HLA-Mismatched Unrelated Donor Peripheral Blood Stem Cell Transplantation With Reduced Dose Post Transplantation Cyclophosphamide GvHD Prophylaxis
Purpose
The goal of this clinical trial is to determine the effectiveness of Reduced Dose Post-Transplant Cyclophosphamide (PTCy) in patients with hematologic malignancies after receiving an HLA-Mismatched Unrelated Donor (MMUD) . The main question[s] it aims to answer are: - Does a reduced dose of PTCy reduce the occurrence of infections in the first 100 days after transplant? - Does a reduced dose of PTCy maintain the same level of protection against Graft Versus Host Disease (GvHD) as the standard dose of PTCy?
Conditions
- Acute Lymphoblastic Leukemia
- Acute Myeloid Leukemia
- Acute Leukemia
- Myelodysplastic Syndromes
- Chronic Myeloid Leukemia
- Chronic Lymphocytic Leukemia
- Myeloproliferative Neoplasm
- Lymphoma
- Chronic Myelomonocytic Leukemia
- Pro-Lymphocytic Leukemia
- Myelofibrosis
Eligibility
- Eligible Ages
- Over 18 Years
- Eligible Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Age ≥ 18 years and < 66 years (chemotherapy-based conditioning) or < 61 years (total body irradiation [TBI]-based conditioning) at the time of signing informed consent 2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and institutional requirements. 3. Stated willingness to comply with all study procedures and availability for the duration of the study. 4. Planned MAC regimen as defined per study protocol 5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred). 6. Product planned for infusion is MMUD T-cell replete PBSC allograft 7. HCT-CI < 5. The presence of prior malignancy will not be used to calculate HCT-CI for this trial to allow for the inclusion of patients with secondary or therapy-related AML or MDS. 8. One of the following diagnoses: 1. Acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or other acute leukemia in 1st remission or beyond with ≤ 5% marrow blasts and no circulating blasts or evidence of extra-medullary disease. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. 2. Patients with MDS with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS). Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. 9. Cardiac function: Left ventricular ejection fraction ≥ 45% based on most recent echocardiogram or multi-gated acquisition scan (MUGA) results. 10. Estimated creatinine clearance ≥ 45mL/min calculated by equation. 11. Pulmonary function: diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for hemoglobin > 50% and forced expiratory volume in first second (FEV1) predicted > 50% based on most recent pulmonary function test (PFT) results 12. Liver function acceptable per local institutional guidelines 13. KPS of ≥ 70% Stratum 2 Recipient Inclusion Criteria: 1. Age ≥18 years at the time of signing informed consent 2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements. 3. Stated willingness to comply with all study procedures and availability for the duration of the study. 4. Planned NMA/RIC regimen per study protocol 5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred). 6. Product planned for infusion is MMUD T-cell replete PBSC allograft 7. One of the following diagnoses: 1. Patients with acute leukemia or chronic myeloid leukemia (CML) with no circulating blasts, no evidence of extramedullary disease, and with < 5% blasts in the bone marrow. Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. 2. Patients with MDS with no circulating blasts and with < 10% blasts in the bone marrow (higher blast percentage allowed in MDS due to lack of differences in outcomes with < 5% or 5-10% blasts in MDS.) Documentation of bone marrow assessment will be accepted within 45 days prior to the anticipated start of conditioning. 3. Patients with chronic lymphocytic leukemia (CLL) or other leukemias (including prolymphocytic leukemia) with chemosensitive disease at time of transplantation 4. Higher risk CMML according to CMML-specific prognostic scoring system or high risk MDS/MPN not otherwise specified are eligible, provided there is no evidence of high-grade bone marrow fibrosis or massive splenomegaly at the time of enrollment. 