Sex and sex hormones can affect responses of patients with nonalcoholic fatty liver disease (NAFLD) to metabolic stress and development of hepatocyte injury and inflammation. We collected data from 3 large US studies of patients with NAFLD (between October 2004 and June 2013) to assess the association between histologic severity and sex, menopause status, synthetic hormone use, and menstrual abnormalities in 1112 patients with a histologic diagnosis of NAFLD. We performed logistic or ordinal logistic regression models, adjusting for covariates relevant to an increase of hepatic metabolic stress. We found that pre-menopausal women were at an increased risk of lobular inflammation, hepatocyte ballooning, and Mallory-Denk bodies than men and also at an increased risk of lobular inflammation and Mallory-Denk bodies than post-menopausal women (P<.01). Use of oral contraceptives was associated with an increased risk of lobular inflammation and Mallory-Denk bodies in pre-menopausal women, whereas hormone replacement therapy was associated with an increased risk of lobular inflammation in post-menopausal women (P<.05). We conclude that being a pre-menopausal woman or a female user of synthetic hormones is associated with increased histologic severity of hepatocyte injury and inflammation among patients with NAFLD at given levels of hepatic metabolic stress.

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Introduction: Antibody-drug conjugate polatuzumab vedotin (pola) targets CD79b on B-cell non-Hodgkin lymphoma. Cytopenias and peripheral neuropathy (PN) are typical pola-associated adverse events (AEs). We reported significantly higher positron emission tomography-complete response (PET-CR) rates and improved duration of response (DOR), progression-free survival (PFS) and overall survival (OS) with pola + bendamustine-rituximab (BR) vs BR in patients (pts) with R/R DLBCL (Sehn et al. ASH 2018). With an additional year of follow up, we report updated results for the Ph Ib/II DLBCL cohorts (NCT02257567). Methods: Methods were previously reported (Sehn et al. ASH 2018). Safety-evaluable population combined Ph Ib and randomized (RAN) Ph II pola + BR arms (N=45) vs RAN BR (N=39) arm. Longer-term safety outcomes for PN and second malignancies were evaluated. Efficacy reported separately for Ph Ib/II RAN DLBCL arms per investigator (INV) assessment. Additional outcomes including DOR for pts with confirmed responses (defined as having two consecutive responses) were assessed. Results: As of March 15 2019, median follow up for pts with R/R DLBCL in the Ph Ib (N=6) and Ph II RAN arms (N=80) was 46 and 30 months (mo), respectively. In the RAN Ph II (pola + BR [N=40]; BR [N=40]; 39 treated per arm), baseline characteristics were largely balanced with median 2 prior lines of therapy; 28% vs 30% of pts had 1 prior line, 28% vs 23% had 2, 45% vs 48% had ≥3 in the pola + BR vs BR arms, respectively. Most pts (75% vs 85%) were refractory to last prior treatment. PN events occurred in 40% (18/45) of pts treated with pola + BR (all grade [Gr] 1-2). At clinical cutoff, median time to PN resolution was approx. 8 days (range 0-69) with 56% (10/18) of pts experiencing complete resolution of PN. Eight pts had ongoing PN: 4 discontinued study early due to death from disease progression or AE (further follow up for PN resolution not possible), 3 had unresolved Gr 1 PN, and 1 had improving PN (max. Gr 1). Second malignancies occurred in 4% (2/45) of pts treated with pola + BR (1 prostate cancer; 1 squamous cell carcinoma and myelodysplastic syndrome [MDS]) and 5% (2/39) of pts in the BR arm (1 epiglottic carcinoma and MDS; 1 papillary thyroid cancer). In the Ph II RAN arms (pola + BR vs BR) updated median INV-assessed PFS (95% confidence interval [CI]) was 7.5 (4.9, 17.0) vs 2.0 (1.5, 3.7) mo (hazard ratio [HR] 0.33; 95% CI 0.20, 0.56); median OS (95% CI) was 12.4 (9.0, 32.0) vs 4.7 (3.7, 8.3) mo (HR 0.41; 95% CI 0.24, 0.71), respectively (Figure). Median time to first response was 2 mo (range 1.8-5.3). Median DOR (95% CI) for all responding pts in the pola + BR (N=28) vs BR (N=13) arms was 12.7 (5.8, 27.9) vs 4.1 (2.6, 12.7) mo (HR 0.42; 95% CI 0.19, 0.91). Median DOR (95% CI) for confirmed responders in the pola + BR (N=19) vs BR (N=7) arms was 27.9 (10.3, NE) vs 12.7 (7.7, NE) mo (HR 0.44; 95% CI 0.14, 1.32). Nearly half (47%, 9/19) of pts with confirmed responses to pola + BR remained event free at clinical cutoff with 8 pts in CR and 1 pt in partial response (downgraded from CR due to missing bone marrow biopsy based on modified Lugano Criteria). Of these 9 pts, 8 had DORs ranging from 22+ to 34+ mo (1 pt consolidated with allogeneic transplant) and 1 pt withdrew early from study after 14.5 mo of response. In the BR arm, 2 pts maintained responses without events; both had consolidative therapy (1 radiation, 1 allogeneic transplant). Baseline characteristics of pts with confirmed responses in the pola + BR arm are shown in the Table. In the Ph Ib cohort, 3/6 pts were confirmed responders: 1 pt progressed at 45 mo, 2 pts had ongoing responses of 29+ and 44+ mo, respectively. Conclusions: No new safety signals were identified with longer follow-up. PN events were low grade, manageable and mostly reversible. Adding pola to BR did not increase risk of second malignancies. While median time-to-event endpoints have not changed significantly since the last data cut, longer follow-up demonstrates notable durability of response in a proportion of pts treated with pola + BR, many of whom had refractory disease and received multiple lines of prior therapy. Pola + BR represents a promising new treatment for pts with transplant-ineligible R/R DLBCL. Disclosures Sehn: Kite Pharma: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; TEVA Pharmaceuticals Industries: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen-Ortho: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Apobiologix: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen-Ortho: Honoraria; TG Therapeutics: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; F. Hoffmann-La Roche/Genentech: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Acerta: Consultancy, Honoraria; Acerta: Consultancy, Honoraria. Matasar:Bayer: Other: Travel, accommodation, expenses; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Seattle Genetics: Consultancy, Honoraria, Other: Travel, accomodation, expenses, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy, Equity Ownership; Roche: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Genentech, Inc.: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding; Bayer: Consultancy, Honoraria, Other. Flowers:BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Karyopharm: Consultancy; Optimum Rx: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Gilead: Consultancy, Research Funding; Spectrum: Consultancy; TG Therapeutics: Research Funding; Eastern Cooperative Oncology Group: Research Funding; V Foundation: Research Funding; Acerta: Research Funding; Burroughs Wellcome Fund: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Millenium/Takeda: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy. Kamdar:Seattle Genetics: Speakers Bureau; Genentech: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. McMillan:Pfizer: Honoraria, Research Funding; MSD: Honoraria; BMS: Honoraria; Celgene: Honoraria, Speakers Bureau; Sandoz: Honoraria; Gilead: Honoraria; Novartis: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau. Hertzberg:Pfizer: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Assouline:F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Kim:Novartis: Consultancy; Sanofi: Consultancy; AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy; Bayer: Consultancy. Kim:F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding. Ozcan:F. Hoffmann-La Roche Ltd: Other: Travel, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria; Jazz: Other: Travel; Sanofi: Other: Travel; BMS: Other: Travel; MSD: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Abdi Ibrahim: Other: Travel; Janssen: Research Funding, Travel; Celgene: Research Funding; Bayer: Research Funding; Archigen: Research Funding. Croft:Genentech, Inc.: Employment. Hirata:F. Hoffmann-La Roche Ltd: Equity Ownership; Genentech, Inc.: Employment. Cheng:F. Hoffmann-La Roche Ltd: Employment. Ku:Genentech, Inc.: Employment. Herrera:Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding. OffLabel Disclosure: GO29365 (pola + BR vs BR in relapsed/refractory DLBCL). Rituximab (Rituxan) is approved for use in relapsed/refractory low-grade NHL and in previously untreated DLBCL with CHOP, but is not approved for use in relapsed/refractory DLBCL. Bendamustine (Levact) is approved for use in relapsed indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia. Polatuzumab vedotin (Polivy) is approved for use in third-line or later treatment of R/R DLBCL in the USA.