Alternative Donor Hematopoietic Cell Transplantation for Patients with Fanconi Anemia.

Abstract Abstract 3081 Hematopoietic cell transplantation (HCT) is the only proven curative therapy for the hematological abnormalities in patients with Fanconi anemia (FA). In the mid-1990s, survival after alternative donor (AD)-HCT was reported to be 18% with excessive rates of regimen-related toxicity, graft failure, graft-versus-host-disease (GVHD) and opportunistic infections (OI). Between 1990 and 2010, 127 FA patients underwent AD-HCT at the University of Minnesota using one of 5 consecutive, prospective phase I-II total body irradiation (TBI) containing clinical trials, representing the largest single center experience. All patients received cyclophosphamide (CY, 40 mg/kg) and single fraction TBI. Sequential changes were made to prevent GVHD, graft failure and OI and ultimately enhance survival; in 1994, all patients received T cell depleted (TCD) bone marrow (BM) or umbilical cord blood (UCB) to reduce GVHD; in 1999, fludarabine (FLU) was added to enhance engraftment; in 2003, thymic shielding (TS) was added to reduce OI risk; and in 2006, TBI dose reduction was evaluated to reduce toxicity. Over this time period, HLA-matched unrelated donor BM was the donor of choice with partially HLA matched BM and UCB only used as alternatives. Neutrophil recovery was twice as likely after FLU-containing regimens than non-FLU containing regimens and was not deleteriously affected by TS or reducing TBI dose to 300cGy. Grade II-IV acute GVHD was significantly reduced by the use of TCD (18%) compared to T replete BM or UCB (50% and 38%, respectively: p 10 years) or CMV seropositive, received any transfusions before HCT, or developed OI before HCT (Table). Mortality was lowest using CY/FLU/ATG, TBI 300 cGy with TS (Trial 5, relative risk [RR] 0.1; p Table: . Factors associated with 3 year mortality: Multivariate analysis Factors Relative Risk of Mortality (95% CI) P-value Trial * 2: CY/ATG/TBI 450-600, CSA/MP 1.0 3: CY/FLU/ATG/TBI 450, CSA/MP 0.3 (0.1–.7) 4: CY/FLU/ATG/TBI 450+TS, CSA/MP 0.2 (0.1–0.7) 0.01 5: CY/FLU/ATG/TBI 300+TS, CSA/MP or MMF 0.1 (0.04–0.3) Donor Type Matched URD Marrow 1.0 Mismatched URD Marrow 0.3 (0.1–0.8) Mismatched RD Marrow 0.3 (0.1–2.3) 0.22 Single or Double UCB 2.0 (0.9–4.6) 0.08 Age at Transplant 1.0 10–17 years 2.4 (1.2–5.0) 0.01 18+ years 3.1 (1.4–7.0) Prior OI None 1.0 Yes 3.2 (1.5–6.9) Prior Transfusions None Yes 2.4 (1.0–5.8) 0.05 CMV Serostatus Patient negative/donor negative 1.0 Patient negative/donor positive 1.5 (0.7–3.4) 0.34 Patient positive 2.2 (1.1–4.3) 0.03 * Trial 1 (CY/TBI 450, MTX/MP or CSA) was excluded as there were only 8 patients in this group and a number of demographic and disease factors were unknown. Substantial progress has been made in the successful application of AD-HCT for FA. These data support the urgency of transplant prior to the onset of severe pancytopenia when risk of OI and transfusions are more likely, particularly when a suitable BM donor is available. While other regimens are being explored, CY/FLU/ATG/TBI300 with TS should be considered a new standard of care for FA patients undergoing AD-HCT. Disclosures: No relevant conflicts of interest to declare.