Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia treated with azacitidine or conventional care

Hartmut Döhner, Anna Dolnik, Lin Tang, John F Seymour, Mark D Minden, Richard M Stone, Teresa Bernal Del Castillo, Haifa Kathrin Al-Ali, Valeria Santini, Paresh Vyas, C L Beach, Kyle J MacBeth, Barry S Skikne, Steve Songer, Nora Tu, Lars Bullinger, Hervé Dombret, Hartmut Döhner, Anna Dolnik, Lin Tang, John F Seymour, Mark D Minden, Richard M Stone, Teresa Bernal Del Castillo, Haifa Kathrin Al-Ali, Valeria Santini, Paresh Vyas, C L Beach, Kyle J MacBeth, Barry S Skikne, Steve Songer, Nora Tu, Lars Bullinger, Hervé Dombret

Abstract

Older patients with newly diagnosed acute myeloid leukemia (AML) in the phase 3 AZA-AML-001 study were evaluated at entry for cytogenetic abnormalities, and a subgroup of patients was assessed for gene mutations. Patients received azacitidine 75 mg/m2/day x7 days (n = 240) or conventional care regimens (CCR; n = 245): intensive chemotherapy, low-dose cytarabine, or best supportive care only. Overall survival (OS) was assessed for patients with common (occurring in ≥10% of patients) cytogenetic abnormalities and karyotypes, and for patients with recurring gene mutations. There was a significant OS improvement with azacitidine vs CCR for patients with European LeukemiaNet-defined Adverse karyotype (HR 0.71 [95%CI 0.51-0.99]; P = 0.046). Azacitidine-treated patients with -5/5q-, -7/7q-, or 17p abnormalities, or with monosomal or complex karyotypes, had a 31-46% reduced risk of death vs CCR. The most frequent gene mutations were DNMT3A (27%), TET2 (25%), IDH2 (23% [R140, 15%; R172, 8%]), and TP53 (21%). Compared with wild-type, OS was significantly reduced among CCR-treated patients with TP53 or NRAS mutations and azacitidine-treated patients with FLT3 or TET2 mutations. Azacitidine may be a preferred treatment for older patients with AML with Adverse-risk cytogenetics, particularly those with chromosome 5, 7, and/or 17 abnormalities and complex or monosomal karyotypes. The influence of gene mutations in azacitidine-treated patients warrants further study.

Conflict of interest statement

H. Döhner: Advisory Boards (with honoraria): AbbVie, Agios, Amgen, Astellas, Astex Pharmaceuticals, Celator, Celgene Corporation, Janssen, Jazz Pharmaceuticals, Novartis, Seattle Genetics, Sunesis. J.F.S.: Advisory Committees, AbbVie, Celgene Corporation, Genentech, Gilead, Janssen, Roche, Takeda; Consultancy, AbbVie, Celgene Corporation, Genentech, Gilead, Janssen, Roche, Takeda; Honoraria, AbbVie, Celgene Corporation, Genentech, Gilead, Janssen, Roche, Takeda; Travel support, AbbVie, Celgene Corporation; Research Funding, AbbVie, Janssen; Speakers Bureau, AbbVie, Celgene Corporation, Gilead, Janssen, Roche. R.M.S.: Consultancy, AbbVie, Agios, Amgen, BristolMeyersSquibb, Celator, Celgene Corporation, Janssen, Juno Therapeutics, Karyopharm, Merck, Novartis, Roche/Genentech, Pfizer, Seattle Genetics, Sunesis Pharmaceuticals, Xenetic Biosciences; Research Funding, Agios, Celator, Karyopharm, Novartis, Pfizer; Advisory Committees, Celgene Corporation. H.K.A.-A.: Consultancy, Honoraria and Research Funding, Celgene; Consultancy, Honoraria and Research Funding, Novartis. V.S.: Consultancy, Amgen, Astex, Celgene Corporation, Janssen, Novartis, Onconova; Honoraria, Celgene Corporation, Janssen, Novartis; Research Funding, Celgene Corporation. P.V.: Honoraria and Research Funding, Celgene Corporation. S.S., C.L.B., L.T., K.J.M., B.S.S.: Employment and equity ownership, Celgene Corporation. L.B.: Advisory Committees BristolMeyersSquibb, Boehringer Ingelheim, Celgene Corporation, Jazz Pharmaceuticals, Novartis, MSD Sharp & Dohme GmbH, Merck, Seattle Genetics. The remaining authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Patient subgroups according to modified 2010 ELN criteria* and frequency of specific chromosomal abnormalities or karyotypes
Fig. 2
Fig. 2
Overall survival associated with cytogenetic risk groups (per modified 2010 ELN criteria)
Fig. 3
Fig. 3
Overall survival associated with monosomal and complex karyotypes and with specific cytogenetic abnormalities occurring in ≥10% of patients
Fig. 4
Fig. 4
a Proportions of patients with specific gene mutations. b Oncoplot showing gene mutations in individual patients with intermediate-I/II risk (green) or poor-risk (orange) cytogenetics
Fig. 5
Fig. 5
Kaplan–Meier curves for gene mutations significantly (P < 0.05) associated with overall survival within treatment arms (mutant vs wild-type)

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