Successful Reduced Intensity Alternative Donor Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Non-Malignant Disorders

Background: Hematopoietic stem cell transplantation (HSCT) is curative for many non-malignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies.  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).  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 non-malignant disorders using alternative donors and PT/Cy.

Design: We transplanted 9 patients with non-malignant conditions (CGD=3, DKC=2, DBA=1, HyperIgM=1, XIAP=1, IPEX=1) 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 stable mixed 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.