GlaxoSmithKline Biologicals SA.

Background: We evaluated an inactivated quadrivalent influenza vaccine (IIV4) in children 6–35 months of age in a phase III, observer-blind trial. Methods: The aim of this analysis was to estimate vaccine efficacy (VE) in preventing laboratory-confirmed influenza in each of 5 independent seasonal cohorts (2011−2014), as well as vaccine impact on healthcare utilization in 3 study regions (Europe/Mediterranean, Asia-Pacific and Central America). Healthy children were randomized 1:1 to IIV4 or control vaccines. VE was estimated against influenza confirmed by reverse transcription polymerase chain reaction on nasal swabs. Cultured isolates were characterized as antigenically matched/mismatched to vaccine strains. Results: The total vaccinated cohort included 12,018 children (N = 1777, 2526, 1564, 1501 and 4650 in cohorts 1−5, respectively). For reverse transcription polymerase chain reaction confirmed influenza of any severity (all strains combined), VE in cohorts 1−5 was 57.8%, 52.9%, 73.4%, 30.3% and 41.4%, respectively, with the lower limit of the 95% confidence interval >0 for all estimates. The proportion of vaccine match for all strains combined in each cohort was 0.9%, 79.3%, 72.5%, 24.1% and 28.6%, respectively. Antibiotic use associated with influenza illness was reduced with IIV4 by 71% in Europe, 36% in Asia Pacific and 59% in Central America. Conclusions: IIV4 prevented influenza in children 6−35 months of age in each of 5 separate influenza seasons in diverse geographical regions. A possible interaction between VE, degree of vaccine match and socioeconomic status was observed. The IIV4 attenuated the severity of breakthrough influenza illness and reduced healthcare utilization, particularly antibiotic use.

The treatment landscape for myelofibrosis (MF) has reached the molecular era by targeting different pathways that are implied in this myeloproliferative neoplasm. A few years ago, the first-in-class JAK1/JAK2 inhibitor ruxolitinib, demonstrated reductions in both constitutional symptoms and splenomegaly, leading to the US FDA approval. The development or worsening of cytopenias in patients receiving ruxolitinib uncovered an unmet need that has been addressed by alternative approaches. Pacritinib, a dual JAK2 and FLT3 inhibitor which also inhibits IRAK1, has demonstrated the ability to favorably impact MF-associated splenomegaly and symptom burden, while having limited myelosuppression with manageable gastrointestinal toxicity. Herein, we provide an overview of pacritinib, from early preclinical studies to the latest and ongoing PAC203 trial, as an emerging therapy for MF.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin Lymphoma (NHL) accounting for approximately 30-40% of NHL cases. Approximately 40% of all newly diagnosed DLBCL patients are either refractory or relapsed following initial response to therapy and represent a population with high unmet need for new therapeutic strategies to achieve or regain disease remission. Because of the near ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop compounds with novel mechanisms of action targeting CD20. However, CD20's non-internalizing nature has, to date, leveraged only cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity to which resistance can arise and has impeded the development of agents that internalize a cytotoxic payload. MT-3724 is a novel engineered toxin body designed to overcome this limitation by combining the specific target selectivity of a single chain variable fragment with the lethality of a genetically fused Shiga-like toxin A subunit that facilitates both internalization and cell killing by inactivating ribosomal protein synthesis. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro (IC50 <1 nM) and in CB17 SCID and PDX mice (Rajagopalan 2016; Huang 2018). As a direct-kill immunotoxin against CD20, MT-3724 has achieved clinical response in subjects with relapsed NHL regardless of acquired resistance to other treatments. Thus, MT-3724 could be a valuable addition to the armamentarium of treating DLBCL. Study Design and Methods: MT-3724 is being evaluated in this Phase 2 study as monotherapy (NCT02361346) in adult subjects with histologically confirmed, relapsed or refractory DLBCL. The primary objective is to determine the efficacy of MT-3724 as monotherapy based on the overall response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to immunomodulatory therapy criteria (LYRIC), hereinafter referred to as "revised Lugano Criteria" (Cheson 2014, 2016). Overall response rate is defined as the proportion of subjects with either a complete response or a partial response as determined by independent, blinded central review. Secondary objectives include safety, progression‐free survival, investigator‐assessed ORR, duration of response, and overall survival as well as pharmacokinetics and pharmacodynamics, immunogenicity, and quality of life. To be eligible, patients must have histologically confirmed, relapsed or refractory DLBCL, have received at least 2 standard of care systemic NHL treatment regimens, and have measurable disease according to the revised Lugano criteria. Since rituximab and MT-3724 compete for the same CD20 domain, subjects must have serum rituximab levels < 500 ng/mL before the start of treatment to allow adequate binding of MT-3724. This single arm phase 2 study is being conducted in three stages, where the first two stages will follow the Simon two-stage optimal design [Simon 1989]. Subjects will be enrolled in successive cohorts with each cohort evaluated for efficacy before opening the subsequent cohort, toward a total sample size of 100 subjects. Subjects will receive MT-3724 as an IV infusion over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. All subjects will be treated with a 50 µg/kg/dose of MT-3724, which was the recommended Phase 2 dose, as determined in the Phase 1/1b portion of the trial. Sites are open and recruiting in the US, Canada, and Europe. Disclosures Persky: Sandoz: Consultancy; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. Musteata:Arensia EM: Other: Principal Investigator; Institute of Oncology: Employment. Strack:Molecular Templates, Inc.: Employment. Burnett:Molecular Templates, Inc.: Employment. Wilson:Molecular Templates, Inc.: Employment. Baetz:Bristol Meyers Squibb: Other: Advisory board; Merck: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board.

