T-cell replete haploidentical bone marrow transplantation and post-transplant cyclophosphamide for patients with inborn errors.

Introduction Matched donor hematopoietic stem cell transplantation (HSCT) cures most patients with inborn hematopoietic disorders, but haploidentical HSCT was historically associated with graft rejection, GVHD and infections. In leukemia, in vivo depletion of alloreactive T-cells with post-transplant cyclophosphamide (pTCy) results in outcomes comparable to those with matched related or unrelated donors. Objectives To assess safety and efficacy of haploidentical HSCT with pTCy in patients with inborn errors of hematopoiesis who lack a suitable matched donor or have failed a previous matched donor HSCT. Methods Nineteen patients (10 primary immunodeficiencies, 7 hemoglobinopathies, 1 congenital erythropoietic porphyria, 1 bone marrow failure) with a median age of 9 years (0-22) were treated prospectively on an institutional protocol with a conditioning regimen of alemtuzumab 0.4mg/kg, rituximab 375mg/m², fludarabine 150mg/m², treosulfan 42g/m², thiotepa 10mg/kg and cyclophosphamide 29mg/kg followed by haploidentical bone marrow transplantation, pTCy and tacrolimus/MMF. In four patients who were in bone marrow aplasia after non-engraftment of a first HSCT, thiotepa was omitted and treosulfan reduced to 24g/m². Results After a median follow-up of 42 months (3-87), overall survival is 95% (18/19). One patient died on day +7 from suspected fludarabine neurotoxicity. Two patients experienced autologous reconstitution, one of whom had a successful second HSCT. Two patients have stable mixed chimerism predominantly of donor origin and remain disease free. All others exhibit complete donor chimerism. This results in event free survival of 84% (16/19) and disease free survival of 89% (17/19). Engraftment occurred after 17days (6-61) for neutrophils and 28 days (14-191) for platelets. The incidences of acute GVHD II-IV° and of chronic GVHD were 0%, respectively. Two patients (11%) developed GVHD I° of the skin.Viral reactivations were observed in 53% (10/19) of patients (8 CMV, 1ADV, 1 VZV), but only one patient developed overt disease (ADV). Immune reconstitution was swift with mean CD3+ and CD19+ counts of 793/µl and 271/µl on day +100. Other complications were bacterial bloodstream infections in 5 patients (26%) and moderate severity VOD in one (5%). No renal or hepatic toxicities greater than CTCAE grade 2 were observed. No patient developed hemorrhagic cystitis. Four patients had anti-donor HLA antibodies pre-HSCT, three of whom were treated with plasmapheresis; all engrafted. Conclusion Chemotherapy based conditioning and haploidentical HSCT with pTCy was safe and resulted in good disease free survival in this cohort of patients with inborn errors in the absence of relevant GHVD. These results compare well with outcomes achieved with matched donors in similar cohorts of patients, but larger multi-center studies are warranted to further evaluate this approach.