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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
368
The conditioning regimen consists of: Fludarabine (Flu)30 mg/m2 IV Days -6, -5, -4, -3, -2 Cyclophosphamide (Cy) 14.5 mg/kg IV Days -6, -5 Total body irradiation (TBI) 200cGy Day -1 The GVHD prophylaxis regimen consists of: Cy 50 mg/kg IV Days 3, 4 Tacrolimus (IV or PO) beginning Day 5 Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day 5 until Day 35
The preparative regimen consists of: Fludarabine 40 mg/m2 IV Days -6, -5, -4,-3, -2 Cyclophosphamide 50 mg/kg IV Day -6 Total Body Irradiation (TBI) 200 cGy Day -1 for patients who have received cytotoxic chemotherapy within the 3 months of enrollment or an autologous transplant within 24 months of enrollment or 300 cGy Day -1 for patients who have not received cytotoxic chemotherapy within the 3 months of enrollment and who have not received an autologous transplant within 24 months of enrollment. The GVHD prophylaxis regimen consists of: Cyclosporine beginning Day -3 with dose adjusted to maintain a trough level of 200-400 ng/mL. Mycophenolate mofetil (MMF) 15 mg/kg po three times a day, maximum dose 1 g po TID beginning Day -3 until Day 35
University of Alabama at Birmingham
Birmingham, Alabama, United States
Arizona Cancer Center
Phoenix, Arizona, United States
City of Hope National Medical Center
Duarte, California, United States
University of California at Los Angeles
Los Angeles, California, United States
Stanford Hospital and Clinics
Stanford, California, United States
Percentage of Participants With Progression Free Survival (PFS)
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.
Time frame: Year 2
Percentage of Participants With PFS by Treatment Arms in Subgroups
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.
Time frame: Year 2
Percentage of Participants With Neutrophil Recovery
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.
Time frame: Day 56
Percentage of Participants With Platelet Recovery
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.
Time frame: Day 100
Participants With Primary Graft Failure
Primary graft failure is defined as less than 5% donor chimerism on all measurements up to and including Day 56.
Time frame: Day 56
Percentage of Participants With Secondary Graft Failure
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.
Time frame: Year 2
Percentage of Participants With Acute Graft-versus-Host Disease (aGVHD)
The cumulative incidences of grade II - IV and III - IV acute aGVHD will be determined.
Time frame: Day 180
Percentage of Participants With Chronic Graft-versus-Host Disease (cGHVD)
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.
Time frame: Year 2
Percentage of Participants With Overall Survival
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.
Time frame: Year 2
Percentage of Participants With Treatment-related Mortality (TRM)
The cumulative incidence of TRM will be estimated, event for this endpoint is death without evidence of disease progression or recurrence.
Time frame: Day 100, Day 180, Year 1, and Year 2
Percentage of Participants With Relapse/Progression
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.
Time frame: Year 1, year 2
Toxicities
They are all Grade ≥ 3 toxicities based on NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.
Time frame: Day 28, Day 56, Day 180, 1 year, and 2 years
Participants With Infections
All Grade 2 and 3 infections will be reported. Grade 1 CMV infections through Day 56 will also be reported.
Time frame: Up to 2 years
Hospital Admission and Length of Stay
Total Time Alive and Not Hospitalized within 6 Months Post Randomization
Time frame: Month 6
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University of Florida College of Medicine (Shands)
Gainesville, Florida, United States
Florida Hospital Cancer Institute
Orlando, Florida, United States
Emory University
Atlanta, Georgia, United States
BMT Program at Northside Hospital
Atlanta, Georgia, United States
University of Kansas Hospital
Kansas City, Kansas, United States
...and 29 more locations