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 the First Prospective Multicenter Trial for Pediatric, Adolescent, and Young Adult Patients with High Risk Acute Leukemias and Myelodysplastic Syndrome

Promising results have been reported for patients with high-risk hematologic malignancies undergoing T-cell-replete myeloablative bone marrow transplant (BMT) from HLA-haploidentical donors with post-transplantation cyclophosphamide (PT/Cy). Here, we report results from the first prospective multicenter pilot trial in the Pediatric Blood and Marrow Transplant Consortium (PBMTC) for pediatric, adolescent, and young adult patients with high risk acute leukemias and myelodysplastic syndrome (MDS) in the US and Canada. Nine centers transplanted 32 patients with acute leukemias or MDS in complete remission (CR) who received myeloablative conditioning consisting of IV Busulfan (pharmacokinetically adjusted) and Cyclophosphamide (Cy, 50 mg/kg/day) days –2 and –1 except for patients with acute lymphocytic leukemia who received Cy (50 mg/kg/day x 2) and total body irradiation (1200cGy). 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 90-180 days. Median age of patients was 12y (range, 1-23) and donors was 35y (range, 4-53). Diagnoses included AML (CR1 = 7, CR2 = 6), ALL (CR1 = 8, CR2 = 5), mixed lineage leukemia (1), and MDS (5). One patient had received a prior BMT. Donor engraftment occurred in 27/32 (84%). Primary graft failures included 3 patients with MDS and 2 with AML (CR1 = 1, CR2 = 1); three of these patients had received suboptimal bone marrow grafts (TNC/kg ≤2e8) and all successfully engrafted after second transplants. Median time to neutrophils >500/μL was 22 days and platelets >20,000/μL was 21 days. Transplant related mortality (TRM) at 180 days, our primary objective, was 0%. Cumulative incidence of acute GVHD grades II-IV at Day 100 was 13%. No patients developed severe acute GVHD grades III-IV. The cumulative incidence of mod-severe chronic GVHD at 1 year was 4%. The cumulative incidence of relapse at 1y was 32%. With a median follow-up of surviving patients of 477 days (range, 180-1127), actuarial overall survival is 77% at 1y. With a median follow-up of event-free patients of 451 days (180-1127), actuarial event-free survival is 68% at 1y. For this first reported multicenter pediatric myeloablative HLA-haploidentical HSCT for high-risk leukemias and MDS with T-cell replete bone marrow and PT/Cy, we have demonstrated a 0% TRM, low cumulative incidences of acute and chronic GVHD, and favorable rates of relapse and survival. Further investigation as to potential reasons for graft failure and consideration of any changes needed to ensure engraftment for certain disease groups are underway. A larger trial comparing haploidentical BMT with other alternative donor sources is in development.