Abstract: Background: The oral selective BCL-2 inhibitor, venetoclax, is FDA-approved for the treatment of Chronic Lymphocytic Leukemia (CLL) patients with 17p deletion [del(17p)] who have received at least one prior therapy.Multiple clinical trials investigating its activity in patients with relapsed or refractory CLL are ongoing, and longer term follow-up is now available since the original publications of the initial Phase 1 and 2 trials. In order to define the response rate and durability of response across a broader population than studied in any individual trial, we performed a pooled analysis of current data available from four ongoing studies. Methods: Data were analyzed from the following venetoclax trials - NCT01328626 (M12-175 study): phase 1, venetoclax monotherapy in patients with relapsed or refractory CLL (n=116, data as of 04APR2016,); NCT02141282 (M14-032 study): phase 2, venetoclax monotherapy for CLL patients who have progressed on ibrutinib or idelalisib (n=64, data as of 28JUN2016, and excludes safety expansion patients whose long term data are not available); NCT01889186 (M13-982 study): phase 2, venetoclax monotherapy in relapsed or refractory CLL patients with del(17p) (n=158, data as of 29MAR2016); NCT01682616 (M13-365 study): phase 1b, venetoclax plus rituximab in relapsed or refractory CLL (n=49; data as of 04MAR2016). Bone marrow minimal residual disease (MRD) status was determined using data from the M13-982 and M13-365 studies (n=207). MRD data for the M14-032 study is not yet available and MRD assessment was not systematically performed for the M12-175 study. Del(17p) status was assessed using fluorescence in situ hybridization and TP53 mutation status was determined by next generation sequencing. Descriptive statistics (median, range, proportion) were calculated for demographics, baseline characteristics, and overall response. All post-baseline data were included to determine the overall response and did not account for differences in the follow-up times between studies. Kaplan-Meier methodology was used to calculate 24-month estimates and associated 95% confidence interval (CI) for duration of response (DOR) and progression free survival (PFS). Results: A total of 387 patients were included in this analysis [median age: 66 years (range: 29 - 88)]. Bulky nodes (≥5 cm) were present in 194/386 (50%) patients and del(17p) was confirmed in 211/356 (59%) patients with available data; 207/387 (53%) patients had ≥3 prior therapies. Venetoclax doses ranged from 150 mg/day to 1200 mg/day; 299/387 (77%) patients received the recommended phase 2 dose (RPTD) of 400 mg/day. Across all four studies, the median duration on venetoclax was 15.3 (range: 0 - 51.8) months and the median time on study was 16.6 months (range: 0 - 51.8). 54% of the patients continue on venetoclax; 46% have discontinued due to: progressive disease (30%), adverse events (9%), stem cell transplant (3%), withdrew consent (3%), investigator request, lost to follow-up, non-compliance (n=1, 0.25% each). The overall response rate (ORR) in all patients was 77% (Table 1). The CR/CRi (complete remission/complete remission with incomplete marrow recovery) rate was 22% and the number increased over time on venetoclax [median time to CR/CRi = 8.3 (range: 2.6 - 28.6) months] ; MRD-negativity in the marrow was achieved by 21% (44/207) of patients, including 12% (19/157) of those with del(17p). The impact of clinical response, marrow MRD negativity, and del(17p) or TP53 status on DOR and PFS is summarized in Table 2. For all four studies combined, the median DOR was 29.2 months (95% CI=25.1, 40.1) and the median PFS was 27.9 months (95% CI=24.9, 30.5). The 24-month estimate for DOR in all patients was 64.3% (95% CI=55.5, 71.8) and that for PFS was 56.9% (95% CI=50.3, 63). Patients who achieved marrow MRD negativity had the highest 24-month DOR estimate of 96.6% (95% CI= 77.9, 99.5), followed by those with CR+CRi [89.8% (95% CI=73.5, 96.3)] and those without del(17p) or TP53 mutation [74.6 (95% CI=62.3, 83.4)] . Similar trends were seen for the 24-month PFS estimates. Conclusions: Pooled data from the four studies show that venetoclax induces deep (22% CR/CRi and 21% marrow MRD negativity rates) and durable responses in patients with relapsed/refractory CLL. DOR and PFS were the most favorable in patients who achieved marrow MRD negativity and CR/CRi and those without del(17p) or TP53 mutation. Disclosures Roberts: Servier: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding. Seymour: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; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: 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; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Eichhorst:Abbvie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding. Davids:Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Honoraria, Research Funding; Infinity: Honoraria, Research Funding. Gerecitano:AbbVie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Samus: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Popovic:AbbVie Inc.: Employment, Other: may own stock. Chyla:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Verdugo:AbbVie: Employment, Other: may own stock. Potluri:AbbVie Inc.: Employment, Other: may own stock. Lash:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie Inc.: Employment, Other: may own stock. Hallek:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.

