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Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.

ABSTRACT: Tests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.To determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML.Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (mean age, 50.8 years) treated with standard induction chemotherapy at a single site starting in March 2002, with follow-up through January 2015. In addition, deep digital sequencing was performed on paired diagnosis and remission samples from 50 patients (including 32 with intermediate-risk AML), approximately 30 days after successful induction therapy. Twenty-five of the 50 were from the cohort of 71 patients, and 25 were new, additional cases.Whole-genome or exome sequencing and targeted deep sequencing. Risk of identification based on genetic data.Mutation patterns (including clearance of leukemia-associated variants after chemotherapy) and their association with event-free survival and overall survival.Analysis of comprehensive genomic data from the 71 patients did not improve outcome assessment over current standard-of-care metrics. In an analysis of 50 patients with both presentation and documented remission samples, 24 (48%) had persistent leukemia-associated mutations in at least 5% of bone marrow cells at remission. The 24 with persistent mutations had significantly reduced event-free and overall survival vs the 26 who cleared all mutations. Patients with intermediate cytogenetic risk profiles had similar findings. [table: see text].The detection of persistent leukemia-associated mutations in at least 5% of bone marrow cells in day 30 remission samples was associated with a significantly increased risk of relapse, and reduced overall survival. These data suggest that this genomic approach may improve risk stratification for patients with AML.

SUBMITTER: Klco JM

PROVIDER: S-EPMC4621257 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.

Klco Jeffery M JM Miller Christopher A CA Griffith Malachi M Petti Allegra A Spencer David H DH Ketkar-Kulkarni Shamika S Wartman Lukas D LD Christopher Matthew M Lamprecht Tamara L TL Helton Nicole M NM Duncavage Eric J EJ Payton Jacqueline E JE Baty Jack J Heath Sharon E SE Griffith Obi L OL Shen Dong D Hundal Jasreet J Chang Gue Su GS Fulton Robert R O'Laughlin Michelle M Fronick Catrina C Magrini Vincent V Demeter Ryan T RT Larson David E DE Kulkarni Shashikant S Ozenberger Bradley A BA Welch John S JS Walter Matthew J MJ Graubert Timothy A TA Westervelt Peter P Radich Jerald P JP Link Daniel C DC Mardis Elaine R ER DiPersio John F JF Wilson Richard K RK Ley Timothy J TJ

JAMA 20150801 8

<h4>Importance</h4>Tests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.<h4>Objectives</h4>To determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML.<h4>Design, setting, and participants</h4>Whole-genome or exome sequencing was performed on samples obtained at disease presentation from 71 patients with AML (mean age, 50.8 years) treated with standard ind ...[more]

PMID: 26305651

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Project description:BACKGROUND:The majority of studies that provide insights into the influence of the microbiome on the health of hematologic malignancy patients have concentrated on the transplant setting. Here, we sought to assess the predictive capacity of the gastrointestinal microbiome and its relationship to infectious outcomes in patients with acute myeloid leukemia (AML). METHODS:16s rRNA-based analysis was performed on oral swabs and stool samples obtained biweekly from baseline until neutrophil recovery following induction chemotherapy (IC) in 97 AML patients. Microbiome characteristics were correlated with clinical outcomes both during and after IC completion. RESULTS:At the start of IC, higher stool Shannon diversity (hazard ratio [HR], 0.36; 95% confidence interval [CI], .18-.74) and higher relative abundance of Porphyromonadaceae (HR, 0.36; 95% CI, .18-.73) were associated with increased probability of remaining infection-free during neutropenia. A baseline stool Shannon diversity cutoff of <2 had optimal operating characteristics for predicting infectious complications during neutropenia. Although 56 patients received therapy >72 hours with a carbapenem, none of the patients had an infection with an extended spectrum ?-lactamase-producing organism. Patients who received carbapenems for >72 hours had significantly lower ?-diversity at neutrophil recovery (P = .001) and were approximately 4 times more likely to have infection in the 90 days following neutrophil recovery (HR, 4.55; 95% CI, 1.73-11.93). CONCLUSIONS:Our results suggest that gut microbiome evaluation could assist with infectious risk stratification and that improved targeting of antibiotic administration during IC could decrease subsequent infectious complications in AML patients.Baseline microbiome diversity is a strong independent predictor of infection during acute myeloid leukemia induction chemotherapy (IC) among clinical and microbiome covariates. Higher baseline levels of Porphyromonadaceae appear protective against infection, while carbapenem use is associated with consequences to the microbiome and infection susceptibility post-IC.

Dataset Information

Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.

Publications

Association Between Mutation Clearance After Induction Therapy and Outcomes in Acute Myeloid Leukemia.

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