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Systematic Review and Meta-analysis of Prospective Clinical Trials

John Koreth, MBBS, DPhil; Richard Schlenk, MD; Kenneth J. Kopecky, PhD; Sumihisa Honda, PhD; Jorge Sierra, MD, PhD; Benjamin J. Djulbegovic, MD, PhD; Martha Wadleigh, MD; Daniel J. DeAngelo, MD, PhD; Richard M. Stone, MD; Hisashi Sakamaki, MD, PhD; Frederick R. Appelbaum, MD; Hartmut Döhner, MD; Joseph H. Antin, MD; Robert J. Soiffer, MD; Corey Cutler, MD, MPH, FRCPC

JAMA. 2009;301(22):2349-2361.

Context  The optimal treatment of acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Current consensus, based on cytogenetic risk, recommends myeloablative allogeneic stem cell transplantation (SCT) for poor-risk but not for good-risk AML. Allogeneic SCT, autologous transplantation, and consolidation chemotherapy are considered of equivalent benefit for intermediate-risk AML.

Objective  To quantify relapse-free survival (RFS) and overall survival benefit of allogeneic SCT for AML in CR1 overall and also for good-, intermediate-, and poor-risk AML.

Methods  Systematic review and meta-analysis of prospective trials evaluating allogeneic SCT vs nonallogeneic SCT therapies for AML in CR1. The search used the combined search terms allogeneic; acut* and leukem*/leukaem*/leucem*/leucaem*/aml; myelo* or nonlympho* in the PubMed, Embase, and Cochrane Registry of Controlled Trials databases in March 2009. The search identified 1712 articles.

Study Selection  Prospective trials assigning adult patients with AML in CR1 to undergo allogeneic SCT vs nonallogeneic SCT treatment(s) based on donor availability and trials reporting RFS and/or overall survival outcomes on an intention-to-treat, donor vs no-donor basis were identified.

Data Extraction  Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (HRs) with 95% confidence intervals (CIs) were determined.

Data Synthesis  Overall, 24 trials and 6007 patients were analyzed (5951 patients in RFS analyses and 5606 patients in overall survival analyses); 3638 patients were analyzed by cytogenetic risk (547, 2499, and 592 with good-, intermediate-, and poor-risk AML, respectively). Interstudy heterogeneity was not significant. Fixed-effects meta-analysis was performed. Compared with nonallogeneic SCT, the HR of relapse or death with allogeneic SCT for AML in CR1 was 0.80 (95% CI, 0.74-0.86). Significant RFS benefit of allogeneic SCT was documented for poor-risk (HR, 0.69; 95% CI, 0.57-0.84) and intermediate-risk AML (HR, 0.76; 95% CI, 0.68-0.85) but not for good-risk AML (HR, 1.06; 95% CI, 0.80-1.42). The HR of death with allogeneic SCT for AML in CR1 was 0.90 (95% CI, 0.82-0.97). Significant overall survival benefit with allogeneic SCT was documented for poor-risk (HR, 0.73; 95% CI, 0.59-0.90) and intermediate-risk AML (HR, 0.83; 95% CI, 0.74-0.93) but not for good-risk AML (HR, 1.07; 95% CI, 0.83-1.38).

Conclusion  Compared with nonallogeneic SCT therapies, allogeneic SCT has significant RFS and overall survival benefit for intermediate- and poor-risk AML but not for good-risk AML in first complete remission.

Author Affiliations: Division of Hematologic Malignancies, Dana Farber Cancer Institute, Boston, Massachusetts (Drs Koreth, Wadleigh, DeAngelo, Stone, Antin, Soiffer, and Cutler); University Hospital of Ulm, Ulm, Germany (Drs Schlenk and Döhner); Fred Hutchinson Cancer Research Center, Seattle, Washington (Drs Kopecky and Appelbaum); Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan (Dr Honda); Hospital de la Santa Creu i Sant Pau, Barcelona, Spain (Dr Sierra); University of South Florida, Center for Evidence Based Medicine and Health Outcomes and H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida (Dr Djulbegovic); and Tokyo Metropolitan Komagome Hospital, Tokyo, Japan (Dr Sakamaki).

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