Faculty Bibliography

[Formula presented] Background: Patients with relapsed or refractory (R/R) DLBCL generally have a poor prognosis, particularly if they are not candidates for autologous stem cell transplantation (ASCT) or experience relapse following approved CAR-T therapies. The UNITY-NHL study systematically explored the efficacy and tolerability of the PI3K-d/CK1-e inhibitor, umbralisib, alone (umbra), and in combination with the glycoengineered anti-CD20 monoclonal antibody ublituximab (U2), followed by a cohort treated with U2 plus bendamustine (U2+benda). Herein we report on the experience in a large cohort of patients with R/R DLBCL.
Method(s): This study explored a sequential combination design as described above. Eligible patients had histologically confirmed R/R DLBCL and were ineligible for ASCT, with no limit on number or type of prior treatment. Umbra was given orally at 800 mg once daily in 28-day cycles (C) until disease progression or unacceptable tolerability. Ublituximab was administered intravenously (IV) on Days 1, 8, and 15 of C1, on Day 1 of C2-6, and on Day 1 every 3C through C24. Benda was administered IV (90 mg/m ²) on Days 1/2 of C1-6. Cell of origin, NGS, and c-myc (FISH) were analyzed centrally. The primary endpoint of the study was overall response rate (ORR) as assessed by an independent review committee. Secondary endpoints included duration of response, progression-free survival, time to response, and safety.
Result(s): 226 patients with DLBCL were enrolled as follows: umbra monotherapy (n=30), U2 (n=66), and U2+benda (n=130). The population demographics included the following features: median age was 72 years (range 32-95); 59% were male; 64% of patients had stage III or IV disease; 58% were refractory to their immediate prior therapy; and the median number of prior therapies was 2 (range 1-8). There were no substantive differences in these characteristics across cohorts. Median follow-up for the umbra, U2, and U2+benda arms was 51 months (range 47-61), 46 months (range 41-57), and 40 months (range 35-47), respectively. Overall and complete response rates for the umbra mono, U2, and U2+benda arms were 13.3% (CR 3.3%), 31.8% (CR 10.6%), and 43.1% (CR 16.9%), respectively. Results pertaining to secondary endpoints are listed in Table 1. Correlation of response to cell of origin and mutation/c-myc status is ongoing and will be available at the time of presentation. Adverse events (AEs) were similar across the cohorts, with the exception of hematologic AEs which were increased in patients receiving benda. The most common all-grade AEs by treatment arm (umbra, U2, and U2+benda, respectively) were diarrhea (47%; 41%; and 48%), nausea (40%; 45%; and 45%), fatigue (33%; 30%; and 41%) and neutropenia (3.3%; 18%; and 32%). All-grade AEs of special interest included non-infectious colitis (3.3%, 1.5%, and 2.3%) and pneumonitis (3%, 1.5%, and 1.5%) in umbra, U2 and U2+benda treated patients respectively. Grade 3/4 AEs were uncommon, with the only events >10% being limited to neutropenia (11% for U2; 27% for U2+benda), and anemia (17% for U2+benda).
