Alternate Donor HSCT for Fanconi Anemia (FA): Results of a Total Body Irradiation (TBI) Dose De-Escalation Study.

Major advances have been made that have improved survival in FA patients undergoing alternate donor hematopoietic stem cell transplantation (AD-HSCT). While addition of fludarabine (FLU) to cyclophosphamide (CY) and single dose total body irradiation (450 cGy TBI) has been the single most important factor improving engraftment rates in FA patients, risks of infection and late effects remain important challenges. Seeking to reduce these risks, we hypothesized that FA patients undergoing AD-HSCT could reliably achieve neutrophil engraftment with less or no irradiation due to the profound immunosuppressive effects of FLU. Therefore, we conducted a single center, single arm, TBI dose de-escalation trial designed to determine the lowest possible dose of TBI required for engraftment in recipients of T cell depleted bone marrow (TCD BM) or umbilical cord blood (UCB) from AD. All patients received CY 10 mg/kg x 4 days, FLU 35 mg/m2 x 4 days, ATG 30 mg/kg x 5 days and a single fraction of TBI with CT guided thymic shielding. TBI dose de-escalation strata were: TBI 300 cGy (cohort 1); TBI 150 cGy (cohort 2); no TBI (cohort 3). All patients received CSA and methylprednisolone as GVHD prophylaxis and G-CSF 5 ug/kg/day until engraftment. The decision to proceed with each stepwise decrease in TBI is based upon achieving primary neutrophil engraftment in 10 of 10 patients at each dose level or 14 of 15 patients if one graft failure is observed in the first 10 patients. More than 1 graft failure in 15 patients was considered unacceptable and the next higher TBI dose level was thereafter to be considered the optimal dose. Between July 2006-July 2007, 13 FA patients were enrolled with 11 in cohort I (as patient 11 was enrolled prior to proven engraftment in patient 10) and 2 thus far in cohort 2. All patients achieved primary engraftment at a median of 11 days after HSCT. One patient (TBI 300) however developed secondary graft failure at day 178 and died at day 253. Two patients developed grade II acute GVHD and none developed chronic GVHD. With a median follow up of 10.2 months, 12 of 13 patients are alive with complete chimerism and no active GVHD.

The results demonstrate that TBI 450 cGy is not required for engraftment in recipients of CY-FLU-ATG and HLA matched or mismatched TCD BM or UCB from AD. While longer followup is needed to quantitate the impact of lower dose radiation on risks of infection and therapy-related late effects, TBI 450 cGy should no longer be considered the standard of care.