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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. Time-dependent 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, 140/194 (72%) patients in the VenR arm completed 2 years of therapy; 54/194 (28%) patients prematurely discontinued treatment. Inferior PFS was observed in patients prematurely discontinuing venetoclax for any reason (disease progression excluded; p

Patients with chronic lymphocyticleukemia (CLL) typically have innate/adaptive immune system dysregulation, thus the protective effect of coronavirus disease 2019 (COVID-19) vaccination remains uncertain. This prospective review evaluates vaccination response in these patients, including seropositivity rates by CLL treatment status, type of treatment received, and timing of vaccination. Antibody persistence, predictors of poor vaccine response, and severity of COVID-19 infection in vaccinated patients were also analyzed. Practical advice on the clinical management of patients with CLL is provided. Articles reporting COVID-19 vaccination in patients with CLL, published January 1, 2021-May 1, 2022, were included. Patients with CLL displayed the lowest vaccination responses among hematologic malignancies; however, seropositivity increased with each vaccination. One of the most commonly reported independent risk factors for poor vaccine response was active CLL treatment; others included hypogammaglobulinemia and age >65-70 years. Patients who were treatment-naive, off therapy, in remission, or who had a prior COVID-19 infection displayed the greatest responses. Further data are needed on breakthrough infection rates and a heterologous booster approach in patients with hematologic malignancies. Although vaccine response was poor for patients on active therapy regardless of treatment type, CLL management in the context of COVID-19 should aim to avoid delays in antileukemic treatment, especially with the advent of numerous strategies to mitigate risk of severe COVID-19 such as pre-exposure prophylaxis, and highly effective antivirals and monoclonal antibody therapy upon confirmed infection. Patients with CLL should remain vigilant in retaining standard prevention measures such as masks, social distancing, and hand hygiene.

Introduction: The approval of several new, targeted agents has been transformative in the treatment of CLL. Prospective clinical trial data support the use of Ven after Ibr in CLL (Jones JA et al. Lancet Oncol 2018); however, limited data are available on the inverse sequencing of these agents (Mato AR et al. Br J Haematol 2018; Anderson M et al. Blood 2017). Given the recent FDA approval of Ven + obinutuzumab in first-line (1L) CLL, an upsurge in Ibr-naïve pts needing therapy post-Ven is likely; characterizing this sequencing is of the upmost importance. Here we present a US multicentre, retrospective, chart-review analysis to explore outcomes of Ibr post-Ven, in Ibr-naïve pts with CLL. Methods: Efficacy and safety outcomes were investigated for pts with Ibr-naïve CLL, treated with Ven +/- CD20 monoclonal antibody (mAb), who developed progressive disease ([PD] or discontinued Ven) and received Ibr salvage therapy (+/- CD20 mAb). Analyses included pts in 1L or relapsed/refractory setting. Pts were treated between Feb 14, 2012 and Jun 6, 2019, across four institutions (US); data cutoff was Jul 18, 2019. Results: Data were available for 27 pts with CLL who received Ibr post-Ven - the largest cohort to date. Median age was 64 (41-79) years, median time from diagnosis to first therapy was 9.0 (0-117.7) months (mo), and the median number of therapies prior to Ven was 2 (0-9). Prior therapies were varied and included: 1 Bruton's tyrosine kinase inhibitor (BTKi; not Ibr), 3 lenalidomide, 1 pt received 9 lines of therapy (including: idelalisib, lenalidomide, anti-CD22 and temsirolimus), others received chemo- or chemoimmunotherapy, or CD20 mAb only. Median time from diagnosis to initiation of Ven was 56.3 (0-157.7) mo. At baseline, the median lymphocyte count was 2.2 (0.2-220.0) K/µL; 8/24 (33.3%) pts had a lymph node ≥ 5cm. All evaluable pts (26/26) had ≥1 unfavourable prognostic risk factor; 12/20 (60.0%) pts had del17p, 10/16 (62.5%) had del11q, 12/24 (50.0%) had complex karyotype (CK) and 13/15 (86.7%) pts had unmutated IGHV. A complete or partial response (CR or PR) to Ven