Conclusion(s): In the DLBCL cohort of UNITY-NHL, the U2+benda triplet regimen was active and well tolerated in patients with R/R DLBCL who were unsuitable for transplant or who had relapsed following ASCT. Umbra monotherapy and U2 were also well tolerated but resulted in lower ORR than in the U2+benda cohort. [Formula presented] Disclosures: Burke: X4 Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; SeaGen: Consultancy, Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Roche/Genentech: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy; Kura: Consultancy; MorphoSys: Consultancy; AstraZeneca: Consultancy; Kymera: Consultancy; AbbVie: Consultancy; Verastem: Consultancy. Fonseca: Amgen: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Speakers Bureau; Dava Oncology: Honoraria; Epizyme: Honoraria; Karyopharm: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria. Jurczak: Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Research Funding; Morphosys: Research Funding; Mei Pharma: Research Funding; Merck: Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Epizyme: Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Islas-Ohlmayer: Seagen Inc.: Research Funding. Reeves: Apollomics, Inc.: Research Funding; Tarveda Therapeutics: Research Funding; Ascentage Pharmaceuticals: Research Funding; Clovis Oncology: Research Funding; Arvinas: Research Funding; Pfizer: Research Funding; Ellipses: Research Funding; ImmunoGen: Research Funding; Karyopharm Therapeutics: Honoraria, Research Funding; Moderna: Research Funding; Thrive: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Astellas Pharma: Research Funding; IDEAYA Biosciences: Research Funding; Pharmacyclics: Research Funding; Loxo Oncology: Research Funding; AbbVie Inc.: Research Funding; Celgene: Research Funding; GSK: Research Funding; Jiangsu Hengrui Medicine Co.: Research Funding; Arcus Biosciences: Research Funding; Calithera: Research Funding; Amgen: Research Funding; Mirati Therapeutics, Inc.: Research Funding; Array BioPharma Inc.: Research Funding; Taiho Pharmaceutical: Research Funding; Boehringer Ingelheim: Research Funding; GI Therapeutics Inc.: Research Funding; Hutchison: Research Funding; MacroGenics: Research Funding; Ipsen: Research Funding; MedImmune, LLC.: Research Funding; BeiGene: Research Funding; TG Therapeutics: Research Funding; Acerta Pharma: Research Funding; Verastem: Research Funding; Janssen Pharmaceuticals: Research Funding, Speakers Bureau; Eisai Co.: Research Funding, Speakers Bureau; Roche Pharma: Research Funding; Novartis Pharmaceuticals: Research Funding; Daiichi Sankyo: Research Funding; Arvinas: Research Funding; CytomX: Research Funding; Sermonix Pharmaceutical: Research Funding; Seattle Genetics: Research Funding; AstraZeneca: Research Funding; Evelo Biosciences: Research Funding. Wrobel: Takeda: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria; Janssen: Honoraria, Speakers Bureau. Pagel: Incyte/MorphoSys: Consultancy; MEI Pharma: Consultancy; Pharmacyclics/AbbVie: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy; Actinium Pharmaceuticals: Consultancy; Kite, a Gilead Company: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy. Goldschmidt: Ontada: Current Employment; Blue Ridge Cancer Care: Current Employment; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; TG Therapeutics: Honoraria; G1 Therapeutics: Honoraria, Speakers Bureau. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. O'Connor: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company; Nomocan: Consultancy; Dren: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Myeloid Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Kymera: Consultancy, Current equity holder in publicly-traded company; Mundipharma: Consultancy. Ghosh: Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Genmab: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau.
Copyright

Background New York City (NYC) has borne the greatest burden of COVID-19 in the United States, but information about characteristics and outcomes of racially/ethnically diverse individuals tested and hospitalized for COVID-19 remains limited. In this case series, we describe characteristics and outcomes of patients tested for and hospitalized with COVID-19 in New York City's public hospital system. Methods We reviewed the electronic health records of all patients who received a SARS-CoV-2 test between March 5 and April 9, 2020, with follow up through April 16, 2020. The primary outcomes were a positive test, hospitalization, and death. Demographics and comorbidities were also assessed. Results 22254 patients were tested for SARS-CoV-2. 13442 (61%) were positive; among those, the median age was 52.7 years (interquartile range [IQR] 39.5-64.5), 7481 (56%) were male, 3518 (26%) were Black, and 4593 (34%) were Hispanic. Nearly half (4669, 46%) had at least one chronic disease (27% diabetes, 30% hypertension, and 21% cardiovascular disease). Of those testing positive, 6248 (46%) were hospitalized. The median age was 61.6 years (IQR 49.7-72.9); 3851 (62%) were male, 1950 (31%) were Black, and 2102 (34%) were Hispanic. More than half (3269, 53%) had at least one chronic disease (33% diabetes, 37% hypertension, 24% cardiovascular disease, 11% chronic kidney disease). 1724 (28%) hospitalized patients died. The median age was 71.0 years (IQR 60.0, 80.9); 1087 (63%) were male, 506 (29%) were Black, and 528 (31%) were Hispanic. Chronic diseases were common (35% diabetes, 37% hypertension, 28% cardiovascular disease, 15% chronic kidney disease). Male sex, older age, diabetes, cardiac history, and chronic kidney disease were significantly associated with testing positive, hospitalization, and death. Racial/ethnic disparities were observed across all outcomes. Conclusions and Relevance This is the largest and most racially/ethnically diverse case series of patients tested and hospitalized for COVID-19 in the United States to date. Our findings highlight disparities in outcomes that can inform prevention and testing recommendations.

