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Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides, located within the intergenic stretches or overlapping antisense transcripts of protein coding genes. LncRNAs are involved in numerous biological roles including imprinting, epigenetic regulation, apoptosis, and cell cycle. To determine whether lncRNAs are associated with clinical features and recurrent mutations in older patients (aged ≥60 y) with cytogenetically normal (CN) acute myeloid leukemia (AML), we evaluated lncRNA expression in 148 untreated older CN-AML cases using a custom microarray platform. An independent set of 71 untreated older patients with CN-AML was used to validate the outcome scores using RNA sequencing. Distinctive lncRNA profiles were found associated with selected mutations, such as internal tandem duplications in the FLT3 gene ( FLT3 -ITD) and mutations in the NPM1 , CEBPA , IDH2 , ASXL1 , and RUNX1 genes. Using the lncRNAs most associated with event-free survival in a training cohort of 148 older patients with CN-AML, we derived a lncRNA score composed of 48 lncRNAs. Patients with an unfavorable compared with favorable lncRNA score had a lower complete response (CR) rate [ P < 0.001, odds ratio = 0.14, 54% vs. 89%], shorter disease-free survival (DFS) [ P < 0.001, hazard ratio (HR) = 2.88] and overall survival (OS) ( P < 0.001, HR = 2.95). The validation set analyses confirmed these results (CR, P = 0.03; DFS, P = 0.009; OS, P = 0.009). Multivariable analyses for CR, DFS, and OS identified the lncRNA score as an independent marker for outcome. In conclusion, lncRNA expression in AML is closely associated with recurrent mutations. A small subset of lncRNAs is correlated strongly with treatment response and survival. Significance Long noncoding RNAs (lncRNAs) are involved in numerous biological roles including epigenetic regulation, apoptosis, and cell cycle. Whereas lncRNAs contribute to epigenetic gene regulation, metastasis, and prognosis in solid tumors, their role in acute myeloid leukemia (AML) has not been hitherto reported. Here, we show that lncRNA expression profiles are associated with recurrent mutations, clinical features, and outcome in AML. A fraction of these lncRNAs may have a functional role in leukemogenesis. Furthermore, lncRNAs could be used as biomarkers for outcome in AML. The identification of patients likely to achieve complete remission with standard therapy alone, based on lncRNA expression, is a significant advance potentially sparing such patients from other toxicities and focusing investigational approaches on postremission studies.

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design. Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.

The constitutively active BCR-ABL tyrosine kinase is the cause of chronic myeloid leukemia. Imatinib is the first small synthetic molecular inhibitor of the BCR-ABL tyrosine kinase with clinical activity in chronic-phase myeloid leukemia. This 5-year follow-up of patients with the disease who began continuous treatment with imatinib reports that the drug can induce durable hematologic and cytogenetic responses in a high proportion of patients. This 5-year follow-up of patients with chronic myeloid leukemia who began continuous treatment with imatinib reports that the drug can induce durable hematologic and cytogenetic responses in a high proportion of patients. Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the expansion of a clone of hematopoietic cells that carries the Philadelphia chromosome (Ph). 1 The Ph chromosome results from a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11). 2 The molecular consequence of this translocation is a novel fusion gene, BCR-ABL, which encodes a constitutively active protein, tyrosine kinase. 3 – 5 Imatinib (Gleevec, Novartis; formerly called STI571) is a relatively specific inhibitor of the BCR-ABL tyrosine kinase and has efficacy in CML. 6 – 11 Before the availability of imatinib, interferon alfa plus cytarabine was considered standard therapy for patients . . .

In this work, we study the survival outcomes of patients with lung adenocarcinoma in four independent cohorts. By classifying patients with KRAS mutations into three subgroups based on their mutation status of TP53 and SMARCA4, our analysis indicates that patients harboring both KRAS and SMARCA4 mutations do not benefit from the treatment with nonimmunotherapy or immune checkpoint inhibitor‐based immunotherapy. Alternative treatment strategy is requested for this subset of patients. KRAS is a key oncogenic driver in lung adenocarcinoma (LUAD). Chromatin‐remodeling gene SMARCA4 is comutated with KRAS in LUAD; however, the impact of SMARCA4 mutations on clinical outcome has not been adequately established. This study sought to shed light on the clinical significance of SMARCA4 mutations in LUAD. The association of SMARCA4 mutations with survival outcomes was interrogated in four independent cohorts totaling 564 patients: KRAS‐mutant patients with LUAD who received nonimmunotherapy treatment from (a) The Cancer Genome Atlas (TCGA) and (b) the MSK‐IMPACT Clinical Sequencing (MSK‐CT) cohorts; and KRAS‐mutant patients with LUAD who received immune checkpoint inhibitor‐based immunotherapy treatment from (c) the MSK‐IMPACT (MSK‐IO) and (d) the Wake Forest Baptist Comprehensive Cancer Center (WFBCCC) immunotherapy cohorts. Of the patients receiving nonimmunotherapy treatment, in the TCGA cohort (n = 155), KRAS‐mutant patients harboring SMARCA4 mutations (KS) showed poorer clinical outcome [P = 6e‐04 for disease‐free survival (DFS) and 0.031 for overall survival (OS), respectively], compared to KRAS‐TP53 comutant (KP) and KRAS‐only mutant (K) patients; in the MSK‐CT cohort (n = 314), KS patients also exhibited shorter OS than KP (P = 0.03) or K (P = 0.022) patients. Of patients receiving immunotherapy, KS patients consistently exhibited the shortest progression‐free survival (PFS; P = 0.0091) in the MSK‐IO (n = 77), and the shortest PFS (P = 0.0026) and OS (P = 0.0014) in the WFBCCC (n = 18) cohorts, respectively. Therefore, mutations of SMARCA4 represent a genetic factor leading to adverse clinical outcome in lung adenocarcinoma treated by either nonimmunotherapy or immunotherapy.

This study outlines the development of a microRNA signature in patients with cytogenetically normal acute myeloid leukemia (AML) with high-risk molecular features. This type of AML constitutes approximately 65% of cases of cytogenetically normal AML and one third of all AML cases involving patients under the age of 60 years. The microRNA signature correlated not only with the clinical outcome but also with the expression of genes encoding proteins of the innate immune system. This study outlines the development of a microRNA signature in patients with cytogenetically normal AML with high-risk molecular features. The microRNA signature correlated not only with the clinical outcome but also with the expression of genes encoding proteins of the innate immune system. In almost half of patients with acute myeloid leukemia (AML), no cytogenetic abnormality is detectable in the leukemic cells. Such patients are in an intermediate-risk prognostic category, 1 but among them are subgroups of patients who have molecular markers associated with either a favorable prognosis or an unfavorable prognosis. 2 Gene-expression profiling can also identify subgroups of patients who have cytogenetically normal AML with different outcomes. 3 – 5 Patients with internal tandem duplication in the fms-related tyrosine kinase 3 gene ( FLT3 -ITD) and those without FLT3 -ITD but with the wild-type nucleophosmin ( NPM1 ) gene are in a high-risk group, whereas . . .

Targeted mutation assessment of 81 genes in 1021 adults with de novo acute myeloid leukemia (AML) identified recurrent mutations in the neurofibromin 1 (NF1) gene in 52 (5.1%) patients, including 36 (5.2%) younger and 16 (4.8%) older patients, which suggests NF1 belongs to the 20 most frequently mutated genes in adult AML. NF1 mutations were found throughout the gene, and comprised missense, frameshift, and nonsense mutations. One mutation hotspot, at amino acid threonine 676 (Thr676), was found in 27% of AML patients with NF1 mutations. NF1-mutated patients belonged more often to the adverse European LeukemiaNet (ELN) risk category than NF1 wild-type patients. Among patients aged <60 years, the presence of NF1 Thr676 mutations was associated with lower complete remission (CR) rates (P = 0.04) and shorter overall survival (OS; P = 0.01), as was the presence of any NF1 mutation in patients in the adverse ELN risk category (CR, P = 0.05; OS, P < 0.001). CR rates were also lower in NF1-mutated patients aged ≥60 years compared with NF1 wild-type patients (P = 0.001). In summary, our findings provide novel insights into the frequency of NF1 mutations in AML, and are suggestive of an adverse prognostic impact in patients treated with standard chemotherapy.

