Citations

Abstract Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients. Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications. Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks. Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients. Disclosures Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.

AbstractBackgroundHuman pegivirus (HPgV) is a single-strand RNA virus belonging to the Flaviviridae. Although no definitive association between HPgV infection and disease has been identified, previous studies have suggested an association of HPgV viremia with risk of lymphomas.MethodsWe conducted a systematic review and meta-analysis, including 1 cohort study and 14 case-control studies, assessing the association of HPgV viremia with adult lymphomas. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model, overall and by geographic region and lymphoma subtype.ResultsThe overall OR for lymphoma was 2.85 (95% CI, 1.98–4.11), with statistically significantly elevated ORs observed in 8 of 15 studies. There was a small amount of heterogeneity among studies (I2 = 28.9%; Q = 18.27, P = .16), and the funnel plot provided no evidence for publication bias. The strongest association with lymphoma risk was observed for studies from Southern Europe (OR, 5.68 [95% CI, 1.98–16.3]), whereas weaker ORs (with 95% CIs) were observed for studies from North America (2.24 [1.76–2.85]), Northern Europe (2.90 [.45–18.7), and the Middle East (2.51 [.87–7.27]), but all of similar magnitude. Participants with HPgV viremia had statistically significantly increased risks (OR [95% CI]) for developing diffuse large B-cell (3.29 [1.63–6.62]), follicular (3.01 [1.95–4.63]), marginal zone (1.90 [1.13–3.18]), and T-cell (2.11 [1.17–3.89]) lymphomas, while the risk for Hodgkin lymphoma (3.53 [.48–25.9]) and chronic lymphocytic leukemia (1.45 [.45–4.66]) were increased but did not achieve statistical significance.ConclusionsThis meta-analysis supports a positive association of HPgV viremia with lymphoma risk, overall and for the major lymphoma subtypes.

Scattered tubular-like cells (STCs) contribute to repair neighboring injured renal tubular cells. Mitochondria mediate STC biology and function but might be injured by the ambient milieu. We hypothesized that the microenviroment induced by the ischemic and metabolic components of renovascular disease impairs STC mitochondrial structure and function in swine, which can be attenuated with mitoprotection. CD24+/CD133+STCs were quantified in pig kidneys after 16 wk of metabolic syndrome (MetS) or lean diet (Lean) with or without concurrent renal artery stenosis (RAS) ( n = 6 each). Pig STCs were isolated and characterized, and mitochondrial structure, membrane potential, and oxidative stress were assessed in cells untreated or incubated with the mitoprotective drug elamipretide (1 nM for 6 h). STC-protective effects were assessed in vitro by their capacity to proliferate and improve viability of injured pig tubular epithelial cells. The percentage of STCs was higher in MetS, Lean + RAS, and MetS + RAS kidneys compared with Lean kidneys. STCs isolated from Lean + RAS and MetS + RAS pigs showed mitochondrial swelling and decreased matrix density, which were both restored by mitoprotection. In addition, mitochondrial membrane potential and ATP production were reduced and production of reactive oxygen species elevated in MetS, Lean + RAS, and MetS + RAS STCs. Importantly, mitoprotection improved mitochondrial structure and function as well as the capacity of MetS + RAS STCs to repair injured tubular cells in vitro. Renovascular disease in swine is associated with a higher prevalence of STCs but induces structural and functional alterations in STC mitochondria, which impair their reparative potency. These observations suggest a key role for mitochondria in the renal reparative capacity of STCs.

Background: Female patients have historically received less aggressive lipid management than male patients. Contemporary care patterns and the potential causes for these differences are unknown. Methods and Results: Examining the Patient and Provider Assessment of Lipid Management Registry—a nationwide registry of outpatients with or at risk for atherosclerotic cardiovascular disease—we compared the use of statin therapy, guideline-recommended statin dosing, and reasons for undertreatment. We specifically analyzed sex differences in statin treatment and guideline-recommended statin dosing using multivariable logistic regression. Among 5693 participants (43% women) eligible for 2013 American College of Cardiology/American Heart Association Cholesterol Guideline–recommended statin treatment, women were less likely than men to be prescribed any statin therapy (67.0% versus 78.4%; P <0.001) or to receive a statin at the guideline-recommended intensity (36.7% versus 45.2%; P <0.001). Women were more likely to report having previously never been offered statin therapy (18.6% versus 13.5%; P <0.001), declined statin therapy (3.6% versus 2.0%; P <0.001), or discontinued their statin (10.9% versus 6.1%; P <0.001). Women were also less likely than men to believe statins were safe (47.9% versus 55.2%; P <0.001) or effective (68.0% versus 73.2%; P <0.001) and more likely to report discontinuing their statin because of a side effect (7.9% versus 3.6%; P <0.001). Sex differences in both overall and guideline-recommended intensity statin use persisted after adjustment for demographics, socioeconomic factors, clinical characteristics, patient beliefs, and provider characteristics (adjusted odds ratio, 0.70; 95% CI, 0.61–0.81; P <0.001; and odds ratio, 0.82; 95% CI, 0.73–0.92; P <0.01, respectively). Sex differences were consistent across primary and secondary prevention indications for statin treatment. Conclusions: Women eligible for statin therapy were less likely than men to be treated with any statin or guideline-recommended statin intensity. A combination of women being offered statin therapy less frequently, while declining and discontinuing treatment more frequently, accounted for these sex differences in statin use.

