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Supplementary Data from Long-term Follow-up of Patients with Relapsed or Refractory Non–Hodgkin Lymphoma Treated with Venetoclax in a Phase I, First-in-Human Study

Purpose:We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non–Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts.Patients and Methods:All patients (n = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated.Results:At a median follow-up of 38.5 months (range, 30.0–46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5–8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7–27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year.Conclusions:Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.

Background Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status.Methods We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27).Findings Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35.2 months (IQR 31.5-41.3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths.Interpretation Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Purpose: We previously reported a 44% overall response rate (ORR) with the oral BCL-2 inhibitor venetoclax in a phase I study of relapsed/refractory non–Hodgkin lymphoma (NHL). Complete response (CR) was observed in patients with mantle cell lymphoma [(MCL), 21%, n = 6/28] and follicular lymphoma [(FL), 17%, n = 5/29], and partial response (PR) noted in several patients with Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Here, we report the long-term outcomes of these four cohorts. Patients and Methods: All patients (n = 106) received venetoclax monotherapy in dose cohorts of 200 to 1,200 mg daily until disease progression or unacceptable toxicity. ORR, progression-free survival (PFS), duration of response (DoR), and adverse events (AEs) were evaluated. Results: At a median follow-up of 38.5 months (range, 30.0–46.5), the median PFS for all 106 patients was 5.4 [95% confidence interval (CI), 3.5–8.4] months (FL, 10.8; MCL, 11.3; MZL, 21.2; and WM, 30.4). The median DoR was 14.9 (95% CI, 9.7–27.6) months (FL, 26.6; MCL, 15.7; MZL, 20.1; and WM, 25.3). Achievement of CR versus PR predicted longer DoR in both MCL (31.5 vs. 10.1 months) and FL (37.6 vs. 9.7 months). All grade hematologic AEs were infrequent: neutropenia (19%), anemia (19%), and thrombocytopenia (17%), with no new cytopenias after 2 years on therapy. Nonhematologic AEs included nausea (49%), diarrhea (46%), fatigue (44%), with decreased incidence after 1 year. Conclusions: Venetoclax monotherapy has a manageable safety profile and achieves durable responses in a subset of patients with FL, MCL, WM, and MZL, particularly in those who achieve CR. Further research is warranted on combination strategies to enhance the durability of response to venetoclax.

The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years’ follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% (P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10−7). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.

Venetoclax is approved as monotherapy and in combination with rituximab for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Two Phase 1 studies (M12-175 [NCT01328626]; M13-365 [NCT01682616]) were conducted in which patients who initially responded and then progressed on venetoclax monotherapy could receive added rituximab. Ten patients were evaluated (M12-175, n = 8; M13-365, n = 2), and five (50%) responded again upon addition of rituximab, including three complete and two partial responses. Responses were ongoing after 5-10 months of follow-up. Addition of rituximab was well tolerated. These findings indicate potential clinical benefit with rituximab added to venetoclax post-progression in some patients with R/R CLL.

Fixed-duration venetoclax plus rituximab (VenR) has a manageable safety profile and improves survival in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We present data from the phase III MURANO study on the impact of venetoclax modification or premature discontinuation on outcomes in patients with R/R CLL. Timedependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of venetoclax discontinuation/ modification on investigator-assessed progression-free survival (PFS) and overall survival (OS). Analyses were performed retrospectively (without type-1 error control) in intention-to-treat patients from the VenR arm of MURANO. Overall, 140 of 194 (72%) patients in the VenR arm completed 2 years of therapy; 54 of 194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; P

We reviewed the literature (January 2010-June 2021) on the effectiveness of debulking strategies before venetoclax initiation in patients with chronic lymphocytic leukemia to reduce tumor burden, downgrade tumor lysis syndrome (TLS) risk, and avoid hospitalization. Low TLS incidence and reduced TLS risk based on tumor burden were reported following debulking in clinical trials. Real-world observational studies reporting debulking regimens recorded no TLS events, and those without debulking strategies had greater TLS incidence. Debulking prior to venetoclax considerably reduces TLS incidence. Further clinical trials and real-world studies may provide additional evidence on effectiveness of debulking in reducing TLS incidence and hospitalization need.

Introduction: The randomized Phase III MURANO study (NCT02005471) compared fixed-duration VenR with standard bendamustine-rituximab (BR) in R/R CLL. Deep responses with uMRD were associated with superior progression-free survival (PFS) of VenR vs BR with 48 months (mo) follow-up (f/u). We now report long-term MRD kinetics and updated efficacy outcomes, including re-exposure to VenR (to be presented), with a 5 year (yr) median follow-up (clinical cutoff date May 8, 2020). Methods: As published, pts were randomized to VenR (Ven 400 mg daily for 2 yrs + standard dose R for the first 6 mo) or B (70 mg/m2)R (6 mo). A sub-study was introduced in 2018, allowing pts who developed progressive disease (PD) following Tx with BR or VenR to receive the MURANO VenR regimen. PFS was based on investigator assessment. Peripheral blood MRD was analyzed centrally by allele-specific oligonucleotide polymerase chain reaction and/or flow cytometry. Pts were categorized by MRD status as previously reported, using Results: 389 pts were enrolled (VenR, n=194; BR, n=195). With a median f/u of 59.2 (range, 0-71.5) mo, the PFS benefit with VenR over BR was sustained (HR, 0.19 [95% CI: 0.15-0.26]; p Improved OS outcome was observed among the VenR pts that reached EOT without PD and had uMRD (83/118) compared with those with MRD (35/118), with 3-yr post-EOT survival estimates of 95.3% (95% CI: 90.0-100.0) vs 85.0% (95% CI: 72.8-97.2), respectively (Figure 1). Of the pts with uMRD at EOT, 32/83 had not shown PD and remained uMRD at the 5-yr update, 4/83 had PD without prior confirmed MRD conversion and 47/83 had MRD conversion. Median time to MRD conversion from EOT was 19.4 (95% CI: 8.7-28.3) mo. Of the 47/83 pts with confirmed MRD conversion, 19 subsequently developed PD by International Workshop on CLL criteria with a median time to PD from MRD conversion of 25.2 (95% CI: 19.4-30.4) mo. These 19 pts exhibited more rapidly increasing rates of MRD post-EOT than pts that had MRD conversion but were PD-free (Figure 2). Among pts that were uMRD at EOT, the baseline presence of del(17p), GC and unmutated immunoglobulin heavy chain gene (IGVH) were each associated with increased risk of MRD conversion and subsequent PD post-EOT (Table 1). All 4 pts with del(17p) experienced MRD conversion with subsequent PD. 8/18 (44%) pts with GC vs 8/40 (20%) pts without GC eventually converted to MRD and developed PD. The rate of MRD conversion with eventual PD was also higher among those with unmutated IGVH (21/56; 37%) than those without (1/23; 4%). Once uMRD at EOT was achieved, pts without del(17p) or GC, or with mutated IGVH, were more likely to maintain uMRD or experience MRD conversion without subsequent PD at this follow-up (Table 1). No new safety signals were identified. Excluding non-melanoma skin cancers, 2 second primary malignancies (VenR [acute myeloid leukemia and multiple myeloma]) were reported since the previous update. Rates of Richter transformation remained balanced between treatment arms (7 on VenR, 6 on BR). Following PD on the main study, 29 pts were enrolled in the sub-study (re-treatment; n=21, crossover; n=8). Further data on their biologic profile, updated response rates, and MRD in the re-treatment cohort will be presented. Conclusions: Five-yr data from MURANO demonstrate sustained PFS and OS benefit with VenR vs BR. In the VenR cohort, uMRD at EOT is associated with improved OS. Unmutated IGVH, del(17p) and GC (≥3 CNV) are associated with higher rates of MRD conversion and subsequent PD after attaining uMRD at EOT. Overall, a substantial proportion of pts who completed Ven Tx retained uMRD 36 mo after treatment cessation, displaying durable response following 2-yr fixed-duration VenR. Disclosures Kater: Janssen: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Roche: Research Funding; Genentech: Research Funding. Kipps:Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees. Eichhorst:F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding; ArQule: Consultancy, Honoraria, Other: travel support, Research Funding; Oxford Biomedica: Consultancy, Honoraria, Other: travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: travel support, Research Funding; BeiGene: Consultancy, Honoraria, Other: travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: travel support, Research Funding. Hillmen:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Astra Zeneca: Honoraria; F. Hoffmann-La Roche: Honoraria, Research Funding; Pharmacyclics: Research Funding; Gilead: Research Funding. D'Rozario:F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Owen:AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. Assouline:AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding. Lamanna:MingSight: Other: Institutional research grants, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno: Other: Institutional research grants, Research Funding; Loxo: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Columbia University Medical Center: Current Employment; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria; Sandoz, Janssen, AbbVie, Roche, Gilead: Consultancy. de la Serna:F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; Abbvie, AstraZeneca: Other: Travel, Accommodations, Expenses; Abbvie, Janssen: Speakers Bureau; Gilead, AstraZeneca, Abbvie, Janssen, Sandoz, F. Hoffmann-La Roche: Consultancy; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Jaeger:F. Hoffmann-La Roche: Honoraria, Research Funding. Cartron:Celgene: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead: Honoraria; Jansen: Honoraria; Abbvie: Honoraria. Montillo:Gilead: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Verastem: Honoraria. Mellink:Genentech, Inc: Research Funding; Amsterdam University Medical Centre: Current Employment. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Wilson:Roche Products Limited: Current Employment. Wu:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Jiang:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Lefebure:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Boyer:Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Seymour:Mei Pharma: Consultancy, Honoraria; Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Background: Venetoclax is a selective B-cell lymphoma-2 (BCL-2) inhibitor approved for use as monotherapy or with rituximab in patients with chronic lymphocytic leukemia (CLL). The objectives of the current analysis of observed data from adult patients randomized to venetoclax–rituximab in the phase III MURANO study were to characterize venetoclax pharmacokinetics (PKs) using a Bayesian approach, evaluate whether a previously developed population PK model for venetoclax can describe the PKs of venetoclax when administered with rituximab, and to determine post hoc estimates of PK parameters for the exposure–response analysis. Methods: Parameter estimates and uncertainty estimated by a population PK model were used as priors. Additional covariate effects (CLL risk status, geographic region, and 17p deletion [del(17p)] status) were added to the model. The updated model was used to describe venetoclax PKs after repeated dosing in combination with rituximab, and to determine post hoc estimates of PK parameters for exposure–response analysis. Results: The PK analysis included 600 quantifiable venetoclax PK samples from 182 patients in the MURANO study. Model evaluation using standard diagnostic plots, visual predictive checks, and normalized prediction distribution error plots indicated no model deficiencies. There was no significant relationship between venetoclax apparent clearance (CL/F) and bodyweight, age, sex, mild and moderate hepatic and renal impairment, or coadministration of weak cytochrome P450 3A inhibitors. The chromosomal abnormality del(17p) and CLL risk status had no apparent effect on the PKs of venetoclax. A minimal increase in venetoclax CL/F (approximately 7%) was observed after coadministration with rituximab. CL/F was 30% lower in patients from Central and Eastern Europe (n = 60) or Asia (n = 4) compared with other regions (95% confidence interval [CI] 21–39%). Apparent central volume of distribution was 30% lower (95% CI 22–38%) in females (n = 56) compared with males (n = 126). No clinically significant impact of region or sex was observed on key safety and efficacy outcomes. Conclusions: The Bayesian model successfully characterized venetoclax PKs over time and confirmed key covariates affecting PKs in the MURANO study. The model was deemed appropriate for further use in simulations and for generating individual patient PK parameters for subsequent exposure–response evaluation.

