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.
Highlights
These authors contributed : Lars Bullinger, Hervé DombretCo-senior authors: Lars Bullinger, Hervé DombretElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Melbourne, and University of Melbourne, Parkville, Australia 4 University of Toronto, Toronto, ON, Canada 5 Dana-Farber Cancer Institute, Boston, MA, United StatesAcute myeloid leukemia (AML) is associated with a range of recurring cytogenetic abnormalities and gene mutations [1,2,3,4]
The influence of VAFs of mutant TP53, NRAS, FLT3TKD, and TET2 at baseline on Overall survival (OS) vs. wild-type genes in the Cox model stratified by treatment showed a significant increase in relative hazards on OS with increasing mutant TP53 (P < 0.0001) and TET2 (P = 0.042) VAFs
Prognosis is dismal for older patients with acute myeloid leukemia (AML) and Adverse-risk cytogenetics, including those with complex or monosomal karyotypes
Summary
These authors contributed : Lars Bullinger, Hervé Dombret. Acute myeloid leukemia (AML) is associated with a range of recurring cytogenetic abnormalities and gene mutations [1,2,3,4]. Cytogenetics and gene mutations influence survival in older patients with acute myeloid leukemia. AML with mutated RUNX1 and AML with BCR-ABL1, have been included in the 2016 update of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia [7]. Mutational testing for NPM1, CEBPA, and FLT3 is advised in the 2010 European LeukemiaNet (ELN) recommendations for AML [1], and the 2017 update to the ELN recommendations lists three additional genes—RUNX1, ASXL1, and TP53—that can inform risk stratification, mainly based on experience with intensive chemotherapy (IC) in relatively younger patients [4]. Patterns of comutations have been identified that have distinct prognostic implications in AML [3]
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