Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM

Multiple myeloma (MM) remains incurable, and treatment of relapsed/refractory (R/R) disease is challenging. There is an unmet need for more targeted therapies in this setting; deep cellular and molecular phenotyping of the tumor and microenvironment in MM could help guide such therapies. This phase 1b study (NCT02431208) evaluated the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo) alone or in combination with the standard of care (SoC) treatments lenalidomide (Len) or pomalidomide (Pom) and/or daratumumab (Dara) in patients with R/R MM. Study endpoints included incidence of adverse events (AEs) and overall response rate (ORR). A novel unsupervised integrative multi-omic analysis was performed using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples from patients receiving Atezo monotherapy or Atezo+Dara. A similarity network fusion (SNF) algorithm was applied to preprocessed data. Eighty-five patients were enrolled. Treatment-emergent deaths occurred in 2 patients; both deaths were considered unrelated to study treatment. ORRs ranged from 11.1% (Atezo+Len cohorts, n=18) to 83.3% (Atezo+Dara+Pom cohort, n=6). High-dimensional multi-omic profiling of the tumor microenvironment and integrative SNF analysis revealed novel correlations between cellular and molecular features of the tumor and immune microenvironment, patient selection criteria, and clinical outcome. Atezo monotherapy and SoC combinations were safe in this patient population and demonstrated some evidence of clinical efficacy. Integrative analysis of high dimensional genomics and immune data identified novel clinical correlations that may inform patient selection criteria and outcome assessment in future immunotherapy studies for myeloma

Statin use, survival and incidence of thrombosis among older patients with polycythemia vera and essential thrombocythemia

Abstract Background Polycythemia vera (PV) and essential thrombocythemia (ET) are linked to increased risk of cardiovascular morbidity and mortality. In addition to the reduction in of arterial thrombotic events, statins may prevent venous thrombosis including among patients with cancer. As previous registry‐ and claims‐based studies revealed that the use of statins may improve the survival of patients with various malignancies we evaluated their impact on outcomes of older adults with PV and ET. Methods We identified 4010 older adults (aged 66–99 years at diagnosis) with PV (n = 1809) and ET (n = 2201) in a population‐based cohort study using the Surveillance, Epidemiology, and End Results‐Medicare database with median follow‐up of 3.92 (interquartile range: 2.58–5.75) years. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) approaches were utilized to assess potential association between statins and overall survival. Multivariable competing risk models with death as a competing risk were used to evaluate possible relationship between statins and the incidence of thrombosis. Results 55.8% of the patients used statins within the first year after PV/ET diagnosis, and statin use was associated with a 22% reduction in all‐cause mortality (PSM: hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.63–0.98, p = 0.03; IPTW: HR = 0.79, 95% CI: 0.64–0.97, p = 0.03). Statins also reduced the risk of thrombosis in this patient population (PSM: HR = 0.63, 95% CI: 0.51–0.78, p < 0.01; IPTW: HR = 0.57, 95% CI: 0.49–0.66, p < 0.01) as well as in PV and ET subgroups. Conclusions These findings suggest that it may be important to incorporate statins into the therapeutic strategy for older adults with PV and ET

A highly efficient and faithful MDS patient-derived xenotransplantation model for pre-clinical studies

Comprehensive preclinical studies of Myelodysplastic Syndromes (MDS) have been elusive due to limited ability of MDS stem cells to engraft current immunodeficient murine hosts. Here we report a MDS patient-derived xenotransplantation model in cytokine-humanized immunodeficient "MISTRG" mice that provides efficient and faithful disease representation across all MDS subtypes. MISTRG MDS patient-derived xenografts (PDX) reproduce patients' dysplastic morphology with multi-lineage representation, including erythro- and megakaryopoiesis. MISTRG MDS-PDX replicate the original sample's genetic complexity and can be propagated via serial transplantation. MISTRG MDS-PDX demonstrate the cytotoxic and differentiation potential of targeted therapeutics providing superior readouts of drug mechanism of action and therapeutic efficacy. Physiologic humanization of the hematopoietic stem cell niche proves critical to MDS stem cell propagation and function in vivo. The MISTRG MDS-PDX model opens novel avenues of research and long-awaited opportunities in MDS research

Whole-exome sequencing in evaluation of patients with venous thromboembolism

Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P 1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias.C.R.P. was supported by the National Health and Medical Research Council of Australia. A.R.R. was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute R01 HL062565.Peer reviewe

Whole-exome sequencing in evaluation of patients with venous thromboembolism

Genetics play a significant role in venous thromboembolism (VTE), yet current clinical laboratory-based testing identifies a known heritable thrombophilia (factor V Leiden, prothrombin gene mutation G20210A, or a deficiency of protein C, protein S, or antithrombin) in only a minority of VTE patients. We hypothesized that a substantial number of VTE patients could have lesser-known thrombophilia mutations. To test this hypothesis, we performed whole-exome sequencing (WES) in 64 patients with VTE, focusing our analysis on a novel 55-gene extended thrombophilia panel that we compiled. Our extended thrombophilia panel identified a probable disease-causing genetic variant or variant of unknown significance in 39 of 64 study patients (60.9%), compared with 6 of 237 control patients without VTE (2.5%) (P 1 variant. Sanger sequencing performed in family members of 4 study patients with and without VTE showed generally concordant results with thrombotic history. WES and extended thrombophilia testing are promising tools for improving our understanding of VTE pathogenesis and identifying inherited thrombophilias