T-Cell-Replete Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Patients with X-Linked Adrenoleukodystrophy: An Immediate Choice for an Urgent Situation

X-linked adrenoleukodystrophy (X-ALD) is a demyelinating disease caused by the deficiency of the ABCD1 gene that encodes for a peroxisomal protein membrane. The most severe form of X-ALD is the cerebral variant, which leads to severe disability and death during the first two decades. To date, allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment that has shown to significantly change the natural history of the disease, enhancing survival and stabilizing neurological lesions and symptoms. In the absence of a matched sibling or unrelated donor, haploidentical family members might be an option in these rapidly progressing diseases. Haploidentical HSCT has been performed using a T cell depleted graft, but is often associated with higher rates of graft failure and delayed immune reconstitution. Haploidentical HSCT using post-transplant cyclophosphamide has been performed in series of malignant and non-malignant diseases and has shown similar outcomes compared to other alternative donor sources. Here we show our experience with 8 patients with X-ALD treated with haploidentical HSCT with post-transplant cyclophosphamide. Between november 2012 and august 2013, 8 patients with X-ALD (ages 6 to 18 years) underwent haploidentical related HSCT in two different institutions, two patients received two transplants with different related donors. One patient received a second transplant after failure of a double cord blood transplant. Pre-transplant MRI showed Loes score of 2,5 to 18, all patients had neuropsychological evaluation with performance IQ above 90. Donor was the father (n=7), the uncle (n=2) or brother (n=1). All patients received reduced toxicity conditioning regimen consisted of: fludarabine 150 mg/m², cyclophosphamide 29 mg/kg and total body irradiation 2 Gy. Six patients received also rabbit antithymocyte globulin 4,5 mg/kg. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg/d on days +3 and +4, tacrolimus and mycophenolate mofetil starting on day +5. Seven patients engrafted, 13 to 19 days after transplant. One patient had a primary graft failure and was not eligible for a second transplant due to severe progression of neurological symptoms. Two patients had secondary graft failure with progressive loss of donor chimerism and were successfully rescued with second haploidentical transplants using different related donors. Four patients had grade II-IV acute graft-versus-host disease and four patients had CMV reactivations. One patient with grade III GVHD showed progression of neurologic symptoms of primary disease. Seven patients are alive and engrafted from 3 to 11 months after transplant, with chimerism from 80 to 100% donor cells. In conclusion, haploidentical HSCT with post-transplant cyclophosphamide is a feasible alternative for X-ALD lacking a suitable matched donor. Graft failure is still an obstacle that has to be better prevented.