Abstract: Background: Venetoclax (VEN), an oral B-cell lymphoma 2 inhibitor, is approved for use in adult patients (pts) with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). As a targeted and highly active antitumor agent, VEN induces rapid and profound tumor reduction. Inpatient monitoring for initial doses of VEN is recommended by US Prescribing Information for pts with medium tumor burden and reduced renal function or high tumor burden. Administration of debulking agents, such as obinutuzumab (G), help reduce tumor burden and, consequently, facilitate subsequent administration of VEN in the outpatient setting. However, tumor reduction data are needed to definitively establish the utility of a debulking strategy. This study performed disease restaging after every 2 cycles of debulking to evaluate the safety and efficacy of G ± bendamustine (B) as a debulking regimen before VEN treatment in the outpatient community setting. The safety and efficacy of subsequent VEN+G treatment after debulking was also evaluated. Methods: This open-label, Phase 3b study (NCT03406156) enrolled adult pts with previously untreated CLL/SLL (except those with 17p deletion) who had medium (any lymph node [LN] 5 to & lt;10 cm or absolute lymphocyte count [ALC] ≥25×10 9/L) or high (any LN ≥10 cm or any LN ≥5 cm and ALC ≥25×10 9/L) tumor burden. A maximum of six 28-day cycles of G±B were administered, and disease restaging was performed after every 2 cycles. Once low tumor burden was achieved (all LN & lt;5 cm and ALC & lt;25x10 9/L), VEN+G was administered for 5 cycles followed by VEN monotherapy for a total time on VEN of up to 1 year. Disease assessments were performed at the end of combination therapy (EoCT; 5 mo after last dose of G) and at the end of therapy (EoT; 3 mo after last dose of VEN), and peripheral blood was collected for assessment of minimal residual disease (MRD) using the clonoSEQ assay (Adaptive Biotechnologies). Undetectable MRD was defined as & lt;1 CLL cell/10 4 leukocytes ( & lt;10 -4; uMRD4), & lt;10 -5 (uMRD5), or & lt;10 -6 (uMRD6). The primary endpoints were the percentage of pts achieving low tumor burden after 2, 4, and 6 cycles of G±B debulking and complete remission (CR) and CR with incomplete marrow recovery (CRi) rates among pts receiving VEN. Results: Of 120 pts treated, 81 received G for debulking and 39 received G+B. As of 13 May 2021, 2 pts remained on study treatment, 108 were in posttreatment follow-up, and 10 had discontinued the study for reasons including death (n=7), withdrawn consent (n=2), and COVID-19 infection (n=1). At baseline, 82.5% of pts had ALC ≥25x10 9/L, 33.3% had LN ≥5 cm, and 24.2%/75.0%/0.8% had high/medium/low tumor burden, respectively. Low tumor burden was achieved in 91.6% (109/119) of evaluable pts receiving G±B debulking. In the all-treated population (N=120), the objective response rate (ORR) was 90.0% and the CR/CRi rate was 35.8%. Among pts receiving VEN with disease assessment at EoT (N=76), the ORR was 98.7% and the CR/CRi rate was 44.7% (Table). The best uMRD4 rates in peripheral blood were 89.2% (107/120) for all-treated and 98.2% (107/109) for evaluable pts. Among evaluable pts, the uMRD4 rates were 100% (100/100) and 97.1% (68/70) at EoCT and EoT, respectively. Among pts with MRD assessments at both timepoints (N=67), 19.4% had a deepening of their MRD response from EoCT to EoT, and 67.2% maintained the same MRD level (Figure). At a median follow-up of 24.0 mo, 7 deaths (6 related to COVID-19 infection and 1 from cardiac complication after pancreatic mass resection) and no incidences of disease progression were reported; the estimated 18-mo PFS was 94.1%. In pts treated with G vs G+B debulking, respectively, the incidences of Grade ≥3 TEAEs were 71.6% vs 84.6% (most common was neutropenia at 28.4% vs 41.0%) and serious AEs were 23.5% vs 17.9% (most common were pneumonia and COVID-19 pneumonia, each at 3.7% vs 2.6%). Conclusion: In this study, most (91.6%) pts achieved low tumor burden after debulking. The uMRD4 rate was 98.2% among MRD-evaluable pts (89.2% among all pts), with 100% and 97.1% uMRD4 rates at EoCT and EoT, respectively. Overall, these results highlight the utility of G±B as an effective debulking strategy that can facilitate VEN treatment initiation in the outpatient setting. The efficacy and safety results are consistent with other VEN+G trials. Preventive measures for COVID-19 should be continuously emphasized for pts with CLL. Figure 1 Figure 1. Disclosures Flinn: AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Andorsky: AbbVie: Research Funding; Celgene/Bristol Myers Squibb: Consultancy; Celgene/Bristol Myers Squibb: Research Funding; Epizyme: Research Funding; AstraZeneca: Other: served on steering committees; AbbVie: Consultancy. Melear: TG Therapeutics: Speakers Bureau; Astrazeneca: Speakers Bureau; Janssen: Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Kolibaba: TG Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Atara Biotechm: Consultancy; McKesson Specialty Health: Consultancy; Sunitomo Dainippon Pharma: Consultancy; Tolero Pharma: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Yimer: GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau; Sanofi: Speakers Bureau; Amgen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Texas Oncology: Current Employment. Burke: Kura: Consultancy; Epizyme: Consultancy; Kymera: Consultancy; Adaptive Biotechnologies: Consultancy; Roche/Genentech: Consultancy; Beigene: Consultancy, Speakers Bureau; MorphoSys: Consultancy; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; SeaGen: Consultancy, Speakers Bureau. Fanning: BMS: Speakers Bureau; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genmab: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Speakers Bureau; Takeda: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Islas-Ohlmayer: OHC/USON: Current Employment; AbbVie: Honoraria; Rigel: Honoraria, Speakers Bureau. Vizkelety: AbbVie: Current Employment, Current equity holder in publicly-traded company. Pesko: AbbVie: Current Employment, Current equity holder in publicly-traded company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Jiang: AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman: Pharmacyclics LLC, an AbbVie Company: Consultancy; BMS: Consultancy; Lilly: Consultancy; BeiGene: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy.

Abstract: 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.

Abstract: Background: Venetoclax (VEN), a B-cell lymphoma 2 inhibitor, is an oral agent with demonstrated efficacy in patients (pts) with chronic lymphocytic leukemia (CLL). VEN treatment induces rapid tumor reduction, posing a risk for tumor lysis syndrome (TLS), particularly in pts with high tumor burden, and may require inpatient monitoring at the initiation of therapy. Agents such as obinutuzumab (G), ibrutinib, and bendamustine (B) have been used in clinical studies to debulk tumors prior to treatment with VEN. However, the benefits of these debulking regimens could not be established conclusively, as disease restaging was rarely performed. In the present study, disease restaging was performed every 2 cycles to evaluate the efficacy and safety of G, with or without B, as a debulking therapy in untreated pts with CLL, prior to VEN treatment in an outpatient community setting. Methods: This open-label, phase 3b trial (NCT03406156) enrolled adult pts with previously untreated CLL/small lymphocytic lymphoma (excluding those with 17p deletion) who had Eastern Cooperative Oncology Group performance status of ≤1 and medium (any lymph node [LN] 5 to & lt;10 cm or absolute lymphocyte count [ALC] ≥25 × 109/L) or high (any LN ≥10 cm or ALC ≥25 × 109/L and any LN ≥5 cm) tumor burden. Pts received at least 2 cycles of debulking therapy (G±B), which could be repeated for a maximum of six 28-day cycles until low tumor burden (ALC & lt;25 × 109/L and all LN & lt;5 cm) was achieved. B was administered at investigator discretion, with protocol recommendation for pts with LN & gt;10 cm or with del(11q) and LN & gt;5 cm. Restaging data were obtained after every 2 cycles of debulking therapy. When low tumor burden was achieved, VEN was administered (5-week ramp-up schedule) as combination therapy with G (VEN+G) for 5 months, and then as monotherapy (VEN mono) for a total of 1 year. Response assessments were scheduled at week 38 and week 65 post-VEN initiation. Adverse events (AEs) were monitored throughout the study. Primary endpoints were the reduction in tumor burden after debulking therapy and the complete remission (CR)/CR with incomplete marrow recovery (CRi) rates of pts subsequently treated with VEN. We report the results of a planned interim analysis when 50 pts had completed their week 38 disease assessment. Results: As of 3 Feb 2020, 117 pts were treated with study drug(s): 80 (68%) received G and 37 (32%) received G+B for debulking; 113 pts were active in study (7 in the debulking phase; 106 completed debulking therapy and initiated VEN, including 26 in posttreatment follow-up). Four pts discontinued study due to withdrawal by pt (n=2; 1 at debulking and 1 at VEN treatment phase) and physician decision (n=1; at VEN treatment phase) and other (n=1; at debulking). At baseline, 85% of pts had ALC ≥25 × 109/L, 9% had LN ≥10 cm, 23% had LN 5-10 cm; 74%/26% had medium/high TLS risk, respectively, per investigator assessment (1 pt with low TLS risk was enrolled and subsequently discontinued). After 2 cycles of debulking therapy, low tumor burden was achieved in 85% (89/105) of evaluable pts: 86% (63/73) with G and 81% (26/32) with G+B. Reductions by pt subgroups and genetic features are presented in Figure. For pts debulked with G, similar debulking efficacy was observed among the subgroups being explored (Figure). Of the 50 pts with a week 38 disease assessment, 17 pts had an initial response of partial remission and await confirmation per IWCLL criteria. Objective response rate was 96% (48/50) overall, with 95% (37/39) for those debulked with G and 100% (11/11) for those debulked with G+B. The rate of CR or CRi was 52% (26/50) overall, with 54% (21/39) achieving CR/CRi for those debulked with G and 45% (5/11) for those debulked with G+B (Figure). More grade ≥3 AEs were observed in pts receiving G+B than those receiving G: debulking, 62% vs 40%; VEN+G, 43% vs 34%; VEN