Background: In an exploratory analysis of an inactivated quadrivalent influenza vaccine (IIV4) trial in children 6–35 months without risk factors for influenza, we evaluated clinical presentation of influenza illness and vaccine impact on health outcomes. Methods: This phase III trial was conducted in 13 geographically diverse countries across 5 influenza seasons (2011–2014). Children were randomized 1:1 to IIV4 or control. Active surveillance was performed for influenza-like episodes (ILE); influenza was confirmed by reverse transcription polymerase chain reaction (RT-PCR). The total vaccinated cohort was evaluated (N = 12,018). Results: 5702 children experienced ≥1 ILE; 356 (IIV4 group) and 693 (control group) children had RT-PCR-confirmed influenza. Prevalence of ILE was similar in RT-PCR-positive and RT-PCR-negative cases regardless of vaccination. Breakthrough influenza illness was attenuated in children vaccinated with IIV4; moderate-to-severe illness was 41% less likely to be reported in the IIV4 group than the control group [crude odds ratio: 0.59 (95% confidence intervals: 0.44−0.77)]. Furthermore, fever >39°C was 46% less frequent following vaccination with IIV4 than with control [crude odds ratio: 0.54 (95% confidence intervals: 0.39−0.75)] in children with breakthrough illness. Health outcome analysis showed that, each year, IIV4 would prevent 54 influenza cases per 1000 children and 19 children would need to be vaccinated to prevent 1 new influenza case. Conclusions: In addition to preventing influenza in 50% of participants, IIV4 attenuated illness severity and disease burden in children who had a breakthrough influenza episode despite vaccination.

No abstract

Background: Alemtuzumab (LemtradaTM) is a recombinant humanized anti-CD52 monoclonal antibody that targets T and B lymphocytes, monocytes and eosinophils. It is a Food and Drug administration (FDA) approved drug (approved in November 2014) for relapsing remitting multiple sclerosis (RRMS). Alemtuzumab is also being used occasionally for immune disorders like graft versus host disease (GVHD) and aplastic anemia as well as for B- chronic lymphocytic leukemia (B-CLL) (FDA approved) and sometimes as a part of conditioning regimen for solid and bone marrow transplantations (Campath-1H®). As an interesting paradox to its anti-immune effects, the most serious adverse effects of Alemtuzumab apart from infections are autoimmune effects (AE) (black box warning issued by FDA), affecting various organs mainly thyroid and bone marrow (mainly immune thrombocytopenia). Rare singular cases are emerging of autoimmune hemolytic anemia (AIHA) occurring months after Alemtuzumab infusion; therefore, herein we present the first case series along with review of all the reported cases of AIHA after Alemtuzumab infusion used for treatment of RRMS. Methods: We did a retrospective chart review of 4 cases of AIHA developing after Alemtuzumab infusion which included 3 cases from the CARE MS-I/II and CARE MS Extension trials (Randomized controlled trials comparing Alemtuzumab versus Interferon beta 1a) (courtesy Sanofi/Genzyme) and 1 case encountered at UT health San Antonio. Simultaneously, we did a literature search using multiple available online databases (PubMed, Ovid, MEDLINE and Cochrane Library) from January 1, 2010 to May 1, 2018 for AIHA associated with Alemtuzumab infusion and found additional 3 reported cases. All of the cases were Direct Antiglobulin test (DAT/Coombs) positive and no other cause of hemolysis was identified. All the analysis was descriptive and exploratory. Results & Discussion: Out of the total 7 cases reviewed, there were 4 males and 3 females. The common theme amongst all the cases was presence of coombs positive autoimmune intravascular hemolysis occurring 3-15 months (Mean±SD=10±3 months) after the last dose of Alemtuzumab (table 1). In 71% (5/7) of the cases hemoglobin dipped below 5gm/dl requiring multiple transfusions with 1 reported death due to multiorgan failure from complication of severe AIHA. 70% (4/6) cases where steroids were used were not responsive to them requiring the use of some other therapeutic interventions such as Intravenous Immunoglobulin (IVIG), plasmapheresis and second line agents like Rituximab. Interestingly, Alemtuzumab has also been successfully used as a 2nd line agent to treat AIHA especially associated with B-CLL and other immune phenomenon (GVHD, aplastic anemia, conditioning regimen for transplantations) immediate and sustained lymphopenia effect. The proposed mechanism for this "paradoxical" AE related to Alemtuzumab is the reduced diversity and increased regeneration of "self-reactive" T cells during delayed time frame of the "recovery period" of lymphocytes. The reported post marketing incidence of AIHA for Alemtuzumab in RRMS is around 0.13%. Alemtuzumab associated AIHA when used for B-CLL has also been rarely reported. Conclusion: Severe coombs positive AIHA is a rare life-threatening complication that can occur after Alemtuzumab infusion for RRMS. It can be rapidly progressive, intravascular, severe (hemoglobin frequently reaching to <5gm/dl) and frequently refractory to steroids. It usually occurs between 3-15 months after the Alemtuzumab infusion and can be fatal (with 1 reported death so far). Higher level of awareness is needed by the consulting hematologists of such a rare serious adverse effect that can occur specifically few months after Alemtuzumab infusion and calls for a closer monitoring of patient's hematological status during this recovery period. Disclosures No relevant conflicts of interest to declare.