Epithelial growth factor-like 7 (EGFL7) is a protein that is secreted by endothelial cells and plays an important role in angiogenesis. Although EGFL7 is aberrantly overexpressed in solid tumors, its role in leukemia has not been evaluated. Here, we report that levels of both EGFL7 mRNA and EGFL7 protein are increased in blasts of patients with acute myeloid leukemia (AML) compared with normal bone marrow cells. High EGFL7 mRNA expression associates with lower complete remission rates, and shorter event-free and overall survival in older (age ≥60 y) and younger (age <60 y) patients with cytogenetically normal AML. We further show that AML blasts secrete EGFL7 protein and that higher levels of EGFL7 protein are found in the sera from AML patients than in sera from healthy controls. Treatment of patient AML blasts with recombinant EGFL7 in vitro leads to increases in leukemic blast cell growth and levels of phosphorylated AKT. EGFL7 blockade with an anti-EGFL7 antibody reduced the growth potential and viability of AML cells. Our findings demonstrate that increased EGFL7 expression and secretion is an autocrine mechanism supporting growth of leukemic blasts in patients with AML.

Background Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study. Methods We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes. Results Our classification identified core-binding factor and NPM1 -mutated/ FLT3 -ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%. Conclusions By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies. Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).

Recently, a novel knowledge bank (KB) approach to predict outcomes of individual patients with acute myeloid leukemia (AML) was developed using unbiased machine learning. To validate its prognostic value, we analyzed 1612 adults with de novo AML treated on Cancer and Leukemia Group B front-line trials who had pretreatment clinical, cytogenetics, and mutation data on 81 leukemia/cancer-associated genes available. We used receiver operating characteristic (ROC) curves and the area under the curve (AUC) to evaluate the predictive values of the KB algorithm and other risk classifications. The KB algorithm predicted 3-year overall survival (OS) probability in the entire patient cohort (AUC KB  = 0.799), and both younger (< 60 years) (AUC KB  = 0.747) and older patients (AUC KB  = 0.770). The KB algorithm predicted non-remission death (AUC KB  = 0.860) well but was less accurate in predicting relapse death (AUC KB  = 0.695) and death in first complete remission (AUC KB  = 0.603). The KB algorithm’s 3-year OS predictive value was higher than that of the 2017 European LeukemiaNet (ELN) classification (AUC 2017ELN  = 0.707, p  < 0.001) and 2010 ELN classification (AUC 2010ELN  = 0.721, p  < 0.001) but did not differ significantly from that of the 17-gene stemness score (AUC 17-gene  = 0.732, p  = 0.10). Analysis of additional cytogenetic and molecular markers not included in the KB algorithm revealed that taking into account atypical complex karyotype, infrequent recurrent balanced chromosome rearrangements and mutational status of the SAMHD1 , AXL and NOTCH1 genes may improve the KB algorithm. We conclude that the KB algorithm has a high predictive value that is higher than those of the 2017 and 2010 ELN classifications. Inclusion of additional genetic features might refine the KB algorithm.

An acute leukemia diagnosis can be an extremely stressful experience for most patients. Posttraumatic growth (PTG) is positive psychological change experienced following a struggle with highly challenging life circumstances. The current study is the first longitudinal investigation of predictors of PTG and distress in adult acute leukemia patients undergoing induction chemotherapy. Findings suggest that these patients report PTG, and levels of PTG appear to increase over the weeks following leukemia diagnosis and induction chemotherapy. Variables associated with higher total PTG scores over time included greater number of days from baseline, younger age, and greater challenge to core beliefs. Variables associated with higher distress included greater number of days from baseline, greater perceived cancer threat, higher symptom severity, and lower spiritual well-being. Results underscore the critical role that examination of one’s core beliefs may play in the development of PTG over time.