Reduced Intensity Hematopoietic Cell Transplantation for Non-Fanconi Anemia Marrow Failure Syndromes

Background: Hematopoietic cell transplantation (HCT) remains the only potentially curative option for majority of the inherited marrow failure syndromes and for patients with aplastic anemia who don't respond to immune suppression. It is challenging to rule out inherited marrow failure syndromes with certainty in patients who present with pancytopenia at very young age, with the possibility of them carrying yet unidentified genetic mutation/s. This in turn makes it difficult to treat them similar to patients with idiopathic aplastic anemia or using myeloablative preparative regimens/regimens containing total body irradiation (TBI). The inherent chemotherapy and radiation sensitivity of some of the congenital marrow failure syndromes (e.g. Shwachman-diamond syndrome (SDS), Dyskeratosis Congenita (DC)) leads to increased toxicity with intensive conditioning regimens. Here we report our experience with reduced intensity preparative regimen for Non-Fanconi anemia marrow failure syndromes.

Methods: Total twenty two Non-FA marrow failure syndromes and/or aplastic anemia patients were transplanted using a RIC regimen containing alemtuzumab, fludarabine and Melphalan. Patients with Alemtuzumab doses and schedules varied somewhat depending on size of the patients (<10kg – got 0.2mg/kg/dose x 5 days) and on risk of GVHD vs. mixed chimerism (alemtuzumab on days -22 to 18 vs from day -14 to 10). All patients received fludarabine 30mg/M2 (1mg/kg if <10kg) on days -8 to -4, and melphalan 140mg/M2 (4.7mg/kg if <10kg) on day -3.  Melphalan was reduced by 50% in 3 patients with DC and 2 patients with known chromosome sensitivity, due to concern for excessive toxicity with full dose melphalan.  GVHD prophylaxis consisted of methylprednisolone and cyclosporine in all. Fourteen patients additionally received methotrexate.

Results:  Patient and transplant characteristics along with results are shown in Table 1. Overall, one year probability of survival was 84% with 95% confidence interval of 67.0-100%.  This is a significant improvement compared to historical results. Eighteen patients are alive, well and remain 100% engrafted at a median follow-up of 1.4 years (range 0.3-6.26).

Conclusion:  We conclude that allogeneic HCT, using alemtuzumab, fludarabine and melphalan-based reduced intensity conditioning results in durable engraftment and an excellent survival in pediatric patients with marrow failure syndromes.