5. Patients with lymphoma with chemosensitive disease at the time of transplantation 8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure 9. Estimated creatinine clearance ≥ 45mL/min calculated by equation 10. Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted >50% based on most recent PFT results 11. Liver function acceptable per local institutional guidelines 12. KPS of ≥ 60% Stratum 3 Recipient Inclusion Criteria: 1. Age ≥18 years at the time of signing informed consent 2. Patient or legally authorized representative has the ability to provide informed consent according to the applicable regulatory and local institutional requirements. 3. Stated willingness to comply with all study procedures and availability for the duration of the study. 4. Planned NMA/RIC regimen per study protocol 5. Available partially HLA-MMUD (4/8-7/8 at HLA-A, -B, -C, and -DRB1 is required) with age ≥ 18 and ≤ 40 years (≤ 35 preferred). 6. Product planned for infusion is MMUD T-cell replete PBSC allograft 7. Diagnosis of primary myelofibrosis with risk features making them eligible for HCT. Myelofibrosis secondary to essential thrombocythemia, polycythemia vera, or MDS with grade 4 fibrosis are also eligible. Patients with a myelofibrosis diagnosis require sponsor approval before enrolling. 8. Cardiac function: Left ventricular ejection fraction ≥ 40% based on most recent echocardiogram or MUGA results with no clinical evidence of heart failure 9. Estimated creatinine clearance ≥ 45 mL/min calculated by equation 10. Pulmonary function: DLCO corrected for hemoglobin > 50% and FEV1 predicted >50% based on most recent PFT results 11. Liver function acceptable per local institutional guidelines 12. KPS of ≥ 60% Donor Inclusion Criteria (note: donors are not research subjects): 1. Must be unrelated to the subject and high-resolution HLA-matched at 4/8, 5/8, 6/8, or 7/8 (HLA-A, -B, -C, and -DRB1. 2. Donor must be typed at high-resolution for a minimum of HLA-A, -B, -C, -DQB1, and -DPB1. 3. Age ≥ 18 years and ≤ 40 years at the time of signing informed consent for PBSC donation. Note: donors are preferred to be ≤ 35. 4. Meet the donor registries' medical suitability requirements for PBSC donation. 5. Must undergo eligibility screening according to current Food and Drug Administration (FDA) requirements. Donors who do not meet one or more of the donor screening requirements may donate under urgent medical need. 6. Must agree to donate PBSC. 7. Must have the ability to give informed consent according to standard (non-study) informed consent according to applicable donor regulatory requirements. Recipient
Exclusion Criteria
(Strata 1, 2, and 3): 1. Suitable HLA-matched related or 8/8 high-resolution matched unrelated donor available 2. Subject unwilling or unable to give informed consent, or unable to comply with the protocol including required follow-up and testing 3. Subjects with a prior allogeneic transplant 4. Subjects with an autologous transplant within the past 3 months 5. Females who are breast-feeding or pregnant 6. Uncontrolled bacterial, viral, or fungal infection at the time of the transplant preparative regimen 7. Concurrent enrollment on a preventative GvHD and/or infectious disease prevention clinical trial. 8. Subjects who undergo desensitization to reduce anti-donor HLA antibody levels prior to transplant. 9. Patients who are HIV+ with persistently positive viral load. HIV-infected patients on effective anti-retroviral therapy (ART) with undetectable viral load within 6 months are eligible for this trial. Patients with well controlled HIV are eligible provided resistance panels are negative, the patient is compliant with ART, and their disease remains well controlled. Donor Exclusion Criteria: 1. Donor unwilling or unable to donate. 2. 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 prior to donor mobilization and initiation of recipient preparative regimen.
