Abstract

FA is the most common heritable marrow failure syndrome with a high predisposition to myelodysplastic syndrome and leukemia. Great strides have been made in optimizing the conditioning regimen and GVHD prophylaxis, necessarily tailored to these patients as a result of their underlying defect in DNA repair. Prior to 1995, survival rates after alternate donor hematopoietic cell transplantation (AD-HCT) were exceptionally poor (<20%). After 1999, the addition of fludarabine (FLU) significantly improved engraftment and survival. However, risks of infection and late effects remained important challenges. Seeking to reduce these risks, we conducted a single center, single arm, TBI dose deescalation trial designed to determine the lowest possible dose of TBI required for engraftment in recipients of T cell depleted AD marrow (TCD BM). All patients received cyclophosphamide (CY) 10 mg/kg × 4 days, FLU 35 mg/m2 × 4 days, ATG 30 mg/kg ×5 days and a single fraction of TBI with CT guided thymic shielding (TS). TBI dose deescalation 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 was 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 any of the first 10 patients. More than 1 graft failure in 15 patients was considered unacceptable and the next higher TBI dose level was then considered the optimal dose. Between July 2006-May 2008, 19 FA patients were enrolled with 17 in cohort 1 and 2 in cohort 2. Five patients received 5–6/6 unmanipulated UCB because a marrow donor could not be identified. All patients achieved primary engraftment at a median of 11 days after AD-HCT. However, 2/2 patients who received TBI 150 developed secondary graft failure at 76 and 114 days after HCT. The dose de-escalation was stopped with TBI 300 cGy identified as the lowest possible dose in the context of FLU/CY given concomitantly. Thus far, 17 patients have been treated with TBI 300. As shown, results compare favorably with prior regimens using TBI 450 with and without TS (table).

Outcomes after AD-HCT in Standard Risk FA Patients

 Neutrophil Engraftment Acute GVHD Chronic GVHD 1 Year Survival 
TS = thymic shielding 
TBI 450 no TS 21 95% 24% 19% 67% 
TBI 450 +TS 12 92% 42% 8% 83% 
TBI 300 +TS 17 94% 25% 0% 92% 
 Neutrophil Engraftment Acute GVHD Chronic GVHD 1 Year Survival 
TS = thymic shielding 
TBI 450 no TS 21 95% 24% 19% 67% 
TBI 450 +TS 12 92% 42% 8% 83% 
TBI 300 +TS 17 94% 25% 0% 92% 

Our results demonstrate that TBI 300 cGy is sufficient for consistent engraftment in recipients of CY-FLU-ATG and HLA matched or mismatched TCD AD BM or UCB and represents a new standard of care for this patient population. Longer follow up is needed to quantitate the impact of lower dose radiation on immune recovery, risks of infection, cancer risk and other therapy-related late effects.

Disclosures: No relevant conflicts of interest to declare.

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