This phase II trial investigates two strategies and how well they work for the reduction of graft versus host disease in patients with acute leukemia or MDS in remission. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient, they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.
Acute lymphocytic leukemia (ALL) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
Acute myeloid leukemia (AML) in first or subsequent morphological remission (< 5% marrow blasts by morphology).
Other acute leukemia or related neoplasm (including but not limited to 'mixed phenotype' 'biphenotypic', 'acute undifferentiated' or 'ambiguous lineage' acute leukemia, blastic plasmacytoid dendritic cell neoplasm, lymphoblastic lymphoma, Burkitt leukemia/lymphoma, mast cell leukemia, chronic myeloid leukemia [CML] with blast crisis or other chronic myeloproliferative neoplasm) in first or subsequent morphological remission (<5% marrow blasts by morphology).
Myelodysplastic syndrome (MDS) with a history of excess blasts (≥ approximately 5% in marrow blasts by morphology) and a history of receiving cytoreductive therapy (including but not limited to BCL-2 inhibitors or cytotoxic chemotherapy) within the past 3 months.
Patients with central nervous system (CNS) involvement refractory to intrathecal chemotherapy and/or standard cranial-spinal radiation. A patient may have a history of CNS disease. However, any CNS disease must be cleared by the end of the pre-conditioning evaluation time frame. If CNS disease is identified on cerebrospinal fluid (CSF) evaluation within 30 days of the start of the preparative regimen a repeat CSF evaluation must be performed and show no evidence of disease in order for the patient to be eligible for the protocol.
Patients on other experimental protocols for prevention of GVHD.
Patients with HLA-matched related donors will be excluded if they weigh >= 110 kg.
Patients with HLA-matched unrelated donors will be excluded if they weigh >= 110 kg and must be discussed with the Fred Hutch protocol principal investigator (PI) if they weigh >= 90 kg.
Parallel
Total-Body Irradiation
RadiationUndergo TBI
Thiotepa
DrugGiven IV
Fludarabine
DrugGiven IV
Tacrolimus
DrugGiven IV
Allogeneic CD34+-enriched and CD45RA-depleted PBSCs
Biological/VaccineGiven IV
Methotrexate
DrugGiven IV
Cyclophosphamide
DrugGiven IV
Peripheral Blood Stem Cell
Biological/VaccineGiven IV
Cyclosporine
DrugGiven IV
Sirolimus
DrugGiven IV
Busulfan
DrugGiven IV
Bone Marrow Aspiration and Biopsy
Procedure/SurgeryUndergo bone marrow aspiration/biopsy
Echocardiography
Procedure/SurgeryUndergo ECHO
Multigated Acquisition Scan
Procedure/SurgeryUndergo MUGA
Biospecimen Collection
Procedure/SurgeryUndergo blood sample collection
6
Treatment groupsSee each treatment group below.
Graft versus host disease (GVHD)-free relapse-free survival (RFS)
Will be defined as survival-free of a history of: a) relapse after hematopoietic cell transplantation (HCT), b) grade III-IV acute GVHD after HCT, moderate or severe chronic GVHD meeting National Institutes of Health (NIH) criteria and requiring systemic pharmacologic immunosuppression for treatment of GVHD. RFS distribution will be estimated for each arm by the Kaplan-Meier curve, starting from the time of HCT. A 90% confidence interval (CI) will be constructed at 1 and 2-year post-HCT timepoints.
Overall survival (OS)
Death will be considered as the event, and the OS distribution will be estimated for each group by the Kaplan-Meier method, starting from the time of HCT. A 90% CI will be constructed at the 1 and 2-year post-HCT time points.
Relapse
Will be defined as recurrence of leukemia (\>= 5% leukemic blasts by flow or morphology) in bone marrow, circulating leukemic blasts or extramedullary disease (extramedullary disease definite i.e. proven by biopsy or probably based on clinical assessment if biopsy not feasible). Lower levels of leukemia in bone marrow or blood will be recorded and reported as 'measurable residual disease' but will not be considered relapse.
Proportion of patients alive and off prednisone (or equivalent systemic corticosteroid) for treatment of GVHD
Graft rejection or irreversible graft failure (> 14 days duration)
Will be operationally defined as failure to achieve an absolute neutrophil count (ANC) \>= 0.5 x 10\^9/L before death or second HCT, or decrease to ANC \< 0.1 x 10\^9/L for 14 consecutive days (date of graft failure defined as the 14th day) after an established donor graft despite daily administration of granulocyte colony-stimulating factor (subcutaneously or intravenously) and =\< 20% bone marrow cellularity on bone marrow aspirate or biopsy any time in the first 2 years following HCT. If the delay or reduction in ANC is due to relapse (as determined by histopathology, flow cytometry or cytogenetic or molecular studies) this will not be considered graft failure. If a patient dies from organ toxicity and/or infection prior to day 28 without ANC \>= 0.5 x 10\^9/L this will not be considered graft failure.
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Fred Hutchinson Cancer Center
Lead sponsor
National Cancer Institute (NCI)
Collaborator
