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)
Key Points Exome sequencing of adult ETP-ALL reveals new recurrent mutations; in particular, DNMT3A is frequently mutated in adult ETP-ALL. More than 60% of all adult patients with ETP-ALL harbor a mutation that could potentially be targeted by a specific therapy.
IntroductionIn 2008, the World Health Organization classification of Tumors of the Hematopoietic and Lymphoid Tissues included "AML with mutated CEBPA" as a provisional favorable prognostic entity, and a routine CEBPA mutation screening was recommended for all acute myeloid leukemia (AML) patients with no detectable chromosomal abnormalities. 1,2 However, only patients with mutations in both CEBPA alleles (biCEBPA-mutated AML) have a prognostically favorable outcome. [3][4][5][6][7] The biCEBPA patients typically have a combination of an N-terminal frameshift mutation leading to a 30-kDa dominant-negative CEBPA isoform and a C-terminal in-frame mutation in the bZIP region, disrupting dimerization and DNA-binding activities of CEBPA. In murine bone marrow transplantation models, distinct but collaborative roles of both types of CEBPA mutations have been detected. 8 Furthermore, a combination of an N-and C-terminal disruption of the CEBPA gene synergistically resulted in fast and efficient development of leukemia in mice. [8][9][10] These experiments suggest that a biallelic disruption of CEBPA might be responsible for both the differentiation block and the enhanced proliferation of progenitor cells and thus be sufficient for leukemogenesis. Indeed, biCEBPA mutant AML represents as a very homogeneous AML subgroup with a distinct immunophenotype 11 and a characteristic gene expression profile. 3,6,7,12 Furthermore, biCEBPA mutant AML patients rarely have mutations in genes that are frequently mutated in CN-AML, such as the nucleophosmin (NPM1) gene, internal tandem duplications (ITDs) of the FLT3 gene, partial tandem duplications (PTDs) of the MLL gene (MLL-PTD), [3][4][5] or mutations in the TET2, isocitrate dehydrogenase (IDH)-1 and 2 or DNMT3A genes. [13][14][15] To identify potentially cooperating mutations associated with biCEBPAmutated AML, we performed whole exome sequencing. Thereby, we discovered a high frequency of N-terminal zinc finger (ZF1) mutations of GATA2 in patients with biCEBPA-mutated AML. GATA2 is a zinc finger transcription factor important for hematopoietic stem cell proliferation [16][17][18][19] and normal megakaryocytic development. 20 Somatic mutations affecting the C-terminal zinc finger (ZF2) of GATA2 are associated with the progression of chronic myeloid leukemia (CML), 21 Submitted January 12, 2012; accepted The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From whereas hereditary GATA2 ZF2 mutations predispose to AML and myelodysplastic syndrome. 22 Mutations targeting either of the 2 ZFs were described as a rare event in the M5 subtype of AML. 23 Here, we report a unique association of GATA2 ZF1 mutations and biCEBPA mutations in AML. Methods PatientsIn this analysis, we included diagnostic bone marrow or peripheral blood samples from 160 adult AML p...
P hiladelphia-like B-cell precursor acute lymphoblastic leukemia (Ph-like ALL) is characterized by distinct genetic alterations and inferior prognosis in children and younger adults. The purpose of this study was a genetic and clinical characterization of Ph-like ALL in adults. Twenty-six (13%) of 207 adult patients (median age: 42 years) with B-cell precursor ALL (BCP-ALL) were classified as having Ph-like ALL using gene expression profiling. The frequency of Ph-like ALL was 27% among 95 BCP-ALL patients negative for BCR-ABL1 and KMT2A-rearrangements. IGH-CRLF2 rearrangements (6/16; P=0.002) and mutations in JAK2 (7/16; P<0.001) were found exclusively in the Ph-like ALL subgroup. Clinical and outcome analyses were restricted to patients treated in German Multicenter Study Group for Adult ALL (GMALL) trials 06/99 and 07/03 (n=107). The complete remission rate was 100% among both Ph-like ALL patients (n=19) and the "remaining BCP-ALL" cases (n=40), i.e. patients negative for BCR-ABL1 and KMT2A-rearrangements and the Ph-like subtype. Significantly fewer Phlike ALL patients reached molecular complete remission (33% versus 79%; P=0.02) and had a lower probability of continuous complete remission (26% versus 60%; P=0.03) and overall survival (22% versus 64%; P=0.006) at 5 years compared to the remaining BCP-ALL patients. The profile of genetic lesions in adults with Ph-like ALL, including older adults, resembles that of pediatric Ph-like ALL and differs from the profile in the remaining BCP-ALL. Our study is the first to demonstrate that Ph-like ALL is associated with inferior outcomes in intensively treated older adult patients. Ph-like adult ALL should be recognized as a distinct, high-risk entity and further research on improved diagnostic and therapeutic approaches is needed.
The revised 2017 European LeukemiaNet (ELN) recommendations for genetic risk stratification of acute myeloid leukemia have been widely adopted, but have not yet been validated in large cohorts of AML patients. We studied 1116 newly diagnosed AML patients (age range, 18-86 years) who had received induction chemotherapy. Among 771 patients not selected by genetics, the ELN-2017 classification reassigned 26.5% of patients into a more favorable or, more commonly, a more adverse-risk group compared with the ELN-2010 recommendations. Forty percent of the cohort, and 51% of patients ≥60 years, were classified as adverse-risk by ELN-2017. In 599 patients <60 years, estimated 5-year overall survival (OS) was 64% for ELN-2017 favorable, 42% for intermediate-risk and 20% for adverse-risk patients. Among 517 patients aged ≥60 years, corresponding 5-year OS rates were 37, 16, and 6%. Patients with biallelic CEBPA mutations or inv(16) had particularly favorable outcomes, while patients with mutated TP53 and a complex karyotype had especially poor prognosis. DNMT3A mutations associated with inferior OS within each ELN-2017 risk group. Our results validate the prognostic significance of the revised ELN-2017 risk classification in AML patients receiving induction chemotherapy across a broad age range. Further refinement of the ELN-2017 risk classification is possible.
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