Abstract
Relevant molecular tools for treatment stratification of patients ≥65 years with acute myeloid leukemia (AML) are lacking. We combined clinical data with targeted DNA- and full RNA-sequencing of 182 intensively and palliatively treated patients to predict complete remission (CR) and survival in AML patients ≥65 years. Intensively treated patients with NPM1 and IDH2R172 mutations had longer overall survival (OS), whereas mutated TP53 conferred lower CR rates and shorter OS. FLT3-ITD and TP53 mutations predicted worse OS in palliatively treated patients. Gene expression levels most predictive of CR were combined with somatic mutations for an integrated risk stratification that we externally validated using the beatAML cohort. We defined a high-risk group with a CR rate of 20% in patients with mutated TP53, compared to 97% CR in low-risk patients defined by high expression of ZBTB7A and EEPD1 without TP53 mutations. Patients without these criteria had a CR rate of 54% (intermediate risk). The difference in CR rates translated into significant OS differences that outperformed ELN stratification for OS prediction. The results suggest that an integrated molecular risk stratification can improve prediction of CR and OS and could be used to guide treatment in elderly AML patients.
Highlights
Acute myeloid leukemia (AML) is characterized by clonal expansion of early myeloid precursors
Among patients treated with intensive chemotherapy, 59% achieved complete remission and the median overall survival was 8.2 months when including all treatment regimens
Outcomes have rarely been characterized based on mutational status in older patients and gene expression data by RNA-seq in this AML population is lacking
Summary
Acute myeloid leukemia (AML) is characterized by clonal expansion of early myeloid precursors. As for most hematological malignancies, AML incidence increases with age, whereas survival rapidly decreases in older patients[1,2]. Patients above the age of 65, which constitutes more than 50% of all AML cases, differ considerably regarding patient-specific and leukemia-specific features compared to younger AML patients[2]. In elderly AML patients, favorable cytogenetics are less common whereas patients have higher prevalence of comorbidities and worse performance status, both risk factors for poor outcome[4,5]. Patients more frequently present with a secondary AML, either therapy-related (t-AML) after previous cytotoxic treatment or following an antecedent hematological disorder, (AHD–AML), such as myeloproliferative neoplasms (MPN) or MDS4,6. Agerelated sensitivity to drug toxicity and interactions with other drugs that elderly often take simultaneously may exacerbate drug toxicity in this group[3]
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