Treatment of Graft Failure with Fludarabine (Flu), Antithymocyte Globulin (ATG) and a Second Allogeneic Stem Cell Transplantation (SCT).

Failure to engraft after SCT is a life-threatening complication. In a pilot trial, we assessed the feasibility of a second SCT after conditioning with Flu and ATG. Primary graft failure was defined by the inability to achieve any donor cell engraftment and to sustain an absolute neutrophil count (ANC) >0.5 x 10⁹/l, for 3 consecutive days by day 28 after SCT. Secondary graft failure was defined as recurrent neutropenia with an ANC < 0.5 x 10⁹/l for at least 7 consecutive days. Between July 1998 and April 2003, nine patients (pts) with various hematological malignancies (chronic myeloid leukemia [CML] n=5, acute myeloid leukemia [AML] n=2, myelodysplastic syndromes [MDS] n=2) were prospectively studied. Their median age was 38 years (range, 33-75). Eight had a primary and one had a secondary graft failure after conditioning with Bu/Cy (N=3), Flu/Bu (N=1), Melphalan/Flu (N=3), and Cy/Thiotepa/TBI (N=2). Cultures for CMV, Parvo-virus and HSV-6 were all negative. Median time between the first and the second SCT was 54 days (range, 31–140 days). All pts received Flu 25 mg/m² intravenously (IV)/day on days −5 to −1, and ATG 20 mg/kg/day IV on days −3, −2, −1. Transplantation was provided on day 0. Tacrolimus was used for graft-versus-host disease (GVHD) prophylaxis. Eight pts received their second SCT from the peripheral blood of same donor [matched siblings (sib) =3, one-antigen mismatched sib =2, two-antigen mismatched sibling =1, haplo-identical sibling=1] whereas one had a cord blood (CB) transplant. The median dose of CD34+cells infused was 8 x 10⁶/kg. Three pts had early death and were not evaluable. Six other pts, including the one who received a CB, had engrafted with 100% donor chimerism. Five recovered an ANC> 500 at a median of 18 days (range, 9–42 days). Complete disease response was documented in 4 pts including 3 with CML who achieved molecular response, and one with MDS. Three pts had grade 2, and three grade 3–4 acute GVHD. Median survival time of all pts was 7 months from their first SCT (range, 2–24 months). We conclude that Flu/ATG is a feasible regimen for second SCT as treatment for graft failure, allowing engraftment of donor hematopoiesis. GVHD was a major problem, and future studies should include more intense immunosuppressive prophylaxis.