Abstract: Introduction: Venetoclax, a selective BCL2 inhibitor, is approved for treatment of chronic lymphocytic leukemia in patients who received at least one prior therapy and is being studied in several other hematological malignancies including acute myeloid leukemia (AML). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax in patients with newly diagnosed AML who are not eligible for standard anthracycline-based induction therapy treated with venetoclax plus a hypomethylating agent (HMA) either azacitidine or decitabine, or low dose cytarabine (LDAC) to inform dose selection. Methods: A population pharmacokinetic model for venetoclax was developed using data from 336 AML subjects. Post hoc pharmacokinetic parameters generated from the model were used to calculate the exposure metric, steady-state area under the plasma concentration-time curve (AUCss), in the exposure-efficacy and exposure-safety analyses. Multivariate cumulative logistic regression analyses were performed using efficacy and safety data. In total, for the venetoclax plus HMA combination, 201 subjects were included in the exposure-efficacy and 212 subjects were included in the exposure-safety analyses. For the venetoclax plus LDAC combination, 83 subjects were included in the exposure-efficacy and 92 subjects were included in the exposure-safety analyses. Predictions based on the exposure-response model parameter estimates were used to explore the exposure- and dose-response relationships and select the optimal venetoclax dose. Results: Venetoclax in Combination with HMAs: Simulations indicated that venetoclax dosage of 400 mg once daily (QD) in combination with HMAs maximizes the probability of a typical subject achieving a response of complete remission (CR).. Venetoclax exposure-response relationship was similar for both azacitidine and decitabine combination (P 〉 0.05). For exposure-safety analyses, only treatment-emergent Grade ≥ 3 infections showed a statistically significant relationship with venetoclax exposures in combination with HMAs across the tested venetoclax dose range (400 - 1200 mg QD). The probability of occurrence of treatment-emergent Grade ≥ 3 infections at venetoclax dose of 400 mg and 800 mg was 51% (95% CI: [43, 58%]) and 59% (95% CI: [50, 66%] ), respectively. Venetoclax in Combination with LDAC: A statistically significant association of best responses was determined with increasing steady-state area under the plasma concentration-time curve (AUCss). Based on the tolerability data, the probability of achieving CR with incomplete count recovery (CRi) or better, and CR was predicted for doses up to 600 mg. The predicted probability of achieving CRi or better was approximately 46% (95% CI: [37, 55%]) and 55% (95% CI: [45 - 66%] ) at exposures associated with the 400 mg and 600 mg dosage regimen given once daily, respectively. Conclusions: The venetoclax exposure- efficacy and exposure-safety analyses supported the 400 mg QD dosage regimen of venetoclax in combination with the HMAs and 600 mg QD dosage regimen of venetoclax in combination with LDAC in treatment naïve AML patients who are ineligible for standard induction chemotherapy. Disclosures Agarwal: AbbVie: Employment, Equity Ownership. Gopalakrishnan:AbbVie: Employment, Equity Ownership. Mensing:AbbVie: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Friedel:AbbVie: Employment, Equity Ownership. Menon:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership.

Abstract: Background: Myelofibrosis (MF) is a rare myeloproliferative neoplasm with limited treatment options and a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potential cure, most patients remain ineligible; other therapies, including approved JAK inhibitors (JAKi), do not control the broad array of manifestations associated with MF. Navitoclax is a potent, small molecule inhibitor of the antiapoptotic B-cell lymphoma 2 (BCL-2) family members BCL-XL, BCL-2, and BCL-w and has been shown to potently enhance cytotoxicity of chemotherapy and radiation in cells derived from multiple tumor types. Preclinical data indicate that navitoclax may overcome JAK2 inhibitor resistance. Preliminary data from a Phase 2 study (NCT03222609) of navitoclax with ruxolitinib, a JAK1/2i, for patients with primary or secondary MF who have previously received ruxolitinib suggest favorable spleen response rates and an acceptable safety profile (Harrison et al. EHA 2020. EP1081). TRANSFORM-2 aims to evaluate the combination of navitoclax and ruxolitinib vs best available therapy (BAT) in adults with relapsed or refractory MF that is resistant to JAK2 inhibition. Study Design and Methods: This Phase 3, open-label study (NCT04468984) is designed to recruit patients aged ≥18 years with intermediate-2 or high-risk MF, measurable splenomegaly, and who are experiencing MF-related symptoms. Patients must have received a single prior JAK2i for ≥24 weeks that was stopped due to lack of efficacy or for & lt;24 weeks with disease progression while on therapy. Candidates for allo-HSCT, patients who have received prior treatment with a BH3-mimetic compound or & gt;1 prior JAK2i, and patients with platelets & lt;100 × 109/L will be excluded. The study will be conducted at approximately 173 sites in 23 countries. The planned sample size is 330 patients. Patients will be randomized 1:1 to receive either navitoclax plus ruxolitinib, or BAT. Navitoclax will be administered orally at a starting dose of 200 mg (platelet count & gt;150 × 109/L) or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days (platelet count ≤150 × 109/L); navitoclax may be increased to 300 mg once daily after Week 25 Day 1 at the investigator's discretion, based on platelet count for patients with suboptimal spleen response; ruxolitinib will be administered orally at the prior stable dose if on ruxolitinib at study entry or at a dose of 10 mg twice daily if no longer on ruxolitinib. BAT options include hydroxyurea, interferon, ruxolitinib, fedratinib, or danazol, which will be administered at standard doses. Randomization stratification will be by region (US vs Japan vs EU vs rest of world), by Dynamic International Prognostic Scoring System Plus score at randomization (intermediate-2 vs high risk), and by stable ruxolitinib dosing at randomization vs not on ruxolitinib/JAK2i. Treatment can continue until the end of clinical benefit, unacceptable toxicity, or discontinuation criteria have been met; disease assessments will be performed after 12 and 24 weeks even if discontinuing therapy, after which patients will enter posttreatment follow-up (discontinuation without progression) or survival follow-up (after progression). The primary endpoint is ≥35% reduction in spleen volume from baseline (SVR35) at Week 24, measured by magnetic resonance imaging, per International Working Group criteria. Secondary endpoints include ≥50% reduction in total symptom score from baseline at Week 24, SVR35, duration of SVR35, change in fatigue from baseline, time to deterioration of physical functioning, anemia response, overall survival, leukemia-free survival, overall response, composite response, and reduction in grade of bone marrow fibrosis from baseline. Safety will be assessed via adverse event (AE) monitoring, physical examinations, vital sign measurements, electrocardiogram variables, and clinical laboratory testing. AEs will be graded per National Cancer Institute Common Terminology Criteria for AEs v5.0. Statistical analysis of the primary endpoint and binary secondary endpoints will be conducted using a stratified Cochran-Mantel-Haenszel test. Time-to-event secondary endpoints will be analyzed using a stratified log-rank test and Kaplan-Meier methodology. Hazard ratios will be estimated using stratified Cox proportional hazards model. Disclosures Dilley: AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Harb:AbbVie: Current Employment, Other: may hold stock or stock options. Jalaluddin:AbbVie: Current Employment, Other: may hold stock or stock options. Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. OffLabel Disclosure: Navitoclax is an investigational drug for the treatment of myelofibrosis

Abstract: 7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-X L and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 10 9 /L or 〉 150 × 10 9 /L, respectively. RUX was given BID with starting dose based on BL platelet count per local label. The primary endpoint was spleen volume reduction of ≥35% (SVR 35 ) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS 50 ), bone marrow (BM) fibrosis reduction, and anemia response. Adverse events (AEs) were monitored throughout the study. Results: As of Oct 04, 2021, 32 pts received NAV+RUX. Median duration of f/u was 6.1 (range, 1.9 ─ 18.6) mos. 28 (88%) pts received NAV 200 mg and 4 (13%) received 100 mg OD. Median age was 69 (44 ─ 83) yrs, and median spleen volume was 1889.08 cm 3 (645.6 ─ 7339.6). Median NAV and RUX exposures were 24.1 (5.1 ─ 80.9) and 20.1 (0.1 ─ 80.1) wks, respectively. 31 (97%) pts reported ≥1 AE (Grade ≥3 AEs, 25 [78%]; serious AEs, 6 [19%] ). Most common Grade ≥3 AEs were anemia (34%), thrombocytopenia (31%), and neutropenia (19%). 3 (9%) and 2 (6%) pts reported an AE leading to NAV and RUX discontinuation, respectively, and 2 (6%; 1 PD, 1 cardiac disorder unrelated to NAV) AEs led to death ≤30 days after last NAV dose. SVR 35 was achieved by 52% of evaluable pts at wk 24 (SVR 35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR 35 was 12.1 (11 ─ 47) wks. Conclusions: The combination of NAV+RUX was well tolerated and demonstrated early and robust reductions in spleen volume, anemia, and BM fibrosis in pts without prior JAK-2 inhibitor exposure. SVR 35, TSS 50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]

Abstract: This analysis represents the longest‐term follow‐up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine. Adults with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in an open‐label, non‐randomized, multicenter phase 1b trial of venetoclax with azacitidine (AZA; 75 mg/m 2 ; days 1‐7) or decitabine (DEC; 20 mg/m 2 ; days 1‐5). Endpoints included safety, response rates (complete remission [CR], CR with incomplete blood count recovery [CRi] ), response duration and overall survival (OS). The median follow‐up time was 29 and 40 months for patients treated with venetoclax plus AZA and DEC combinations, respectively. Key Grade ≥ 3 AEs (AZA and DEC) were febrile neutropenia (39% and 65%), anemia (30% and 26%), thrombocytopenia (25% and 23%), and neutropenia (20% and 10%). The CR/CRi rate was 71% for venetoclax plus AZA and 74% for venetoclax plus DEC. The median duration of CR/CRi was 21.9 months and 15.0 months, and the median OS was 16.4 months and 16.2 months, for venetoclax plus AZA and DEC, respectively. These results support venetoclax plus hypomethylating agents as highly effective frontline AML therapies for patients unfit for intensive chemotherapy.