Study Design
- Phase
- Phase 2
- Study Type
- Interventional
- Allocation
- Non-Randomized
- Intervention Model
- Parallel Assignment
- Primary Purpose
- Treatment
- Masking
- None (Open Label)
Arm Groups
Arm | Description | Assigned Intervention |
---|---|---|
Experimental Regimen A (MAC: Busulfan and Fludarabine, PBSC HCT; Reduce Dose PTCy |
Patients Receive: Patients receive: Busulfan (≥ 9 mg/kg total dose) IV or PO on days -6 to -3 Fludarabine (150 mg/m2 total dose) IV on days -6 to -2 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant. |
|
Experimental Regimen B (MAC: Fludarabine and TBI, PBSC HCT; Reduce Dose PTCy |
Patients receive: Fludarabine (90 mg/m2 total dose) IV on days -7 to -5 Total body irradiation (TBI) (1200 cGy total dose) on days -4 to -1 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant. |
|
Experimental Regimen C (RIC: Fludarabine and Busulfan; PBSCT HCT; Reduced Dose PTCy |
Patients receive: Fludarabine (150-180 mg/m2 total dose) IV on days -6 to -2 Busulfan (less than or equal to 8 mg/kg PO or 6.4 mg/kg IV) on days -5 and -4 Patients receive a peripheral blood stem cell (PBSC) graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant. |
|
Experimental Regimen D (RIC: Fludarabine and Melphalan; PBSCT HCT; Reduced Dose PTCy |
Patients receive: Fludarabine (125-150 mg/m2 total dose) IV on days -7 to -3 Melphalan (100-140 mg/m2) IV on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant. |
|
Experimental Regimen E (NMA: Fludarabine, Cyclophosphamide, and TBI; PBSCT HCT; Reduced Dose PTCy |
Patients receive: Fludarabine (150mg/m2 total dose) IV on days -6 to -2 Cyclophosphamide (29-50mg/kg) IV on days -6 and -5 TBI (200cGy) on day -1 Patients receive a PBSC graft infusion from a mismatched unrelated donor on Day 0. Patients receive a reduced dose of cyclophosphamide (25mg/kg per dose) on Day 3 and Day 4 post-transplant. First 20 patients with a 4-6/8 mismatched unrelated donor will receive an alternate dose of post-transplant cyclophosphamide of 37.5 mg/kg on Days 3 and Day 4 post-transplant. |
|
Recruiting Locations
Phoenix 5308655, Arizona 5551752 85054
Scottsdale 5313457, Arizona 5551752 85258
Little Rock 4119403, Arkansas 4099753 72205
San Francisco 5391959, California 5332921 94158
Stanford 5398563, California 5332921 94305
Denver 5419384, Colorado 5417618 80218
Jacksonville 4160021, Florida 4155751 32224
Miami 4164138, Florida 4155751 33136
Tampa 4174757, Florida 4155751 33612
Atlanta 4180439, Georgia 4197000 30322
Baltimore 4347778, Maryland 4361885 21201
Boston 4930956, Massachusetts 6254926 02155
Boston 4930956, Massachusetts 6254926 02215
Detroit 4990729, Michigan 5001836 48201
Minneapolis 5037649, Minnesota 5037779 55455
Rochester 5043473, Minnesota 5037779 55902
St Louis 4407066, Missouri 4398678 63110
New York 5128581, New York 5128638 10065
Chapel Hill 4460162, North Carolina 4482348 27599
Columbus 4509177, Ohio 5165418 43210
Portland 5746545, Oregon 5744337 97239
Danville 5186327, Pennsylvania 6254927 17822
Philadelphia 4560349, Pennsylvania 6254927 19104
Pittsburgh 5206379, Pennsylvania 6254927 15232
Nashville 4644585, Tennessee 4662168 37203
Austin 4671654, Texas 4736286 78704
Houston 4699066, Texas 4736286 77030
San Antonio 4726206, Texas 4736286 78229
Charlottesville 4752031, Virginia 6254928 22908
Karen Ballen, M.D.
Seattle 5809844, Washington 5815135 98109
Milwaukee 5263045, Wisconsin 5279468 53226
Sameem Abedin, MD
More Details
- NCT ID
- NCT06001385
- Status
- Recruiting
- Sponsor
- Center for International Blood and Marrow Transplant Research