Haploidentical BMT Using Fully Myeloablative Conditioning, T Cell Replete Grafts, and Post-Transplant Cyclophosphamide (PT/Cy) Has Limited Toxicity and Promising Efficacy in Pediatric Patients with High Risk Hematologic Malignanices

Historically, T cell-replete myeloablative BMT from HLA-haploidentical donors demonstrated excessive rates of severe graft-versus-host-disease (GVHD) and non-relapse mortality (NRM). More promising results have recently been demonstrated for adults with high-risk hematologic malignancies using T cell-replete marrow and post-transplantation cyclophosphamide(PT/Cy). Here, we report the first results using such an approach specifically for pediatric patients. Our single-institution phase II clinical trial initially enrolled subjects with refractory hematologic malignancies, but later added high risk leukemias in remission and chemosensitive lymphomas, to match Children's Oncology Group BMT criteria. 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(ALL) or lymphoblastic lymphoma(LL) who received Cy (50 mg/kg/day) days –5 and –4 and total body irradiation (300cGy /day) days –3 to 0. T-cell-replete bone marrow 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. Twelve patients were treated with a median age of 12 (range, 2-20). Diagnoses include acute myeloid leukemia (3 refractory, 3 CR2), ALL (1 primary refractory CR1, 2 CR2), 1 chronic myeloid leukemia in blast crisis, 1 chemosensitive LL, and 1 chemosensitive mature B cell lymphoma. Two patients had undergone prior myeloablative allogeneic BMTs. Donor engraftment at Day 60 occurred in all evaluable patients. Median time to engraftment of neutrophils >500/μL was 26 days and platelets >20,000/μL was 35 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 42% with all classified mild per NIH cGVHD consensus criteria. One patient required systemic steroids for Grade 3 skin aGVHD and responded completely. The cumulative incidence of NRM at 100 days was 8% (1/12), with one death from veno-occlusive disease in a patient who had received gemtuzumab ozogamicin 3 weeks before BMT. No patients with chemosensitive disease or in remission died from transplant-related causes. With median follow-up of surviving patients of 276 days (range 100–1015), actuarial overall survival (OS) is 80% at one year. Of 8 patients with chemosensitive disease or in remission, 2 have relapsed: one primary refractory ALL and one multi-TKI resistant Ph+ ALL. For pediatric patients with high-risk hematologic malignancies, HLA-haploidentical BMT with T cell replete bone marrow and PT/Cy is associated with excellent rates of engraftment, GVHD, OS, and NRM, similar to myeloablative matched sibling BMT. It is therefore a feasible option for high risk pediatric patients who lack timely access to an HLA-matched donor.