Nucleophosmin (NPM1) mutations are common in acute myeloid leukemia and are associated with high remission rates and prolonged survival with intensive chemotherapy. NPM1 mutations are rare in myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and the clinical outcomes of these patients, when treated with intensive chemotherapy, are unknown. We retrospectively evaluated the clinicopathologic characteristics and the impact of therapy in 31 patients with MDS or MDS/MPN and NPM1 mutations. Next-generation sequencing was performed at diagnosis in 22 patients. Median age was 62 years (range, 19-86). Twenty-four patients (77%) had normal karyotype, and all had multilineage dysplasia. Most patients could be classified as MDS with excess blasts (19/31, 61%). NPM1 mutations were detected at a median allele frequency of 0.38 (range, 0.09-0.49). Mutation burden did not correlate with bone marrow blast frequency, and its clearance seemed to be associated with decreased morphologic dysplasia. Ten of the 31 patients (32%) received cytotoxic chemotherapy, 20 (65%) hypomethylating agents, and 1 (4%) lenalidomide. Sequential sequencing was available in 16 (52%) patients, and mutation burden correlated with disease status and response to therapy. Patients treated with chemotherapy had higher complete response rates (90% vs 28%, P = .004), longer median progression-free survival (not reached vs 7.5 months, P = .023), and overall survival (not reached vs 16 months, P = .047). Intensive chemotherapy and allogeneic stem cell transplantation (SCT) may be associated with improved clinical outcomes in patients with NPM1-mutated MDS or MDS/MPN who are candidates for this form of therapy.

• Atg7 expression is associated with shorter remission duration in AML.• Atg7 inhibition is a proapoptotic phenotype and enhances sensitivity to chemotherapy.Autophagy is a cellular adaptive mechanism to stress, including that induced by chemotherapeutic agents. Reverse phase protein array suggested that high expression of the essential autophagy-related protein, Atg7, was associated with shorter remission in newly diagnosed acute myeloid leukemia (AML) patient samples, indicating a role in chemoresistance. Knockdown of Atg7 in AML cells using short hairpin RNA markedly increased apoptosis and DNA damage following treatment with cytarabine and idarubicin. Interestingly, coculture of AML cells with stromal cells increased autophagy and chemoresistance in the AML cells exposed to chemotherapeutic agents, and this was reversed following Atg7 knockdown. This effect was further enhanced by concomitant knockdown of Atg7 in both AML and stromal cells. These findings strongly suggest that Atg7, and likely microenvironment autophagy in general, plays an important role in AML chemoresistance. Mechanistic studies revealed that Atg7 knockdown induced a proapoptotic phenotype in AML cells, which was manifested by an increased NOXA expression at the transcriptional level. Finally, in a mouse model of human leukemia, Atg7 knockdown extended overall survival after chemotherapy. Thus, the inhibition of Atg7 appears to be a valid strategy to enhance chemosensitivity, and it could indeed improve outcomes in AML therapy. (Blood. 2016;128(9):1260-1269

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Background Impact of FLT3 mutations and mutation burden in cytogenetic subgroups of acute myeloid leukemia (AML) other than normal karyotype (NK-AML) is unclear. Methods Patients with newly diagnosed AML were divided among three cytogenetic subgroups: Core-Binding Factor (CBF) AML, NK-AML, Poor Risk AML. Results A total of 481 patients were included (CBF-AML – 13%, NK-AML – 57%, poor risk – 30%). FLT3 mutations (any) frequency was 20%, 32% and 7.6% in respective cytogenetic subgroups. FLT3 mutation did not impact event free survival (EFS) in patients with CBF (P=0.84) and poor-risk AML (P=0.37). In NK-AML, EFS was worse in the FLT3-internal tandem duplication (ITD) group (20 vs. 41 weeks, P<0.00001) but not in FLT3 tyrosine kinase domain (TKD) point mutation group (61 vs. 41 weeks, P=0.15). Patients with NK-AML and higher FLT3-ITD burden had worse EFS and overall survival (OS), but not so with FLT3-TKD mutation. In multivariate analysis, FLT3-ITD mutation was prognostic for EFS in NK-AML patients (hazard ratio 3.1, P=0.03). Conclusion FLT3 mutations did not have a prognostic impact in AML patients with good and poor-risk karyotype. In patients with NK-AML, FLT3-ITD mutations led to worse survival, more so in patients with high mutation burden.

2CdA is highly active in previously untreated patients with Waldenström's macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients.