Unrelated Donor Transplantation for Fanconi Anemia: Analysis of Prognostic Factors Impacting Engraftment and Survival.
Authors: Wagner John E. , Eapen Mary , Harris Richard E. , MacMillan Margaret L. , Auerbach Arlene D. 
Published: October 2019

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.