BACKGROUND:New York City (NYC) bore the greatest burden of COVID-19 in the United States early in the pandemic. In this case series, we describe characteristics and outcomes of racially and ethnically diverse patients tested for and hospitalized with COVID-19 in New York City's public hospital system. METHODS:We reviewed the electronic health records of all patients who received a SARS-CoV-2 test between March 5 and April 9, 2020, with follow up through April 16, 2020. The primary outcomes were a positive test, hospitalization, and death. Demographics and comorbidities were also assessed. RESULTS:22254 patients were tested for SARS-CoV-2. 13442 (61%) were positive; among those, the median age was 52.7 years (interquartile range [IQR] 39.5-64.5), 7481 (56%) were male, 3518 (26%) were Black, and 4593 (34%) were Hispanic. Nearly half (4669, 46%) had at least one chronic disease (27% diabetes, 30% hypertension, and 21% cardiovascular disease). Of those testing positive, 6248 (46%) were hospitalized. The median age was 61.6 years (IQR 49.7-72.9); 3851 (62%) were male, 1950 (31%) were Black, and 2102 (34%) were Hispanic. More than half (3269, 53%) had at least one chronic disease (33% diabetes, 37% hypertension, 24% cardiovascular disease, 11% chronic kidney disease). 1724 (28%) hospitalized patients died. The median age was 71.0 years (IQR 60.0, 80.9); 1087 (63%) were male, 506 (29%) were Black, and 528 (31%) were Hispanic. Chronic diseases were common (35% diabetes, 37% hypertension, 28% cardiovascular disease, 15% chronic kidney disease). Male sex, older age, diabetes, cardiac history, and chronic kidney disease were significantly associated with testing positive, hospitalization, and death. Racial/ethnic disparities were observed across all outcomes. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:This is the largest and most racially/ethnically diverse case series of patients tested and hospitalized for COVID-19 in New York City to date. Our findings highlight disparities in outcomes that can inform prevention and testing recommendations.

Background: Despite recent advances, follicular lymphoma (FL) remains incurable for most patients. Relapsed/refractory (r/r) FL is associated with decremental treatment responses, accumulating toxicity, and poor survival among early failures of 1st line chemoimmunotherapy. Underscored by the recent approvals of idelalisib, copanlisib, and duvelisib, targeting B-cell receptor (BCR) signaling produces ORR of ~50% in r/r patients; however, new agents with a better therapeutic index over long-term administration are needed. SYK is a key regulator of BCR signaling (upstream of BTK and PI3K), and its inhibition results in clinical activity in FL. Compared with unaffected nodes, lymph nodes from FL patients have greater numbers of follicular helper T cells that express high levels of IL-4, which may support the tumor via the JAK1/3 pathway. Cerdulatinib, an oral, reversible inhibitor of SYK and JAK kinases (JAK1, JAK3, TYK2), previously reported a ~45% overall response rate (ORR) in r/r FL as a single agent. Xenograft studies suggest cerdulatinib may combine with rituximab to enhance antitumor activity. We report updated results from a phase 2a study of single-agent cerdulatinib and initial results in combination with rituximab in r/r FL.
Method(s): This phase 2a study confirmed the safety and efficacy of cerdulatinib 30 mg BID in r/r B- and T-cell lymphoma patients. Dose reductions were permitted to 15 mg BID. Response was assessed by Lugano criteria.
