Fludarabin and rabbit antithymocyte globulin as conditioning for repeat transplantation after primary and secondary graft failure following unrelated hematopoietic stem cell transplantation

Abstract

Introduction: Primary or secondary graft failure is a serious complication of allogeneic stem cell transplantation. The underlying mechanism may be rejection mediated by recipient immunocompetent cells or loss of donor hematopoiesis due to other, often unknown causes. We here report on the results of second transplantation in 8 patients reconditioned with fludarabin and ATG in which an immunological cause of graft failure was either proven or suspected. Patients and Methods: Six male and 2 female patients with hematologic malignancies, median age 45 (22-55) years, receiving unrelated stem cell transplants in our institution within the last 6 years, experienced primary (n = 5) or secondary (n = 3) graft failure. Match was 7/8 in one, 8/8 in three, 8/10 in three and 9/10 in one case. Primary conditioning was myeloablative in all patients and included rabbit ATG either Genzyme or Fresenius in all but one. Graft source was bone marrow in 7 and PBSC in one case, respectively. Mechanism of graft failure was evaluated by morphology, immunophenotyping, chimerism and kinetics and was judged rejection in three and probably immunologically mediated in 5 cases. At a median of 42 (35-71) days following the first transplant 7 patients received PBSC and one patient bone marrow as a second transplant, 4 from the same and 4 from a different unrelated donor. Matches of the new donors were 6/8, 7/8, 8/10 and 10/10. Two earlier patients were given fludarabin 100 and 120 mg/m2 combined with ATG Genzyme 5 mg/kg BW, the later ones fludarabin 150 mg/m2 together with ATG 7.5 mg/kg BW. Results: Seven out of 8 patients engrafted at a median of 14 days after second and 58 days after first transplant. One non-engraftment occurred in a polytransfused patient with refractory anemia and primary rejection, after reconditioning with fludarabin 100 mg/m2 and ATG 5 mg/kg BW and grafting with the same donor. At a median observation time of 555 (266-2020) days 4 patients are alive and well. Four patients died at a median of 135 (75-337) days: two from relapse, one from aGvHD °IV and one from fungal sepsis. Conclusion: In primary and secondary graft failure after allogeneic stem cell transplantation, for reconditioning a highly immunosuppressive regimen with limited toxicity is warranted. Fludarabin 150 mg/m2 and ATG Genzyme 7.5 mg/kg BW is a very efficient and well tolerated combination enabling engraftment even across a two HLA antigen barrier.