mono, 41% vs 28%. Conclusions: Most pts (85%) achieved low tumor burden after 2 cycles of G±B. Similar debulking efficacy was observed across subgroups in pts debulked with G. In this early efficacy analysis, CR/CRi at week 38 was observed in 52% of pts treated with VEN after the debulking phase. Preliminary efficacy results from this study are consistent with other VEN studies in treatment-naive pts. Current study highlights the efficacy of the debulking strategy prior to treatment with VEN; this may allow more pts to have VEN ramp-up in outpatient setting. Figure Disclosures Flinn: Calithera Biosciences: Research Funding; Forma Therapeutics: Research Funding; F. Hoffmann-La Roche: Research Funding; Celgene: Research Funding; Merck: Research Funding; Curio Science: Consultancy; Pfizer: Research Funding; Seattle Genetics: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Constellation Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; BeiGene: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Forty Seven: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Takeda: Consultancy, Research Funding; Incyte: Research Funding; AstraZeneca: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; Agios: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; IGM Biosciences: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Loxo: Research Funding; Genentech, Inc.: Research Funding. Andorsky:AstraZeneca: Research Funding; Celgene: Research Funding; AbbVie: Honoraria. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Manda:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Anz:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials. Kolibaba:Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Verastem: Honoraria; Cell Therapeutics: Research Funding; Celgene: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Atara Biotech: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Acerta: Research Funding; Compass Oncology: Ended employment in the past 24 months; McKesson Life Sciences: Consultancy; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: travel, accommodations, expenses, . Yimer:Sanofi: Speakers Bureau; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; TG Therapeutics: Consultancy; Celgene, a Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; BeiGene: Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Texas Oncology: Current Employment; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Epizyme: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau. Burke:Adaptive: Consultancy; Kura: Consultancy; Morphosys: Consultancy; Celgene: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Seattle Genetics: Speakers Bureau; Roche: Consultancy; Bristol Myers Squibb: Consultancy; Verastem: Consultancy; Astra Zeneca: Consultancy; Epizyme: Consultancy; Adaptive Biotechnologies: Consultancy. Fanning:TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau. Courtright:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Islas-Ohlmayer:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Kambhampati:AbbVie: Other: Investigator in AbbVie-sponsored clinical trials.. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Pesko:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Vizkelety:AbbVie: Current Employment, Other: may hold stock or stock options.. Sharmokh:AbbVie: Current Employment, Current equity holder in publicly-traded company. Sharman:AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding.

Abstract: We report long-term follow-up of the phase 1b study of venetoclax and rituximab (VenR) in patients with relapsed chronic lymphocytic leukemia (CLL), including outcomes with continuous or limited-duration therapy. Patients received venetoclax daily (200-600 mg) and rituximab over 6 months and then received venetoclax monotherapy. Patients achieving complete response (CR), CR with incomplete marrow recovery (CRi), or undetectable minimal residual disease (uMRD) assessed by flow cytometry ( & lt;10−4 cutoff) were allowed, but not required, to discontinue therapy, while remaining in the study and could be retreated with VenR upon progression. Median follow-up for all patients (N = 49) was 5.3 years. Five-year rates (95% CI) for overall survival, progression-free survival, and duration of response were 86% (72-94), 56% (40-70), and 58% (40-73), respectively. Of the 33 deep responders (CR/CRi or uMRD), 14 remained on venetoclax monotherapy (continuous therapy), and 19 stopped venetoclax therapy (limited-duration therapy) after a median of 1.4 years. Five-year estimates of ongoing response were similar between continuous (71%; 95% CI, 39-88) or limited-duration therapy (79% [49-93]). Six of 19 patients in the latter group had subsequent disease progression, all & gt;2 years off venetoclax (range, 2.1-6.4). Four patients were retreated with VenR, with partial responses observed in the 3 evaluable to date. VenR induced deep responses that were highly durable with either continuous or limited-duration therapy. Retreatment with VenR induced responses in patients with CLL progression after discontinuing therapy. Continuous exposure to venetoclax in deep responders does not appear to provide incremental benefit.