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

Abstract

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 MethodsPatients 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 HLAmatched 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. ResultsPlanned 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, 20.8% 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). ConclusionOS 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.

Conditioning intensity in secondary AML with prior myelodysplastic syndrome/myeloproliferative disorders: an EBMT ALWP study

“…This supports the current understanding that allogeneic HCT is likely the best long-term treatment strategy for this highest-risk patient population 28,29 compared with only 10% long-term survival in patients who receive chemotherapy alone. 6 This study indicates that patients who received myeloablative regimens had a lower risk 21 This present study also showed no difference in NRM between the 2 conditioning groups, which is different from many prior retrospective studies in patients with AML/MDS who received allogeneic HCT. [14][15][16][17][18][19][20]30 In the current era of improved supportive care and understanding of management of posttransplantation complications, NRM has overall declined compared with years past, although prospective data still suggest that NRM is generally less in patients who received RICs.…”

“…Although our study included only patients with sAML with high-risk cytogenetics and active disease going into transplant, which typically is considered a very high-risk group, our cumulative incidence of relapse was not higher than what is typically noted in the literature for this population, regardless of the 21,25 This may suggest that even in these very high-risk patients, long-term survival can be achieved. However, our current knowledge of AML now includes a robust understanding of the importance of molecular data in risk stratification of patients.…”

“…However, patients who underwent MAC did have improved relapse-free survival, suggesting that MAC should be the preferred conditioning regimen in patients with MDS/AML who are fit enough to tolerate it. 21 In older and less fit patients in whom MAC is not an option, RIC regimens are effective for AML in first or second complete remission (CR1 or CR2). Although most available data are retrospective in nature and employ a variety of regimens, reported long-term survival rates at 5 years have been described to be approximately 40%.…”

Myeloablative busulfan/cytoxan conditioning versus reduced-intensity fludarabine/melphalan conditioning for allogeneic hematopoietic stem cell transplant in patients with acute myelogenous leukemia

“…Two meta-analyses suggest that RIC may be associated with higher relapse rate (RR) in acute leukemia [5,6]. Furthermore, in the LBA-8 study, which was a prospective randomized trial of MAC (chemotherapy-based or TBI-based) versus RIC regimens for allo-hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) or AML, RIC resulted in a significant reduction in NRM, whereas MAC resulted in significantly lower RR, higher relapse-free survival (RFS), and a trend toward improved overall survival (OS) [7]. These data support MAC as the preferred approach for those able to tolerate it.…”

“…For example, some data suggest that Flu/Mel may be associated with lower RR compared to Flu/Bu, despite both being grouped as RIC regimens [9]. In the LBA-8 study, separate outcomes were not reported for Flu/Mel and Flu/Bu [7]. In studies of MAC versus RIC, results of TBIBC and chemotherapy-based conditioning are often combined; however, patients with AML are increasingly being prepared for allo-HSCT with chemotherapy-based conditioning rather than TBIBC, and review of a large database showed a RFS and OS advantage associated with chemotherapy [10].…”