Abstract: Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries.

Abstract: Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. We recently reported results of the first-line cohort (n=80) of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019) (NCT02756897). Here we report updated data for these 80 pts with focus on MRD results. Methods: Pts with previously untreated CLL meeting 2008 IWCLL treatment criteria were enrolled. All pts had at least one of the following features: del(17p), mutated TP53, del(11q), unmutated IGHV, or an age of 65 years or older. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (assessed by multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy will stop both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of the combination therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 65 years (26-83). The baseline characteristics are shown in Table 1. A total of 30% of the pts were 70 years of age or older. Overall, 92% of the pts had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. The median follow-up for all pts is 22.8 months. Five pts came off study during IBR monotherapy (reasons listed below). 75 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. After 3 cycles of IBR monotherapy, none of the 75 pts had achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 12/74 (16%) achieved BM U-MRD remission. After 6 cycles of the combination, 30/72 (42%) achieved BM U-MRD remission. After 12 cycles of the combination, 45/69 (65%) achieved BM U-MRD remission. After 24 cycles of the combination, 23/29 (79%) achieved BM U-MRD remission. PFS and OS are shown in Figure 2. No pt has had CLL progression. Richter's transformation developed in one pt; this was a 63-year-old man with CLL with high-risk genomics (unmutated IGHV and mutated NOTCH1) in whom back pain developed during dose escalation of venetoclax and who was noted to have DLBCL transformation. Two pts died. One pt was a 60-year-old man who was having headache and numbness on the right side for 1 week before starting ibrutinib. The pt received 1 day of ibrutinib monotherapy, had progressive neurologic symptoms, and was found to have CNS cryptococcal infection. Ibrutinib was discontinued and the pt died 6 months later from complications of disseminated cryptococcal infection. This was deemed unrelated to ibrutinib as the pt had symptoms prior to starting ibrutinib. A second pt received only 2 weeks of ibrutinib and was taken off trial due to development of fungal pneumonia. The pt continued ibrutinib (off trial) and died 2 years later from infectious complications. A total of 12 (15%) pts have come off trial. Five pts came off trial during IBR monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1]. Seven pts came off study during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=1; pneumonia, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia/MDS, n=1] . 54% pts had dose reduction of IBR; 29% had dose reduction of VEN. Conclusions: Combined IBR and VEN is an effective chemotherapy-free oral regimen for pts with high-risk previously untreated CLL. Ongoing randomized studies will further help define the role of this combination approach in CLL. Disclosures Jain: BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding. Thompson:AbbVie: Research Funding; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding. Burger:BeiGene: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria; Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria. Borthakur:Cyclacel: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; Xbiotech USA: Research Funding; Novartis: Research Funding; NKarta: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; PTC Therapeutics: Consultancy; Eli Lilly and Co.: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Fowler:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Bioline RX: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Konopleva:Agios: Research Funding; Astra Zeneca: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding. Alvarado:Abbott: Honoraria; Jazz Pharmaceuticals: Research Funding. DiNardo:jazz: Honoraria; celgene: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; abbvie: Consultancy, Honoraria; daiichi sankyo: Honoraria; medimmune: Honoraria. Bose:Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; Constellation: Research Funding; Pfizer: Research Funding; Astellas: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding. Pemmaraju:mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Jabbour:Pfizer: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; Takeda: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Novartis: Research Funding; Cyclacel: Research Funding; Ariad: Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Astex: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Wierda:Janssen: Research Funding; Xencor: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Pharmacyclics LLC: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

