Alternative Donor Hematopoietic Cell Transplantation for Patients with Fanconi Anemia.
Authors: MacMillan Margaret L. , Blazar Bruce R. , Defor Todd E. , Dusenbery Kathryn E. , Slungaard Arne , Verneris Michael R. , Young Jo-Anne H. , Zierhut Heather , Weisdorf Daniel J. , Wagner John E. 
Published: October 2019

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<0.01). Similarly, chronic GVHD was significantly lower with TCD BM (9%) vs T replete BM or UCB (25% and 15%, respectively; p=0.04). For the entire cohort of 127 patients, the probability of survival was 61% at 1 year and 54% at 5 years with a median follow-up of 9 years. Mortality was higher in recipients who were older (>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<0.01). For 10 patients on Trial 5 who had no prior history of transfusions or OI, incidences of neutrophil and platelet are 100% and 100%, acute and chronic GVHD 17% and 0%, and probability of survival is 92%.
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) <0.01     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) <0.01 Donor Type     Matched URD Marrow 1.0     Mismatched URD Marrow 0.3 (0.1–0.8) <0.01     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     <10 years 1.0     10–17 years 2.4 (1.2–5.0) 0.01     18+ years 3.1 (1.4–7.0) <0.01 Prior OI     None 1.0     Yes 3.2 (1.5–6.9) <0.01 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.