentage of Participants With Progression Free Survival (PFS)	Year 2	The primary endpoint is PFS at 2 years post-randomization. Death or disease relapse/progression will be considered as events. The time to event is defined as the time interval from randomization to relapse/progression, to death or to last follow-up, whichever comes first. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Neutrophil Recovery	Day 56	Neutrophil recovery is defined as achieving an absolute neutrophil count greater than or equal to 500/mm\^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery.
Hospital Admission and Length of Stay	Month 6	Total Time Alive and Not Hospitalized within 6 Months Post Randomization
Percentage of Participants With PFS by Treatment Arms in Subgroups	Year 2	Participants' primary diagnosis was categorized into two large groups: leukemia versus lymphoma. Age was dichotomized into two large groups: age \<= 59 versus age \> 59. The Kaplan-Meier estimate for PFS at 2 years post-randomization are provided for each subgroup.
Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD)	Day 180	The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined.
Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD)	Year 2	The cumulative incidence of cGVHD from the time of transplant will be determined. Data were collected directly from providers and chart review according to the recommendations of the NIH Consensus Conference.
Percentage of Participants With Overall Survival	Year 2	Overall survival is defined as the time interval between date of randomization and death from any cause or for surviving patients, to last follow-up. The time interval between date of transplant and death from any cause or for surviving patients, to last follow-up are also analyzed.
Percentage of Participants With Relapse/Progression	Year 1, year 2	Incidence of relapse/progression will be estimated using cumulative incidence function, treating death in remission as a competing risk. Relapse is defined by either morphological or cytogenetic evidence of acute leukemia consistent with pre-transplant features, or radiologic evidence of progressive lymphoma. When in doubt, the diagnosis of recurrent or progressive lymphoma should be documented by tissue biopsy. Minimal residual disease will not be considered evidence of relapse, however, minimal residual disease that progresses will be considered as relapse and the date of relapse will be the date of detection of minimal residual disease that prompted an intervention by the treating physician. Finally, institution of any therapy to treat persistent, progressive or relapsed disease, including withdrawal of immunosuppressive therapy or DLI, will be considered evidence of relapse/progression regardless of whether the criteria described above are met.
Toxicities	Day 28, Day 56, Day 180, 1 year, and 2 years	They are all Grade ≥ 3 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.
Participants With Primary Graft Failure	Day 56	Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56.
Percentage of Participants With Platelet Recovery	Day 100	Platelet recovery is defined by two different metrics as the first day of a sustained platelet count greater than 20,000/mm\^3 or greater than 50,000/mm\^3 with no platelet transfusions in the preceding seven days. The first day of the sustained platelet count will be designated the day of platelet engraftment.
Percentage of Participants With Secondary Graft Failure	Year 2	Secondary graft failure is defined as initial donor chimerism ≥ 5% declining to \< 5% on subsequent measurements with time to secondary graft failure beginning at the first day of primary engraftment.
Percentage of Participants With Treatment-related Mortality (TRM)	Day 100, Day 180, Year 1, and Year 2	The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence.
Participants With Infections	Up to 2 years	All Grade 2 and 3 infections will be reported. Grade 1 CMV infections through Day 56 will also be reported.

Trial Locations

Locations (39): Stony Brook University Medical Center
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Stony Brook, New York, United States
Mt. Sinai Medical Center
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New York, New York, United States
Roswell Park Cancer Center
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Buffalo, New York, United States
Memorial Sloan Kettering Cancer Center
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New York, New York, United States
West Virginia University
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Morgantown, West Virginia, United States
Penn State College of Medicine - The Milton S. Hershey Medical Center
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Hershey, Pennsylvania, United States
University of California at Los Angeles
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Los Angeles, California, United States
Emory University
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Atlanta, Georgia, United States
BMT Program at Northside Hospital
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Atlanta, Georgia, United States
Johns Hopkins University
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Baltimore, Maryland, United States
DFCI Brigham & Women's Hospital
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Boston, Massachusetts, United States
Univeristy of Minnesota
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Minneapolis, Minnesota, United States
Duke University Medical Center
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Durham, North Carolina, United States
University Hospitals of Cleveland, Case Western
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Cleveland, Ohio, United States
Cleveland Clinic Foundation
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Cleveland, Ohio, United States
Ohio State / Arthur G. James Cancer Hospital
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Columbus, Ohio, United States
University of Pennsylvania Cancer Center
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Philadelphia, Pennsylvania, United States
Univesity of Texas, MD Anderson CRC
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Houston, Texas, United States
Texas Transplant Institute
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San Antonio, Texas, United States
Fred Hutchinson Cancer Research Center
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Seattle, Washington, United States
Stanford Hospital and Clinics
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Stanford, California, United States
DFCI Massachustts General Hospital
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Boston, Massachusetts, United States
Jewish Hospital BMT Program
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Cincinnati, Ohio, United States
City of Hope National Medical Center
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Duarte, California, United States
University of Rochester Medical Center
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Rochester, New York, United States
University of Kansas Hospital
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Kansas City, Kansas, United States
University of Alabama at Birmingham
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Birmingham, Alabama, United States
Arizona Cancer Center
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Phoenix, Arizona, United States
University of Florida College of Medicine (Shands)
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Gainesville, Florida, United States
Florida Hospital Cancer Institute
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Orlando, Florida, United States
Karmanos Cancer Institute/BMT
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Detroit, Michigan, United States
University of North Carolina Hospital at Chapel Hill
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Chapel Hill, North Carolina, United States
Vanderbilt University Medical Center
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Nashville, Tennessee, United States
Virginia Commonwealth University
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Richmond, Virginia, United States
Medical College of Wisconsin
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Milwaukee, Wisconsin, United States
Mayo Clinic Rochester
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Rochester, Minnesota, United States
Medical University of South Carolina
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Charleston, South Carolina, United States
University of Michigan Medical Center
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Ann Arbor, Michigan, United States
University of Oklahoma Medical Center
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Oklahoma City, Oklahoma, United States