Phase 3 Trial Supports High-intensity Pretransplant Myeloablative Regimens for MDS, AML
Results of a phase 3 randomized trial support high intensity conditioning prior to allogeneic stem cell transplantation as standard of care.
ORLANDO – Results of a phase 3 randomized trial support high intensity conditioning with myeloablative regimens prior to allogeneic stem cell transplantation as standard of care for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)K who are candidates for such treatment.1
Patients receiving myeloablative regimens have a significantly higher relapse-free survival, Bart L. Scott, MD, of the Fred Hutchinson Cancer Research Center and University of Washington in Seattle, WA, reported at the 57th American Society of Hematology (ASH) Annual Meeting.
The trial also confirmed that reduced intensity conditioning resulted in higher relapse rates—albeit lower treatment-related mortality—compared with myeloablative regimens.
“Although reduced intensity conditioning has a lower toxicity profile and lower treatment-related mortality, retrospective analyses have shown higher relapse rates and similar overall survival when compared to myeloablative regimens in patients with myeloid malignancies,” Dr. Scott said.
To compare outcomes by conditioning intensity, the Blood and Marrow Transplant Clinical Trials Network enrolled 272 patients, 54 with MDS and 218 with AML, and randomly assigned them to receive a myeloablative regimen (135 patients) or a reduced intensity regimen (137 patients).
Reduced intensity regimens were fludarabine (120 mg/m2-180 mg/m2) with busulfan (≤8 mg/kg oral or IV equivalent) (110 patients) or melphalan (<150 mg/m2) (27 patients). The myeloablative regimens were busulfan (16 mg/kg oral or 12.8 mg/kg IV) with cyclophosphamide (120 mg/kg) (40 patients) or fludarabine (120 mg/m2-180 mg/m2) (87 patients); or cyclophosphamide (120 mg/kg) and total body irradiation (1200cGy-1420 cGy) (8 patients).
Seven patients did not receive a transplant, 4 in the reduced intensity group and 3 in the myeloablative group, primarily due to relapse. The majority of patients randomly assigned to reduced intensity conditioning (80.3%) received a busulfan-based regimen.
At 18 months postrandomization, overall survival—the primary end point—was 67.7% for patients on the reduced intensity conditioning arm, compared with 77.4% for those on the myeloablative arm.
Although survival was higher with the myeloablative regimens, the difference was not statistically significant (difference of 9.7%; 95% CI: -0.9–20.3; P = .07).
At 18 months, treatment-related mortality on the reduced intensity conditioning arm was 4.4% versus 15.8% on the myeloablative arm (P = .02). Relapse-free survival was 47.3% versus 68.8%, respectively; this difference was statistically significant (difference of 20.4%; 95% CI: 8.8–31.9; P < .01), Dr. Scott reported.
At day 100, grade 2-4 acute graft-versus-host disease (GVHD) was 31.6% on the reduced intensity conditioning arm compared with 44.7% on the myeloablative arm (P = .024).
A total of 44 patients in the reduced intensity conditioning arm died, with relapse the primary cause of death (86%). Among patients who received a myeloablative regimen, 31 died, with GVHD the primary cause of death (52%), followed by relapse (32%).
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The planned enrollment was 356 patients; however, accrual was stopped early due to a presumed benefit of the myeloablative regimens, as assessed by an independent safety review, Dr. Scott said.
“Myeloablative conditioning remains the treatment of choice over reduced intensity conditioning for those patients who are eligible to receive a high intensity-based regimen,” Dr. Scott said, concluding that “novel, less toxic myeloablative or effective posttransplant maintenance regimens are needed to improve disease control in those patients who require reduced intensity conditioning regimens.”
- Scott BL, Pasquini MC, Logan B, et al. Results of a phase III randomized, multi-center study of allogeneic stem cell transplantation after high versus reduced intensity conditioning in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Oral presentation at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 8, 2015; Orlando, FL.