was achieved in 4/26 (15.4%) and 18/26 (69.2%) evaluable pts, respectively. The median time to PD on Ven was 29.0 (1.0-118.0) mo, with a median treatment duration of 18.0 (0.1-64.3) mo. Pts discontinued Ven due to PD (n=18), consent withdrawal (n=2), non-compliance (n=1), and other (n=6; allogeneic stem cell transplantation n=2, physician decision n=3, not evaluable n=1). Prior to initiation of Ibr, the median lymphocyte count was 1.9 (0.01-179.0) K/µL; 15/26 (57.7%) pts had adenopathy, and 5/13 (38.5%) had a lymph node ≥ 5cm. Risk factors included: del17p (4/10; 40.0%), del11q (4/9; 44.4%), CK (8/17; 47.1%) and unmutated IGHV (11/14; 78.6%). Median time from Ven initiation to Ibr initiation was 31.9 (1.8-60.3) mo; median time to Ibr initiation post-Ven was 0.7 (0-39.7) mo. The overall response rate to Ibr was 56.0% (CR: 1/25, PR: 13/25). The time to progression on Ibr, post-Ven, varied from 3.0 to 53.0 mo (n=10). The median duration of Ibr therapy was 18.3 (3.7-53.2) mo and 20.0 (4.9-44.3) mo for those remaining on Ibr (8/27); the median follow-up time matched the median therapy duration. Nineteen pts discontinued Ibr due to: PD (n=9), physician decision (n=4), adverse events (AEs; n=2), transplant (n=2), symptomatic deterioration and unknown reason (n=1 each). The median number of therapies prior to Ven for the 9 pts who discontinued Ibr due to PD was 2 (1-9); 4/9 pts received novel targeted therapies. Richter's transformation occurred in 1 pt (1/9). The 2 pts who discontinued Ibr due to AEs experienced either atrial fibrillation (AF)/brain abscess or pneumonia after 11.6 and 18.2 mo of Ibr, respectively. Other notable AEs were: major bleeding (n=1), AF (n=2), infection (n=1), neutropenia (n=1), myalgia/arthralgia (n=2), and other cardiac event (n=1). Ibr dose reductions due to fatigue and general malaise occurred in 1 pt. Conclusions: With the limitations of a retrospective series using real-world data, these data suggest that Ibr had substantial clinical activity post-Ven in heavily pre-treated, high-risk CLL pts; no new safety signals arose. Larger, prospective studies are required to fully characterize the efficacy of Ibr after Ven. Meanwhile, salvage therapy with Ibr remains a good option for pts with CLL who relapse after Ven. Disclosures Brown: Sunesis: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Invectys: Other: Data safety monitoring board; Octapharma: Consultancy; Morphosys: Other: Data safety monitoring board; Janssen: Honoraria; Dynamo Therapeutics: Consultancy; Teva: Honoraria; Sun Pharmaceuticals: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy, Research Funding; BeiGene: Consultancy; Catapult Therapeutics: Consultancy; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie: Consultancy; Juno/Celgene: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Research to Practice: Honoraria; AbbVie, Acerta Pharma, Adaptive, Biotechnologies, Astra-Zeneca, Genentech, Gilead Sciences, Janssen, Pharmacyclics, TG therapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie, Astra-Zeneca, Genentech, Janssen, MEI, Pharmacyclics, Syros Pharmaceuticals, Verastem: Consultancy; Acerta Pharma, Ascentage Pharma, Genentech, MEI pharma, Pharmacyclics, Surface Oncology, TG Therapeutics, Verastem: Research Funding. Chang:Genentech: Research Funding; Celgene: Research Funding; Adaptive Biotechnologies: Research Funding. Ma:Kite: Consultancy; Xeme: Research Funding; Abbvie: Research Funding; Beigene: Research Funding; Bioverativ: Consultancy; Incyte: Research Funding; Genentech: Consultancy; Astra Zeneca: Consultancy, Research Funding, Speakers Bureau; Gilead: Research Funding; Janssen: Consultancy, Speakers Bureau; Novartis: Research Funding; Juno: Research Funding; Acerta: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau. Biondo:Genentech, Inc.: Employment; F. Hoffmann-La Roche Ltd: Equity Ownership. Mun:Genentech: Employment, Equity Ownership. Breuleux:F. Hoffmann - La Roche Ltd: Employment, Equity Ownership; Gilead: Equity Ownership; Basilea Ltd: Equity Ownership. Wierda:Janssen: Research Funding; Xencor: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Miragen: Research Funding; Juno Therapeutics: Research Funding; GSK/Novartis: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Loxo Oncology Inc.: Research Funding; Genentech: Research Funding; Acerta Pharma Inc: Research Funding.

