Haplo Recipients Research Articles

Sirolimus and tacrolimus allow engraftment of haploidentical and other alternative donor stem cells after non-myeloablative conditioning

Sirolimus (Rapamycin) was added to an established non-myeloablative regimen in order to examine its effects on engraftment and GVHD. Between 5/2001 and 7/2003 32 patients with advanced hematological malignancies received alternative donor hematopoietic cell transplantation. Ages ranged from 22–72 (median 62), and prior therapies from 1–6 (median 3). All received cyclophosphamide 1 gram/M2 days -7 and -6, and fludarabine 25 mg/M2 days -7 through -3 (5 doses). Sirolimus began on day -7 and tacrolimus on day -4, with methotrexate 5 mg/M2 days 1, 3, and 6 after stem cell infusion. Graft sources included haploidentical related donors (3 or 4/6 antigen matched-haplo)-11 cases, 5/6 matched related donors-8 cases, matched unrelated donors (URD) 12 cases, and in one case cord blood. Patients receiving haplo stem cells also received anti-thymocyte globulin 30 mg/M2 days -1, 1, 3, and 6. Engraftment was assessed by whole blood RFLP analysis or XY FISH (sex mismatched transplants). 30/32 patients, including all 11 haplo-stem cell recipients and all 12 unrelated donor recipients, engrafted stably. Only transient, incomplete engraftment was seen in the cord blood recipient and one 5/6 matched recipient. Engraftment was >90% donor in 19/32 (59%) by day 30 and in 20 of 25 (80%) evaluable patients by day 100. 3/5 patients with suboptimal engraftment at day 100 had residual circulating CLL cells. Significant renal dysfunction (creatinine >2.5mg/dl) occurred in 15/32 by Day 100 with 2 patients needing dialysis. Renal failure resolved or abated greatly when tacrolimus was reduced or discontinued. Day 100 transplant related mortality was 3/11 (36%) in haplo-transplant patients and 1/20 (5%) of URD or 5/6 (low risk) transplant patients. Acute GVHD (<D100) was seen in 21 of 32 patients (66%), but was in general easily managed with steroids, particularly after low risk transplants. Day 100 transplant related mortality was 3 of 11 haplo recipients and 1 of 19 low risk patients. In total 20/32 patients survive at a median 209 days post-transplant. 14 of these 20 patients have been free of progression of malignancy since transplant and one more has been disease free for 16 months since chemotherapy and donor lymphocyte infusion (ie. 47% currently progression free). Sirolimus added to tacrolimus and methotrexate appears to facilitate engraftment, minimize graft versus host disease, and potentially contribute to control of malignant disease.