Abstract: Background Patients receiving the BTK inhibitor ibrutinib (ibr) for CLL rarely achieve complete remission (CR) with undetectable minimal residual disease (U-MRD) and their disease is managed with continuous ibr. Long-term therapy (Rx) with ibr results in a cumulative risk of AEs leading to Rx discontinuation. The risk of progression is highest in patients with complex karyotype and/or del(17p); some series suggest increased risk in patients with del(11q) or persistently elevated β2-microglobulin The Bcl-2 inhibitor venetoclax (ven) is synergistic with ibr. The combination is well-tolerated and active in first-line (1L) and relapsed/refractory (R/R) patients with CLL. We hypothesized that adding ven to ibr in patients at high risk for CLL progression, who had been on ibr for more than 12 months (mo) would achieve U-MRD and allow treatment discontinuation. Methods We designed a phase II, investigator-initiated, response-adapted clinical trial with the addition of ven to ibr in patients (pts) with one or more high risk features for disease progression who had received at least 1y of ibr therapy (either as 1L therapy or for R/R disease). Pts had detectable disease at time of study entry without meeting IWCLL criteria for progression. High risk was defined as any of: del(17p); complex karyotype; del(11q); elevated β2-microglobulin; TP53 mutation. Ibr was continued at 140-420mg/d and standard dose-escalation of ven was performed to the target dose of 400mg/d. Rx with combined ibr and ven continued for a maximum duration of 2y. Pts had bone marrow evaluation for MRD measurement using 4 color flow cytometry (sensitivity 10-4) and CT scan for re-staging every 6mo. Pts in CR with U-MRD on two consecutive evaluations, 6mo apart, stopped ven, but could continue ibr at physician discretion. Pts not in CR with U-MRD at final re-staging after 2 years of combination therapy stopped ven and continued ibr. The primary endpoint is achievement of U-MRD after 12mo of combination Rx. Results: Forty-five pts have enrolled. Pre-treatment characteristics are shown in the table. U-MRD in BM was achieved in 17/42 pts (40%) at 6m (2 pts off study; 1 too early - TE) and in 21/33 (64%) at 12m (3 off study, 9 TE), Figure. Two patients (4%) were in CR prior to ven. At 12m, 45% were in CR. Twenty-three pts discontinued Rx (2 prior to first response assessment): 1 was found to be ineligible soon after commencing treatment; 1 developed metastatic melanoma; 1 developed metastatic lung Ca requiring chemotherapy after achieving U-MRD CR at 6mo. Of the remaining 20: 7 stopped prior to 24m (5 at 12m and 2 at 18m) after achieving U-MRD CR, per protocol; 13 completed 24m of therapy (MRD+ CR, n=3; U-MRD CR, n=4; U-MRD PR n=6). 3/11 patients with U-MRD CR continued ibrutinib per physician discretion. No pt came off study due to toxicity, no pt developed Richter Transformation and no pt died while on study. One pt had CLL progression after 18 months of combination Rx. Treatment has been well-tolerated. There was no clinical or laboratory tumor lysis syndrome. Adverse events of all grades occurring in at least 20% of pts, regardless of attribution, were: diarrhea (n=26, 58%), neutropenia (n=17, 38%), non-melanoma skin cancer (n=14, 31%), nausea (n=13, 29%), fatigue (n=12, 27%). Grade 3 adverse events occurred in 20/45 pts (most common: neutropenia, n=8; hypertension, n=4; infections, n=4; thrombocytopenia, n=2). Grade 4 neutropenia occurred in 2 pts, grade 4 metastatic mucinous adenocarcinoma of the lung in 1 pt and myelodysplasia in 1 pt, who previously received chemoimmunotherapy. Ven was dose-reduced in 13/45 patients (to 300mg in 6 pts, 200mg in 5 pts and 100mg in 2 pt), most commonly due to neutropenia (n=7) or diarrhea (n=4). Ibr was dose-reduced in 6 pts to 140mg, most commonly due to bruising/bleeding (n=2) or neutropenia (n=2) and discontinued in 4 pts (due to AF in 2 patients, unexplained syncope in one patient and bleeding in one patient). These 4 patients continued venetoclax monotherapy on study. Conclusions: Ven added to ibr in pts with high-risk CLL as consolidation was well tolerated and associated with a high likelihood of achieving U-MRD in BM and CR within 12 months of combination. This allowed Rx discontinuation in patients with high-risk CLL. Risk of disease progression during combination Rx was very low. Longer-term follow-up, including serial analysis of MRD in peripheral blood, will establish the durability of deep responses in the absence of continuous ibr Rx. Disclosures Thompson: Pharmacyclics: Research Funding; Janssen-Cilag: Honoraria; AbbVie: Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy. Jain:BMS: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: 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; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; ADC Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Cellectis: Research Funding. Kadia:Novartis: Honoraria; Ascentage: Research Funding; Pulmotec: Research Funding; Celgene: Research Funding; BMS: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding; Cyclacel: Research Funding; Incyte: Research Funding; Astellas: Research Funding; Pfizer: Honoraria, Research Funding; Astra Zeneca: Research Funding. Bose:Celgene Corporation: Honoraria, Research Funding; Constellation Pharmaceuticals: Research Funding; Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Astellas Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer, Inc.: Research Funding. Pemmaraju:Stemline Therapeutics: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Cellectis: Research Funding; LFB Biotechnologies: Honoraria; SagerStrong Foundation: Other: Grant Support; Pacylex Pharmaceuticals: Consultancy; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; Plexxikon: Research Funding; DAVA Oncology: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Blueprint Medicines: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria; Roche Diagnostics: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria. Short:AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding.

