Abstract: Introduction: Venetoclax is a potent BCL-2 inhibitor that is approved as monotherapy and in combination with rituximab for patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) in the United States, and as a monotherapy for patients with 17p deletion or TP53 mutation in the European Union and other countries. Here we report the long-term efficacy and safety of the combination of venetoclax and rituximab from this phase 1b study with a median follow up of 〉 4 years, two years beyond when initially published. Methods: Patients received daily venetoclax (200 - 600mg) and 6 - 9 doses of rituximab over 6 months, then venetoclax monotherapy.(NCT01682616; Seymour, et al. Lancet Oncol. 2017; 18(2):230-240.) Minimal residual disease (MRD) was assessed in bone marrow (BM) using ≥4-color flow cytometry (min sensitivity: 0.01%). As amended in specific protocol versions, patients who achieved complete remission (CR) or BM MRD-negativity regardless of CR status (collectively considered as deep responses) could stop venetoclax and remain on study, retreating with venetoclax +/- rituximab at clinical disease progression (iwCLL criteria). Results: Forty-nine patients, with a median 2 (range: 1 - 5) prior therapies, were enrolled. As of June 4, 2018 (N=49), the median time on study was 4.1 years (range: 0 - 5.8) and the median time on venetoclax was 2.5 years (range: 0 - 5.8). The overall response rate (N=49) was 86%, CR rate was 51%, and BM MRD-negativity rate was 61%. The 48-month estimates (N=49) for overall survival was 89% (95% CI: 75%, 95%), progression free survival was 61% (95% CI: 45%, 74%), and duration of response was 64% (95% CI: 46%, 77%) (for patients with BM MRD-negativity, 88% [95% CI: 66%, 96%]). The adverse events of any grade occurring in 〉 15% of patients beyond 2 years of treatment were upper respiratory infection, neutropenia, and diarrhea (Table). Disease progression occurred in 17 patients, 14 while on continuous therapy: 5 with Richter transformation at a median of 5 months (range 1 - 8), 9 with CLL progression at a median of 29 months (range: 12 - 55). Three patients (2 MRD-positive CR and 1 MRD-negative CR with CLL cells detectable below the threshold of 10-4) progressed after stopping venetoclax (asymptomatic progression at 23, 24 and 38 months off venetoclax). All three have been re-treated with venetoclax plus rituximab, resulting in CR in one patient (duration of ongoing subsequent CR, 17 months), one partial response (PR) followed by progressive disease 18 months later, and results are pending for the third patient. Fifteen additional patients stopped venetoclax per protocol following the achievement of a deep response (median duration [range] of treatment 19 months (range: 8 - 40);13 MRD-negative CR, 2 MRD-negative PR) (Figure). Four have discontinued the study (withdrew consent [n=4] ) and 11 remain on study in long term follow up with a median duration of ongoing response of 49 months (range: 32 - 59), and a median of 33 months (range: 12 - 58) off venetoclax to date. Twelve patients who have received continuous venetoclax and remain on study, remain free of disease progression: 8 in CR (7 MRD-negative, 1 MRD-positive) and 4 in MRD-negative PR. Median duration of response on therapy is 51 months (range: 44 - 66). The 4 patients with PR do not meet CR criteria because of lack of BM biopsy results (n=2) and residual adenopathy (n=2; max node dimension; 17 and 23 mm). The other 5 patients have discontinued because of withdrawal of consent (n=2; 1 without response, 1 MRD-positive PR) and adverse events (n=3; tumor lysis syndrome, worsening peripheral neuropathy, both without response, and fatal ischemic heart disease considered unrelated to therapy in MRD-negative CR [n=1]). Conclusions: Venetoclax with rituximab induces deep and durable responses in patients with previously treated CLL, with 51% achieving CR and 61% achieving BM MRD-negativity. Those with a deep response can discontinue venetoclax and maintain prolonged treatment-free remission of more than three years, especially if MRD-negative. Disclosures Brander: Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Teva: Consultancy, Honoraria; BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Seymour:Celgene: Consultancy; 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. Ma:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Acerta: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: 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; Genentech: Membership on an entity's Board of Directors or advisory committees. Anderson:Genentech: Research Funding; AbbVie, Inc: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties. Choi:Genentech: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Rigel: Consultancy; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Kipps:Genentech Inc: Consultancy, Research Funding; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; 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; Verastem: 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; Verastem: Membership on an entity's Board of Directors or advisory committees. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Nandam:AbbVie, Inc: Employment, Equity Ownership. Kim:Abbvie: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Roberts:AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax.