Introduction : Current treatment options for CLL or small lymphocytic leukemia (SLL) include novel oral therapies that are taken until disease progression. Ibrutinib is approved in frontline and relapsed/refractory CLL and is the most common oral treatment since Food and Drug Administration approval in 2014. Despite favorable responses with ibrutinib, treatment discontinuation occurs (41-50%) (Mato et al. Haematologica 2018; Sharman et al. Blood 2017) and increases the risk of poor overall survival (Follows GA and UK CLL Forum. Poster Presentation 14th International Conference on Malignant Lymphoma Palazzo dei Congressi, Lugano Switzerland, 2017). Previous studies have reported that in addition to disease progression, intolerance and toxicity were primary reasons for discontinuation. However, hospitalizations have not been explored to date. This study used a large US claims database to evaluate ibrutinib treatment patterns and toxicity-related hospitalizations among patients with CLL. Methods : A retrospective analysis of Truven Health MarketScan® Commercial Claims Database was conducted. Patients were included if they initiated ibrutinib treatment (index) between 2/12/2014 and 3/31/2017 and were diagnosed with CLL or CLL along with SLL. Patients were excluded if they had other cancers, did not have at least 180 days of continuous enrollment pre-index (baseline), were treated with ibrutinib within this baseline period, or had less than 180 days of observation after ibrutinib initiation. Patients were categorized into 1 of 3 treatment cohorts: (1) those who had continuous ibrutinib claims without any gap (Users), (2) those who had a treatment gap, but had at least 1 ibrutinib claim after the gap (Retreated), and (3) those who completely discontinued ibrutinib treatment or switched to another treatment (Discontinued/Switched). A gap in treatment was defined as a period of ≥60 days after the end of treatment exposure (Mato et al. Cancer Biology & Therapy 2018). Patient demographics, time to first treatment discontinuation, and frequency of hospital-related adverse events (AEs) were determined for each cohort. AEs were obtained in the 60 days prior to the last ibrutinib claim (pre-discontinuation) and in the exposure period for the last claim plus 60 days after (post-discontinuation). AEs were assessed for the User cohort based on a proxy derived from a median time from initial treatment to discontinuation in the Retreated and Discontinued groups and using the +/- 60-day time window. Results : There were 714 patients included in the analyses. Most patients were male (69%) and the average age at CLL diagnosis was 55.8 years. There were 451 (63%) in the User cohort, 96 (13%) in the Retreated cohort, and 167 (24%) in the Discontinued/Switched cohort. The median time from ibrutinib initiation to end of study observation was 16.8 (6.0-44.2) months. The median time to ibrutinib discontinuation was 4.9 (1.0-40.4) and 6.0 (1.0-34.1) months for the Retreated and Discontinued/Switched cohorts, respectively. For the Retreated cohort, patients were off ibrutinib treatment for a median of 3.2 (2.0-32.0) months before restarting ibrutinib again. Among the Discontinued/Switched cohort, 61% discontinued ibrutinib treatment without receiving any further treatment and 39% switched to another treatment. Retreated and Discontinued/Switched cohorts had higher hospitalization rates compared to the User cohort. The 5 most common inpatient diagnoses were pneumonia, pancytopenia/neutropenia, fever, sepsis, and atrial fibrillation across both the Retreated and Discontinued/Switched cohorts (Table 1). Discontinued/Switched cohort were more likely to have any hemorrhage diagnosis for hospitalization (6%). Conclusion : Consistent with other studies (median follow-up of 17-20 months) (Mato et al. Haematologica 2018; Sharman et al. Blood 2017), the overall treatment discontinuation with ibrutinib in our study was approximately 37% with a median follow-up of 16.8 months. A limitation is that exact reasons for stopping treatment cannot be ascertained from claims data. However, patients who paused or stopped ibrutinib were more likely to have higher rates of hospital-related AEs than those who continued treatment. As treatment discontinuation is likely to occur during a long treatment exposure, oral agents with a finite duration of treatment and with better tolerability are needed for patients with CLL. Disclosures To: Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Yeh:Genentech, Inc.: Employment, Other: May own stock/stock options at Roche. Biondo:Roche: Equity Ownership; Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Masaquel:Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche.

