Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML.

IDH1 and IDH2 mutations are recurring genetic changes in AML. They constitute a poor prognostic factor in CN-AML with mutated NPM1 without FLT3-ITD, which allows refined risk stratification of this AML subset.

To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P ‫؍‬ .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediaterisk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P ‫؍‬ .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P ‫؍‬ .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P ‫؍‬ .02 and P ‫؍‬ .22, respectively) and overall survival in younger intensively treated patients (P ‫؍‬ .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment. (Blood. 2011;117(7): 2137-2145)

We defined clinically relevant time points for NPM1(mut) MRD assessment that allow for the identification of patients with AML who are at high risk of relapse. Monitoring of NPM1(mut) transcript levels should be incorporated in future clinical trials to guide therapeutic decisions.

Key Points• In FLT3-ITD-positive AML, high allelic ratio and ITD insertion site in TKD1 predict for low complete remission rates and poor survival.• In FLT3-ITD-positive AML, allogeneic HSCT in first CR outweighs the negative impact of high allelic ratio on survival.The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P 5 .004) and IS in the tyrosine kinase domain 1 (TKD1, P 5 .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n 5 121) or autologous hematopoietic stem cell transplantation (HSCT, n 5 17), an allelic ratio ‡ 0.51 was associated with an unfavorable relapse-free (RFS, P 5 .0008) and overall survival (OS, P 5 .004); after allogeneic HSCT (n 5 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P 5 .02; OS, P 5 .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P 5 .38; OS, P 5 .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242. (Blood. 2014;124(23):3441-3449)