Unrelated Donor Transplantation for Fanconi Anemia: Analysis of Prognostic Factors Impacting Engraftment and Survival.

While allogeneic transplantation is the only approach that can correct hematological complications of Fanconi anemia (FA), unrelated donor transplantation has been severely limited by graft rejection and regimen-related toxicity with resultant poor survival. Therefore we evaluated the impact of potential prognostic factors on hematopoietic recovery, graft-versus-host disease (GVHD) and overall survival in 98 recipients of unrelated donor transplantation, transplanted in 1990 to 2003. Median age at transplantation was 12 years (range 0.8 – 33). Of the 67 patients with known complementation group, 35 were in group A, 12 in group C and 7 in other groups and, 45 of 98 (46%) had diepoxybutane (DEB) T cell mosaicism. Sixty-nine percent had aplastic anemia prior to transplantation; 56% received prior androgen therapy and 24% received > 20 blood product transfusions. Fifty-four percent received cyclophosphamide and irradiation and, 46% received a fludarabine-containing preparative regimen (FLU). All patients received bone marrow grafts and 78% were matched at HLA A, B, (low resolution) and DRB1 or mismatched (22%) at a single locus. Seventy-one percent of grafts were T-cell depleted. In order to adjust for differences in follow up between recipients treated with and without FLU-containing preparative regimens (median 21 vs. 135 months; FLU was used exclusively after 1998), all patients were censored at 12 months for transplant-outcomes. Neutrophil recovery (>500/ul) was significantly less likely with non-FLU containing preparative regimens in patients with DEB mosaicism (cumulative incidence 52%, p<0.0001) than without DEB mosaicism (89%); however, neutrophil recovery was not influenced by DEB mosaicism with FLU containing preparatory regimens (94% and 93%). Similarly, platelet recovery (>20,000) was less likely with non-FLU containing preparatory regimens (19% vs. 76%, p<0.0001); favorable risk factors were absence of myelodysplasia/leukemia and < 20 blood product transfusions prior to transplantation. Acute and chronic GVHD were significantly lower in recipients of T-cell depleted grafts (17% and 18%, respectively) than recipients of non T cell depleted grafts (62% and 47%, respectively). Mortality was significantly higher with non-FLU containing preparative regimens (Relative Risk [RR] 3.24, 95% CI 1.86 – 5.66, p<0.0001), than with FLU containing preparative regimens. Corresponding probabilities of overall survival were 17% and 57%, respectively. Mortality was also significantly higher in patients who had received > 20 blood product transfusions (RR 2.10, 95% CI 1.16 – 3.76, p=0.01). Age, disease status at transplantation, HLA disparity, complementation group, DEB mosaicism or DEB sensitivity, and donor-recipient CMV status did not affect mortality. Based on these results significant practice changes should be considered: use of a FLU containing preparative regimen and transplantation prior to > 20 blood product transfusions.