Autologous Transplant/Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency

s / Biol Blood Marrow Transplant 21 (2015) S79eS107 S102 success using HLA-matched related donors; however, use of alternative donors has been associated with increased graft failure, graft versus host disease (GVHD), and transplantrelated mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable to that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant disorders using alternative donors and PT/Cy. Design: We transplanted 9 patients with non-malignant conditions (CGD1⁄43, DKC1⁄42, DBA1⁄41, HyperIgM1⁄41, XIAP1⁄41, IPEX1⁄41) using an alemtuzamab/fludarabine based reduced intensity conditioning (RIC). All patients received GVHD prophylaxis with PT/Cy, with the addition of mycophenolate mofetil and tacrolimus for HSCT with haploidentical donors and for alkylator-sensitive diagnoses (DKC). Six patients had 10/10 HLA-matched unrelated donors, and 3 had HLA-haploidentical related donors. Results: All 9 patients successfully engrafted by day 30. Ultimately, all patients have had sustained donor engraftment sufficient to eliminate manifestations of their underlying diseases. 6 of 9 patients are full donor chimeras off immunosuppression,1 patient is a stablemixed donor chimera (76% CD3+ T cells) off immunosuppression, 1 patient is a stable mixed donor chimera on a calcineurin inhibitor (CNI), and 1 patient had secondary graft failure but was ultimately retransplanted with myeloablative conditioning using the same donor, resulting in full donor chimerism and elimination of disease. One patient developed Grade 1 and one patient Grade 2 acute GVHD, both treated successfully with steroids and a CNI. Mild skin chronic GVHD developed in 1 patient, treated successfully with phototherapy. No serious infections occurred and there was no TRM. 1 patient developed veno-occlusive disease, treated successfully with defibrotide. Disease-free survival is 89% with a median follow-up of 14 months (6-30 months). The patient with secondary graft failure is now disease-free after myeloablative transplant, for an overall disease-free survival of 100% at a median of 14 months follow-up (6-60 months). Overall survival is 100%. Conclusion: We have observed successful engraftment sufficient to eliminate manifestations of disease, limited GVHD, and no TRM in 9 patients with nonmalignant disorders using alternative donors, RIC, and PT/Cy. RIC HSCT with PT/Cy shows promise for curing nonmalignant pediatric disorders, and potentially eliminates the need for CNI use after MUD BMT. Development of prospective clinical trials to confirm these observations is warranted.