Abstract: Introduction: Venetoclax (VEN) is a selective, orally bioavailable BCL-2 inhibitor. This is a phase 1b, study of VEN plus rituximab (R) to determine safety, PK and preliminary efficacy in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL). The recommended phase 2 dose for VEN plus R was previously reported to be 400mg/day. The aims of this analysis were to evaluate progression-free survival (PFS), overall survival (OS), and the durability of responses off all therapy in pts achieving CR. We also assessed minimal residual disease (MRD) status, which has previously been shown to be strongly predictive of PFS and OS after chemoimmunotherapy. Methods: Pts began once daily VEN (20 or 50 mg) to final cohort doses (200-600 mg/day) followed by R, given every 4 weeks for a total of 6 doses. VEN dosing was continuous. Responses were assessed by iwCLL criteria with CT scan and bone marrow (BM) biopsy after combination therapy (Month 7). MRD was assessed on BM aspirates in local laboratories using ≥4 color flow cytometry (minimum sensitivity of 0.01%). Results: 49 pts (48 CLL/1 SLL) were enrolled in 5 dose escalation cohorts (n=41; 200-600mg/day) and a safety expansion cohort (n=8; 400mg/day); results herein combine data from all cohorts. Median (range) age was 68 (50-88) years. The median (range) number of prior regimens was 2 (1-5). 45 (92%) received prior R and 14 (29%) had R-refractory disease; 29 (59%) received prior fludarabine and 9 (18%) had fludarabine-refractory disease. Of pts with available data, 9/46 (20%) had del(17p); 19/27 (70%) expressed unmutated IGHV. As of June 4, 2015, 12 pts have discontinued the study: 6 due to PD (5 were Richter's transformation), 3 due to AEs (neuropathy, TLS, and myelodysplasia [heavily pretreated and hypocellular marrow at study entry; pt achieved MRD-negative CR with incomplete marrow recovery, CRi, and proceeded to transplant]), and 3 withdrew consent (1 after achieving MRD-negative CR). The investigator-assessed ORR was 86% (42/49) with 20 (41%) CR/CRi, 1 (2%) nPR and 21 (43%) PR. 4 had SD, 2 had PD, and 1 died before assessment (fatal TLS). 9 with PR or SD at the 7 month assessment achieved CR after a median (range) additional time of VEN monotherapy of 6 (2-9) months. BM MRD was evaluated in 40 pts. MRD-negativity was achieved in 15/20 (75%) pts who achieved a CR/CRi and 26/49 (53%) overall. Disease has progressed in 5/42 (12%) responders; 89% are free from progression at 12-months. The median PFS has not been reached. At 12 and 24 months, actuarial PFS is 87% and 84%, respectively, with a median (range) follow-up for pts without events of 17.5 (0.03-32) months. 94% were alive at 12 months; the median OS has not been reached. Although the numbers are small, the ORR, CR rates, PFS, and OS were not significantly impacted by high-risk subgroups. 8 pts stopped VEN after achieving CR/CRi, 6 of whom were MRD-negative at the time. 2 withdrew from the study after achieving CR/CRi without evidence of progression; 6 remain in follow-up with a median (range) of 15 (4-24) months off VEN. The 2 MRD-positive pts had asymptomatic progression with rising lymphocytosis after 19 and 24 months off VEN; both are eligible for retreatment with VEN when clinically appropriate. Treatment-emergent AEs in 〉 25% of pts were neutropenia (55%), diarrhea (53%), nausea (49%), upper respiratory tract infection (45%), fatigue and pyrexia (each 37%), cough (35%), and headache (33%). Grade 3/4 AEs in 〉 10% were neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leukopenia (10%). 1 treatment-emergent AE (TLS) led to death; no other fatal TLS events occurred after a protocol modification aimed at TLS risk management and prophylaxis. 2 deaths occurred after PD. Key efficacy data are summarized in the table. Conclusions: VEN plus R induces a high rate of deep and durable responses, independent of adverse prognostic factors, with a tolerable safety profile. 41% of pts achieved CR/CRi and 53% achieved BM MRD-negativity. Remission off all therapy has been maintained in pts achieving MRD-negative CR. The median PFS and OS have not yet been reached; 24-month PFS is estimated to be 84%. The high rate of MRD-negativity is an encouraging step towards prolonged PFS and durable elimination of CLL/SLL. VEN plus R versus bendamustine plus R is being evaluated in a phase 3 trial in pts with previously treated CLL (MURANO; NCT02005471). Table 1. Table 1. Disclosures Ma: Genentech, Pharmacyclics/Janssen and Gilead: Speakers Bureau; Genentech, Pharmacyclics/Janssen and Gilead: Consultancy; NCCN, AbbVie, Pharmacyclics, Novartis, Gilead, Celgene, and Xeme: Research Funding. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication.. Seymour:Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: 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; Genentech, Inc.: 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, Other: Travel support, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kipps:Roche: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria. Barrientos:Gilead, Pharmacyclics, and AbbVie: Research Funding; Pharmacyclics, Celgene, and Genentech: Membership on an entity's Board of Directors or advisory committees. Davids:Genentech: Other: ad board; Pharmacyclics: Consultancy; Janssen: Consultancy. Anderson:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Choi:AbbVie: Consultancy, Other: Advisory Board, Research Funding; Gilead: Consultancy, Other: Advisory Board, Speakers Bureau. Tam:Roche: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria. Mason-Bright:AbbVie: Employment, Equity Ownership. Prine:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Kim:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Roberts:Walter and Eliza Hall Institute of Medical Research: Employment; Genentech: Research Funding; AbbVie: Research Funding; Servier: 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.