Introduction: At a median follow-up of 5 years (cutoff of May 8, 2020), the MURANO trial (NCT02005471) demonstrated deeper responses, including superior rates of undetectable (u)MRD and progression-free survival, in patients (pts) with relapsed/refractory (R/R) CLL treated with fixed-duration VenR vs bendamustine-rituximab (BR). With longitudinal MRD assessments in peripheral blood (PB), we now report kinetics of MRD growth after end of treatment (EOT), and the clinical and molecular factors associated with MRD growth rates. Methods: Pts were randomized to VenR (venetoclax 400mg daily for 2 years + standard-dose rituximab for the first 6 months) or BR (6 months). PB MRD samples were collected every 3-6 months and analyzed centrally by allele-specific oligonucleotide-polymerase chain reaction and/or flow cytometry; uMRD threshold was For longitudinal analysis of MRD growth dynamics, a population-based logistic growth model with a nonlinear mixed effects approach was developed as previously described (Al-Sawaf et al. EHA 2021). Pts who completed treatment (Tx) without progressive disease (PD) and who had ≥2 measurable time points post-EOT were included; data below the lower limit of quantification in those pts was handled by a likelihood-based method (Bergstrand & Karlsson, AAPS J 2009). Prognostic markers and patient demographics were screened as covariates for impact on key model parameters, based on statistical and graphical assessments. Variables with >20% missing data or with low representation ( Results: Overall, 284 pts completed the study Tx without PD. Pts with no MRD data (n=23), pts with MRD data only on-Tx (n=6) or only after PD/next-line of Tx (n=2), or pts with The median MRD level at EOT was significantly lower after VenR (1.88 x 10 −5) than BR (7.06 x 10 −4; p=5.1 x 10 −8, Figure 1A). In the VenR arm, no statistically significant difference in median MRD level at EOT was seen in pts with mutated or unmutated immunoglobulin heavy chain variable gene (IGHV), or pts with or without TP53 mutation (Table 1). However, in the BR arm, pts with TP53 mutation had significantly higher median MRD levels at EOT than those with TP53 wild-type (Table 1). Overall, median MRD doubling time post-EOT was significantly longer for pts treated with VenR (93 days; n=91) than BR (53 days; n=120; p=1.2 x 10 −7, Figure 1B). Based on covariate screening of 27 prognostic markers and patient demographics, age (< or ≥65 years), VenR Tx, IGHV status, TP53 mutation status, and disease burden at study initiation (low/medium risk of tumor lysis syndrome vs high risk) showed significant impact on MRD growth rate (Table 1). The median MRD doubling time was 53 days in pts aged Conclusion: Using a robust, population-based model of MRD growth dynamics, we demonstrate that post-EOT MRD growth was slower in pts with R/R CLL treated with VenR compared with BR. Together with similar observations in the frontline setting of venetoclax-obinutuzumab Tx, these results suggest that, compared with chemoimmunotherapy, fixed-duration venetoclax plus anti-CD20 therapy may contribute to prolonged CLL disease control by slowing the growth of the residual disease clones. It also implies that clonal growth may be influenced by biological and Tx-related parameters. The underlying mechanisms need to be further explored. Figure 1 Figure 1. Disclosures Kater: Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Lu: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current holder of individual stocks in a privately-held company. Langerak: Erasmus MS, University Medical Center: Current Employment; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Research Funding; Gilead: Research Funding; Janssen: Speakers Bureau. Mellink: Cytogenetic Field: Consultancy; Genome Diagnostics Laboratory, AUMC: Current Employment; Financial support related to microarray analysis of Murano samples: Research Funding. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Wu: Genentech, Inc.: Current Employment; Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Boyer: Roche: Current Employment. Lefebure: F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Roche: Current Employment. Jiang: F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Genentech, Inc./F.Hoffmann-La Roche Ltd: Current Employment. Seymour: Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction: In the MURANO trial (NCT02005471), fixed-duration VenR (2 yrs Ven + R for the first 6 mo) improved survival and rates of undetectable minimal residual disease (MRD) over bendamustine (Benda)-R in pts with R/R CLL. Novel recurrent mutations in BCL2 and family genes (eg BAX and PMAIP1 [encoding Noxa]) have been linked to Ven resistance. We analyzed MRD+ samples from VenR-treated pts in MURANO to assess the nature and frequency of acquired mutations in BCL2 family genes (marker of emergent Ven resistance) and TP53 (may negatively impact response to re-Tx). We also analyzed the impact of these mutations on time to next CLL Tx (TTNT) and subsequent response. Methods: Pts included in this analysis received up to 2 yrs of VenR and had, at any time, ≥1 CLL cell per 100 leukocytes (high MRD+) in peripheral blood. Deep next generation sequencing (NGS) was performed without cell selection using a custom targeted NGS panel, encompassing 87 cell death related genes (coding regions and selected promoters). A CD19-enriched pre-Tx sample, analyzed by whole-exome sequencing, was available for all pts for comparison. Data cutoff was May 8, 2020, for the MURANO main study and Oct 13, 2020, for the substudy (where pts received next-line VenR following progression after initial VenR Tx). TTNT was calculated using the main study Ven completion/discontinuation date and the date of the first subsequent CLL Tx. Results: 107 samples from 42 pts, collected 21-42 mo post-Tx initiation, were evaluable. No BCL2 mutations were identified (limit of detection - variant allele frequency [VAF] 1%). Acquired BAX and PMAIP1 mutations were seen in 4 and 2 pts, respectively. Discordance between VAF and CLL MRD, and lack of proportionality in results with serial testing, suggested presence of BAX mutations in the non-CLL compartment in some pts, with further testing of sorted populations needed to clarify the source. All BAX mutations identified have been predicted to lead to loss of protein function, including 4 frameshift mutations. PMAIP1 mutations included a frameshift mutation (T86fs) and a mutation affecting gene splicing, both suggesting a loss-of-function effect. Nineteen TP53 mutations in 15/42 pts were observed across longitudinal samples (8/19 mutations in 6 pts present at baseline, 11/19 in 11 pts newly acquired, and 2 pts with both baseline and acquired mutations). Co-occurrence of TP53mut with BAXmut or PMAIP1mut was observed in 3/15 and 1/15 pts, respectively; based on VAF and assuming heterozygosity, these were likely in different clones. After Ven cessation, 28/42 (66.7%) had received an additional anti-CLL Tx by the cutoff; 19 pts received Ven-based regimens (15 in the substudy; 4 received other Ven-containing regimens per investigators' choice), 8 pts received ibrutinib (Ibr) monotherapy and 1 pt received Benda. Of the 19 pts who received Ven-based regimens (median 22.6 mo [range 11.9-38.1] post-main study end of Tx), 8 had TP53mut (5 acquired, 3 baseline), with 5/8 (63%) responding (complete response, 3 pts; partial response [PR], 2 pts). Six/11 pts (55%) with TP53-wild-type (WT) responded, all PRs. Two pts with TP53mut received Ibr as next Tx (one responded) vs 6 TP53-WT pts (all responded). The one pt treated with Benda without response had coexisting TP53mut and BAXmut. One patient with BAXmut received Ven re-Tx without response, while in pts with BAXmut and PMAIP1mut, responses to Ibr were 100% (2/2 pts) and 50% (1/2 pts), respectively (Table). No association was apparent between acquired TP53mut and TTNT, median 784 days (d; range 248-1051) vs 617 d (range 302-1142) in TP53-WT pts. Pts harboring BAXmut (n=5) had a shorter median TTNT (305 d; range 248-874) than BAX-WT pts (678 d; range 302-1142). Conclusion: No acquired BCL2 mutations were found in this analysis of pts from MURANO who received fixed-duration VenR Tx and subsequently manifest high MRD+. This suggests that fixed-duration Tx may reduce the propensity for selection of BCL2 resistance mutations, although confirmation using orthogonal methodology with higher sensitivity is required. Acquired TP53 mutations, noted in ~40% of pts, did not preclude response to subsequent Tx (primarily Ven-based regimens). Consistent with the TP53-independent mechanism of Ven, Ven re-Tx may be effective for pts with MRD+ disease who have relapsed following initial fixed-duration VenR Tx. More data are needed to better understand the significance of BAX or PMAIP1 mutations. Figure 1 Figure 1. Disclosures Seymour: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Wu: Roche/GNE: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Genentech, Inc.: Current Employment. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Eichhorst: Consultant Department I for Internal Medicine: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Research Funding, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodation, expenses, Speakers Bureau; Adaptive Biotechnologies: Speakers Bureau; Hexal: Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Oxford Biomedica (UK): Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; University Hospital of Cologne: Current Employment. Hillmen: University of Leeds: Current Employment; Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Research Funding; Pharmacyclics: Honoraria, Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria. Kipps: European Research Initiative on CLL (ERIC): Honoraria; DAVA Pharmaceuticals: Speakers Bureau; Bionest Partner: Other; Celgene: Consultancy, Honoraria, Other, Research Funding; Genetech: Honoraria, Other; Genentech-Roche: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other, Speakers Bureau; Janssen: Consultancy, Honoraria, Other, Research Funding, Speakers Bureau; Roche: Honoraria, Other; MD Anderson Cancer Center: Research Funding; Velos: Research Funding; CRIM: Research Funding; Indy Hematology Review: Other; TG Therapeutics: Other; Verstem: Other, Speakers Bureau; University of California, San Diego: Current Employment; Pharmacyclics/AbbVie: Honoraria, Research Funding; Breast Cancer Research Foundation: Research Funding; SCOR - The Leukemia and Lymphoma Society: Research Funding; National Cancer Institute/NIH: Honoraria, Research Funding; DAVAOncology: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other, Speakers Bureau; Oncternal Therapeutics, Inc.: Current holder of stock options in a privately-held company, Other: Stock or other ownership, Patents & Royalties: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory., Research Funding; Genentech/Roche: Honoraria; Moores Cancer Center: Current Employment; MedImmune Inc: Research Funding; GlaxoSmithKline: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics LLC, an Abbvie Company: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbott Laboratories: Consultancy, Research Funding. Langerak: Janssen: Speakers Bureau; Gilead: Research Funding; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Research Funding; Erasmus MS, University Medical Center: Current Employment. Owen: Incyte: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Honoraria; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Servier: Honoraria; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Honoraria. Dubois: Abbvie: Research Funding; Genentech: Research Funding; Roche: Research Funding. Mellink: Cytogenetic Field: Consultancy; Genome Diagnostics Laboratory, AUMC: Current Employment; Financial support related to microarray analysis of Murano samples: Research Funding. Van Der Kevie-Kersemaekers: Amsterdam University Medical Centers: Current Employment. Dunbar: AbbVie: Current Employment. Jiang: Genentech, Inc./F.Hoffmann-La Roche Ltd: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Boyer: Roche: Current Employment. Thadani-Mulero: Roche: Current Employment, Current equity holder in publicly-traded company. Lefebure: Roche: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Harrup: AstraZeneca: Other: Advisory board. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding.

