Azacitidine for Front-Line Therapy of Patients with AML: Reproducible Efficacy Established by Direct Comparison of International Phase 3 Trial Data with Registry Data from the Austrian Azacitidine Registry of the AGMT Study Group

Lisa Pleyer, Hartmut Döhner, Hervé Dombret, John F Seymour, Andre C Schuh, C L Beach, Arlene S Swern, Sonja Burgstaller, Reinhard Stauder, Michael Girschikofsky, Heinz Sill, Konstantin Schlick, Josef Thaler, Britta Halter, Sigrid Machherndl Spandl, Armin Zebisch, Angelika Pichler, Michael Pfeilstöcker, Eva M Autzinger, Alois Lang, Klaus Geissler, Daniela Voskova, Wolfgang R Sperr, Sabine Hojas, Inga M Rogulj, Johannes Andel, Richard Greil, Lisa Pleyer, Hartmut Döhner, Hervé Dombret, John F Seymour, Andre C Schuh, C L Beach, Arlene S Swern, Sonja Burgstaller, Reinhard Stauder, Michael Girschikofsky, Heinz Sill, Konstantin Schlick, Josef Thaler, Britta Halter, Sigrid Machherndl Spandl, Armin Zebisch, Angelika Pichler, Michael Pfeilstöcker, Eva M Autzinger, Alois Lang, Klaus Geissler, Daniela Voskova, Wolfgang R Sperr, Sabine Hojas, Inga M Rogulj, Johannes Andel, Richard Greil

Abstract

We recently published a clinically-meaningful improvement in median overall survival (OS) for patients with acute myeloid leukaemia (AML), >30% bone marrow (BM) blasts and white blood cell (WBC) count ≤15 G/L, treated with front-line azacitidine versus conventional care regimens within a phase 3 clinical trial (AZA-AML-001; NCT01074047; registered: February 2010). As results obtained in clinical trials are facing increased pressure to be confirmed by real-world data, we aimed to test whether data obtained in the AZA-AML-001 trial accurately represent observations made in routine clinical practice by analysing additional AML patients treated with azacitidine front-line within the Austrian Azacitidine Registry (AAR; NCT01595295; registered: May 2012) and directly comparing patient-level data of both cohorts. We assessed the efficacy of front-line azacitidine in a total of 407 patients with newly-diagnosed AML. Firstly, we compared data from AML patients with WBC ≤ 15 G/L and >30% BM blasts included within the AZA-AML-001 trial treated with azacitidine ("AML-001" cohort; n = 214) with AAR patients meeting the same inclusion criteria ("AAR (001-like)" cohort; n = 95). The current analysis thus represents a new sub-analysis of the AML-001 trial, which is directly compared with a new sub-analysis of the AAR. Baseline characteristics, azacitidine application, response rates and OS were comparable between all patient cohorts within the trial or registry setting. Median OS was 9.9 versus 10.8 months (p = 0.616) for "AML-001" versus "AAR (001-like)" cohorts, respectively. Secondly, we pooled data from both cohorts (n = 309) and assessed the outcome. Median OS of the pooled cohorts was 10.3 (95% confidence interval: 8.7, 12.6) months, and the one-year survival rate was 45.8%. Thirdly, we compared data from AAR patients meeting AZA-AML-001 trial inclusion criteria (n = 95) versus all AAR patients with World Health Organization (WHO)-defined AML ("AAR (WHO-AML)" cohort; n = 193). Within the registry population, median OS for AAR patients meeting trial inclusion criteria versus all WHO-AML patients was 10.8 versus 11.8 months (p = 0.599), respectively. We thus tested and confirmed the efficacy of azacitidine as a front-line agent in patients with AML, >30% BM blasts and WBC ≤ 15 G/L in a routine clinical practice setting. We further show that the efficacy of azacitidine does not appear to be limited to AML patients who meet stringent clinical trial inclusion criteria, but instead appears efficacious as front-line treatment in all patients with WHO-AML.

