Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia

Abstract

Key Points• We present comprehensive information on genetic driver events in a uniformly treated cohort of 664 adult AML patients aged 18 to 86 years.• Mutations in NPM1, FLT3, CEBPA, TP53, and, in patients ,60 years, DNMT3A and RUNX1, are the most important molecular risk factors in AML.The clinical and prognostic relevance of many recently identified driver gene mutations in adult acute myeloid leukemia (AML) is poorly defined. We sequenced the coding regions or hotspot areas of 68 recurrently mutated genes in a cohort of 664 patients aged 18 to 86 years treated on 2 phase 3 trials of the German AML Cooperative Group (AMLCG). The median number of 4 mutations per patient varied according to cytogenetic subgroup, age, and history of previous hematologic disorder or antineoplastic therapy. We found patterns of significantly comutated driver genes suggesting functional synergism. Conversely, we identified 8 virtually nonoverlapping patient subgroups, jointly comprising 78% of AML patients, that are defined by mutually exclusive genetic alterations. These subgroups, likely representing distinct underlying pathways of leukemogenesis, show widely divergent outcomes. Furthermore, we provide detailed information on associations between gene mutations, clinical patient characteristics, and therapeutic outcomes in this large cohort of uniformly treated AML patients. In multivariate analyses including a comprehensive set of molecular and clinical variables, we identified DNMT3A and RUNX1 mutations as important predictors of shorter overall survival (OS) in AML patients <60 years, and particularly in those with intermediate-risk cytogenetics. NPM1 mutations in the absence of FLT3-ITD, mutated TP53, and biallelic CEBPA mutations were identified as important molecular prognosticators of OS irrespective of patient age. In summary, our study provides a comprehensive overview of the spectrum, clinical associations, and prognostic relevance of recurrent driver gene mutations in a large cohort representing a broad spectrum and age range of intensively treated AML patients. (Blood. 2016;128(5):686-698)

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

“…Therefore, patients with adverse genetic characteristics were underrepresented due to their lower response rates, and outcomes in general were relatively favorable compared to cohorts of untreated AML patients. 14 However, RFS and OS of our cohort were similar to the outcomes of all patients treated on the AMLCG-2008 trial who reached CR/CR i , suggesting that our results can be generalized to patients in CR/CR i after intensive induction chemotherapy.…”

“…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. 14 Additionally, NPM1 and CEBPA mutations and FLT3 internal tandem duplications (FLT3-ITDs) were tested by standard methods. [23][24][25][26][27] Genotyping of T lymphocytes was performed for selected patients as described in the Supplement.…”

“…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. 14 We aimed to study associations between persistence of AML-associated somatic mutations during remission and patient outcomes in the context of other known prognostic factors, including the most recent European LeukemiaNet (ELN) classification of baseline genetic risk. 15 Since post-remission treatment is an important factor that may affect the ultimate outcome of patients harboring persisting pre-leukemic clones after the initial line of therapy, we also studied the impact of allogeneic transplantation on relapse risk in patients with and without mutation persistence.…”

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

“…33 Next-generation sequencing (NGS) studies indicate that mutp53-AML cells display mostly heterozygous mutations. 34 However, the heterozygous status is often unstable, as TP53 mutations are frequently followed by loss of heterozygosity (LOH) during cancer progression. Indeed, p53 LOH is frequently found in t-AML, AML postmyeloproliferative Ph1-negative neoplasms, and in LFS-related AML.…”

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

“…Therefore, it will now be important to understand the effects of spliceosomal gene mutations in the context of other genetic abnormalities commonly co-occurring with them. These include mutations in SF3B1 and inv(3)/t(3;3), which activate the proto-oncogene ecotropic viral integration-1 (EVI1) [78], as well as commonly co-existing mutations in SRSF2 and IDH2 and U2AF1 and ASXL1 [79][80][81]. These studies may reveal novel contributions of splicing mutations to cancer and potentially open a novel path to develop therapeutic strategies for spliceosomal mutant cancers.…”