Dataset Information

Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation.

ABSTRACT: To determine the association of somatic mutations in acute myeloid leukemia (AML) with risk of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT), we retrospectively studied pre-transplantation genetic profiles obtained from next-generation sequencing of 26 genes in 112 adult patients with AML who underwent alloHSCT. Univariable and multivariable regression analyses were used to assess the association between the presence of a pathogenic mutation and risk of relapse after alloHSCT. Eighty-six percent (96 of 112) of patients had at least 1 pathogenic mutation. Mutations in TP53, WT1, and FLT3-internal tandem duplication (ITD) were associated with an increased risk of relapse after alloHSCT (adjusted hazard ratio [aHR], 2.90; P?=?.009; aHR, 2.51; P=?.02; and aHR, 1.83; P?=?.07, respectively). DNMT3A mutation in the absence of FLT3-ITD and NPM1 mutations was associated with a lower relapse risk (aHR, .22; P?=?.04). Comparison of pre-alloHSCT and post-alloHSCT genetic profiles showed clonal evolution in 6 of 6 patients, including acquisition of actionable mutations in 4 patients. In summary, genetic profiling is useful for assessing relapse risk in patients with AML undergoing alloHSCT and may identify patients in need of strategies to reduce this risk. Clonal evolution is present at post-alloHSCT relapse and repeat genetic profiling may uncover acquired actionable mutations.

SUBMITTER: Luskin MR

PROVIDER: S-EPMC5067228 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Publications

Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation.

Luskin Marlise R MR Carroll Martin M Lieberman David D Morrissette Jennifer J D JJD Zhao Jianhua J Crisalli Lisa L Roth David B DB Luger Selina M SM Porter David L DL Reshef Ran R

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 20160728 11

To determine the association of somatic mutations in acute myeloid leukemia (AML) with risk of relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT), we retrospectively studied pre-transplantation genetic profiles obtained from next-generation sequencing of 26 genes in 112 adult patients with AML who underwent alloHSCT. Univariable and multivariable regression analyses were used to assess the association between the presence of a pathogenic mutation and risk of relapse afte ...[more]

PMID: 27478011

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Project description:Minimal residual disease (MRD) in acute myeloid leukemia (AML) is typically measured using multiparameter flow cytometry (MFC). Detection of leukemia mutations using multigene next-generation sequencing (NGS) can potentially be used to measure residual disease. We used a targeted 28-gene NGS panel to detect mutations and different-from-normal 10-color MFC to measure MRD in AML patients before allogeneic hematopoietic stem cell transplantation (HCT). Residual disease was defined when any abnormal blast population was detected using MFC and when any leukemia allele was detected with a variant allele frequency (VAF) ≥ 5% using NGS. We tracked the clearance of leukemia alleles between AML diagnosis and immediately before HCT and found that mutations in DNMT3A, TET2, and JAK2 were less likely to be cleared than NPM1, IDH 1/2, and FLT3-ITD. Despite varying sensitivities, the concordance rate of residual disease detection before HCT using the 2 assays was 44 of 62 (71%) evaluable cases. Discordance could be explained by residual mutations in DNMT3A and TET2 that were not detected by MFC and presence of residual leukemia mutations with VAF below the established thresholds for mutation calling. Presence of flow MRD and residual mutations immediately before HCT using the 2 assays was associated with relapse risk (MFC: hazard ratio, 4.62; 95% confidence interval [CI], 1.32 to 16.09; P = .016 and NGS: hazard ratio, 4.35; 95% CI, 1.63 to 11.6; P = .003) and survival (MFC: hazard ratio, 2.44; 95% CI, 1 to 5.97; P = .05 and NGS: hazard ratio, 2.1; 95% CI, .97 to 4.55; P = .059) after HCT. Residual disease detected concurrently by MFC and NGS conferred the highest relapse risk compared with patients who were either negative by both assays or had discordant status (overall, P = .008). Although MFC is universally applicable, a multigene NGS approach to measuring residual disease in AML provides additional information on differential clearance of disease alleles and can assess clonal architecture before transplantation.

Dataset Information

Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation.

Publications

Clinical Utility of Next-Generation Sequencing for Oncogenic Mutations in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation.

Similar Datasets

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