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TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.

ABSTRACT: BACKGROUND:Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). METHODS:Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. RESULTS:TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53-mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ?60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ? .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). CONCLUSIONS:The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484-3491. © 2016 American Cancer Society.

SUBMITTER: Kadia TM

PROVIDER: S-EPMC5269552 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.

Kadia Tapan M TM Jain Preetesh P Ravandi Farhad F Garcia-Manero Guillermo G Andreef Michael M Takahashi Koichi K Borthakur Gautam G Jabbour Elias E Konopleva Marina M Daver Naval G NG Dinardo Courtney C Pierce Sherry S Kanagal-Shamanna Rashmi R Patel Keyur K Estrov Zeev Z Cortes Jorge J Kantarjian Hagop M HM

Cancer 20160726 22

<h4>Background</h4>Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML).<h4>Methods</h4>Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis.<h4>Results</h4>TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitu ...[more]

PMID: 27463065

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Project description:BackgroundTP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53-mutated (TP53m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA).MethodsWe conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), duration of response (DoR), and overall response rate (ORR) among patients with TP53m AML receiving first-line treatment with IC, HMA, or VEN + HMA.ResultsSearches of EMBASE and MEDLINE identified 3006 abstracts, and 17 publications describing 12 studies met the inclusion criteria. Random-effects models were used to pool response rates, and time-related outcomes were analyzed with the median of medians method. IC was associated with the greatest CR rate of 43%, and CR rates were 33% for VEN + HMA and 13% for HMA. Rates of CR/CRi were comparable for IC (46%) and VEN + HMA (49%) but were lower for HMA (13%). Median OS was uniformly poor across treatments: IC, 6.5 months; VEN + HMA, 6.2 months; and HMA, 6.1 months. For IC, the EFS estimate was 3.7 months; EFS was not reported for VEN + HMA or HMA. The ORR was 41% for IC, 65% for VEN + HMA, and 47% for HMA. DoR was 3.5 months for IC, 5.0 months for VEN + HMA, and was not reported for HMA.ConclusionsDespite improved responses seen with IC and VEN + HMA compared to HMA, survival was uniformly poor, and clinical benefits were limited across all treatments for patients with newly diagnosed, treatment-naïve TP53m AML, demonstrating a significant need for improved treatment for this difficult-to-treat population.

Dataset Information

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.

Publications

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.

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