Reported here are studies of Fanconi anemia fetal cells that led to the first use of umbilical cord blood for hematopoietic reconstitution in a clinical trial. Prenatal diagnosis and HLA typing were performed in fetuses at risk for Fanconi anemia (FA) to identify, prior to birth, those that were unaffected with the syndrome and were HLA-identical to affected siblings. Umbilical cord blood was harvested at the delivery of these infants; assays of progenitor cells indicated the presence of colony-forming units-granulocyte-macrophage (CFU-GM) in numbers similar to those of bone marrow CFU-GM that are associated with successful engraftment in HLA-matched allogeneic bone marrow transplantation. The possibility that umbilical cord blood from a single individual can be used as an alternative to bone marrow for hematopoietic reconstitution has now been demonstrated by the successful engraftment of two patients with FA. Progenitor cell assays of umbilical cord blood collected at the birth of a child affected with FA, who had been misdiagnosed on the basis of chorionic villus sampling (CVS) studies, indicated a profound deficiency in colony formation, consistent with previously reported abnormalities in the growth of FA cells in vitro. These results suggest that the hematopoietic disorder in FA is related to an underlying problem with cell proliferation.

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.

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