Background Onartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non–small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. Methods Patients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics. Results Efficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%). Conclusion Onartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

Introduction: Venetoclax (Ven) has changed the chronic lymphocytic leukemia (CLL) treatment landscape with the ability to produce deep responses that result in improved long-term outcomes with well-tolerated fixed-duration regimens. Due to its potent pro-apoptotic effect on CLL cells, Ven poses a risk of inducing tumor lysis syndrome (TLS). If not managed promtly and appropriately, metabolic abnormalities (laboratory TLS) can progress to clinical TLS, including renal insufficiency, cardiac arrhythmias, seizures, and death. Current Ven TLS mitigation measures include TLS risk assessment, 5-wk dose ramp-up, prophylaxis with hydration and oral uric acid reducers, and close monitoring of blood chemistry based on risk level (Davids. Clin Cancer Res. 2018;24:4371). Debulking strategies have been effectively used to lower TLS risk before Ven therapy. In this analysis, rates of TLS and outcomes in the clinical trial and post-marketing settings are evaluated. Methods: Trial data from patients treated with current TLS mitigation measures implemented since May 2014 were pooled from 8 studies (N=1138; n=304 treatment naïve; n=834 relapsed/refractory [R/R]). This was a retrospective descriptive analysis of adverse events (AEs) of TLS and cases meeting laboratory and clinical TLS using Howard criteria (Howard. N Engl J Med. 2011;364:1844). Post-marketing data included reports of TLS from the AbbVie Global Safety Database (GSD) collected from Apr 2016 - Dec 2019 (N=236) and 5 publications of real-world usage (n=817 patients over all studies). The review of trial data focused on Ven ramp-up (ie, first 5 weeks of dosing). Results: In 1138 patients receiving Ven from pooled clinical studies, AEs of TLS and laboratory values meeting Howard criteria are shown in Table 1. With current recommended mitigation measures, the incidence of TLS AEs was 1.8% (n=20), with 15 laboratory TLS AEs (1.3%) and 5 clinical TLS AEs (0.4%) reported. TLS was transient in all cases, and patients resumed therapy without permanent sequelae. With the currently recommended measures, no deaths from TLS were reported in the 1138 patients in clinical trials. Approximately 20,000 patients with CLL have initiated Ven outside of clinical trials from 2016-2019 based on commercial tracking. In this post-marketing setting, 236 reports of TLS were identified in the GSD, and 17 had severe consequences that could be attributed to TLS (13 fatal, 4 requiring dialysis), all in patients with R/R CLL. These patients had typical demographic characteristics of CLL, with a median age of 69 years and multiple comorbidities, where reported, including 7 patients with renal dysfunction. Ten patients (59%) were hospitalized before receiving Ven. In those with available data, TLS occurred in patients with high (n=3), medium (n=6), and low (n=1) TLS risk. TLS mostly occurred after the 20-mg dose (n=8) but also after the 50- (n=1), 100- (n=6), and 400-mg (n=1) doses. Noting the incomplete data available, blood monitoring and interventions were not reported in most patients; recommended dose ramp-up was reportedly not followed in 4 cases. Concomitant anti-CLL therapies or contraindicated therapies (CYP3A inhibitors) were used in 3 and 2 cases, respectively. Key factors contributing to TLS in the post-marketing setting are summarized in Table 2. Five real-world studies, mostly in patients with R/R CLL, reported on the incidence of TLS (n=817 patients; VeRVe observational study; Mato. Haematologica. 2018;103:1511; Clin Cancer Res. 2019;25:4264; Kohler. Leuk Lymphoma. 2020; Nabhan. J Clin Oncol. 2018;36[suppl, abstr]:7529). TLS incidence ranged from 6%-13% (clinical TLS, 1%-6%). Reported TLS risk distribution ranged from 38%-45% (low), 34%-37% (medium), and 19%-28% (high). Conclusion: This report's findings indicate that TLS mitigation measures implemented in clinical studies (N=1138) successfully mitigated the risk of TLS with Ven in patients with CLL, with clinical TLS occurring in Disclosures Seymour: Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gribben:Janssen: Honoraria, Research Funding; Celgene: Research Funding; Abbvie: Honoraria; AstraZeneca: Honoraria, Research Funding. Davids:Sunesis: Consultancy; Research to Practice: Honoraria; Zentalis: Consultancy; Syros Pharmaceuticals: Consultancy; Novartis: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Surface Oncology: Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Ascentage Pharma: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Eli Lilly: Consultancy; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Celgene: Consultancy; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Gilead Sciences: Consultancy; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy. Mato:Loxo: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; BeiGene: Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Cyr:AbbVie: Current Employment, Current equity holder in publicly-traded company. Bartkus:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pena:AbbVie: Current Employment, Current equity holder in publicly-traded company. Boyer:Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Rosenberg:AbbVie: Current Employment, Current equity holder in publicly-traded company.

