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TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

ABSTRACT: BACKGROUND:The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS:We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS:Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS:Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).

SUBMITTER: Welch JS

PROVIDER: S-EPMC5217532 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Welch John S JS Petti Allegra A AA Miller Christopher A CA Fronick Catrina C CC O'Laughlin Michelle M Fulton Robert S RS Wilson Richard K RK Baty Jack D JD Duncavage Eric J EJ Tandon Bevan B Lee Yi-Shan YS Wartman Lukas D LD Uy Geoffrey L GL Ghobadi Armin A Tomasson Michael H MH Pusic Iskra I Romee Rizwan R Fehniger Todd A TA Stockerl-Goldstein Keith E KE Vij Ravi R Oh Stephen T ST Abboud Camille N CN Cashen Amanda F AF Schroeder Mark A MA Jacoby Meagan A MA Heath Sharon E SE Luber Kierstin K Janke Megan R MR Hantel Andrew A Khan Niloufer N Sukhanova Madina J MJ Knoebel Randall W RW Stock Wendy W Graubert Timothy A TA Walter Matthew J MJ Westervelt Peter P Link Daniel C DC DiPersio John F JF Ley Timothy J TJ

The New England journal of medicine 20161101 21

<h4>Background</h4>The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear.<h4>Methods</h4>We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles ...[more]

PMID: 27959731

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Project description:BackgroundTP53 mutation (TP53mut ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53mut confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53mut AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).MethodsPatients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53mut was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.ResultsAmong 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53mut AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53mut versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone.ConclusionsPatients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.

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TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Publications

TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

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