Result(s): A planned interim analysis was performed on July 18, 2019, in which enrollment was 40 patients in the single-agent cohort and 19 patients in the rituximab combination cohort. For the single-agent cohort, median age (range) was 64 (42-81) years and median prior therapies (range) was 3 (1-9). Ninety-five percent of patients had prior anti-CD20 therapy, and 25% had prior therapy with BCR pathway inhibitors. For the combination cohort, median age (range) was 67 (47-85) years and median prior therapies (range) was 3 (1-10). Eighty-eight percent of patients had prior anti-CD20 therapy, and 32% had prior therapy with BCR pathway inhibitors. The safety profile appeared similar in both cohorts. The most common treatment-emergent grade 3+ adverse events in >=5% of patients for both cohorts were lipase increase (27%), neutropenia (18%), diarrhea (12%), amylase increase (10%), hypertension (8%), nausea (7%), and pneumonia (5%). Grade 3+ infections occurred in 17.5% of single-agent cohort patients and 15.8% of combination cohort patients. Amylase and lipase increases generally were not associated with abdominal pain or pancreatitis. In addition, to date there has been no evidence of cumulative toxicity. The ORR was 45% as a single agent (12.5% complete response [CR], 32.5% partial response [PR], with 25% stable disease [SD] and 5% progressive disease [PD] in 40 evaluable patients) and 59% in the combination cohort (11.7% CR, 47% PR, with 27.8% SD and no PD in 17 evaluable patients). Responses typically occurred after 2 cycles, generally improved over time, and were durable in the single-agent cohort, with 10 patients on drug for >1 year. Enrollment in the combination cohort is ongoing. Updated safety and efficacy will be presented.
Conclusion(s): The recommended cerdulatinib phase 2 dose of 30 mg BID was tolerable and efficacious in heavily pretreated r/r FL. The cerdulatinib + rituximab combination appears to be well tolerated, with tumor reductions in all evaluable patients. The safety profile and unique mechanism of action of cerdulatinib support further combination studies in FL. Disclosures: Smith: Pharmacyclics: Research Funding; Denovo Biopharma: Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Acerta Pharma BV: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb (spouse): Research Funding; Ignyta (spouse): Research Funding; Ayala (spouse): Research Funding; Merck Sharp & Dohme Corp: Consultancy, Research Funding. Munoz: AstraZeneca: Speakers Bureau; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding, Speakers Bureau; Kite Pharma: Consultancy, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Fosunkite: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Bayer: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Portola: Research Funding; Incyte: Research Funding. Stevens: Astellas: Consultancy. Smith: Portola Pharmaceuticals: Research Funding. Feldman: Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Viracta: Research Funding; Trillium: Research Funding; Roche: Research Funding; Amgen: Research Funding; Cell Medica: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Pfizer: Research Funding; Portola Pharma: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau. Ye: MingSight: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Onyx: Research Funding; Celgene: Research Funding; Takeda: Research Funding; AbbVie: Research Funding; Portola Pharmaceuticals: Research Funding. de Vos: Verastem: Consultancy; Portola Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy. Miller: Verastem: Consultancy, Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau. Birrell: Portola Pharmaceuticals: Employment, Equity Ownership. Leeds: Portola Pharmaceuticals: Employment, Equity Ownership. Coffey: Portola Pharmaceuticals: Employment, Equity Ownership, Research Funding. Conley: Portola Pharmaceuticals: Employment, Equity Ownership. Michelson: Portola Pharmaceuticals: Employment, Equity Ownership. Curnutte: Portola Pharmaceuticals: Employment, Equity Ownership.
