LAUSR

Background Post-transplant cyclophosphamide (PTCy) enables allogeneic hematopoietic cell transplant (Allo-HCT) across the human leukocyte antigen barrier. Allo-HCT for severe transfusion dependent thalassemia is restricted in its application due to limited donor availability, graft rejection, and regimen-related toxicities. We explored the use of a common non-myeloablative (NMA) conditioning regimens with PTCy based graft-versus-host disease (GvHD) prophylaxis for matched related, haploidentical, and unrelated donors in the setting of a collaborative consortium. Methods A multicenter learning collaboration involving 3 centers used an augmented NMA conditioning with PTCy developed by John Hopkins group (Bolanos-Meade, Blood 2012). All patients received common conditioning regimen consisting of ATG 4.5 mg/kg, fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg, thiotepa (10 mg/kg on day -7) and TBI 200 cGy. Graft versus host disease (GvHD) prophylaxis was PTCy 50 mg/kg on days +3 and +4, MMF, and sirolimus. To improve engraftment rates, all patients received preconditioning with hydroxyurea 30mg/kg x 60 days (Figure 1). Most patients received G-primed bone marrow as stem cell source. Two patients received matched related donor (MRD), 4 patients haploidentical, and 3 patients matched unrelated donor (I-MUD, 2-mismatched MUD) bone marrow transplants (Figure 2). Results A total of 9 patients with transfusion dependent thalassemia were included with a median follow-up time of 371 days. One case of primary graft failure was seen in the haploidentical cohort at D+32; 89% (8/9) patients successfully engrafted. Two cases each of mild gut and skin acute GvHD and one case each of limited gut and skin chronic GvHD were seen in transplanted patients. No cases of grades III-IV acute or severe, chronic GvHD were seen. All patients are alive, thalassemia free survival (TFS) was 100% in the MRD and M/MUD recipients, but 75% (3/4) in the haploidentical cohort. There was no statistical difference between groups in regards to neutrophil or platelet engraftment, age, TNC or CD34+ cell dose. No engrafted patient required long-term immunosuppression therapy, and all remain transfusion independent. Conclusion We have shown the feasibility of NMA conditioning with PTCy plus thiotepa for severe transfusion dependent thalassaemia. A phase II study will help determine the optimal regimen with least toxicity and improved thalassaemia free survival.