Keywords: AZA-AML-001 trial; Austrian Azacitidine Registry (AAR); acute myeloid leukaemia (AML); azacitidine; real-world data.

Conflict of interest statement

Lisa Pleyer has been a consultant for Agios, Celgene, Bristol-Myers Squibb and Novartis and reports receiving honoraria and travel support from Agios, Celgene, Bristol-Myers Squibb, Novartis and AOP Orphan Pharmaceuticals. Hartmut Döhner has been a consultant for Celgene and reports having received honoraria from Celgene. Hervé Dombret has been a consultant for Celgene, Amgen and Erytech Pharma, reports receiving research funding from Amgen, Roche-Genentech, Novartis, Ariad, Kite Pharma, Oncoethix and Ambit and reports receiving honoraria from Celgene, Amgen, Roche-Genentech, Novartis, Ariad, Kite Pharma, Daiichi Sankyo, Pfizer, Servier, Sanofi, Astellas, Janssen, Sunesis, Agios, Seattle Genetics, Cellectis, Boehringer-Ingelheim, Karyopharm and Lilly. John F. Seymour has been a consultant to Celgene and received honoraria and travel support. Andre C. Schuh has been a consultant for Celgene, Amgen and Lundbeck and reports receiving honoraria from Celgene, Amgen and Lundbeck. CL Beach and Arlene S. Swern are full time employees and stockholders of Celgene Corp. Sonja Burgstaller has been a consultant for Celgene and Novartis, a member on the Board of Directors or advisory committees for Celgene and Novartis and reports receiving research funding from Celgene and honoraria from AOP Orphan Pharmaceuticals, Celgene, Mundipharma and Novartis. Reinhard Stauder has been a consultant and a member on the Board of Directors or advisory committees for Celgene and reports receiving research funding and honoraria from Celgene, Teva (Ratiopharm) and Novartis. Michael Girschikofsky has been a consultant for Mundipharma and reports receiving honoraria from Mundipharma and Pfizer and research funding from Pfizer. Heinz Sill reports receiving research funding from Celgene and has been an advisory board member for Celgene. Sigrid Machherndl Spandl has been a member of an advisory board for Celgene. Armin Zebisch reports receiving honoraria from Celgene. Michael Pfeilstöcker has been a consultant for Celgene and Novartis and reports receiving honoraria from Celgene, Novartis and Janssen-Cilag. Alois Lang has been a consultant for Celgene. Klaus Geissler has been a member of advisory boards for Celgene. Wolfgang R. Sperr has been a consultant for Celgene. Richard Greil reports receiving honoraria from Bristol-Myers-Squibb, Cephalon, Amgen, Eisai, Mundipharma, Merck, Janssen-Cilag, Genentech, Novartis, AstraZeneca, Boehringer Ingelheim, Pfizer, Roche and Sanofi Aventis, research funding from Cephalon, Celgene, Amgen, Mundipharma, Genentech, Pfizer, GSK and Ratiopharm and has been a consultant for Bristol-Myers-Squibb, Cephalon and Celgene. The other authors declare that no competing interests exist.

Figures

Figure 1
Figure 1
CONSORT diagram. a Subset of patients included in pooled analysis (AML-001-like).
Figure 2
Figure 2
Overall survival (OS) in AML patients with >30% BM blasts and A) Total patient cohorts; (B) AML-MRC; (C) AML with NCCN poor-risk cytogenetics; (D) AML with NCCN intermediate-risk cytogenetics; and (E) Normal karyotype.
Figure 3
Figure 3
Median OS and one-year survival rates in AML patients with >30% BM blasts and A) Total patient cohorts; (B) AML-MRC; (C) AML with NCCN poor-risk cytogenetics; (D) AML with NCCN intermediate-risk cytogenetics; and (E) Normal karyotype.

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