Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes

Abstract

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

Figures

Fig 1.

Trial profile. ITT, intent to treat; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning. (*) One patient received an RIC regimen, one patient did not proceed to hematopoietic cell transplantation (HCT) because of physician decision, one patient experienced relapse before conditioning, one patient withdrew consent after random assignment and did not undergo HCT; this latter patient was censored at the time of consent withdrawal. (†) One patient received a MAC regimen, and four patients experienced relapse before HCT and did not undergo HCT.

Fig 2.

(A) Overall survival (OS) and incidence of relapse by treatment arm and (B) relapse-free survival (RFS). MAC, myeloablative conditioning; RIC, reduced-intensity conditioning.

Fig 3.

Overall survival (OS) and incidence of relapse by treatment arm in patients with (A) acute myeloid leukemia and (B) myelodysplastic syndromes. MAC, myeloablative conditioning; RIC, reduced-intensity conditioning.

Fig 4.

Incidence of treatment-related mortality (TRM) by treatment arm. MAC, myeloablative conditioning; RIC, reduced-intensity conditioning.

Fig A1.

Forest plot of hazard ratios for overall survival for myeloablative conditioning (MAC) versus reduced-intensity conditioning (RIC) in various subgroup. AML, acute myeloid leukemia; Bu4/Cy, busulfan with cyclophosphamide (MAC); Flu/Bu2, fludarabine with busulfan (RIC); Flu/Bu4, fludarabine with busulfan (MAC); Flu/Mel, fludarabine with melphalan (RIC); HCT, hematopoietic cell transplantation; KPS, Karnofsky performance score; MDS, myelodysplastic syndromes.

Fig A2.

Core and protocol-specific toxicity (grade > 2) by treatment arm: (A) myeloablative conditioning and (B) reduced-intensity conditioning.