Reduced Intensity Alternative Donor Transplantation with Post-Transplant Cyclophosphamide Is Highly Effective in Inherited Immune Deficiencies and Bone Marrow Failure Syndromes

Abstract

Background Allogeneic Bone Marrow Transplantation (alloBMT) is the only cure for many primary immune deficiencies (PID) and inherited bone marrow failure syndromes (IBMFS). There has been great success using HLA-matched related donors; however, use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplant related mortality (TRM). BMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PT/Cy) has been previously reported by our institution with no TRM, and low rates of graft failure and GVHD. Here, we present outcomes on an additional 8 patients treated, along with updated results of the previously reported 11 patients. Design We transplanted 19 patients (CGD n = 8; DKC n = 2; DBA n = 2; CVID n = 1; CTLA4 def n = 1; Glanzmann's n = 1; HLH n = 1; HyperIgM n = 1; IPEX n = 1; XIAP n = 1) using an alemtuzamab/fludarabine/melphalan-based preparative regimen (Figure 1), with or without total body irradiation. GVHD prophylaxis was PT/Cy alone (n = 4), or PT/Cy with mycophenolate mofetil and tacrolimus or sirolimus (n = 15). Donors were HLA-haploidentical related (n = 11), 10/10 HLA-identical unrelated (n = 6), and 9/10 (n = 1) or 5/8 (n = 1) HLA-mismatched unrelated. Results Of 18 evaluable patients, 17 (95%) achieved 100% donor chimerism by day 30 in peripheral blood, and 15 (83%) maintained 100% donor chimerism at day 60. At 1-year post-transplant, 14 (78%) remained >92% donor chimerism. Two patients developed late (>3 years) secondary graft failure, both were re-transplanted and are alive and 100% donor at one and four years post their second BMTs. All evaluable patients have had sufficient sustained donor chimerism to eliminate manifestations of their underlying diseases. Grade 1 or 2 acute GVHD developed in 5 patients, all treated successfully with steroids and a CNI. One patient developed skin-only chronic GVHD, successfully treated with immune suppression and UV light therapy. One patient developed concurrent adenovirus and cytomegalovirus infections early after BMT, which ultimately led to multi-organ failure and death. Two patients developed veno-occlusive disease, successfully treated with defibrotide. With median follow-up of surviving patients of 2 years, ranging 1 to 8 years, overall survival is 95%, disease-free survival (alive without manifestations of underlying disease) is 95%, and event free survival (time from BMT to death or graft loss/re-transplantation) is 72% (Figure 2). Conclusion We have observed high rates of engraftment, limited GVHD, and low TRM in 19 patients with PID and IBMFS using alternative donors, RIC, and PT/Cy. RIC BMT with PT/Cy shows promise for curing these pediatric disorders. Development of a prospective clinical trial is currently underway to confirm these observations and to further study the kinetics of immune reconstitution in these patients.