Genotypic and clinical heterogeneity within NCCN favorable-risk acute myeloid leukemia.

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KITwt); and AML with normal cytogenetics and mutations in NPM1 (NPM1mut); or biallelic mutations in CEBPA (CEBPAmut/mut), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPAmut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1mut AML and CEBPAmut/mut AML show significantly reduced overall survival in comparison with CBF-KITwt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management.

Familial myelodysplastic syndrome/acute myeloid leukemia.

A growing number of inherited genetic loci that contribute to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) development in both children as well as adults are rapidly being identified. In recognition of the clinical impact of this emerging field, the World Health Organization, National Comprehensive Cancer Network, and European LeukemiaNet have all added consideration of inherited predisposition to MDS/AML classification and management. Study of these disorders is providing unique insight into the biology of both sporadic and familial MDS/AML. International collaborative efforts to store germline tissue, document family histories, and pool data are essential to progress in diagnosing and treating both hereditary and sporadic forms of MDS/AML.

TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: a Cancer and Leukemia Group B study.

PURPOSE: To determine the frequency of TET2 mutations, their associations with clinical and molecular characteristics and outcome, and the associated gene- and microRNA-expression signatures in patients with primary cytogenetically normal acute myeloid leukemia (CN-AML). PATIENTS AND METHODS: Four-hundred twenty-seven patients with CN-AML were analyzed for TET2 mutations by polymerase chain reaction and direct sequencing and for established prognostic gene mutations. Gene- and microRNA-expression profiles were derived using microarrays. RESULTS: TET2 mutations, found in 23% of patients, were associated with older age (P < .001) and higher pretreatment WBC (P = .04) compared with wild-type TET2 (TET2-wt). In the European LeukemiaNet (ELN) favorable-risk group (patients with CN-AML who have mutated CEBPA and/or mutated NPM1 without FLT3 internal tandem duplication [FLT3-ITD]), TET2-mutated patients had shorter event-free survival (EFS; P < .001) because of a lower complete remission (CR) rate (P = .007), and shorter disease-free survival (DFS; P = .003), and also had shorter overall survival (P = .001) compared with TET2-wt patients. TET2 mutations were not associated with outcomes in the ELN intermediate-I-risk group (CN-AML with wild-type CEBPA and wild-type NPM1 and/or FLT3-ITD). In multivariable models, TET2 mutations were associated with shorter EFS (P = .004), lower CR rate (P = .03), and shorter DFS (P = .05) only among favorable-risk CN-AML patients. We identified a TET2 mutation-associated gene-expression signature in favorable-risk but not in intermediate-I-risk patients and found distinct mutation-associated microRNA signatures in both ELN groups. CONCLUSION: TET2 mutations improve the ELN molecular-risk classification in primary CN-AML because of their adverse prognostic impact in an otherwise favorable-risk patient subset. Our data suggest that these patients may be candidates for alternative therapies.

A hospital-based case-control study of acute myeloid leukemia in Shanghai: analysis of personal characteristics, lifestyle and environmental risk factors by subtypes of the WHO classification.

OBJECTIVES: The objectives are (1) to investigate and identify potential risk factors (personal characteristics, lifestyle and environmental factors) of acute myeloid leukemia (AML), and (2) to explore the relationships between potential risk factors and AML subtypes according to the World Health Organization (WHO) classification of myeloid neoplasms. MATERIALS AND METHODS: The investigation was a hospital-based case-control study consisting of 722 confirmed AML cases and 1444 individually gender-age-matched patient controls at 29 hospitals in Shanghai. A 17-page questionnaire was used to obtain information on: demographics, medical history, family history, lifestyle risk factors, employment history, residential history, and environmental and occupational exposures. Certain occupations of interest triggered a second questionnaire, which was occupation-specific and asked for more details about jobs, tasks, materials used and work environment. Risk estimates (odds ratios and 95% confidence intervals) were calculated using conditional logistic regression models. RESULTS: Several potential risk factors of AML (all subtypes combined) and individual subtypes were identified; including low-level education, body mass index (BMI), blood transfusion, smoking, alcohol consumption, home or workplace renovation, living on a farm, planting crops, raising livestock or animals, employment as farm workers or in the agricultural industry, and exposures to insecticides or fertilizers. Some risk factors applied to all or several subtypes (such as low-level education and living on a farm), while others were limited to one or two specific subtypes (such as home/office renovation and acute promyelocytic leukemia). An inverse association was found between BMI and overall AML or the sub-category "AML not otherwise categorized", whereas a positive association between BMI and the subtype acute promyelocytic leukemia was detected. An unexpected finding was the association between the use of traditional Chinese medicines and a reduced risk of AML in general as well as several major subtypes. CONCLUSIONS: The study identified a number of risk factors for AML in general as well as for some specific subtypes. Some of the risk factors were subtype-specific. The difference in risk by subtype underscores the importance of investigating the etiologic commonality and heterogeneity of AML by subtype in epidemiologic research.