Introduction: Venetoclax (Ven) is an orally administered, highly selective inhibitor of B-cell lymphoma-2 (BCL-2). Fixed-duration VenR improved outcomes versus standard bendamustine-rituximab (BR) in the randomized Phase III MURANO study (NCT02005471; Seymour et al. N Engl J Med 2018) and is now a standard of care for the treatment of pts with R/R CLL. There are currently limited data to guide subsequent therapies when relapse occurs after fixed-duration VenR and uncertainty regarding the efficacy of repeated VenR treatment. Here, we report the response rates to follow-up therapy with Ven and Ven-based regimens, or exposure to Bruton tyrosine kinase inhibitor (BTKi) salvage therapy, following pts' participation in the MURANO trial. Methods: Pts were randomized to VenR (Ven 400 mg daily for 2 years [yrs] plus monthly R for the first 6 months [mo]) or BR (6 mo). The primary endpoint was investigator-assessed progression-free survival (PFS). Pts in either arm with disease progression were followed for overall survival (OS) and disease response to any subsequent anti-CLL therapeutic regimens. Pts who initiated new anti-CLL therapy, but who had not had a response assessment reported by the principal investigator, were considered unevaluable. Results: 389 pts were enrolled in MURANO (VenR, n=194; BR, n=195). At a clinical cutoff date of May 8, 2020, all main study pts had ceased treatment with a median follow-up of 59 mo (range 0-71.5). PFS and OS benefits were maintained at the 5-yr follow-up (Kater et al. Submitted to ASH 2020). Following disease progression, 67/87 (77.0%) VenR pts and 123/148 (83.1%) BR pts had received subsequent anti-CLL therapy. The time to next therapy (TTNT) from study entry was longer following VenR versus BR, with a median TTNT of 57.8 (95% CI: 55.1-NE) mo versus 23.9 (95% CI: 20.7-29.5) mo (HR, 0.26 [95% CI: 0.20-0.35]; p Of the BR pts receiving subsequent therapy; 99/123 (80.5%) pts received novel targeted therapy alone or in combination with other agents (BTKi, n=72; phosphoinositide 3-kinase inhibitors [PI3Ki], n=10; Ven, n=15; or other investigational medicinal products [IMP], n=2) while the remaining 24 pts received chemoimmunotherapy. Of pts previously treated with BR, the BOR rate to novel targeted agents was 84.4% among evaluable pts (83.9% for BTKi and 80.0% for Ven-based therapy; Table 1). Fifty two of 67 pts in the VenR arm received subsequent novel therapy (BTKi, n=18; PI3Ki, n=1; Ven [alone or in combination], n=32; IMP, n=1). The BOR rate to these targeted agents was 79.4% among evaluable pts. After a median treatment-free interval of 13.5 (range 0.0-41.3) mo, 18 VenR pts received a BTKi as their next line of therapy (all were BTKi naïve). These pts achieved high overall response rates (ORR): 14/14 (100% of pts with an evaluable assessment) at a median treatment duration of 21.9 (range 5.6-59.2) mo, with 10 pts continuing on BTKi therapy at this follow-up. After a median treatment-free interval of 23.7 (range 3.3-43.8) mo, 32 VenR pts were re-treated with Ven-based regimens; 21 were enrolled in the re-treatment arm of the MURANO sub-study and 11 were treated outside of the sub-study. The BOR to re-treatment with Ven or Ven-containing therapies was 72.2% of evaluable pts (Table 1). Among these pts, initial response to VenR at the main study end of combination treatment response visit was 100% (6 complete response [CR]/CR with incomplete hematologic recovery; 12 partial response), with 77.8% (14/18) achieving undetectable minimal residual disease and 15/18 completing the initial 2 yrs of Ven therapy without progression. Median treatment duration in evaluable pts re-treated with Ven-based regimens was 11.4 (range 0.7-37.6) mo with 50% of pts continuing on therapy. Conclusions: Five-yr data from MURANO demonstrated sustained TTNT benefit with VenR versus BR. Despite >80% of relapsed BR pts receiving salvage therapy with a novel agent, OS rates remain superior with VenR therapy. Relapsed VenR pts demonstrated high ORR to either subsequent BTKi therapy or re-exposure to Ven-based regimens. These data show early use of fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response or OS. Disclosures Owen: AbbVie, F. Hoffmann-La Roche, Janssen, Astrazeneca, Merck, Servier, Novartis, Teva: Honoraria. D'Rozario:AbbVie: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak:GSK: Research Funding; Bristol Meyers Squibb: Research Funding; Medical University of Lodz: Current Employment; Morphosys: Research Funding; Takeda: Consultancy; UCB: Honoraria, Research Funding; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Acerta: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Honoraria, Research Funding; Sandoz: Consultancy, Honoraria; UTX-TGR: Research Funding; Momenta: Consultancy; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; BioGene: Honoraria, Research Funding. Kater:Celgene, F. Hoffmann-La Roche/Genentech, Astra Zeneca, Janssen: Honoraria; Celgene, F. Hoffmann-La Roche/Genentech, Astra Zeneca, Janssen: Research Funding. Montillo:AbbVie: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Gilead: Honoraria, Speakers Bureau; Verastem: Honoraria. de la Serna:Abbvie, AstraZeneca: Other: Travel, Accommodations, Expenses; Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria; Gilead, AstraZeneca, Abbvie, Janssen, Sandoz, F. Hoffmann-La Roche: Consultancy; Abbvie, Janssen: Speakers Bureau; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding. Trněný:Bristol Meyers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead Sciences: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Roche: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Bataillard:Imperial College Healthcare NHS Trust: Ended employment in the past 24 months; Roche Products Limited (temporary clinical fellowship as a fixed-term sabbatical from Hematology specialty training fellowship at Imperial College Healthcare NHS Trust): Current Employment. Lefebure:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Boyer:Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Seymour:Mei Pharma: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Nurix: Honoraria; Morphosys: Consultancy, Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding.

Exposure–response relationships from a phase 1b (M13-365) and phase 3 (MURANO) study were investigated to assess benefit/risk of venetoclax 400 mg daily plus rituximab in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Dose intensities were summarized by tertiles of predicted venetoclax steady-state average concentrations based on nominal venetoclax dose (CmeanSS,nominal) for tolerability; exposure–safety analyses used logistic regression. Exposure–progression-free survival (PFS) relationships were assessed using MURANO data, with CmeanSS,nominal as a grouping factor. Covariates were demographics, geographic region, study, baseline disease characteristics, ECOG performance status, responsiveness to prior therapy, and chromosomal abnormalities. There was no significant effect of covariates on grade ≥3 neutropenia/infection or PFS, and no relationship between venetoclax exposure and these endpoints, or venetoclax or rituximab dose intensity. These results support the recommended venetoclax 400 mg daily dose in combination with rituximab in patients with R/R CLL or small lymphocytic leukemia.