Abstract: Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. The rationale for combining IBR and VEN includes: 1) preclinical models showing synergism, 2) non-overlapping toxicities; 3) non-overlapping mechanisms of action. We recently reported results of the first-line cohort of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019). Here we report results of the 80 pts from the R/R CLL cohort of the trial (NCT02756897). Methods: Pts with R/R CLL meeting 2008 IWCLL treatment criteria were enrolled. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to the 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy stopped both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of combined therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death. Results: A total of 80 pts were enrolled. The median age was 61.5 yrs (32-79). The baseline characteristics are shown in Table 1. Overall, 30 (38%) pts had a TP53 aberration. The median follow-up for all pts is 22.3 months. Of the 80 pts, 1 pt was later reclassified as splenic marginal zone lymphoma and is excluded from further analyses. Five pts came off study during IBR monotherapy phase (reasons listed below). 74 pts initiated VEN. Serial BM MRD responses are shown in Figure 1. One pt with a prior allo-SCT had no marrow disease at screening and is therefore excluded from serial MRD analyses. After 3 cycles of IBR monotherapy, none of the 73 pts achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 7/68 (10%) achieved BM U-MRD remission. After 6 cycles of the combination, 15/67 (22%) achieved BM U-MRD remission. After 12 cycles of the combination, 29/60 (48%) achieved BM U-MRD remission. After 24 cycles of the combination, 16/24 (67%) achieved BM U-MRD remission. To assess the incremental benefit of the combined IBR and VEN beyond the first 12 cycles, we analyzed the MRD for pts who had received 24 cycles of combined therapy (n=24). Among these 24 pts, 13 were MRD+ at end of 12 cycles; 4/13 (31%) became U-MRD at end of 18 cycles of combination. Similarly, among these 24 pts, 9 were MRD+ at end of 18 cycles of combination; only 1/9 (11%) achieved U-MRD after 24 cycles of combination. PFS and OS are shown in Figure 2. Two pts had CLL progression after completing 24 cycles of combined therapy. 1 pt was in U-MRD remission at 24 cycles and stopped both IBR and VEN per study design; he relapsed 3 months later and responded to IBR monotherapy. The second pt was MRD+ at 24 cycles of combined therapy and continued IBR monotherapy after 2 yrs per study design; he relapsed few months later and is now in remission post CD19 CAR-T. One pt developed Hodgkin's transformation. Two pts died; both due to infectious complications during the IBR monotherapy. One pt developed severe cytopenias during the VEN dose escalation, was non responsive to multiple therapies for worsening cytopenias, then underwent an allogeneic stem cell transplant. One pt, with prior FCR therapy developed MDS. A total of 15 (19%) pts have come off trial; 5 pts came off study during IBR monotherapy (death from infection, n=2; skin rash, n=1; insurance issue, n=1; pt decision, n=1). Three pts came off trial during VEN ramp up (cytopenias, n=2; noncompliance, n=1). Four pts came off trial during the combination phase of IBR and VEN (arthralgia, n=1; Hodgkin's transformation, n=1; renal cancer, n=1; MDS, n=1). Three pts came off trial after completing 24 cycles of combined therapy (CLL progression, n=2; pt decision to continue VEN beyond 24 cycles, n=1). Grade 3-4 neutropenia occurred in 29% pts. Grade 3-4 thrombocytopenia occurred in 3% pts. Atrial fibrillation occurred in 7 (9%) pts. Conclusions: Combined VEN and IBR is an effective well-tolerated chemotherapy-free oral regimen for pts with R/R CLL. Disclosures Jain: Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Thompson:Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Gilead Sciences: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; AstraZeneca: Honoraria. Borthakur:Cyclacel: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; AbbVie: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Eisai: Research Funding; Janssen: Research Funding; GSK: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Bose:Constellation: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Abbvie: 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. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Konopleva:Ablynx: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Forty-Seven: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; jazz: Honoraria. Pemmaraju:samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Pharmacyclics LLC: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