Abstract: Background: Venetoclax (VEN) is a selective, potent, orally bioavailable BCL-2 inhibitor FDA-approved for patients with del(17p) chronic lymphocytic leukemia (CLL) and who have received ≥1 prior therapy. Based on preclinical evidence of synergy, VEN plus rituximab is being assessed in an ongoing Phase 1b study. Methods: Patients with relapsed/refractory (R/R) CLL received daily VEN with stepwise ramp-up over 3-4 weeks to reach daily doses of 200-600mg. After 1 week at the target dose, monthly rituximab was added for 6 doses. Responses and progression were assessed by iwCLL criteria with CT scan and bone marrow biopsy. Bone marrow assessments were done at screening, completion of combination therapy (month 7), and 2 months after clinical/radiologic criteria of iwCLL response were met. Minimal residual disease (MRD) was assessed in peripheral blood and marrow aspirates using ≥4 color flow cytometry (min sensitivity: 0.01%). Data cutoff was 04March2016, with analysis focusing on updated safety of cytopenias experienced on the course of treatment. Results: Forty-ninepatients enrolled (48 CLL/1 SLL). Patients had received a median of 2 prior therapies (range: 1-5) and disease in 25 (51%) was considered refractory to the most recent therapy. Median time on study was 28 ( 〈 1-42) months, with 31 patients active on study. Eighteen patients discontinued: 11 due to disease progression, 3 due to toxicity (peripheral neuropathy [1], MDS [1] , and death due to TLS [1]), 3 withdrew consent, and 1 was lost to follow up. Across all doses, the most common AEs of any grade were diarrhea (57%), neutropenia (55%), upper respiratory tract infection (55%), and nausea (51%). Peripheral blood cytopenias were the most common Grade 3/4 AEs (neutropenia [53%] , thrombocytopenia [16%], anemia [14%] , febrile neutropenia [12%], and leukopenia [12%] ). Twenty-seven (55%) patients had a history of neutropenia, of whom 6 were receiving G-CSF support prior to starting VEN. Overall, in the first month of therapy, 15 (31%) experienced an AE of neutropenia (any grade). Thereafter, the rate of new AEs of neutropenia decreased over time. While there was individual patient variability, mean ANC was stable over time. Overall, 26 (53%) patients had Grade 3/4 neutropenia. Neutropenia was generally well tolerated and managed by G-CSF support in 24 patients, in addition to ≥1 dose modification in 11 of the 24 patients. Of 8 (16%) patients who experienced grade 3 infections, 2 were while neutropenic. There were no grade 4 infections. Among the 11 (22%) patients who developed any-grade thrombocytopenia, none occurred within 2 weeks of a reported bleeding-related AE. One patient had thrombocytopenia overlapping with disease progression on therapy. Objective response rate for all patients was 86% (n=42), with 51% (n=25) who had complete response (CR/CRi; 12 achieved CR/CRi by month 7). At the completion of combination therapy (month 7), 39 patients had evaluable bone marrow assessments. Thirty (77%) had no histologic evidence of CLL in the bone marrow and 22 patients (56%) had attained bone marrow MRD-negativity. In longer follow up at any point during treatment for all 49 patients, 37 (75%) patients achieved complete marrow clearance and 28 (57%) achieved marrow MRD-negativity. Conclusions: Transient manageable neutropenia was the most common AE, with first onset usually seen within the first month of treatment and the onset of new neutropenia AEs decreased over time. No patients discontinued the study due to cytopenias. Patients were able to continue on study and high rates of response to treatment were observed. VEN given with rituximab achieved rapid and profound reductions in disease burden in peripheral blood and bone marrow. 77% of evaluable patients achieved morphologic clearance by month 7, and 57% were MRD-negative at any point on study. Figure 1 Figure 1. Disclosures Brander: TG Therapeutics: Research Funding; Gilead: Honoraria. Roberts:AbbVie: Research Funding; Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding; Xeme: Research Funding; AbbVie: Research Funding. Lash:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie: Employment. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, 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, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, 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; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.