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

Abstract

IMPORTANCETests that predict outcomes for patients with acute myeloid leukemia (AML) are imprecise, especially for those with intermediate risk AML.OBJECTIVES To determine whether genomic approaches can provide novel prognostic information for adult patients with de novo AML. DESIGN, SETTING, AND PARTICIPANTS 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. EXPOSURES Whole-genome or exome sequencing and targeted deep sequencing. Risk of identification based on genetic data. MAIN OUTCOMES AND MEASURES Mutation patterns (including clearance of leukemia-associated variants after chemotherapy) and their association with event-free survival and overall survival. 10.5 (7.5-22.2) 42.2 (20.6-not estimable) 2.86 (1.39-5.88) 19.3 (7.5-42.3) 46.8 (22.6-not estimable) 2.88 (1.11-7.45) CONCLUSIONS AND RELEVANCEThe 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.

Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

“…This threshold was based on the specificity of our assay (Supplemental Results) and is comparable to previous analyses 11 and in agreement with a working definition of clonal hematopoiesis. 19 Variants were classified as known/putative driver mutations, variants of unknown significance, or germline polymorphisms based on published data, [20][21][22] as reported in detail previously.…”

“…On the other hand, our results are in agreement with a seminal report by Klco and colleagues, who identified persisting mutations in samples obtained approximately 30 days after the start of induction therapy in 24/50 AML patients. 11 In this cohort, which was partially pre-selected based on patient outcomes, mutation persistence associated with shorter EFS, but not OS, in multivariate analyses. Our work and the study by Klco and colleagues used similar VAF thresholds for the detection of persisting mutations (2% and 2.5%, respectively).…”

“…[7][8][9][10] In contrast, in another study analyzing a larger panel of genes in 50 AML patients, mutation persistence associated with shorter event-free and overall survival (OS). 11 Of note, clonal cytogenetic alterations also remain detectable in some patients in morphological remission, and this has been linked to inferior outcomes. 12,13 These conflicting results prompted us to genetically characterize paired samples, obtained at the time of diagnosis and during first remission, from a cohort of intensively treated AML patients.…”

Leukemic stem cells: identification and clinical application

“…MRD frequency measurement has been shown to have independent prognostic impact across different cytogenetic and molecular subgroups [42][43][44][45], and is currently used to refine risk group classifications after induction therapy. In particular, MRD is implemented in the HOVON/SAKK H132 study to guide decisions for transplantation type in intermediate risk patients.…”

Chromosome abnormalities at onset of complete remission are associated with worse outcome in patients with acute myeloid leukemia and an abnormal karyotype at diagnosis: CALGB 8461 (Alliance)

“…Whereas both our study and previous ones [10][11][12][13][14] show that cytogenetic analysis of CR samples can identify patients who have an increased risk of relapse or death, the resolution of cytogenetic analysis is relatively low. Other, more sensitive methodologies, such as mutation detection using DNA-or RNA-based real-time quantitative polymerase chain reaction (RQ-PCR) and/or next-generation sequencing, 25,26 or multiparameter flow cytometry immunophenotyping, [27][28][29] have become available. However, these techniques also have limitations.…”