R-CHOP remains the standard therapy for diffuse large B cell lymphoma (DLBCL), even though long-term disease free survival is achieved in only ~60-70% of the patients. One approach to improve on this cure rate is to implement rationally devised therapeutic strategies that capitalize on a better understanding of lymphoma biology, and on robust pre-clinical data. Still, in many instances clinical translation is limited by the difficulty in inhibiting key lymphomagenic proteins (e.g., MYC), or by subpar clinical responses and/or toxicity associated with the use of inhibitors to well-validated targets (e.g., SYK, BTK, PI3K, VEGF, etc.). Using genome-wide studies, we identified high expression of phosphodiesterase 4B (PDE4B) in fatal DLBCLs (Nat Med. PMID: 11786909). PDE4 hydroxylases cyclic adenosine monophosphate (cAMP) thus terminating its inhibitory signals and promoting B lymphocytes survival. Using in vitro and in vivo models, we showed that PDE4 inhibition augments cAMP signals and suppresses PI3K-AKT activity in DLBCL (Blood, PMID: 15331441). We mapped these events to SYK inhibition downstream of the B cell receptor (BCR) (Blood, PMID: 19369227). PDE4 inhibitors also suppress the pro-angiogenic lymphoma microenvironment by directly inhibiting the endothelium, and by decreasing VEGF production/secretion by the lymphoma cells, as we showed in a mouse engineered to develop lymphoma in a Pde4b KO background (Leukemia, PMID: 26503641). Earlier, we built on these pre-clinical data to test the safety and pharmacodynamics of the PDE4 inhibitor roflumilast (FDA-approved for COPD) in patients with relapsed/refractory mature B cell malignancies. In that first-in-cancer drug-repurposing study (NCT01888952), we found that roflumilast was well tolerated, clinically active, and that it suppressed PI3K activity, which correlated with the degree of clinical response (Clin. Cancer Res PMID: 27542768). Aberrant BCR signaling and angiogenesis are integral to the pathogenesis of DLBCL. Yet, combination of either ibrutinib or bevacizumab with R-CHOP was not beneficial in this disease. Thus, considering the pleiotropic anti-lymphoma properties of PDE4 inhibitors (seeBloodPMID: 27756749), which includes BCR suppression and anti-angiogenesis, we opened a trial to test the combination of roflumilast with R-CHOP in treatment naïve DLBCLs (NCT03458546). This is a single center, phase Ib, open label, non-randomized single arm study of roflumilast + R-CHOP (RR-CHOP) aimed at untreated high-risk DLBCL patients. Key eligibility criteria include: non-GCB DLBCL (Han's algorithm), NCCN-IPI risk score of ≥ 2, Ann Arbor stage II-IV; key exclusion criteria include active CNS involvement and documented history of severe depression (a specific concern related to the use of roflumilast). Patients will receive R-CHOP every 21 days for 6 cycles, and roflumilast PO daily (500 mcg) throughout the 18-week treatment period. Given the anti-angiogenic properties of PDE4 inhibitors that we documented pre-clinically, and the prohibitive cardiotoxicity of bevacizumab + R-CHOP combination, we will monitor serum levels of troponin and B-type natriuretic peptide, as biomarkers for cardiac toxicity. In addition, PBMC, plasma and urine samples will be collected for measurement SYK/PI3K/AKT activity and VEGF levels at baseline and before cycles 3 and 6. Exome sequencing of germline and tumor DNA is to be performed too. Adverse events will be assessed and documented according to the CTCAE version 4.03 criteria. Eligible patients will be included in the intent-to-treat analysis. The primary objective of this study is to test safety and tolerability of RR-CHOP; the secondary objectives are to preliminarily assess anti-tumor efficacy of the combination and the biomarker potential of SYK/PI3K/AKT activity and VEGF levels. Given its exploratory nature, this study was designed for a cohort of 10 patients, in which no statistical assessment of response or sample size calculation was included. To date, we have met ~50% of the target accrual, with half of those patients being of Hispanics ethnicity. If RR-CHOP is proven safe, the next step will be to initiate a randomized trial that compares RR-CHOP to R-CHOP in untreated DLBCL patients, which should conclusively validate (or refute) our extensive, biologically-informed, pre-clinically data on the benefits of PDE4 inhibitors for the treatment of mature B cell malignancies. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: roflumilast - PDE4 inhibitor, FDA-approved for COPD patients.