Copyright

BACKGROUND:Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease. METHODS:We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies. FINDINGS:In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively. INTERPRETATION:In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines. FUNDING:UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Background. Methicillin-resistant Staphylococcus aureus (MRSA) causes serious, ofen life-threatening, infections. Exotoxins such as alpha-hemolysin (AH), Panton Valentine leukocidin (PVL), and Toxic shock syndrome toxin 1 (TSST-1) mediate pathogenesis and inhibition of toxin production is an important consideration in choosing appropriate treatments. Vancomycin is recommended for severe MRSA infections; however, increasing vancomycin resistance, poor clinical outcomes and nephrotoxicity are serious concerns. Tus newer agents are needed, including those that block bacterial toxin production. In the current study, we compared the effects of sub-inhibitory doses (sub-MIC) of two folic acid inhibitor antibiotics (iclaprim, trimethoprim) with cell wall-active agents (nafcillin, vancomycin) on transcription and translation of AH, PVL and TSST-1 in two clinical MRSA isolates. Methods. Community-acquired MRSA strains 1560 (a USA400 strain; AH⁺, TSST-1^+-) and 04014 (CDC strain 368-04; AH⁺, TSST-1^-+) were studied. MICs were determined by standard microbroth dilution. Gene expression was studied by northern blotting and/or qRT-PCR; toxins were quantitated by ELISA (PVL and TSST-1) and rabbit erythrocyte lysate assay (AH). Results. In agreement with our previous findings, nafcillin increased production of AH, TSST-1, and PVL compared with untreated control cultures. In both MRSA strains, iclaprim and trimethoprim delayed the onset of mRNA production and shifed its peak production to later time points. Both iclaprim and trimeth-oprim suppressed AH production in both strains of MRSA and delayed, but did not reduce, maximal TSST-1 production in MRSA1560. Trimethoprim significantly increased maximal PVL production over both untreated and iclaprim-treated cultures. Conclusion. The folic acid antagonist antibiotics, iclaprim and trimethoprim, altered both mRNA synthesis dynamics and protein toxin production in MRSA at concentrations below those that inhibit bacterial growth. These results, plus the fact that iclaprim is 15-fold more active than trimethoprim (MICs = 0.13 and 2.0 ug/ml, respectively), provide additional rationale for the use of iclaprim to treat complicated MRSA infections

Background: Subsets of B cell malignancies are addicted to B cell antigen receptor (BCR) signaling for survival. Co-stimulation of the BCR with IL-2 or IL-4 in normal B cells significantly enhances cellular activation relative to BCR or cytokine stimulation alone, and combining SYK selective and JAK selective inhibitors synergize to suppress this response (Coffey et al., 2013). Hence, BCR/SYK and cytokine JAK/STAT signals cooperate to control B cell activation. This cooperation appears to be relevant to B cell malignancies as well. IL-4 promotes the survival of CLL cells in culture via up-regulation of MCL1 and BCLXL, protecting the tumor from death induced by fludarabine and chlorambucil (Steele et al., 2010) and by idelalisib and ibrutinib (Aguilar-Hernandez et al., 2016). Also, unlike ibrutinib, combined SYK and JAK inhibition by cerdulatinib induces apoptosis in primary CLL cells and leads to down-regulation of MCL1 and BCLXL (Blunt et al., 2015) and induces apoptosis in cells from ibrutinib-resistant CLL patients (Guo et al., 2017). It also induces apoptosis in primary DLBCL and DLBCL cell lines that carry BCR pathway mutations resistant to ibrutinib (Ma et al, 2015). Combined SYK/JAK inhibition may therefore represent a powerful strategy to control B cell malignancies. A phase I dose escalation study of cerdulatinib in 43 patients with relapsed/refractory CLL and NHL was recently completed (Hamlin et al., EHA Congress 2016). Inhibition of both BCR/SYK and JAK/STAT signaling pathways by >90% in peripheral blood assays was well tolerated. Durable PRs and 1 CR were observed in CLL and FL, including in patients who had relapsed on prior BCR inhibitor therapy. No consistent hepatic toxicity, anemia, thrombocytopenia or neutropenia was observed. Two grade 3 dose limiting toxicities were observed at 45 mg BID (fatigue, pancreatitis). 