Augmenting Non-Myeloablative BMT with Ptcy Using Thiotepa or 400 Cgy TBI Improves Engraftment in Patients with Transfusion Dependent Thalassemia: Results of a Haploidentical Transplant Consortium for Hemoglobinopathies (ICHH)

Abstract

Introduction Post-transplant cyclophosphamide (PTCy) enables blood and marrow transplantation (BMT) across the HLA barrier. BMT for transfusion dependent thalassemia (TDT) is restricted due to limited donor availability, graft rejection, and regimen-related toxicity. We explored the use of non-myeloablative (NMA) allogeneic BMT using best available donor with PTCy in the setting of a collaborative consortium to improve donor engraftment and estimate transplant-related mortality (TRM) and event-free survival. Methods A multicenter collaboration (3 centers in U.S. and U.K.) used common NMA conditioning with ATG, fludarabine, cyclophosphamide, and TBI and GvHD prophylaxis with PTCy, MMF, and sirolimus developed by the John Hopkins group (Bola–os-Meade, Blood 2012; Figure 1). Twenty-seven patients with TDT were transplanted. Local IRB approvals were obtained. 4 initial patients received established conditioning, 50% (2/4) had primary graft failure with autologous reconstitution, and 2 achieved neutrophil engraftment on D+29 and +38 with mixed chimerism. To improve donor engraftment rates: i, group A received pre-conditioning with hydroxyurea (HU) plus 400 cGy TBI, ii. group B were pre-conditioned with HU +/- azathioprine and hypertransfusion plus thiotepa. Twenty-one patients received haplo-BMT, 5 MRD and 1 MMUD transplant. Stem cells were G-primed BM for group B and unmanipulated BM for group A. Results Median follow-up was 16 months. In Group A, all patients engrafted with 100% OS and TFS; 18% (2/11) had grade-II aGvHD, but no cGVHD. In Group B, there was 1 case of graft failure, 2 deaths from idiopathic pulmonary syndrome and macrophage activation syndrome, 3 cases each of grades II-III aGvHD and limited cGvHD, with an 83% OS and TFS. No statistical differences were found between groups for neutrophil or platelet engraftment, age, TNC, or CD34+ cell dose. Engrafted patients remain transfusion independent, Figure 2. Conclusion NMA-BMT with PTCy augmented with either 400 cGy TBI or thiotepa, and at least HU preconditioning appears feasible in patients with TDT. A phase II study will help determine the optimal regimen with least toxicity and improved thalassaemia free survival.