8028 Background: Ven + rituximab (VenR) has a manageable safety profile and improves survival in patients (pts) with R/R CLL, but discontinuation/interruption is frequent. We present new data from the Phase III MURANO study on the impact of Ven early discontinuation/interruption on outcomes in pts with R/R CLL. Methods: Time-dependent Cox proportional hazards regression models, stratified by 17p deletion and risk status, evaluated the impact of Ven discontinuation/interruption on investigator-assessed PFS and OS. Analyses were performed retrospectively (without type-1 error control) in intent-to-treat pts with R/R CLL from the fixed-duration VenR arm of MURANO (NCT02005471; data cut-off: May 8, 2019). Results: 140/194 pts (72%) in the VenR arm completed 2 years of therapy. Early discontinuation occurred in 54/194 (28%) pts (adverse events [AEs]: 29, disease progression [PD]: 12, withdrawal: 5, physician decision: 3, death: 2, other: 2, non-compliance: 1). Median Ven durations for pts discontinuing due to AEs and PD: 11.3 (0.5–24.6) and 17.1 (4.6–25.1) months, respectively (p = 0.08). Inferior PFS was observed in pts who discontinued Ven early for any reason except PD or due to AEs, versus those who completed therapy (Table). Greater cumulative Ven exposure significantly reduced risk of a PFS/OS event (PFS: HR 0.93, 95% CI 0.88–0.99, p = 0.0168; OS: HR 0.85, 95% CI 0.79–0.92, p < 0.0001). Treatment interruption for AEs occurred in 134/194 (69%) pts, most commonly due to neutropenia (84/194; 43%), per protocol requirements. Median duration of interruption: 9 (1–93) days. Treatment interruption, regardless of duration, had no impact on PFS or OS (Table). 36 (19%) pts with interruptions later discontinued Ven. Conclusions: In MURANO, early Ven discontinuation was associated with suboptimal outcomes; Ven interruption was not. These data highlight the importance of effective control of toxicity to realize the full benefit of VenR treatment. Clinical trial information: NCT02005471 . [Table: see text]

International audience; BACKGROUND: Venetoclax inhibits BCL2, an antiapoptotic protein that is pathologically overexpressed and that is central to the survival of chronic lymphocytic leukemia cells. We evaluated the efficacy of venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia. METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 389 patients to receive venetoclax for up to 2 years (from day 1 of cycle 1) plus rituximab for the first 6 months (venetoclax-rituximab group) or bendamustine plus rituximab for 6 months (bendamustine-rituximab group). The trial design did not include crossover to venetoclax plus rituximab for patients in the bendamustine-rituximab group in whom progression occurred. The primary end point was investigator-assessed progression-free survival. RESULTS: After a median follow-up period of 23.8 months, the rate of investigator-assessed progression-free survival was significantly higher in the venetoclax-rituximab group (32 events of progression or death in 194 patients) than in the bendamustine-rituximab group (114 events in 195 patients); the 2-year rates of progression-free survival were 84.9% and 36.3%, respectively (hazard ratio for progression or death, 0.17; 95% confidence interval [CI], 0.11 to 0.25; P\textless0.001 by the stratified log-rank test). The benefit was maintained across all clinical and biologic subgroups, including the subgroup of patients with chromosome 17p deletion; the 2-year rate of progression-free survival among patients with chromosome 17p deletion was 81.5% in the venetoclax-rituximab group versus 27.8% in the bendamustine-rituximab group (hazard ratio, 0.13; 95% CI, 0.05 to 0.29), and the 2-year rate among those without chromosome 17p deletion was 85.9% versus 41.0% (hazard ratio, 0.19; 95% CI, 0.12 to 0.32). The benefit of venetoclax plus rituximab over bendamustine plus rituximab was confirmed by an independent review committee assessment of progression-free survival and other secondary efficacy end points. The rate of grade 3 or 4 neutropenia was higher in the venetoclax-rituximab group than in the bendamustine-rituximab group, but the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-rituximab group was 3.1% (6 of 194 patients). CONCLUSIONS: Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab. (Funded by Genentech and AbbVie; ClinicalTrials.gov number, NCT02005471 .).

The first two authors contributed equally. Introduction: VenR (2 years of Ven, plus R during the first 6 months) improved progression-free/overall survival (PFS/OS) vs bendamustine + R (BR) in patients (pts) in with R/R CLL in MURANO (Seymour et al. N Eng J Med 2018). MURANO also showed early, sustained and durable undetectable minimal residual disease (uMRD) status with VenR, which is associated with prolonged survival in CLL (Kater et al. J Clin Oncol 2019). Here we explore associations between baseline molecular characteristics and VenR-induced MRD responses and PFS based on the 4-year follow-up of MURANO. Methods: DNA specimens from CD19-enriched baseline samples (313/389 enrolled pts) were analyzed with whole-exome sequencing (WES). Genetic complexity (GC) was assessed by array comparative-genomic hybridization. Gene expression data were generated by RNA sequencing from matched RNA samples (209 pts). Univariate analysis determined the impact of gene mutations, GC, and BCL-2 (family) expression on MRD and PFS at end of combination therapy (EOCT) and end of treatment (EOT). MRD (peripheral blood only) was categorized as uMRD Results: Mutation frequencies/GC status at baseline were equally distributed between arms. All 313 pts had CLL cells with non-silent, deleterious mutations by WES (mean 47/pt; 0.97±0.3 mutations/megabase). Of 44 frequently mutated genes, 202/313 (65%) pts had ≥1 frequent mutation; 69/313 (22%) pts had ≥2. Frequencies (%) of deleterious mutations were TP53 21.7, ATM 18.8, NOTCH1 17.9, SF3B1 12.5, XPO1 9.9, BIRC3/POT1/BRAF/EGR2 5.1-5.4, rest WES data: BIRC3 mut and BRAF mut tended to be enriched in pts with detectable MRD at EOCT (% MRD+ in mutation vs wild type: 62.5% vs 23.7% [p=0.146] and 55.6% vs 21.4% [p=0.027] respectively) (Table 1). At EOT, NOTCH1 mut and TP53 mut were negatively associated with uMRD (35.3% vs 63.5% [p=0.10]; 41.7% vs 63.9% [p=0.028]) (Table 1). These observations were concordant with observed PFS outcomes (Figure 1). Array data: Negative effects on MRD status were seen in pts with either del17p at EOCT (p=0.055) and at EOT (p=0.054) or del13q14bi at EOCT (p=0.018) (Table 1). Trends were seen for gain 2p, loss 18p/4q/trisomy 12 at EOCT and gain 2p/8q, loss 14q/18p/4q and trisomy 12 at EOT. High MRD+ at EOT was also associated with low and high GC vs non-complex GC (p=0.042) (Figure 2). PFS was shorter in high but not low GC pts at 36-mo follow-up (HR 3.2, p=0.0055; HR 1.1, p=0.77). Conversely, after 4-years follow-up, low GC pts had reduced PFS benefit vs non-complex GC (HR 2.0, p=0.025; Figure 3), differing from previously reported findings (Lugano, 3-year follow-up). The delayed deterioration in PFS benefit in low GC pts was unprecedented, and warrants further investigation into prognostic risks associated with this subgroup. RNA expression data: Gene-specific and pathway-level enrichment analyses are ongoing to explore associations between RNA sequencing data and MRD status. Preliminary gene expression analyses showed that pts with MRD+ at EOCT expressed higher BCL-2 than those with uMRD (p=0.028), but not at EOT (Table 1). There was a trend towards increased MCL-1 expression from high MRD to low MRD and uMRD at EOT. Conclusions: We identified genomic alterations having impact on MRD response at EOCT and EOT (i.e. BIRC3, BRAF, NOTCH1, TP53): mutations mostly were associated with increased MRD and del17p tended to lead to increase in high and low clones of MRD+. Low/high GC negatively impacted long-term PFS with VenR and may represent high-risk pt subgroups. High BCL-2 may associate with MRD+ at EOCT but not at EOT. Given the small size of the genomic alteration cohort, further validation of these findings are needed. Studying the large CLL clinicogenomic data in MURANO helped determine whether VenR combinations overcome challenges posed by CLL/SLL with unfavorable clinical characteristics, and further identify biomarkers that may predict clinical benefits in these pts. Disclosures Kater: AbbVie: Consultancy, Honoraria, Research Funding; Roche: Other: Travel funding, Research Funding; Genentech: Research Funding. Wu:Genentech, Inc.: Employment, Equity Ownership. Bolen:F. Hoffmann-La Roche: Equity Ownership; Genentech, Inc.: Employment. Assaf:Genentech, Inc.: Employment, Equity Ownership. Hillmen:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Apellis: Research Funding; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding. Eichhorst:AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ArQule: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Eldering:Genetech, Roche, AbbVie: Research Funding. Kipps:AstraZeneca, Inc.: Membership on an entity's Board of Directors or advisory committees; Verastem: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceutical Companies of Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Velos-Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Langerak:Gilead: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; F. Hoffmann-La Roche Ltd: Research Funding; Genentech, Inc.: Research Funding. Mellink:Roche/Genentech: Research Funding. Van Der Kevie-Kersemaekers:Array analysis is financed by Roche/Genentech: Research Funding. Owen:AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Teva: Honoraria; Merck: Honoraria; Acerta: Research Funding. Chyla:Abbvie, Inc: Employment, Other: Stock or options. Punnoose:Roche: Other: Stock/stock options; Genentech, Inc.: Employment. Wang:Roche: Equity Ownership; Genentech, Inc.: Employment. Lefebure:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment. Humphrey:F. Hoffmann-La Roche Ltd: Employment. Jiang:Genentech: Employment, Equity Ownership; F. Hoffman-La Roche: Equity Ownership. Seymour:Roche: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Acerta: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy.

