Further Analysis of Trials With Azacitidine in Patients With Myelodysplastic Syndrome: Studies 8421, 8921, and 9221 by the Cancer and Leukemia Group B Lewis R. Silverman, David R. McKenzie, Bercedis L. Peterson, James F. Holland, Jay T. Backstrom, C.L. Beach, and Richard A. Larson A B S T R A C T Purpose Within the last two decades, a new understanding of the biology of myelodysplastic syndrome (MDS) has developed. With this understanding, new classification systems, such as the WHO diagnostic criteria, and the International Prognostic Scoring System and response criteria guidelines reported by the International Working Group (IWG) have been developed. We report the combined results of three previously reported clinical trials (n = 309) with azacitidine using the WHO classification system for MDS and acute myeloid leukemia (AML) and IWG criteria for response. Patients and Methods Data from three sequential Cancer and Leukemia Group B trials with azacitidine were recollected and reanalyzed as part of the New Drug Application process. The trials were conducted with either intravenous or subcutaneous azacitidine (75 mg/m 2 /d for 7 days every 28 days). Results Complete remissions were seen in 10% to 17% of azacitidine-treated patients; partial remissions were rare; 23% to 36% of patients had hematologic improvement (HI). The median number of cycles to first response was three, and 90% of responses were seen by cycle 6. Using current WHO criteria, 103 patients had AML at baseline; 35% to 48% had HI or better responses. The median survival time for the 27 AML patients randomly assigned to azacitidine was 19.3 months compared with 12.9 months for the 25 patients assigned to observation. Furthermore, azacitidine did not increase the rate of infection or bleeding above the rate caused by underlying disease. Conclusion Azacitidine provides important clinical benefits for patients with high-risk MDS. J Clin Oncol 24:3895-3903. © 2006 by American Society of Clinical Oncology INTRODUCTION In 1984, the Cancer and Leukemia Group B (CALGB) began a series of clinical trials with aza- citidine (Vidaza; Pharmion Corporation, Over- land Park, KS) in patients with myelodysplastic syndrome (MDS). 1-4 These studies and other sup- portive data culminated in the 2004 US Food and Drug Administration approval of azacitidine for treatment of symptomatic patients with MDS. During the intervening two decades, a greater un- derstanding of the biology of myelodysplasia has evolved, along with a new classification system developed by WHO that more clearly distin- guishes MDS from acute myeloid leukemia (AML) and from chronic myeloproliferative dis- orders. 5,6 In addition, an International Working Group (IWG) sponsored by the National Cancer Institute (NCI) has published new response crite- ria for evaluation of new treatments for MDS. 7,8 As part of the New Drug Application process, Pharmion recollected and reanalyzed the CALGB data, including expert pathology review of blood and bone marrow slides. Some of the CALGB data from these three trials was previously published using the protocol-specified diagnostic and re- sponse criteria. Here, we report the combined results of a reanalysis using the WHO classifica- tion for MDS and AML and the IWG criteria for response in MDS. PATIENTS AND METHODS Data Collection For the reanalysis, data were recollected from pa- tients enrolled onto CALGB Protocols 8421, 8921, and 9221. 1-3 A comprehensive retrospective collection and re- verification of all clinical data in the original protocols From the Mount Sinai School of Medi- cine, New York, NY; Pharmion Corpora- tion, Overland Park, KS; Cancer and Leukemia Group B Statistical Center and Duke University, Durham, NC; and the University of Chicago, Chicago, IL. Submitted February 2, 2006; accepted June 15, 2006. Supported by federal grants from the US Food and Drug Administration, by National Cancer Institute (NCI) Grant No. CA31946 to the Cancer and Leukemia Group B, and by NCI Grants No. CA04457, CA33601, and CA41287. The subsequent recollec- tion and further analyses were spon- sored by Pharmion Corporation. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors’ disclosures of potential con- flicts of interest and author contribu- tions are found at the end of this article. Address reprint requests to Lewis R. Silverman, MD, Division of Hematology/ Oncology, Mount Sinai School of Medi- cine, One Gustave L. Levy Place, Box 1129, New York, NY 10029; e-mail: lewis.silverman@mssm.edu. © 2006 by American Society of Clinical Oncology 0732-183X/06/2424-3895/$20.00 DOI: 10.1200/JCO.2005.05.4346 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 24  NUMBER 24  AUGUST 20 2006 3895 Downloaded from ascopubs.org by 3.238.176.130 on June 16, 2022 from 003.238.176.130 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.