35 mg BID was identified as the Phase 2 dose based on Phase 1 data and on PK/PD modeling. Aims: The primary aim of the study was to understand the safety and activity of cerdulatinib in B-cell malignancies. Methods: This is an open-label study with 28-day cycles. Twice daily (BID; 30 mg and 35 mg) dosing was evaluated. Pharmacokinetics (PK), pharmacodynamics (PD), and safety were monitored, as well as an assessment of efficacy. Clinical response was assessed by standard criteria. Potency and specificity for SYK and JAK pathway inhibition were measured in whole blood assays by monitoring signaling responses following ligation of the BCR and receptors for IL-4. Serum markers of inflammation, minimal residual disease (MRD) and apoptosis in CLL patients were also measured. Results: A phase 2 study was initiated in May 2016 to enroll up to 40 patients in each of three cohorts; 1) relapsed/refractory CLL/SLL, 2) relapsed/refractory indolent NHL, and 3) relapsed DLBCL, MCL and transformed FL. As of March 1, 2017, 37 patients have been enrolled, 17 with CLL/SLL, 15 with indolent NHL (10 FL, 4 MZL, 1 WM), and 5 with aggressive NHL (3 DLBCL, 1 MCL, 1 tFL). Median patient age is 70 years (range, 51-93). The median number of prior therapies is 3 (range 1-7). 11 patients had prior BTK or PI3K inhibitor therapy. The safety profile has been similar to what was seen in the Phase 1 study. However, 3 patients at 35 mg BID achieved higher than expected drug concentrations and had SAEs (2 grade 5 infections, 1 grade 3 pancreatitis). The starting dose was reduced to 30 mg BID and a PK monitoring and dose reduction strategy has been implemented. To date, this has resulted in a better safety profile without PK outliers. The most common AEs of any grade have been diarrhea (27%), fatigue (27%) and nausea (24%). Grade 3+ AEs occurring in more than 1 patient are infection (5 patients), abdominal pain (3 patients) and hypertension (3 patients). As seen in phase 1, significant inhibition of SYK and JAK signaling pathways in peripheral blood is observed. Evidence for tumor cell mobilization to peripheral blood in CLL/SLL is consistently observed following one week of therapy. PRs have been seen in all 3 cohorts including 10 of 13 (77%) CLL/SLL and 3 of 6 (50%) FL patients evaluated. Of these 13 PRs, 12 are still on drug with 4 patients in response for greater than 6 months. In addition, PRs have been seen in patients who relapsed on ibrutinib (FL patient, 8+ months) and venetoclax (SLL patient, 7+ months) therapy. As demonstrated preclinically, we have seen evidence of apoptosis (Annexin V+ B-cells) in 6 CLL patients. 5 of these patients had a PR at the end of the 2nd cycle (Figure 1). (Table Presented) Summary/Conclusions: Cerdulatinib demonstrates clinical activity in heavily pretreated patients with CLL/B-cell NHL and is generally well tolerated. Consistent activity is seen in patients with CLL and FL. Accrual is proceeding; updated PK/PD, safety and efficacy will be presented

BACKGROUND: While unannounced standardized patients (USPs) have been used to assess physicians' clinical skills in the ambulatory setting, they can also provide valuable information on patients' experience of the health care setting beyond the physician encounter. This paper explores the use of USPs as a methodology for evaluating patient-centered care in the health care system. METHODS: USPs were trained to complete a behaviorally-anchored assessment of core dimensions of patient-centered care delivered within the clinical microsystem, including: 1) Medical assistants' safe practices, quality of care, and responsiveness to patients; 2) ease of clinic navigation; and 3) the patient-centeredness of care provided by the physician. Descriptive data is provided on these three levels of patient-centeredness within the targeted clinical microsystem. Chi-square analyses were used to signal whether variations by teams within the clinical microsystem were likely to be due to chance or might reflect true differences in patient-centeredness of specific teams. RESULTS: Sixty USP visits to 11 Primary Care teams were performed over an eight-month period (mean 5 visits/team; range 2-8). No medical assistants reported detecting an USP during the study period. USPs found the clinic easy to navigate and that teams were functioning well in 60% of visits. In 30% to 47% of visits, the physicians could have been more patient-centered. Medical assistants' patient safety measures were poor: patient identity was confirmed in only 5% of visits and no USPs observed medical assistants wash their hands. Quality of care was relatively high for vital signs (e.g. blood pressure, weight and height), but low for depression screening, occurring in only 15% of visits. In most visits, medical assistants greeted the patient in a timely fashion but took time to fully explain matters in less than half of the visits and rarely introduced themselves. Physicians tried to help patients navigate the system in 62% of visits. CONCLUSIONS: USP assessment captured actionable, critical, behaviorally-specific information on team and system performance in an urban community clinic. This methodology provides unique insight into the patient-centeredness and quality of care in medical settings.