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

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 HMAbased 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.

Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine

“…We did not find any association between TP53 alterations (including mutation and/or deletion) and response to azacitidine but an association with shorter OS which was significant in univariable analysis (12.6 months in TP53wt versus 7.9 months in TP53mut [p<0.001]] and just below the threshold of significance in multivariable analysis (HR = 1.49; 95% CI = [0.95-2.34]; p = 0.081). This finding is comparable to recent data from phase II trial testing frontline decitabine in AML deemed unfit for IC [7,41]. Survival outcomes in our cohort are also in line with the biomarker cohort of the phase 3 trial AZA-AML-001 [22], which have a median OS of 7.2 months in TP53mut patients compared to 12 months in TP53wt patients.…”

Outcomes of newly diagnosed acute myeloid leukemia with myelodysplasia related changes and elderly acute myeloid leukemia following decitabine therapy in combination with priming regimen

“…On the other hand, the multivariate analysis showed that only TP53 mutation and platelets not doubling after treatment were independent prognostic factors affecting the OS of patients. Although it has been reported that demethylating drugs such as decitabine could improve the remission rate of patients with TP53 mutation, they could not improve their OS [19,20], which is in line with our findings herein concerning survival of patients harboring TP53 mutation. Platelet doubling after treatment was a predictive indicator for patients to achieve remission.…”

The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia

“…Eight of 45 patients had TP53 mutations, and five of these patients also had 17p loss. CR, PR, and ALE rates were similar in patients with TP53 mutations and those with wild-type TP53, but OS appeared to be worse in patients with mutated TP53 (p = 0.036) [38].…”

“…TP53 aberrations seem to predict favorable responses to hypomethylating treatment with decitabine. Becker et al analyzed outcomes associated with chromosome 17p loss or TP53 gene mutations in unfit elderly patients with AML [38]. In that study, 25 of 178 patients had loss of 17p, of whom 24 had a complex (CK?)…”