Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia

Heiko Becker,Milena Pantic,Konstanze Döhner,Lars Bullinger,Ulrich Germing,Dietmar Pfeifer,Hartmut Döhner,Anne Hagemeijer,Justus Duyster,Julius Wehrle,Pierre W Wijermans,Andrea Kuendgen,Arnold Ganser,Björn Hackanson,Uwe Platzbecker,Gabriele Ihorst,Michael Lübbert,Björn H Rüter

doi:10.1007/s00277-020-04082-7

Abstract

TP53 aberrations reportedly predict favorable responses to decitabine (DAC) in acute myeloid leukemia (AML). We evaluated clinical features and outcomes associated with chromosome 17p loss or TP53 gene mutations in older, unfit DAC-treated AML patients in a phase II trial. Of 178 patients, 25 had loss of 17p in metaphase cytogenetics; 24 of these had a complex (CK+) and 21 a monosomal karyotype (MK+). In analyses in all patients and restricted to CK+ and MK+ patients, 17p loss tended to associate with higher rates of complete remission (CR), partial remission (PR), or antileukemic effect (ALE). Despite favorable response rates, there was no significant OS difference between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort. TP53 mutations were identified in eight of 45 patients with material available. Five of the eight TP53-mutated patients had 17p loss. TP53-mutated patients had similar rates of CR/PR/ALE but shorter OS than those with TP53 wild type (P = 0.036). Moreover, patients with a subclone based on mutation data had shorter OS than those without (P = 0.05); only one patient with TP53-mutated AML had a subclone. In conclusion, 17p loss conferred a favorable impact on response rates, even among CK+ and MK+ patients that however could not be maintained. The effect of TP53 mutations appeared to be different; however, patient numbers were low. Future research needs to further dissect the impact of the various TP53 aberrations in HMA-based combination therapies. The limited duration of favorable responses to HMA treatment in adverse-risk genetics AML should prompt physicians to advance allografting for eligible patients in a timely fashion.

Highlights

The hypomethylating agents (HMA) decitabine (DAC) and azacitidine (AZA) are a standard of care in acute myeloid leukemia (AML) and higher risk MDS patients not eligible for intensive treatment
We described that patients with AML or MDS and a monosomal karyotype (MK+) benefitted from DAC treatment, when multiple monosomies were present. [3, 9, 15] The MK+ status is closely associated with the presence of a complex karyotype (CK+) [15], and MK+ and CK+ are associated with mutations in TP53 [16,17,18,19]
Patients with loss of 17p overall tended to have favorable response rates in comparison with patients without loss of 17p (CR/partial remission (PR)/antileukemic effect (ALE) vs stable disease (SD)/progressive disease (PD)/early death (ED), P = 0.08). This was true when analyses were conducted only among patients with CK+ (P = 0.01) or MK+ (P = 0.05). Despite these favorable response rates and the median overall survival (OS) was longer for patients with loss of 17p especially in the CK+ and MK+ cohort, there was no significant difference in the OS between patients with or without loss of 17p in the entire cohort or in the CK+ and MK+ cohort, as the OS curves crossed shortly after the 6-month mark

Summary

Introduction

The hypomethylating agents (HMA) decitabine (DAC) and azacitidine (AZA) are a standard of care in AML and higher risk MDS patients not eligible for intensive treatment. While dynamic features, such as early platelet response [1], can be. Several studies reported associations between outcomes of patients with MDS or AML receiving HMAs and genetic aberrations, DNA methylation, mRNA or microRNA expression, or other markers (e.g., HbF) [2,3,4,5,6,7,8,9,10,11,12,13,14]. Among patients with chromosome 17p aberrations, those treated with AZA tended to have a better overall survival (OS) than those treated with conventional care regimens [16]

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Conclusion