International audience; Evidence before this study We searched PubMed on June 30, 2016, for English-language cohort studies published since Jan 1, 1980, of patients with invasive listeriosis worldwide with the keywords " listeria " , " listeriosis " , " maternal " , and " neurolisteriosis ". Studies had to include epidemiological or clinical data on listeriosis. All clinical forms of infection were included (bacteraemia, neurolisteriosis, and maternal–neonatal infection). Host risk factors for listeriosis have been well identified, but the clinical features and prognostic factors of the disease are based on retrospective studies compiling heterogeneous data or random collected cases. Furthermore, no clinical trial has ever been done and medical management is not evidence based. Added value of the study Our study is the first prospective clinical study focusing on all forms of invasive listeriosis. The study is based on a national mandatory system that allowed the nearly complete capture of microbiologically proven cases. The study shows a higher burden of listeriosis than reported before: more than 80% of infected mothers experienced major fetal or neonatal complications (fetal loss, very high prematurity, early or late onset disease); only 39% of patients with neurolisteriosis survived and fully recovered. The study provides important new data to improve management and predict outcome in listeriosis, such as determination of the time window for fetal losses (

Introduction The treatment options for squamous cell non–small-cell lung cancer (NSCLC) are limited. We assessed the efficacy and safety of onartuzumab plus platinum-doublet chemotherapy in previously untreated advanced squamous cell NSCLC. Patients and Methods The patients were randomized to receive onartuzumab plus paclitaxel plus carboplatin/cisplatin (n = 55) or placebo plus paclitaxel plus carboplatin/cisplatin (n = 54). Randomization was stratified by MET diagnostic status: MET immunohistochemistry (IHC)-positive (MET IHC 3+/2+) or MET IHC-negative (MET IHC 1+/0). The co-primary endpoints were investigator-assessed progression-free survival in the intent-to-treat and the MET IHC + populations. Results The risk of disease progression or death was similar between the 2 treatment arms in both the intent-to-treat (stratified hazard ratio, 0.95; 95% confidence interval, 0.63-1.43) and MET IHC + populations (unstratified hazard ratio, 1.27; 95% confidence interval, 0.69-2.32). Comparable results were obtained for overall survival and the objective response rate. In all safety-evaluable patients, the grade 3 to 5 adverse events occurring at a > 5% greater incidence in the onartuzumab-containing versus the placebo-containing arm were neutropenia (14.8% vs. 5.8%) and pulmonary embolism (5.6% vs. 0%). Eight patients died as a result of adverse events: 1 case each of pneumonitis, pneumonia, cardiac failure, and unexplained death in the onartuzumab arm and 1 case each of hemorrhage, cardiac arrest, hemoptysis, and febrile neutropenia in the placebo arm. Conclusion Studies using alternative assays of MET activation might help to clarify the role of onartuzumab. However, with the lack of clinical activity seen in the present study, the development of onartuzumab for squamous cell NSCLC will not be pursued further.

As the world becomes more urbanized, concerns over the urban heat island (UHI) are more pronounced. Increased urban temperatures have a negative affect on the natural and human environment by producing increased energy usage and smog formation. Pervious concrete pavement is one technology that may help mitigate increased urban temperatures. Temperature data from an instrumented site in Iowa and heat storage phenomena for various weather patterns are presented. The site contains both pervious concrete pavement with a solar reflectance index (SRI) of 14 and traditional concrete pavement with an SRI of 37. Leadership in Energy and Environmental Design (LEED) accepted a high SRI (>29) as one method to characterize a cool surface. Heat capacities of both systems were studied along with a sensitivity analysis of the inputs. The research supports the conclusion that even though pervious concrete may have a much lower SRI than traditional concrete made with similar materials, it can be considered a cool pavement option. In addition, daytime rainfalls combined with the internal high surface area result in significantly more removal of stored heat from the system, with a more rapid mitigation of UHI impacts and reduction in the potential for thermal shock from impervious surface runoff.

