Dataset Information

Double CEBPA mutations are prognostically favorable in non-M3 acute myeloid leukemia patients with wild-type NPM1 and FLT3-ITD.

ABSTRACT: This study is aimed to investigate the pattern of CEBPA mutations and its clinical significance in Chinese non-M3 acute myeloid leukemia (AML) patients. The entire coding region of CEBPA gene was amplified by PCR and then sequenced in samples from 233 non-M3 AML patients. Fifty mutations were identified in 37 (15.8%) patients with eleven (4.7%) double mutated CEBPA (dmCEBPA) and twenty-six (11.1%) single mutated CEBPA (smCEBPA). dmCEBPA was exclusively observed in M1 and M2 subtypes of FAB classification (P = 0.008), whereas smCEBPA occurred in almost all subtypes (P = 0.401). Patients with dmCEBPA had significantly younger age and higher WBC counts than those with wtCEBPA (P = 0.016 and 0.043, respectively). Both dmCEBPA and smCEBPA were mainly present in cytogenetically normal patients. Patients with dmCEBPA achieved higher rate of complete (CR) than wtCEBPA patients (88% vs. 51%, P = 0.037), whereas smCEBPA and wtCEBPA groups are similar (47% vs. 51%, P = 0.810). Patients with dmCEBPA had a superior overall survival (OS) compared with patients with wtCEBPA (P = 0.033), whereas patients with smCEBPA had a similar OS as patients with wtCEBPA (P = 0.976). dmCEBPA but not smCEBPA was also associated with favorable outcome in patients with wild-type NPM1 and FLT3-ITD (NPM1(wt)FLT3-ITD(wt) ). Our data confirm that dmCEBPA but not smCEBPA is prognostically favorable in NPM1(wt)FLT3-ITD(wt) AML, and suggest that the entity AML with mutated CEBPA should be definitely designated as AML with dmCEBPA in WHO classification and smCEBPA should be excluded from the favorable risk of molecular abnormalities.

SUBMITTER: Wen XM

PROVIDER: S-EPMC4230151 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Double CEBPA mutations are prognostically favorable in non-M3 acute myeloid leukemia patients with wild-type NPM1 and FLT3-ITD.

Wen Xiang-Mei XM Lin Jiang J Yang Jing J Yao Dong-Ming DM Deng Zhao-Qun ZQ Tang Chun-Yan CY Xiao Gao-Fei GF Yang Lei L Ma Ji-Chun JC Hu Jia-Bo JB Qian Wei W Qian Jun J

International journal of clinical and experimental pathology 20140915 10

This study is aimed to investigate the pattern of CEBPA mutations and its clinical significance in Chinese non-M3 acute myeloid leukemia (AML) patients. The entire coding region of CEBPA gene was amplified by PCR and then sequenced in samples from 233 non-M3 AML patients. Fifty mutations were identified in 37 (15.8%) patients with eleven (4.7%) double mutated CEBPA (dmCEBPA) and twenty-six (11.1%) single mutated CEBPA (smCEBPA). dmCEBPA was exclusively observed in M1 and M2 subtypes of FAB class ...[more]

PMID: 25400766

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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.

Project description:ObjectiveWe aimed to retrospectively discern the heterogeneity of outcomes from clinicopathological characteristics and next-generation sequencing (NGS) data in adult patients with NPM1-mutated (NPM1mut ) acute myeloid leukemia (AML) induced with standard-dose (SD, 100-200 mg/m2 ) and intermediate-dose (ID, 1000-2000 mg/m2 ) cytarabine arabinose (Ara-C).MethodsIn the entire cohort and FLT3-ITD subgroups, multivariate Logistic and Cox regression analyses were used to analyze the comprehensive complete remission (cCR) rate after one or two induction cycles, event-free survival (EFS), and overall survival (OS).ResultsAmong a total of 203 NPM1mut patients evaluable for clinical outcome, 144 (70.9%) received a first SD-Ara-C induction and 59 (29.1%) received ID-Ara-C induction. Early death was recorded in seven (3.4%) after one or two cycles of induction. Focusing analysis on the NPM1mut /FLT3-ITD(-) subgroup, independent factors showing inferior outcome were presence of TET2 mutation [cCR rate, OR = 12.82 (95%CI 1.93-85.28), p = 0.008; EFS, HR = 2.92 (95%CI 1.46-5.86), p = 0.003], increasing age [EFS, HR = 1.49 (95%CI 1.10-2.02), p = 0.012 by every 10-years elevation], white blood cell count ≥60 × 109 /L [EFS, HR = 3.30 (95%CI 1.63-6.70), p = 0.001], and ≥4 mutated genes at initial diagnosis [OS, HR = 5.54 (95%CI 1.77-17.33), p = 0.003]. In contrast, when focusing on the NPM1mut /FLT3-ITD(+) subgroup, factors showing superior outcome were ID-Ara-C induction [cCR rate, OR = 0.20 (95%CI 0.05-0.81), p = 0.025; EFS, HR = 0.27 (95%CI 0.13-0.60), p = 0.001] and allo-transplantation [OS, HR = 0.45 (95%CI 0.21-0.94), p = 0.033]. Factors showing inferior outcome included CD34(+) [cCR rate, OR = 6.22 (95%CI 1.86-20.77), p = 0.003; EFS, HR = 2.01 (95%CI 1.12-3.61), p = 0.020] and ≥5 mutated genes [OS, HR = 2.85 (95%CI 1.33-6.10), p = 0.007].ConclusionWe conclude that TET2(+) , age, and white blood cell count convey an outcome risk modulation for AML with NPM1mut /FLT3-ITD(-) , as does CD34 and ID-Ara-C induction for NPM1mut /FLT3-ITD(+) . The findings permit re-stratification of NPM1mut AML into distinct prognostic subsets to guide risk-adapted individualized treatment.

Dataset Information

Double CEBPA mutations are prognostically favorable in non-M3 acute myeloid leukemia patients with wild-type NPM1 and FLT3-ITD.

Publications

Double CEBPA mutations are prognostically favorable in non-M3 acute myeloid leukemia patients with wild-type NPM1 and FLT3-ITD.

Similar Datasets

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