A randomized study of pomalidomide vs placebo in persons with myeloproliferative neoplasm-associated myelofibrosis and RBC-transfusion dependence

RBC-transfusion dependence is common in persons with myeloproliferative neoplasm (MPN)-associated myelofibrosis. The objective of this study was to determine the rates of RBC-transfusion independence after therapy with pomalidomide vs placebo in persons with MPN-associated myelofibrosis and RBC-transfusion dependence. Two hundred and fifty-two subjects (intent-to-treat (ITT) population) including 229 subjects confirmed by central review (modified ITT population) were randomly assigned (2:1) to pomalidomide or placebo. Trialists and subjects were blinded to treatment allocation. Primary end point was proportion of subjects achieving RBC-transfusion independence within 6 months. One hundred and fifty-two subjects received pomalidomide and 77 placebo. Response rates were 16% (95% confidence interval (CI), 11, 23%) vs 16% (8, 26% P=0.87). Response in the pomalidomide cohort was associated with ⩽4 U RBC/28 days (odds ratio (OR)=3.1; 0.9, 11.1), age ⩽65 (OR=2.3; 0.9, 5.5) and type of MPN-associated myelofibrosis (OR=2.6; 0.7, 9.5). Responses in the placebo cohort were associated with ⩽4 U RBC/28 days (OR=8.6; 0.9, 82.3), white blood cell at randomization >25 × 10(9)/l (OR=4.9; 0.8, 28.9) and interval from diagnosis to randomization >2 years (OR=4.9; 1.1, 21.9). Pomalidomide was associated with increased rates of oedema and neutropenia but these adverse effects were manageable. Pomalidomide and placebo had similar RBC-transfusion-independence response rates in persons with MPN-associated RBC-transfusion dependence

Oncolytic Measles Virotherapy and Opposition to Measles Vaccination

Recent measles epidemics in US and European cities where vaccination coverage has declined are providing a harsh reminder for the need to maintain protective levels of immunity across the entire population. Vaccine uptake rates have been declining in large part because of public misinformation regarding a possible association between measles vaccination and autism for which there is no scientific basis. The purpose of this article is to address a new misinformed antivaccination argument-that measles immunity is undesirable because measles virus is protective against cancer. Having worked for many years to develop engineered measles viruses as anticancer therapies, we have concluded (1) that measles is not protective against cancer and (2) that its potential utility as a cancer therapy will be enhanced, not diminished, by prior vaccination

HemaMax™, a Recombinant Human Interleukin-12, Is a Potent Mitigator of Acute Radiation Injury in Mice and Non-Human Primates

HemaMax, a recombinant human interleukin-12 (IL-12), is under development to address an unmet medical need for effective treatments against acute radiation syndrome due to radiological terrorism or accident when administered at least 24 hours after radiation exposure. This study investigated pharmacokinetics, pharmacodynamics, and efficacy of m-HemaMax (recombinant murine IL-12), and HemaMax to increase survival after total body irradiation (TBI) in mice and rhesus monkeys, respectively, with no supportive care. In mice, m-HemaMax at an optimal 20 ng/mouse dose significantly increased percent survival and survival time when administered 24 hours after TBI between 8–9 Gy (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by increases in plasma interferon-γ (IFN-γ) and erythropoietin levels, recovery of femoral bone hematopoiesis characterized with the presence of IL-12 receptor β2 subunit–expressing myeloid progenitors, megakaryocytes, and osteoblasts. Mitigation of jejunal radiation damage was also examined. At allometrically equivalent doses, HemaMax showed similar pharmacokinetics in rhesus monkeys compared to m-HemaMax in mice, but more robustly increased plasma IFN-γ levels. HemaMax also increased plasma erythropoietin, IL-15, IL-18, and neopterin levels. At non-human primate doses pharmacologically equivalent to murine doses, HemaMax (100 ng/Kg and 250 ng/Kg) administered at 24 hours after TBI (6.7 Gy/LD50/30) significantly increased percent survival of HemaMax groups compared to vehicle (p<0.05 Pearson's chi-square test). This survival benefit was accompanied by a significantly higher leukocyte (neutrophils and lymphocytes), thrombocyte, and reticulocyte counts during nadir (days 12–14) and significantly less weight loss at day 12 compared to vehicle. These findings indicate successful interspecies dose conversion and provide proof of concept that HemaMax increases survival in irradiated rhesus monkeys by promoting hematopoiesis and recovery of immune functions and possibly gastrointestinal functions, likely through a network of interactions involving dendritic cells, osteoblasts, and soluble factors such as IL-12, IFN-γ, and cytoprotectant erythropoietin

Targeting the IGF-1R signaling and mechanisms for epigenetic gene silencing in human multiple myeloma

Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of clonal plasmablast/plasma cells within the bone-marrow. It is well established that the bone-marrow microenvironment has a pivotal role in providing critical cytokines and cell–cell interactions to support the growth and survival of the MM tumor clone. The pathogenesis of MM is, however, only fragmentarily understood. Detailed genomic analysis reveals a heterogeneous and complex pattern of structural and numerical chromosomal aberrations. In this review we will discuss some of the recent results on the functional role and potential clinical use of the IGF-1R, one of the major mediators of growth and survival for MM. We will also describe some of our results on epigenetic gene silencing in MM, as it may indeed constitute a novel basis for the understanding of tumor initiation and maintenance in MM and thus may change the current view on treatment strategies for MM