Introduction Venetoclax (Ven) is a highly selective oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway, which is constitutively overexpressed in CLL. Efficacy and safety of VenR given for a fixed duration in R/R CLL was evaluated in the randomized Phase III MURANO study compared with standard bendamustine + rituximab (BR). A first pre-planned analysis, when the majority of patients (pts) were still on study treatment (median follow-up 23.8 mo), established a superior PFS of VenR over BR (Seymour et al. NEJM 2018). With all pts having completed therapy, we analysed long-term outcome with a median follow up of 36.0 mo. Methods Pts were randomized to receive 6 cycles of VenR followed by Ven 400mg once daily for a total of 2 yrs, or 6 cycles of BR. Disease status was assessed by CT scan at screening, Cycle (C) 4 and 2−3 mo after end of combination therapy (EOCT). During Ven single agent and at follow-up visits, response was determined by clinical assessment every 3 mo until 3 yrs of follow-up, then every 6 mo thereafter or until PD. PFS status was based on investigator assessment. Peripheral blood (PB) minimal residual disease (MRD) was analysed centrally by ASO-PCR and/or flow cytometry at C4, EOCT and every 3/6 mo thereafter. All p values are descriptive. Results In total, 389 pts were enrolled in VenR (n=194) or BR (n=195) arms. As of May 8 2018, all pts were off treatment. For BR, 154 (79%) had completed 6 cycles. In the VenR arm, 174 (90%) completed the VenR combination phase and 130 (67%) had completed 2 yrs of Ven. The remainder had PD (11%), died (1%), or withdrew due to AEs (15%) or other reason (6%). Median Ven exposure duration and relative dose intensity were 24.4 (range 0-27.9) mo and 97.4% (26-100%), respectively, overall and 17.7 (0.5-21.9) mo and 99% during Ven single-agent therapy. With a median time off Ven after 2 yrs treatment of 9.9 (1.4-22.5) mo, PFS with VenR remains superior to BR (HR, 0.16 [95% CI 0.12, 0.23]; p1% in PB at Mo 24 (when Ven single agent was scheduled to cease) and 10/16 pts had del(17p)/TP53 mutation at baseline. Clinical and cytogenetic risk factors in pts with and without PD after Mo 24 are in Table 1. In this analysis, OS improvement was seen with VenR over BR (HR, 0.50 [95% CI 0.30, 0.85]; p=0.0093; 3-yr rate: 87.9% vs 79.5%; Figure 4). Subsequent CLL-directed treatment was given after PD in 91 pts in the BR arm. 71/91 (78%) BR arm pts received novel targeted agents, including 45 who had ibrutinib and 7 who had Ven. 27/194 (14%) pts in the VenR arm received subsequent therapy: 13/27 (44%) had novel targeted agents as next treatment, including 8 pts who had ibrutinib and 3 who were re-treated with Ven. See Table 2 for a safety overview for VenR combination and Ven single-agent periods. During Ven single agent: 17/171 pts (10%) had an AE leading to drug withdrawal; 7/171 pts (4%) had an AE leading to dose reduction; 44/171 pts (26%) had a Ven dose interruption due to an AE; 7/171 pts (4%) had a fatal AE (4 other cancers, 2 cardiac, 1 pneumonia). Grade 3-4 AEs occurred in 59/171 pts (35%); the most frequent were neutropenia (20 pts, 12%), anemia (5 pts, 3%), and thrombocytopenia (3 pts, 2%). 12/171 (7%) pts had a grade 3-4 infection in the Ven single-agent phase. The total number of Richter transformation events was 7 with VenR and 6 with BR. Conclusions With all pts off treatment and 3 yrs' median follow-up, continued substantial benefit was observed with VenR, with PFS and OS superior to BR. There were no new safety signals; most pts were able to complete treatment. The rate of CLL progression in the first 12 mo after Ven completion was modest (13%), supporting the feasibility and safety of a time-limited VenR duration. The protocol has been amended to include assessment of response and durability of disease control with VenR reintroduction at PD. This updated analysis of this Phase III global randomized study demonstrates clinically meaningful benefit of the VenR chemotherapy-free regimen with a fixed duration in all pts with R/R CLL. Disclosures Seymour: AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Consultancy. Kipps:Genentech Inc: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Celgene: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Gilead Sciences, Inc.: Honoraria, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Assouline:Pfizer: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; BMS: Honoraria, Research Funding, Speakers Bureau. Owen:Teva: Honoraria; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Merck: Honoraria; AbbVie: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; AstraZeneca: Honoraria, Research Funding. Robak:Janssen: Consultancy, Honoraria; Gilead: Consultancy; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria. de la Serna:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Jaeger:Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Takeda-Millenium: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cartron:Gilead Sciences: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding. Lamanna:Acerta: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Punnoose:Genentech Inc: Employment; Roche: Equity Ownership. Jiang:Genentech Inc: Employment, Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Mobasher:F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC; Genentech Inc: Employment. Kater:Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Acerta: 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; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: The management of CLL has been transformed in recent years by the introduction of a number of targeted agents including the BCL2 inhibitor VEN, and the Bruton's tyrosine kinase inhibitor IBR. In the US and EU, VEN is currently approved for patients who have received at least 1 prior therapy, whereas IBR has wider indications that include front-line therapy as well as R/R CLL. The mechanisms of action of VEN and IBR are complementary (Bose et al. F1000Research 2017); this has led to studies of combination therapy in patients with CLL (Wierda et al. J Clin Oncol Suppl. 2018). In addition, the documented activity of VEN in patients with IBR R/R disease (Jones et al. J Clin Oncol Suppl. 2016), together with current approvals, has resulted in VEN being suggested as a reasonable treatment choice for patients who discontinue IBR (Byrd et al. J Clin Oncol Suppl. 2018). However, the clinical benefit of IBR in patients pretreated with VEN is less clear. We present a post-hoc series, obtained after follow-up of 8 patients with R/R CLL who received IBR after fixed-duration VEN+rituximab (R) therapy in the MURANO randomized phase 3 study (NCT02005471) (Seymour et al. N Engl J Med 2018). Methods: In MURANO, 389 patients with R/R CLL were enrolled and treated with 6 cycles of VEN+R followed by VEN monotherapy once-daily for up to 2 years, or 6 cycles of bendamustine (B)+R. Progression-free survival (PFS), the primary study endpoint, was based on investigator assessment. The present case series focuses on VEN+R patients from MURANO who developed progressive disease (PD), and who subsequently received IBR. Eight patients in the VEN+R group with PD subsequently received IBR (Table 1). The number of lines of therapy prior to VEN+R ranged from 1 (n=7) to 4 (n=1; median 1). Prior to VEN+R therapy, 7 of the patients (87.5%) received fludarabine+cyclophosphamide+R (FCR); of these, 3 patients (42.8%) achieved a complete response (CR), 3 (42.8%) achieved a partial response (PR), and 1 patient (14.2%) had stable disease (SD). Of these 7 patients, 2 were considered refractory to FCR before VEN+R therapy. At baseline (before VEN+R), three of the patients (37.5%) had chromosome 17p-deletion, and two patients (25%) had baseline lymph nodes ≥5 cm- Four of the 8 patients had IBR dose interruption or modification due to neutropenia (n=2), clarithromycin treatment (n=1), or cutaneous nevus biopsy (n=1). Multiple skin abscesses were reported in 1 patient. One patient had atrial fibrillation, and 2 patients had arthralgia (1 had nearly resolved on follow-up), and there were no reports of major bleeding. Conclusions: In this series of patients with R/R CLL who received IBR following prior VEN+R in the MURANO study, IBR showed clinical activity and acceptable tolerability, with no new safety signals. Our results suggest that the use of IBR after relapse following VEN+R is a reasonable option in patients with CLL. More data will be collected from MURANO on patients progressing after VEN+R who are subsequently treated with IBR monotherapy. Disclosures Greil: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding. Fraser:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria. Leber:Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marks:BMS: Honoraria; Servier: Honoraria; Merck: Honoraria. Middeke:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees. Schary:AbbVie: Employment. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Breuleux:Roche: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea: Patents & Royalties; Novartis: Patents & Royalties. Crompton:Roche: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Marlton:Pfizer: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Introduction Although CLL minimal residual disease (MRD) status is used in contemporary clinical trials aimed at maximizing response or determining treatment duration, its role as a predictive factor for PFS has only been established following chemoimmunotherapy. In contrast, whether MRD is a valuable tool for treatment choice in the era of novel targeted agents for CLL is unknown. Unlike kinase inhibitors, the BCL2 inhibitor venetoclax does result in undetectable MRD (uMRD). MURANO demonstrated significant PFS benefit for venetoclax + rituximab (VenR) given for a fixed duration vs bendamustine + rituximab (BR) in relapsed/refractory (R/R) CLL. Here we present analysis of peripheral blood (PB) MRD kinetics in relation to PFS in MURANO with long follow up, when all pts have completed therapy. Methods Pts were randomized to VenR (Ven 400mg/d for 2 yrs + R for first 6 mo) or BR (6 mo). Response was assessed clinically using complete blood count and physical exam at follow-up visits. PB MRD was analysed centrally by ASO-PCR and/or flow cytometry at Cycle 4, end of combination therapy (EOCT; mo 9) and every 3 mo thereafter until 3 yrs, then every 6 mo. As strong concordance between PB and bone marrow (BM) MRD with VenR was previously shown (Hillmen et al. ASCO 2018), we focus on PB MRD. Pts were categorized into uMRD ( Results As of May 8 2018, median follow-up was 36.0 mo. VenR pts achieved high PB uMRD rates at EOCT (62% vs 13% for BR). The same pattern was observed through mo 24, when Ven single-agent treatment was scheduled to cease: 48% uMRD in VenR vs 2% in BR, and 16% int-MRD+ in VenR vs 7% in BR (Table 1). By then, 18% pts in the VenR arm had progressed/died/withdrew from study vs 66% in BR. Consistently high uMRD rates were observed in all VenR subgroups, including pts with high-risk cytogenetics and molecular factors: del(17p) and/or TP53 mutated: 57% at EOCT and 36% at mo 24; IGHV unmutated: 61% at EOCT and 51% at mo 24. Landmark analysis of PFS by MRD status in PB at the EOCT response visit showed that, regardless of treatment arm, uMRD status was associated with longer PFS. Within MRD+ pts, the int-MRD+ group had improved PFS over high-MRD+ pts (Fig 1). Due to the very low rate of uMRD in the BR arm, all further analyses were performed in VenR pts; PFS curves overlapped for pts with uMRD, regardless of whether in CR or PR by investigator assessment, while inferior PFS for MRD+ PR/nPR pts becomes manifest from mo 18 after EOCT (Fig 2). MRD+ pts in CR (all int-MRD+) did as well as uMRD, but numbers are very small. 130 pts in VenR arm completed 2 yrs Ven treatment without PD; among them: 83 (64%) were uMRD, 23 (18%) were int-MRD+, 14 (10%) were high-MRD+ and 10 (8%) had missing data at mo 24. With 9.9 mo median follow-up from Ven completion, amongst uMRD pts at mo 24, the majority remained uMRD (57/83, 69%) and 26/83 (31%) converted to confirmed MRD+ (2 serial assay positive). Conversions were mainly to int-MRD+ (21/26, 81%), all of whom remain PFS event-free; 19% (5/26) converted to high-MRD+, 2 had PD per iwCLL criteria (Fig 3). Of pts converting from uMRD to MRD+ after cessation of Ven at mo 24, 40% (10/25) carried del(17p) and/or TP53 mutation, vs 23% (12/53) among those who did not convert. Of int-MRD+ pts at mo 24, 9/23 (39%) became high-MRD+ (2 had PD); there was 1 PD among the remaining 14. PD was seen in 11/14 (79%) of pts who were high-MRD+ at mo 24. Conclusion The higher PB uMRD rate observed at EOCT in the VenR arm vs BR arm was maintained at completion of Ven treatment, including in high-risk subgroups, consistent with maintained PFS benefit seen with longer follow up. VenR pts who achieved uMRD or int-MRD+ had durable PFS. MRD status powerfully identified distinct outcomes for pts with PR/nPR; longer follow-up is needed to determine the impact of MRD status among CR/CRi. In the first yr post-completion of fixed-duration VenR treatment, majority of uMRD pts remained uMRD; reemergence of MRD+, mainly at int levels, is seen in a minority of pts, and has shown a low rate of progression to clinical PD to date. These data are the first to demonstrate the value of PB MRD as a predictive marker of clinical outcome for the fixed-duration chemotherapy-free regimen, VenR. Our data corroborate that uMRD and int-MRD+ rate is a meaningful endpoint and desirable goal of CLL therapies, including targeted agents. Disclosures Kater: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: 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. Hillmen:F. Hoffmann-La Roche Ltd: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Pharmacyclics: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Honoraria, Research Funding. Eichhorst:AbbVie, Celgene, Gilead, Janssen, Mundipharma, Novartis, Roche: Honoraria, Other: Travel support, Research Funding. Langerak:F. Hoffmann-La Roche Ltd: Research Funding; • InVivoScribe Technologies: Patents & Royalties. Kipps:Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Genentech Inc: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding. Owen:Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Research Funding; Merck: Honoraria; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Teva: Honoraria; Celgene: Research Funding. Boyer:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Punnoose:Genentech Inc: Employment; Roche: Equity Ownership. Wang:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Chyla:AbbVie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Wu:Genentech Inc: Employment. Jiang:Genentech Inc: Employment, Equity Ownership. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Seymour:Celgene: Consultancy; Janssen: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Venetoclax (V), an orally administered, highly selective, potent BCL-2 inhibitor, induces high ORR when given as monotherapy to pts with relapsed/refractory (R/R) CLL, including high-risk populations, e.g. del(17p). V is also well tolerated when combined with rituximab (R) and achieves improved CR rates and minimal residual disease negativity (MRD-). Here, we provide first released data from the primary analysis of MURANO (NCT02005471), the first Phase 3 study of V in pts with R/R CLL, which assessed efficacy/safety of VR vs standard chemoimmunotherapy, bendamustine (B) + rituximab (BR). Methods Eligibility for this open-label, randomized, Phase 3 study included R/R CLL requiring treatment (iwCLL guidelines), 1-3 prior lines of therapy (including ≥1 chemo-containing) and ECOG PS ≤1. Prior B was allowed provided response duration was ≥24 mo. Pts were randomized (1:1) to VR or BR. Stratification factors were del(17p), responsiveness to prior therapy and geographic region. In the VR arm, a 4- or 5-wk graduated dose ramp-up of V from 20-400 mg daily was used to mitigate potential tumor lysis syndrome (TLS) risk. Beginning at Wk 6, R was then given monthly for six 28-day cycles (IV 375 mg/m2 first dose, then 500 mg/m2) in combination with V daily. Pts continued with V 400 mg for a maximum of 2 yr or until disease progression (whichever first). In the BR arm, pts were given B (IV 70 mg/m2) on Days 1 and 2 of each of six 28-day cycles in combination with R using same R dosing schedule. MRD was centrally assessed by ASO-PCR and/or flow cytometry in peripheral blood at screening, Mo. 4 and 9, and 3-monthly follow-up visits. The primary endpoint was investigator (INV)-assessed PFS. An interim analysis was preplanned at ~140 INV-assessed PFS events. On data review, an Independent Data Monitoring Committee recommended study arms to be unblinded to the sponsor as pre-specified statistical boundaries for early stopping were crossed for PFS in favor of VR. Results 389 pts were enrolled in VR (n=194) and BR (n=195) arms, which were well balanced: median (range) age, 64.5 (28-83) vs 66.0 (22-85) yr; 1 prior therapy, 57.2% vs 60.0%; fludarabine refractory, 14.1% vs 15.5%; del(17p), 26.6% vs 27.2%. At data cut-off (8 May 2017; median follow-up, 23.8 mo. [range 0.0-37.4]), INV-assessed PFS was superior for VR vs BR with HR 0.17, 95% CI 0.11-0.25, P Consistent with known safety profiles of the regimens, Grade 3-4 neutropenia was higher in VR arm but there was no increase in febrile neutropenia or Grade 3-4 infection (Table 2). There were 6 (3.1 %) and 2 (1.1%) Grade ≥3 AEs of TLS reported for VR and BR, respectively; one clinical TLS event in each arm (a Grade 4 acute renal failure in BR, transient increase in creatinine in VR; VR event occurred on an earlier 4-week ramp-up schedule). Richter transformation was confirmed in 6 pts and 5 pts for VR vs BR, respectively. AEs leading to death were seen in 5.2% vs 5.9% of pts. Median relative V dose intensity was 97% of protocol-specified drug exposure. Conclusion The primary analysis of MURANO, the first Phase 3 study of V in R/R CLL, shows a profound improvement in PFS vs standard BR chemoimmunotherapy, with consistent effects in all-risk subsets. Key secondary endpoints, including OS, ORR and CR rate, also showed consistent improvements with remarkable rates of peripheral blood MRD- that exceed those previously attained in treatment of R/R CLL. This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for pts with R/R CLL. Disclosures Seymour: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sunesis: 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. Kipps:Celgene: Consultancy; Oncternal: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Eichhorst:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Hillmen:Celgene: Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. D'Rozario:Roche: Consultancy. Assouline:Lundbeck: Other: Advisory Board; Paladin: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myer Squibb: Speakers Bureau; Roche Canada: Consultancy. Owen:AstraZeneca: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Lundbeck: Honoraria; Roche: Honoraria; Merck: Honoraria. Gerecitano:Merck: Consultancy; Mass Medical International: Consultancy; Incyte: Consultancy; Arcus Medica: Consultancy; Aratana: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Samus Therapeutics: Consultancy; Abbvie: Consultancy; Gilead: Consultancy; Orexo: Consultancy. Robak:AbbVie: Honoraria, Research Funding; Akari Therapeutics Plc: Honoraria, Research Funding; Roche: Honoraria, Research Funding. De la Serna:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jaeger:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Honoraria; AOP Orphan: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; GSK: Honoraria; Infinity: Honoraria; Millennium: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Bioverativ: Honoraria, Research Funding. Cartron:Gilead: Honoraria; Janssen: Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria. Montillo:Novartis: Honoraria; Roche: Research Funding; Abbvie: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau. Humerickhouse:AbbVie: Employment, Equity Ownership. Punnoose:Genentech: Employment. Li:Genentech: Employment. Boyer:Roche: Employment. Humphrey:F-Hoffmann-La Roche: Employment, Equity Ownership. Mobasher:Roche: Equity Ownership; Genentech: Employment. Kater:Roche: Consultancy; Acerta/Astra Zeneca: Consultancy, Research Funding; Roche/Genentech: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Research Funding; Sandoz: Consultancy.