Introduction While the initial approval of venetoclax (VEN), a BCL2 inhibitor, was limited to relapsed patients with del17p, the data from the phase 3 MURANO trial demonstrated significant progression-free survival (PFS) benefit with venetoclax in combination with rituximab (R) versus bendamustine + rituximab (BR) and has recently led to the expansion of this approval to any relapsed CLL patient in the USA. Furthermore, several studies have demonstrated efficacy of venetoclax in treatment-naïve patients and a prospective, open-label, multicenter, randomised phase III trial with registration purpose is ongoing to explore venetoclax in the front-line CLL setting. While ibrutinib has demonstrated efficacy in CLL when patients are treated until disease progression, venetoclax trials have a finite duration of treatment in both relapsed and first-line settings. Although we have data demonstrating the efficacy of venetoclax after B-cell receptor inhibitors, including the Bruton's tyrosine kinase inhibitor, ibrutinib (Jones et al. Lancet Oncol, 2018), limited data are available on the efficacy of ibrutinib after venetoclax (Mato AR. Haematol 2018; Anderson M. Blood 2017). Methods We undertook this US multicenter retrospective chart-review data analysis to explore the outcomes of ibrutinib treatment given after venetoclax, in previously ibrutinib-naïve patients treated for R/R CLL. Results Data are available on eleven patients from four centers. Their median time from diagnosis to first therapy was 33.9 (range 4.0-53.0) months and median number of therapies prior to venetoclax was two (range 1-10). One patient had previously received both idelalisib and lenalidomide, but for all other patients venetoclax was their first targeted inhibitor for R/R CLL. The median time from diagnosis to venetoclax therapy was 77.8 (range 14.9-159.6) months. Prior to venetoclax initiation, four of eleven patients had del(17p), six of eleven had del(11q) and three had complex karyotype. Five of six evaluable patients had unmutated IGHV. Seven of eleven had a lymph node ≥ 5 cm. Ten of eleven patients achieved a partial response (PR) to venetoclax and the univariate median time to clinical progression on venetoclax was 19.0 (range 6.0-58.0) months, with a median time on venetoclax of 19.0 (range 1.2-57.5) months. One of eleven patients achieved stable disease on venetoclax, and remained on drug for 19 months. Reasons for discontinuation of venetoclax were: disease progression (n=8), withdrawal of consent (n=1), and allogeneic stem cell transplant after PR (n=2). The median time to ibrutinib treatment initiation, after discontinuing venetoclax, was 1.0 (range 0.1-30.8) month. For all eleven patients, ibrutinib was their next therapy after venetoclax. Ten of eleven patients achieved a PR to ibrutinib. The eleventh patient, who has only been on ibrutinib treatment for 1 month and continues on ibrutinib, has so far achieved stable disease. The time on ibrutinib therapy ranged from 0.5 to 30 months, with only three patients having discontinued. Of the responders, one patient progressed with Richter's transformation at 13 months on therapy and subsequently died. Two other patients stopped ibrutinib, one for an adverse event (AE) [atrial fibrillation and brain abscess] after 11.6 months, and a second for pneumonia that was ultimately fatal after 30 months on ibrutinib. Other notable AEs included one with major bleeding and five of eleven with joint pain. Two patients had ibrutinib dose reductions for fatigue and general malaise. Conclusions With the limitations of a very small dataset, we conclude that the efficacy and toxicity profile of ibrutinib appears similar in the relapsed setting after venetoclax as in patients not yet exposed to venetoclax. A larger dataset is being explored and will be presented at the meeting. Disclosures Brown: Beigene: Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Loxo: Consultancy; Celgene: Consultancy; Janssen: Consultancy; TG Therapeutics: Consultancy; Sunesis: Consultancy; Gilead: Consultancy, Research Funding; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Boehringer: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Sun Pharmaceutical Industries: Research Funding; Roche/Genentech: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Verastem: Consultancy, Research Funding. Davids:Sunesis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Surface Oncology: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Consultancy, Research Funding; Merck: Consultancy; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Surface Oncology: Research Funding; Pharmacyclics: Consultancy, 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Sunesis: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Research Funding; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy; Merck: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; BMS: Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Research Funding; Surface Oncology: Research Funding; Verastem: Consultancy, Research Funding. Chang:Celgene: Research Funding; Genentech: Research Funding. Ma:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Gilead: 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, Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Biondo:Roche: Equity Ownership; Genentech, Inc.: Employment, Other: May own stocks/stock options at Roche. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Mun:Genentech: Employment, Equity Ownership. Mato:AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Sunesis: Honoraria, Research Funding; Abbvie: Consultancy; Prime Oncology: Speakers Bureau; Acerta: Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; TG Therapeutics: Research Funding; Celgene: Consultancy; Regeneron: Research Funding.

