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. 2018 Dec;32(12):2546-2557.
doi: 10.1038/s41375-018-0257-z. Epub 2018 Oct 1.

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

Hartmut Döhner  1 , Anna Dolnik  2 , Lin Tang  3 , John F Seymour  4 , Mark D Minden  5 , Richard M Stone  6 , Teresa Bernal Del Castillo  7 , Haifa Kathrin Al-Ali  8 , Valeria Santini  9 , Paresh Vyas  10 , C L Beach  3 , Kyle J MacBeth  3 , Barry S Skikne  3 , Steve Songer  3 , Nora Tu  3 , Lars Bullinger  2   11 , Hervé Dombret  12
Affiliations

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

Hartmut Döhner et al. Leukemia. 2018 Dec.

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.

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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)
See this image and copyright information in PMC

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