Usually, the blood cell counting activity in haematology laboratory uses the comparison of IQC values to the target values proposed by the manufacturer. We intended to improve the monitoring of the proper functioning of our analytical measure system for 17 main haematologic parameters. To set the allowable critical limits of IQC, we propose our reflection based on several elements: benchmark and expert recommendation, clinical requirements, statistical indicators of the laboratory calculated using IQC values (3 levels, 2 different lots, 2 haematology analysers and 2 passage modes) and the EEQ values, during four months. We exploited the reports obtained from the middleware (our own IQC values), and the interlaboratory comparison reports (obtained from SNCS and EuroCell websites) and we compared our performances to the Ricos objectives, to set clearly argued allowable limits for IQC values. Finally, the allowable limits correspond to the imprecision limits stated by Ricos for 14 parameters (desirable for 11 parametres and minimal for 3 parameters) and personalized limits (more exigent than desirable Ricos limits) for 3 parameters of blood cell counting.

necessary by 72% of radiation oncologists in the survey. The most common reasons for not using hippocampus sparing IMRT were (1) increased cost and problems with obtaining authorization for IMRT planning, (2) necessities for a better dosimetry support and thin slice brain MRI (1.25 -1.50 mm), and (3) time necessary for hippocampus contouring. Use of Memantine and hippocampus sparing IMRT were not associated with demographic factors, such as years of practice and geographic location, as well as WBRT volume and practice setting (academic, non-academic hospital based, or free standing). Conclusions: The majority of surveyed radiation oncologists in the United States do not use Memantine or IMRT planning for hippocampus sparing in patients receiving WBRT. Further validation of the hippocampus sparing concept in a phase 3 trial was felt to be necessary before adopting it in routine clinical practice. Author Disclosure: A. Slade: None. S. Stanic: None.

We report a case of Schistosoma mansoni bilharziasis in a HIV patient 38 y after leaving an endemic region. A viable S. mansoni egg on a liver biopsy sample was diagnostic. Despite severe concomitant immunodeficiency the effective treatment was a single dose of praziquantel. Worms' intravascular longevity and the role of immunodeficiency as a possible factor in eggs retention after such prolonged latent schistosomiasis are discussed.

Past animal studies of the performance-enhancing properties of stimulant drugs, such as caffeine, may have suffered from a number of procedural and ethical problems. For example, the housing condition of the animals was often not taken into consideration. As well, endurance tests, such as the forced swim task, sometimes involved ethically (and procedurally) questionable interference with natural swimming behaviour. Some of the manipulations, such as attaching a weight to the swimming animal's tail to increase the difficulty of the task and using mortality as a dependent variable, seem grotesque, even unnecessary. In this experiment, the performance-enhancing effects of caffeine in a modified forced swim task and a dominance task were evaluated using male and female rats as subjects ( N = 60), housed in either enriched or isolated environments. Analysis indicated that rats respond to caffeine as an interactive function of sex, housing, dose, and task characteristics. It was concluded that performance-enhancing properties of stimulant drugs may be the result of a complex interplay of variables, making simple generalizations questionable.

Macro-defect-free (MDF) cement is fabricated from a calcium aluminate cement and a poly(vinyl alcohol-acetate) (PVA) copolymer. For the composites studied, it was determined that the interphase regions comprised 63 voi % of the total binder content, while the bulk PVA regions comprised 37 vol% of this phase. Mercury intrusion porosimetry showed that a bimodal pore size distribution developed as binder was removed in increasing amounts from heat-treated samples. Larger pores with a characteristic diameter above 30 nm resulted from the removal of bulk PVA, whereas smaller pores approximately 5 nm in size resulted from the removal of water and PVA from the interphase regions. Simulation results obtained from a hard-core/soft-shell continuum percolation model of the MDF microstructure indicate that both the bulk PVA and interphase regions form percolative pathways through the system. Dramatic changes in both moisture absorption kinetics and flexural strength were observed only when a percolative network of larger pores was present in these composites. Hence, the bulk polymer regions are the dominant transport pathway for moisture in MDF cement. Based on this knowledge, processing guidelines have been developed to improve the moisture resistance of these materials.