BMT CTN 2207 will investigate the use of marrow transplantation for treatment of severe aplastic anemia that has not previously been treated.
Age 3 years to 75 years
No suitable fully matched related donor as per Investigator's discretion (6/6 match for HLA A and B at intermediate or high-resolution and DRB1 at high-resolution using deoxyribonucleic acid [DNA]-based typing) available.
Available donor as defined in the protocol.
Participant and/or legal guardian must sign informed consent.
Inherited bone marrow failure syndromes such as Fanconi anemia and short telomere syndromes must be ruled out according to center standards. It is recommended that functional testing for Fanconi Anemia (di-epoxybutane [DEB] chromosomal breakage analysis) and telomere length assessment be performed. If available, genetic panels for inherited bone marrow failure syndromes can be considered as an alternative to functional testing.
Clonal cytogenetic abnormalities consistent with pre-MDS or MDS on marrow examination (e.g., monosomy 7 and other MDS-defining changes per recent pathology guidelines).
Formal diagnosis of MDS by World Health Organization (WHO) 2022 or International Consensus Classification (ICC).
Recipient positive for HLA antibodies against a mismatched HLA in the selected donor determined by the presence of donor specific HLA antibodies (DSA) to any mismatched HLA allele/antigen at any of the following loci (HLA-A, -B, -C, -DRB1, DRB3, DRB4, DRB5, -DQA1, -DQB1, -DPA1, -DPB1) with median fluorescence intensity (MFI) >3000 by microarray-based single antigen bead testing. In patients receiving red blood cell or platelet transfusions, DSA evaluation must be performed or repeated post-transfusion and immediately prior to initiation of recipient preparative regimen to ensure there is confirmation of no DSA to the selected donor when conditioning starts.
Parallel
Haploidentical donor bone marrow transplant
DrugDrugs: 1. Antithymocyte Globulin (ATG) dose will be 0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours. 2. Fludarabine dose will be 30 mg/m\^2 IV daily for 5 days from Day -6 to Day -2. 3. Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days (Day -6 to Day -5) prior to transplantation and 50 mg/kg IV daily for 2 days (Day +3 to Day +4) after transplantation. 4. Tacrolimus should be started on Day +5 and administered to maintain a level of 10-15 ng/mL. 5. Mycophenolate mofetil (MMF) dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day +5 through Day +35. 6. G-CSF will be given IV or SQ starting on Day +5 at 5 mcg/kg/day until ANC is \> 1500 for 3 days. Radiation: 1\. Total Body Irradiation (TBI): will be given as a single dose of 400 cGy on Day -1. Procedure: 1\. HSCT: Eligible patients will receive a haploidentical donor bone marrow transplant.
Unrelated donor bone marrow transplant
DrugDrugs: 1. Antithymocyte Globulin (ATG) dose will be 0.5 mg/kg IV on Day -9 over 6 hours and 2 mg/kg IV on Days -8 and -7 over 4 hours. 2. Fludarabine dose will be 30 mg/m\^2 IV daily for 5 days from Day -6 to Day -2. 3. Cyclophosphamide dose will be 14.5 mg/kg IV daily for 2 days (Day -6 to Day -5) prior to transplantation and 50 mg/kg IV daily for 2 days (Day +3 to Day +4) after transplantation. 4. Tacrolimus should be started on Day +5 and administered to maintain a level of 10-15 ng/mL. 5. Mycophenolate mofetil (MMF) dose will be 15 mg/kg PO three times a day (TID) up to 1 gm TID (or IV equivalent) starting on Day +5 through Day +35. 6. G-CSF will be given IV or SQ starting on Day +5 at 5 mcg/kg/day until ANC is \> 1500 for 3 days. Radiation: 1\. Total Body Irradiation (TBI): will be given as a single dose of 400 cGy on Day -1. Procedure: 1\. HSCT: Eligible patients will receive an unrelated donor bone marrow transplant.
Graft versus host disease (GVHD)-free failure-free survival (GFFS) at One year
The primary endpoint is GFFS at 1 year after initiation of conditioning. Events for GFFS include Grade III-IV aGVHD, cGVHD requiring immunosuppression, primary or secondary graft failure requiring second definitive therapy, failure to receive an HSCT infusion, and death. GFFS is defined as the time interval from start of conditioning until the first of these events occurs. For failure to receive an HSCT infusion, the date will be at the time the decision not to proceed to HSCT is made.
Percentage of Participants with Overall survival (OS) at One year post conditioning
Events for OS include death from any cause. OS is defined as the time interval from initiation of conditioning until death. The OS probability will be assessed at 1 year after initiation of conditioning.
Percentage of Participants with Failure-Free Survival (FFS) at One year post conditioning
Events for FFS include treatment failure or death. Treatment failure is defined as the initiation of treatment with a second definitive therapy. FFS is defined as the time interval from start of conditioning until the start date of a second definitive therapy or death, whichever occurs first.
Participants Alive and Engrafted at One year post conditioning
The proportion of patients who are alive with donor cells present at 1 year after initiation of conditioning will be described, where the presence of donor cells is defined as achieving at least 5% myeloid donor chimerism (whole blood or marrow) in the most recent measurement through 1 year.
Percentage of Participants with Neutrophil Recovery post-transplant
Neutrophil recovery is achieving an ANC ≥ 0.5 x109/L for 3 consecutive measurements on different days, with the first of the 3 days being defined as the day of neutrophil recovery. The cumulative incidences of neutrophil recovery at Day +28 and Day +56 post-HSCT will be estimated.
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Medical College of Wisconsin
Lead sponsor
National Heart, Lung, and Blood Institute (NHLBI)
Collaborator
National Cancer Institute (NCI)
Collaborator
Sanofi
Collaborator