Mesenchymal stromal/stem cells (MSCs) belong to the endogenous cellular reparative system, and can be used exogenously in cell-based therapy. MSCs release extracellular vesicles (EVs), including exosomes and microvesicles, which mediate some of their therapeutic activity through intercellular communication. We have previously demonstrated that metabolic syndrome (MetS) modifies the cargo packed within swine EV, but whether it influences their phenotypical characteristics remains unclear. This study tested the hypothesis that MetS shifts the size distribution of MSC-derived EVs. Adipose tissue-derived MSC-EV subpopulations from Lean ( n = 6) and MetS ( n = 6) pigs were characterized for number and size using nanoparticle-tracking analysis, flow cytometry, and transmission electron microscopy. Expression of exosomal genes was determined using next-generation RNA-sequencing (RNA-seq). The number of EV released from Lean and MetS pig MSCs was similar, yet MetS-MSCs yielded a higher proportion of small-size EVs (202.4 ± 17.7 nm vs. 280.3 ± 15.1 nm), consistent with exosomes. RNA-seq showed that their EVs were enriched with exosomal markers. Lysosomal activity remained unaltered in MetS-MSCs. Therefore, MetS alters the size distribution of MSC-derived EVs in favor of exosome release. These observations may reflect MSC injury and membrane recycling in MetS or increased expulsion of waste products, and may have important implications for development of adequate cell-based treatments.

Background:Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ∼4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia (AML). Ivosidenib (IVO; AG‐120) is an oral, potent, targeted inhibitor of the mutant IDH1 protein (mIDH1) that is approved for the treatment of adults with mIDH1 relapsed or refractory (R/R) AML. Through inhibition of mIDH1, IVO suppresses production of the oncometabolite 2‐hydroxyglutarate, leading to clinical responses via differentiation of malignant cells.Aims:To report safety and efficacy data from patients with R/R MDS enrolled in the first‐in‐human, phase 1, dose escalation and expansion study of IVO in patients with mIDH1 advanced hematologic malignancies (NCT02074839).Methods:This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of IVO. Enrollment was completed on May 8, 2017. In dose escalation, patients received single‐agent IVO orally (dose range, 200–1200 mg daily) in 28‐day cycles. The MTD was not reached and 500 mg QD was selected as the dose for expansion. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR (mCR) according to International Working Group 2006 criteria for MDS. Exploratory biomarker assessments included baseline co‐occurring mutations (next‐generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02–0.04%).Results:Baseline characteristics of the 12 patients with R/R MDS who received 500 mg IVO once daily were: 9 men/3 women; median age 72.5 years (range 52–78), and 42% were ≥75 years of age; median number of prior therapies 1 (range 1–3). As of Nov 2, 2018, 3 of 12 (25.0%) patients remained on treatment; 9 (75.0%) had discontinued (one for allogeneic stem cell transplantation). Median duration of exposure to IVO was 11.4 months (range 3.3–42.5). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n = 4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n = 3 each, 25.0%). No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome was observed in 1 of 12 (8.3%) patients (grade 2). Electrocardiogram QT prolonged was reported in 2 of 12 patients (17%; grade 1 in 1 patient and grade 2 in 1 patient). Five of 12 patients achieved CR (41.7%; 95% CI 15.2%, 72.3%), 1 achieved PR (8.3%), and 5 achieved mCR (41.7%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median duration of CR was not estimable (NE) at the time of datacutoff and the median duration of response was 21.4 months (95% CI 2.3, NE). At 12 months, 60.0% of patients remained in CR. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for ≥56 consecutive days on treatment. Baseline co‐occurring mutations and changes in mIDH1 VAF levels will be presented.Summary/Conclusion:In patients with mIDH1 R/R MDS, IVO monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of IVO as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS.

Exhausted-like CD8 + resident memory T cells in the lung limit immune activation–driven fibrosis.

Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.