Allotransplantation with Reduced Intensity Conditioning Regimens Modified To Lessen Transplant-Related Mortality Is a Useful Treatment for High-Risk Myeloid Diseases.

Our stem cell transplant program treats a spectrum of hematologic malignancies that includes a number of patients with high risk myeloid disease. These challenging patients have lead our adult allotransplant program to employ alternative approaches to standard conditioning over the last three years using reduced intensity conditioning. The regimens are amenable to modification, allowing a goal of maximizing length of remission or period of low tumor burden while minimizing transplant-related mortality. We have conducted a retrospective study of patients receiving modified reduced intensity regimens of fludarabine, melphalan and Campath. Incidence of relapse, survival, tempo of engraftment and incidence of grades I–II and III–IV acute GVHD were compared. Three modifications of the regimen were: fludarabine 30 mg/m² x 5d, melphalan 140 mg/m² x 1d, Campath 20 mg/d x 5 days (Group 1); fludarabine and melphalan the same and Campath 20 mg/d x 3d (Group 2); fludarabine and melphalan the same and Campath 20 mg/d x 1d (Group 3). Fifteen patients with a median age of 48, range 24 to 58 years, were in the study. Twelve patients had AML, two had CML and one had MDS. Six patients were in CR at time of transplant and nine had detectable tumor or disease. Patients were not randomized for a conditioning group but were transplanted in a consecutive fashion; seven patients were in Group 1, five patients in Group 2 and three patients in Group 3. Stem cell sources were related BM for four recipients, related peripheral blood for one, unrelated BM for four, unrelated peripheral blood for four, a combination of related BM and peripheral blood for one, and one cord blood. All patients received an adequate CD34+ cell dose and none of the products was manipulated. Match grade was 6/6 for 13 transplants, 5/6 for one and 4/6 for the cord blood transplant. GVHD prophylaxis was the same for all recipients (standard dose cyclosporine or tacrolimus and MMF) tapering after day 30. No failures to achieve a WBC graft, including the cord blood recipient, occurred. Neutrophils (ANC >500/dl) engrafted at a median of day 13 (range 10 – 48 days). Median follow-up was seven months (range 1.5 – 30 months). Two patients in Group 1 had grade I aGVHD and one continued to chronic GVHD. One patient in Group 2 had grade II and one had grade III aGVHD. None in Group 3 had aGVHD. Relapse occurred in three patients in Group 1 and they received DLI immunotherapy; no relapse occurred in Group 2 or 3. Twelve patients survived to day 100; three from Groups 1 or 2 did not. Four were alive at one year and four others who are still alive have not reached the one year mark. Four of the seven patients who have died were from residual disease; the other three were from treatment-related toxicity within the first 100 days. Eight of 15 patients remain in follow-up. We conclude that the application of fludarabine, melphalan, Campath conditioning regimens has been successful in this high risk group of patients. The cell source from an unrelated or related donor does not impact outcomes. There was a very low incidence of toxicity related to aGVHD, no failure to engraft and no unexpected complications. Lastly, this regimen has allowed modification to enhance its tumoricidal properties to the extent that these patients with myeloid disease have experienced a low 20% incidence of relapse. We will continue to modify and expand the patient selection criteria to elderly (< 70 years old) AML in remission.