Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Bone Marrow Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in Largest Reported Experience with High Risk Hematologic Malignancies

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative hematopoietic stem cell transplantation (HSCT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report the largest patient experience (n=97) for leukemias in complete remission (CR)  and chemosensitive lymphomas with at least a partial remission (PR)  enrolled on, or treated according to, our now completed single-institution phase II clinical trial. Conditioning consisted of IV Busulfan (pharmacokinetically adjusted) days –6 to –3 and Cy (50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia or lymphoblastic lymphoma  who received Cy (50 mg/kg/day) days –5 and –4 and total body irradiation (200 cGy twice daily) days –3 to -1. T-cell-replete bone marrow from haploidentical related donors was used for all patients. Postgrafting immunosuppression consisted of Cy (50 mg/kg/day) days 3 and 4, followed by mycophenolate mofetil for 30 days and tacrolimus for 6 months. Ninety-seven patients with a median age of 42y (range, 1-65) were treated. Diagnoses included AML (CR1=24, CR>2=10, any CR with minimal residual disease= 11), ALL (CR1=9, CR>2=4, any CR with minimal residual disease=6), mixed lineage leukemia (2), MDS (13), CML (chronic phase 2=2), CMML (1), CLL (1), granulocytic sarcoma (2), multiple myeloma (1), lymphoma in chemosensitive PR (5), and lymphoma in CR (6). Donor engraftment occurred in 73/82 (89%) patients evaluable at Day 60. Median time to neutrophils >500/μL was 23 days and platelets >20,000/μL was 27 days. Cumulative incidences of acute GVHD grades II-IV and grades III-IV at day 100 were 17% and 7%, respectively, and chronic GVHD at 6 months was 16%. Transplant related mortality (TRM) at 100 days was 11%.  The cumulative incidence of relapse at 3y was 44%. For leukemia patients in CR with no detectable MRD the cumulative incidence of relapse at 2y was 33% in CR1 and 27% in >CR2. For leukemia patients in any CR with detectable MRD by flow cytometry and/or cytogenetics and/or FISH, the cumulative incidence of relapse at 2 years is 70%.  Among lymphoma patients, the cumulative incidence of relapse at 2y for those in CR is 33% and in PR 25%.  With a median follow-up of surviving patients of 474 days (range, 60-1782), actuarial overall survival is 72% at 1y and 57% at 2y. With a median follow-up of event-free patients of 444 days (60-1782), actuarial event-free survival is 55% at 1y and 49% at 2y. For the largest reported patient population undergoing myeloablative HLA-haploidentical HSCT for high-risk hematologic malignancies with T-cell replete bone marrow and PT/Cy, we have demonstrated acceptable rates of engraftment, GVHD, relapse, survival, and TRM, similar to HLA-matched HSCT. This approach is therefore a feasible option for high risk patients who lack timely access to an HLA-matched donor.