Background: Venetoclax (Ven; BH3 mimetic) and Obinutuzumab (O; CD20 antibody) is an approved, fixed-duration regimen (one year) that induces undetectable minimum residual disease (uMRD) and durable remissions in treatment naïve patients (pts) with chronic lymphocytic leukemia (CLL; Fischer NEJM 2019). In the CLARITY trial of venetoclax-ibrutinib (BTK inhibitor; BTKi) in relapsed or refractory CLL, peripheral blood (PB) MRD response kinetics predicted bone marrow (BM) uMRD and were associated with progression-free survival (Rawstron EHA 2020). We explored MRD as a biomarker to direct treatment duration in an investigator-initiated phase 2 trial of Zanubrutinib (BTKi) and O-Ven (BOVen). We hypothesize that early MRD kinetics will identify a defined cohort of pts with delayed BM MRD clearance, and early recurrent detectable MRD after discontinuation of treatment in pts attaining uMRD. Methods: In this multicenter, phase 2 trial (NCT03824483), eligible pts had previously untreated CLL requiring treatment (iwCLL), ECOG PS ≤2, absolute neutrophil count (ANC) ≥1,000/ul, platelets (PLT) ≥75,000/ul (ANC ≥0/ul, PLT ≥20,000/ul if due to CLL). Informed consent was obtained from all pts. BOVen was administered in 28-day (D) cycles (C): Zanubrutinib 160 mg by mouth (PO) twice daily starting D1; Obinutuzumab 1000 mg IV D1 (split D1-2 if lymphocyte count ≥25,000/ul or lymph node ≥5cm), D8, D15 of C1, and D1 of C2-8; Venetoclax ramp up initiated C3D1 (target 400 mg PO daily). MRD was evaluated by flow cytometry (MRD-FC) and immunosequencing (MRD-IS; Adaptive ClonoSEQ) with uMRD defined as ≤10 -4 for flow and ≤10 -5 for IS. Treatment consisted of 8-24 cycles with duration determined by prespecified MRD criteria. Beginning on C7D1 then every 2 cycles, pts with PB uMRD-FC had BM within 14 days. If BM uMRD, PB MRD was repeated after two additional cycles. Pts with confirmed uMRD-FC in PB and BM discontinued therapy and entered posttreatment surveillance. Response was assessed per iwCLL. Adverse events (AE) were assessed per CTCAE v5. MRD-IS failure free survival (FFS) was calculated from end-of-treatment (EOT) to the date of detectable MRD-IS (≥10 -5) using the Kaplan-Meier method. Results: The study accrued 39 pts (03/19-10/19): median age 59 years (23-73), 3:1 male predominance, 28/39 (72%) IGHV unmutated, 5/39 (12.8%) del(17p)/TP53M. All pts were evaluable for toxicity with 37 evaluable for efficacy. At a median follow up of 26+ months (mo; 4.5-30.5+), 95% (35/37) pts achieved uMRD-FC in PB, among whom 33 (94%) also achieved uMRD-IS. BM uMRD-FC was seen in 89% (33/37) at a median time of 8 mo (6-16), all of whom met prespecified MRD criteria and discontinued therapy after a median of 10 mo (8-18). Three pts discontinued therapy with persistent detectable BM MRD after 24 cycles. The most common AEs were neutropenia (51%), thrombocytopenia (44%), diarrhea (44%), infusion related reaction (41%) and bruising (41%). The most common grade ≥3 AE was neutropenia (15%). No laboratory or clinical TLS occurred (Howard definition). A ≥400-fold reduction in PB MRD-IS after 4 cycles (ΔMRD400) was selected using the Youden Index and was highly predictive of attaining BM uMRD in ≤8mo (sensitivity 88% [21/24], specificity 100% [11/11], PPV 100% [21/21], NPV 79% [11/14]. As a result, the median duration of therapy was shorter among patients who achieved ΔMRD400 (8 vs 13 mo). Of 33 pts who met prespecified uMRD criteria and stopped therapy, 31 (94%) remain uMRD-FC following a median 15 mo (0-20) from EOT, and 2 pts had recurrent MRD (1 with PD recaptured PB uMRD with retreatment). Of 33 pts who discontinued therapy after achieving the prespecified MRD endpoint, MRD-IS was evaluated every 3 months in 31 pts for a median of 12 mo (range, 3-18) from EOT. MRD-IS FFS was longer in pts who achieved ΔMRD400 (log rank p<0.001; Figure) despite shorter treatment duration. We did not observe differences in posttreatment MRD kinetics based on IGHV status or high-risk genetics. Conclusion: BOVen achieved frequent, durable uMRD. All pts completed therapy (median 10 mo treatment), including 89% (33/37) who met the prespecified PB/BM uMRD endpoint. With a median posttreatment follow-up of 15 mo, 31 (94%) remain uMRD-FC. ΔMRD400 identified a cohort of pts (40%) with delayed BM MRD clearance and earlier MRD recurrence, despite longer treatment duration. ΔMRD400 warrants further study as a predictive biomarker for treatment duration. Figure 1 Figure 1. Disclosures Soumerai: Seattle Genetics: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; TG Therapeutics: Consultancy, Research Funding; BostonGene: Research Funding; GlaxoSmithKline: Research Funding. