SUMMARY MicroRNAs and heterogeneous ribonucleoproteins (hnRNPs) are posttranscriptional gene regulators that bind mRNA in a sequence-specific manner. Here, we report that loss of miR-328 occurs in blast crisis chronic myelogenous leukemia (CML-BC) in a BCR/ABL dose- and kinase-dependent manner through the MAPK-hnRNP E2 pathway. Restoration of miR-328 expression rescues differentiation and impairs survival of leukemic blasts by simultaneously interacting with the translational regulator poly(rC)-binding protein hnRNP E2 and with the mRNA encoding the survival factor PIM1, respectively. The interaction with hnRNP E2 is independent of the microRNA’s seed sequence and it leads to release of CEBPA mRNA from hnRNP E2-mediated translational inhibition. Altogether, these data reveal the dual ability of a microRNA to control cell fate both through base pairing with mRNA targets and through a decoy activity that interferes with the function of regulatory proteins.

Background Avelumab, a fully human IgG1 immune checkpoint inhibitor targeting programmed death ligand 1 (PD-L1), has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours. Here, we assessed avelumab treatment in patients with advanced, platinum-treated non-small cell lung cancer (NSCLC). Methods In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 sites in the United States. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or nonsquamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary endpoint was safety and tolerability. Secondary endpoints included best overall response, progression-free survival, overall survival, and clinical activity associated with PD-L1 expression. Responses were evaluated using RECIST v1.1, and analyses of antitumour activity and safety were performed in all patients who received at least one dose of avelumab. This trial is registered with ClinicalTrials.gov (NCT01772004); enrolment in this cohort is closed and the trial is ongoing. Findings Between 10 September 2013 and 24 June 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (interquartile range [first and third quartiles], 7·2–11·9 months). The most common treatment-related adverse events of any grade were fatigue (n=46; 25%), infusion-related reaction (n=38; 21%), and nausea (n=23; 13%). Grade ≥3 treatment-related adverse events occurred in 23 of 184 patients (13%); the most common were infusion-related reaction (n=4; 2%), elevated lipase (n=3; 2%), constipation (n=2; 1%), and dyspnoea (n=2; 1%). 16 of 184 patients (9%) had a serious adverse event related to treatment with avelumab, with infusion-related reaction (4 [2%]) and dyspnoea (2 [1%]) occurring in more than one patient. Immune-related treatment-related events occurred in 22 patients (12%). The confirmed objective response rate, regardless of PD-L1 status, was 12% (95% CI, 8–18), including one complete response and 21 partial responses. Seventy patients had stable disease, for an overall disease-control rate of 50%. Interpretation Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or resistant NSCLC, providing a rationale for additional studies of avelumab in this disease setting. Funding Merck KGaA, Darmstadt, Germany and Pfizer, Inc, New York, USA.

These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily.

Summary How inflammation causes cancer is unclear. IL-15 is a pro-inflammatory cytokine elevated in human large granular lymphocyte (LGL) leukemia. Mice overexpressing IL-15 develop LGL leukemia. Here we show that prolonged in vitro exposure of wild type (WT) LGL to IL-15 results in Myc-mediated up regulation of aurora kinases, centrosome aberrancies, and aneuploidy. Simultaneously, IL-15 represses miR-29b via induction of Myc/NF-κBp65/Hdac-1, resulting in Dnmt3b overexpression and DNA hypermethylation. All this is validated in human LGL leukemia. Strikingly, adoptive transfer of WT LGL cultured with IL-15 led to malignant transformation in vivo. Drug targeting which reverses miR-29b repression, cures otherwise fatal LGL leukemia. We show how excessive IL-15 initiates cancer and demonstrate effective drug targeting for potential therapy of human LGL leukemia.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. This manuscript discusses the management of patients with solitary plasmacytoma, smoldering multiple myeloma, and newly diagnosed multiple myeloma.

No abstract

Introduction: CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials. Methods: Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs). Results: Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved. Conclusions: Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data.

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, workup, treatment, follow-up, and supportive care for patients with monoclonal gammopathy of renal significance, solitary plasmacytoma, smoldering myeloma, and multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates and changes in the 1.2020 version of the NCCN Guidelines for Multiple Myeloma.