Hematopoietic Cell Transplantation for Acute Leukemia and Advanced Myelodysplastic Syndrome in Fanconi Anemia

The presence of acute leukemia or advanced myelodysplastic syndrome (MDS with 5% blasts or more) in Fanconi Anemia (FA) patients is associated with very poor prognosis. The experience of hematopoietic cell transplantation (HCT) in these patients is limited, and the question of pre-transplant chemotherapy remains. We report 21 FA patients with acute myeloid leukemia, acute lymphoblastic leukemia, or advanced MDS who underwent HCT at the University of Minnesota from 1988-2009. 6 patients had biallelic BRCA2 mutations (29%). Median age at transplant was 15.5 years (range 1.1-48.5). 7 patients (33%) received chemotherapy before HCT, with 4 achieving complete remission. HCT conditioning regimen consisted of Cyclophosphamide with either total body irradiation or Busulfan, with the addition of Fludarabine in 13 patients (62%). In vivo T cell depletion with Anti-Thymocyte Globulin was performed in 18 patients (85%), and 11 donor grafts underwent ex vivo T cell depletion (52%). Donor source included HLA-matched sibling (n=3), mismatched related donor (n=1), unrelated marrow (n=12) and unrelated cord blood (n=5). 58% of unrelated donors had at least 1 HLA mismatch. Neutrophil engraftment for the entire cohort was 90%, and 100% for those patients that received Fludarabine. The incidence of acute GVHD was 19% for the entire cohort. 5 year Overall Survival (OS) was 32%, with a relapse rate of 20% (Figure). Of the patients that received Fludarabine, 5 year OS was 38% with a relapse rate of 30%. For the patients with biallelic BRCA2 mutation, 5 year OS was 33% with a relapse rate of 50%.

Our study provides evidence for use of HCT with a Fludarabine containing regimen for FA patients with acute leukemia or advanced MDS, who would otherwise have a dismal prognosis. The role of pre-HCT chemotherapy remains unclear, and requires further investigation. BRCA2 patients are a unique subset of FA patients and require tailored therapy to optimize HCT outcomes.