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; MSKCC: Current Employment; Genentech: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; BeiGene: Consultancy, Research Funding. Dogan: Seattle Genetics: Consultancy; Peer View: Honoraria; Takeda: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Physicians' Education Resource: Honoraria; EUSA Pharma: Consultancy. Joffe: Epizyme: Consultancy; AstraZeneca: Consultancy. Hochberg: Leuko: Consultancy; Intervention Insights: Consultancy. Abramson: Bluebird Bio: Consultancy; Morphosys: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; BeiGene: Consultancy; Novartis: Consultancy; C4 Therapeutics: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Kite Pharma: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Batlevi: TouchIME: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; GLG Pharma: Consultancy; Dava Oncology: Honoraria; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; ADC Therapeutics: Consultancy; Life Sciences: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Seattle Genetics: Consultancy; Bayer: Research Funding; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Matasar: Rocket Medical: Consultancy, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; Juno Therapeutics: Consultancy; Merck: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; GlaxoSmithKline: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Teva: Consultancy; TG Therapeutics: Consultancy, Honoraria; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. Palomba: Ceramedix: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; BeiGene: Consultancy; Lygenesis: Honoraria; Nektar: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; Rheos: Honoraria; Magenta: Honoraria; Pluto: Honoraria; WindMIL: Honoraria; Priothera: Honoraria. Kumar: Abbvie Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Kite Pharmaceuticals: Other: advisory board , Research Funding; Celgene: Honoraria, Other: advisory board, Research Funding; Astra Zeneca: Honoraria, Other: Advisory Board, Research Funding; Adaptive Biotechnologies, Celgene, Abbvie Pharmaceticals, Pharmacyclics, Seattle Genetics: Research Funding; Seattle Genetics: Research Funding. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Thompson: VJHemOnc: Honoraria; MJH Life Sciences: Honoraria; Curio Science: Honoraria. Roshal: Physicians' Education Resource: Other: Provision of services; Auron Therapeutics: Other: Ownership / Equity interests; Provision of services; Celgene: Other: Provision of services. Huang: BeiGene: Current Employment, 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, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Biondo: Roche: Current holder of individual stocks in a privately-held company; Genentech, Inc.: Current Employment. 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. Jacob: Adaptive Biotechnologies: Current Employment. Abdel-Wahab: H3B Biomedicine: Consultancy, Research Funding; Foundation Medicine Inc: Consultancy; Merck: Consultancy; Prelude Therapeutics: Consultancy; LOXO Oncology: Consultancy, Research Funding; Lilly: Consultancy; AIChemy: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Envisagenics Inc.: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Zelenetz: Novartis: Honoraria; Genentech/Roche: Honoraria, Research Funding; BMS/Celgene/JUNO: Honoraria, Other; AstraZeneca: Honoraria; MethylGene: Research Funding; Pharmacyclics: Honoraria; Amgen: Honoraria; MEI Pharma: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Verastem: Honoraria; Beigene: Honoraria, Other, Research Funding; Abbvie: Honoraria, Research Funding; SecuraBio: Honoraria; Janssen: Honoraria; Gilead: Honoraria; MorphoSys: Honoraria; NCCN: Other; LFR: Other. OffLabel Disclosure: Zanubrutinib is administered off-label in combination with venetoclax and obinutuzumab for patients with CLL/SLL.