Abstract: Background: Ibrutinib (IBR) and venetoclax (VEN) combination is a highly effective therapy for patients (pts) with CLL. The ideal treatment duration for the combination therapy is not known. Several ongoing trials are evaluating 1 year (yr), 2 yr, or an MRD-guided strategy for the duration of combination therapy. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for pts with CLL (Jain, NEJM 2019). Here we report updated data for these pts with focus on MRD. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. Response assessments were performed using BM and CT (2008 IWCLL criteria) after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of the combination. U-MRD was defined as & lt;0.01%; low MRD+ 0.01% to & lt;1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Overall survival (OS) was assessed as the time from the start of study drug to death from any cause. Results: A total of 80 pts were enrolled. The median age was 65 yrs. Baseline characteristics are shown in Table 1. The median follow-up was 33.8 months. Five pts came off study during IBR monotherapy; 75 pts initiated VEN. Serial BM MRD assessments are shown in Figure 1 (this includes all 80 pts as denominator, including the 5 pts who never started VEN in an intent-to-treat analysis). After 12 cycles of the combination, 45/80 (56%) achieved BM U-MRD remission; 24/80 (30%) were BM MRD-positive (low MRD+, n=19; high MRD+, n=5); 11/80 (14%) were off study prior to cycle 12 assessment. After 24 cycles of the combination, 53/80 (66%) achieved BM U-MRD remission; 14/80 (17%) were BM MRD-positive (low MRD+, n=13; high MRD+, n=1); 13/80 (17%) were off study prior to cycle 24 assessment. Overall, 60/80 (75%) achieved BM U-MRD at any time. For the 24 pts who were BM MRD+ at the end of cycle 12, with continued combination treatment, 12/24 (50%) achieved BM U-MRD at the end of cycle 24 [low MRD+, 10/19 (53%); high MRD+, 2/5 (40%)]. None of the pretreatment characteristics (age, gender, ALC, HGB, PLT, FISH abnormalities, IGHV status, CD38, ZAP-70, TP53-m, NOTCH1-m, SF3B1-m) were statistically associated with achieving BM U-MRD at 6 cycles, 12 cycles, 24 cycles, or MRD at any time. PFS and OS are shown in Figure 2. PFS by FISH and IGHV status is shown in Figure 3. No pt had CLL progression. Richter's transformation developed in 2 pts (during VEN dose escalation, n=1; during cycle 24 of combination, n=1); both pts are alive in remission after receiving allo-SCT. Three pts died. Two pts came off study during the cycle 1 of IBR monotherapy and died 6 mos and 27 mos later due to infection issues; 1 pt died in U-MRD remission during cycle 19 of the combination therapy when found unresponsive at home, had CPR, and CT scan done in hospital showed b/l pneumonia. This was deemed possibly ibrutinib related. Of the 53 pts who were BM U-MRD at the end of cycle 24 of the combination, 41 pts had a subsequent blood MRD assessment done in follow-up (others are too early) with a median time off study drugs of 11.6 mos; 5 pts had recurrence of blood MRD (range, 0.01-0.05%) without any clinical disease progression. There were 14 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=13; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time (described above). The remaining 13 pts (all low MRD+ in BM, range 0.01-0.56%) are on IBR monotherapy; 4/9 who had a subsequent blood MRD assessment achieved blood U-MRD. Conclusions: Combined IBR and VEN is an effective time-limited oral regimen for pts with CLL. We report 50% conversion of BM MRD+ to U-MRD from cycle 12 to cycle 24 with ongoing combination therapy. Whether this would translate into improved PFS remains to be determined. Given improved MRD response from cycle 12 to cycle 24, we have amended the trial to allow another 12 cycles of the combination for pts who are BM MRD+ at cycle 24. Ongoing studies will further help define the role and the optimal duration of this combination in CLL. Disclosures Jain: ADC Therapeutics: Research Funding; Servier: 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; Cellectis: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics: Research Funding; AbbVie: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Burger:Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau. Borthakur:Incyte: Research Funding; BioLine Rx: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioLine Rx: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; BioTherix: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Novartis: Honoraria; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Ascentage: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Agios: Research Funding. Alvarado:Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding. Yilmaz:Pfizer: Research Funding; Daicho Sankyo: Research Funding; Pint Pharma: Honoraria. DiNardo:Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; ImmuneOnc: Honoraria; Calithera: Research Funding. Bose:Celgene Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding. Pemmaraju:Plexxikon: Research Funding; AbbVie: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MustangBio: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Cellectis: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; Daiichi Sankyo: Research Funding; SagerStrong Foundation: Other: Grant Support; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria. Jabbour:BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Kantarjian:Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved