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Patients with relapsed/refractory (R/R) higher-risk myelodysplastic syndromes (MDS) have a dismal median overall survival (OS) after failing hypomethylating agent (HMA) treatment. There is no standard of care for patients after HMA therapy failure; hence, there is a critical need for effective therapeutic strategies. Herein, we present the safety and efficacy of venetoclax + azacitidine in patients with R/R MDS. This phase 1b, open-label, multicenter study enrolled patients ≥18 years. Patients were treated with escalating doses of oral venetoclax: 100, 200, or 400 mg daily for 14 days every 28-day cycle. Azacitidine was administered on Days 1-7 every cycle at 75 mg/m

Supplementary Table S1. Overall activity and predictors of treatment failure (PD or less than partial response by IWG criteria). Supplementary Figure S1. BCL-2 family protein index at screening. Supplementary Figure S2. Mean (+ SD) venetoclax plasma concentration-time profile at week 6 day 1 (800 mg). Supplementary Figure S3. Study design.

Supplementary Table from Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine

Supplementary Figure from Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine

Primary analyses of cohort 1a of the REFINE trial showed that addition of navitoclax to ruxolitinib induced a 35% or greater reduction in spleen volume (SVRREFINE is a phase 2, multicentre, open-label trial designed to assess the activity and safety of navitoclax alone or in combination with ruxolitinib in patients with primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Cohort 1a of the study included patients who had disease progression or suboptimal response on stable ruxolitinib monotherapy. Patients in cohort 1a, who had previously received ruxolitinib for 12 weeks or more, continued their current stable dose, and navitoclax was orally administered at 50 mg per day and escalated weekly to a maximum of 300 mg per day, based on tolerability. The primary activity endpoint was SVRBetween Nov 14, 2017, and April 10, 2019, 34 patients in cohort 1a received at least one dose of navitoclax plus ruxolitinib. 23 (68%) patients were male, with 32 (94%) being White. At data cutoff (May 6, 2021), the median follow-up for survivors was 26·2 months (IQR 21·9-32·3). 33 patients were evaluable for biomarker analyses; 19 (58%) had high molecular risk mutations. Five (31%) of 16 patients had SVRThese biomarker analyses reveal clinically meaningful splenic responses independent of high molecular risk mutation status in patients treated with navitoclax plus ruxolitinib who were not benefiting from ruxolitinib monotherapy. Furthermore, the overall survival benefit observed in those with an improvement in fibrosis or a reduction in variant allele frequency is suggestive of disease modification, implying the therapeutic potential of adding navitoclax to ruxolitinib for patients with myelofibrosis who had disease progression or suboptimal response to ruxolitinib monotherapy.AbbVie.

PURPOSE Targeting the BCL-XL pathway has demonstrated the ability to overcome Janus kinase inhibitor resistance in preclinical models. This phase II trial investigated the efficacy and safety of adding BCL-XL/BCL-2 inhibitor navitoclax to ruxolitinib therapy in patients with myelofibrosis with progression or suboptimal response to ruxolitinib monotherapy (ClinicalTrials.gov identifier: NCT03222609 ). METHODS Thirty-four adult patients with intermediate-/high-risk myelofibrosis who had progression or suboptimal response on stable ruxolitinib dose (≥ 10 mg twice daily) were administered navitoclax at 50 mg once daily starting dose, followed by escalation to a maximum of 300 mg once daily in once in weekly increments (if platelets were ≥ 75 × 109/L). The primary end point was ≥ 35% spleen volume reduction (SVR35) from baseline at week 24. Secondary end points included ≥ 50% reduction in total symptom score (TSS50) from baseline at week 24, hemoglobin improvement, change in bone marrow fibrosis (BMF) grade, and safety. RESULTS High molecular risk mutations were identified in 58% of patients, and 52% harbored ≥ 3 mutations. SVR35 was achieved by 26.5% of patients at week 24, and by 41%, at any time on study, with an estimated median duration of SVR35 of 13.8 months. TSS50 was achieved by 30% (6 of 20) of patients at week 24, and BMF improved by 1-2 grades in 33% (11 of 33) of evaluable patients. Anemia response was achieved by 64% (7 of 11), including one patient with baseline transfusion dependence. Median overall survival was not reached with a median follow-up of 21.6 months. The most common adverse event was reversible thrombocytopenia without clinically significant bleeding (88%). CONCLUSION The addition of navitoclax to ruxolitinib in patients with persistent or progressive myelofibrosis resulted in durable SVR35, improved TSS, hemoglobin response, and BMF. Further investigation is underway to qualify the potential for disease modification.

Supplementary Table from Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia

Purpose: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion [del(17p)] or progressive disease following B-cell receptor pathway inhibitors.Patients and Methods: We conducted a comprehensive analysis of the safety of 400 mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase I/II studies.Results: Median age was 66 years and 60% had del(17p). Patients had received a median of three prior therapies (range: 0–15); 42% previously received ibrutinib or idelalisib. Median duration of exposure to venetoclax was 16 months (0–56). In the pooled analysis, the most common adverse events (AE) of any grade were diarrhea (41%), neutropenia (40%), nausea (39%), anemia (31%), fatigue (28%), and upper respiratory tract infection (25%). The most common grade 3/4 AEs were neutropenia (37%), anemia (17%), and thrombocytopenia (14%). With the current 5-week ramp-up dosing, the incidence of laboratory TLS was 1.4% (2/166), none had clinical sequelae, and all of these patients were able to ramp-up to a daily dose of 400 mg. Grade 3/4 neutropenia was manageable with growth factor support and dose adjustments; the incidence of serious infections in these patients was 15%. Ten percent of patients discontinued venetoclax due to AEs and 8% died while on study, with the majority of deaths in the setting of disease progression.Conclusions: Venetoclax as a long-term continuous therapy is generally well tolerated in patients with R/R CLL when initiated with the current treatment algorithm. Clin Cancer Res; 24(18); 4371–9. ©2018 AACR.

Supplementary Data from Impact of FLT3 Mutation on Outcomes after Venetoclax and Azacitidine for Patients with Treatment-Naïve Acute Myeloid Leukemia

Purpose:To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML).Patients and Methods:Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle).Results:In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group.Conclusions:Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut.See related commentary by Perl and Vyas, p. 2719

Supplementary Data

PURPOSE There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10–3 in the VIALE-A trial. METHODS The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10–3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS. RESULTS One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10–3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10–3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10–3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10–3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10–3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001). CONCLUSION Patients who achieved CRc and MRD < 10–3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10–3.

This study evaluated venetoclax population pharmacokinetics (popPK) in patients with treatment-naïve acute myeloid leukemia and assessed the relationship between venetoclax exposure and clinical response for venetoclax in combination with either a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). A total of 771 patients who received venetoclax from 5 Phase 1-3 studies were included in the popPK model. Exposure-response analyses included data from 575 patients for venetoclax/placebo plus HMA and 279 patients for venetoclax/placebo plus LDAC. The popPK model successfully characterized venetoclax plasma concentrations over time and confirmed venetoclax exposure did not vary significantly with age, weight, sex, mild to moderate hepatic impairment, or mild to severe renal impairment. Asian patients had 67% higher mean relative bioavailability than non-Asian patients, however the range of exposures in Asian patients was similar to non-Asian patients. For all efficacy endpoints with both treatment combinations, efficacy was higher in the venetoclax treatment groups compared with the respective control arm of placebo plus azacitidine or LDAC. Within patients who received venetoclax, no significant exposure-efficacy relationships were identified for either treatment combination, indicating that the beneficial effects of venetoclax were already maximized in the dose ranges studied. There was no apparent effect of venetoclax exposure on treatment-emergent Grade ≥3 thrombocytopenia or infections for either combination. Rates of treatment-emergent Grade ≥3 neutropenia were higher in the venetoclax treatment arms compared with the respective control arms; however, within patients who received venetoclax, there was only a shallow relationship or no apparent relationship with venetoclax exposure for venetoclax plus HMA or LDAC, respectively. Along with the efficacy and safety data previously published, the exposure-response analyses support the venetoclax dose regimens of 400 mg once daily (QD) plus HMA and 600 mg QD plus LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with FLT3-mutant acute myeloid leukemia. Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). FLT3 mutation was analyzed centrally on pretreatment bone marrow aspirates. Results: In the biomarker evaluable population, FLT3 mutation was detected in 42 (15%) and 22 (19%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc; complete remission (CR) + CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) for FLT3-mutant patients were 67%/36%, median duration of remission (DoR) was 17.3/5.0 months, and median OS was 12.5/8.6 months. The CRc rates among FLT3 wild-type patients were 67%/25%, median DoR 18.4/13.4 months, and median OS 14.7/10.1 months. In patients treated with venetoclax + azacitidine, CRc in patients with FLT3-ITD and FLT3-TKD was 63% and 77% and median OS was 9.9 and 19.2 months, and in comutated FLT3-ITD + NPM1 patients, CRc was 70%, median DoR was not reached, and median OS was 9.1 months. There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: When treated with venetoclax + azacitidine, patients with FLT3 mutations and FLT3 wild-type had similar outcomes. Future analyses in larger patient populations may further define the impact of venetoclax + azacitidine in patients harboring FLT3-ITD. See related commentary by Perl and Vyas, p. 2719

Background: Venetoclax (ven) in combination with hypomethylating agents or low dose cytarabine leads to rapid and durable remission in patients (pts) with acute myeloid leukemia (AML) unfit for intensive chemotherapy (IC), however, pts with TP53 mutations (TP53mut) exhibit adverse prognosis. Here, we identify dysregulation of the integrated stress response (ISR) pathway in pts with TP53mut, specifically through the actions of DAP3 binding cell death enhancer 1 (DELE1) and its activating protease OMA1. Methods: RNA sequencing was performed on pre-treatment bone marrow-derived mononuclear cells (BMMCs) from pts with AML ineligible for IC across four clinical trials (NCT02993523, NCT02203773, NCT03069352, and NCT02287233). CRISPR-Cas9 editing of TP53-intact AML cell lines was used to generate TP53-/-, TP53mut, DELE1-/-, OMA1-/- and TP53/DELE1 double deficient cell lines. Quantification of BCL2 and Myeloid cell leukemia 1 (MCL1) complexes with BCL2 interacting mediator (BIM) was performed using chemiluminescence assays. A drug screen to assess viability and gene expression was performed in cells treated with ven in combination with 63 drugs. Results: In total 401 pts were included in the analyses, of which 17% harbored TP53mut and 83% were TP53wt. Analysis of genes differentially expressed (DE) between pts with TP53mut and TP53wt AML revealed 19 DE genes shared across all trials. DELE1, an ISR adaptor, was associated with genes mapping to the ISR-related eukaryotic initiation factor-α (eIF2α) in TP53mut AML BMMCs. Deletion of DELE1 or OMA1 in AML cell lines blocked eIF2α activation and induction of the transcription factor ATF4, a critical ISR effector, in response to the mitochondrial stressor FCCP, ven, and azacitidine, and resulted in ven resistance similar to that of TP53 deficient cells. All modified AML cell lines exhibited a concomitant decrease in the pro-apoptotic regulator PMAIP1, encoding NOXA, and a 14-18-fold increase in MCL1-BIM complexes following ven treatment, as well as increased MCL1 expression, compared to parental lines. Further screening of these cell lines for ven sensitizing activity revealed the BH3 mimetic S63845, which targets MCL1, as the top hit, suggesting that combined BH3 mimetics may overcome ven resistance during ISR pathway defects. As DELE1 is located on chromosome 5 (CH); the frequent loss of CH 5q among TP53mut AML may contribute to low DELE1 expression. Conclusions: These data suggest that defective ISR signaling may be a factor in TP53mut AML treatment outcome and point to DELE1 dysregulation as a driver of ISR inactivation in pts with TP53mut AML. The ISR induces the expression of NOXA, which displaces MCL1 from BIM and lowers the apoptotic threshold. Our data identify p53, DELE1, and OMA1 as regulators of NOXA expression post ven treatment and indicate that co-targeting MCL1 in pts with TP53mut AML may be beneficial to overcome ven resistance. Citation Format: David Sharon, Paul Jung, Yan Sun, Weiguo Feng, Ziping Yang, Valerie Robinson, Diya Mitra, Wei Liu, Pingping Zheng, Tamar Uziel, Lloyd Lam, Mark D. Minden, Jeremy Ross, Wellington Mendes, Jalaja Potluri, Andrew H. Wei, Marina Konopleva, Monique Dail, Brenda Chyla, PK Epling-Burnette. DELE1 loss and dysfunctional integrated stress signaling in TP53 mutated AML is a novel pathway for venetoclax resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2530.

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt. Patients and Methods: We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1–28) + azacitidine (75 mg/m2 days 1–7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally. Results: Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18). For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt. For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively. For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients. Conclusions: In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235

Purpose: To evaluate efficacy and safety of venetoclax + azacitidine among treatment-naïve patients with IDH1/2-mutant (mut) acute myeloid leukemia (AML). Patients and Methods: Data were pooled from patients enrolled in a phase III study (NCT02993523) that compared patients treated with venetoclax + azacitidine or placebo + azacitidine and a prior phase Ib study (NCT02203773) where patients were treated with venetoclax + azacitidine. Enrolled patients were ineligible for intensive therapy due to age ≥75 years and/or comorbidities. Patients on venetoclax + azacitidine received venetoclax 400 mg orally (days 1–28) and azacitidine (75 mg/m2; days 1–7/28-day cycle). Results: In the biomarker-evaluable population, IDH1/2mut was detected in 81 (26%) and 28 (22%) patients in the venetoclax + azacitidine and azacitidine groups. Composite complete remission [CRc, complete remission (CR)+CR with incomplete hematologic recovery (CRi)] rates (venetoclax + azacitidine/azacitidine) among patients with IDH1/2mut were 79%/11%, median duration of remission (mDoR) was 29.5/9.5 months, and median overall survival (mOS) was 24.5/6.2 months. CRc rates among patients with IDH1/2 wild-type (WT) were 63%/31%, mDoR 17.5/10.3 months, and mOS 12.3/10.1 months. In patients with IDH1mut, CRc rates (venetoclax + azacitidine/azacitidine) were 66.7%/9.1% and mOS 15.2/2.2 months. In patients with IDH2mut, CRc rates were 86.0%/11.1% and mOS not reached (NR)/13.0 months. Patients with IDH1/2 WT AML treated with venetoclax + azacitidine with poor-risk cytogenetics had inferior outcomes compared with patients with IDH1/2mut, who had superior outcomes regardless of cytogenetic risk (mOS, IDH1/2mut: intermediate-risk, 24.5 months; poor-risk, NR; IDH1/2 WT: intermediate, 19.2 and poor, 7.4 months). There were no unexpected toxicities in the venetoclax + azacitidine group. Conclusions: Patients with IDH1/2mut who received venetoclax + azacitidine had high response rates, durable remissions, and significant OS; cytogenetic risk did not mitigate the favorable outcomes seen from this regimen for IDH1/2mut. See related commentary by Perl and Vyas, p. 2719

Background The phase 3 VIALE-A trial (NCT02993523) reported that venetoclax-azacitidine significantly prolonged overall survival compared with placebo-azacitidine in patients with newly diagnosed acute myeloid leukemia ineligible for intensive chemotherapy. Herein, efficacy and safety of venetoclax-azacitidine are analyzed in the Japanese subgroup of VIALE-A patients. Methods Eligible Japanese patients were randomized 2:1 to venetoclax-azacitidine (N = 24) or placebo-azacitidine (N = 13). Primary endpoints for Japan were overall survival and complete response (CR) + CR with incomplete hematologic recovery (CRi). Venetoclax (target dose 400 mg) was given orally once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously on Days 1–7 of each 28-day cycle. Results Median follow-up was 16.3 months (range, 1.0–20.3). Median overall survival was not reached with venetoclax-azacitidine (hazard ratio 0.409 and 95% confidence interval: 0.151, 1.109); overall survival estimate was higher with venetoclax-azacitidine than placebo-azacitidine at 12 (67 and 46%) and 18 months (57 and 31%), respectively. CR and CRi rates were 67% with venetoclax-azacitidine and 15% with placebo-azacitidine. Most common any-grade adverse events were febrile neutropenia (79 and 39%), thrombocytopenia (54 and 77%), constipation (54 and 54%) and decreased appetite (54 and 38%) in the venetoclax-azacitidine and placebo-azacitidine arms, respectively. Only 1 patient in the venetoclax-azacitidine arm, and no patients in the placebo-azacitidine arm, had grade 4 febrile neutropenia that led to treatment discontinuation. Conclusions This Japanese subgroup analysis of VIALE-A demonstrates comparable safety and efficacy outcomes compared with the global study and supports venetoclax-azacitidine as first-line standard-of-care for Japanese treatment-naive patients with acute myeloid leukemia who are ineligible for intensive chemotherapy.

Background : For patients (pts) with acute myeloid leukemia (AML), preserving and measuring perceptions of health-related quality of life (HRQoL) is important, particularly for those ineligible for intensive chemotherapy and with a poor prognosis, especially when evaluating new treatment regimens. This analysis from 2 Phase 3 trials, Viale-A (NCT02993523) and Viale-C (NCT03069352), evaluated HRQoL, including key symptoms and aspects of functioning, in pts with AML receiving venetoclax (VEN) co-administered with azacitidine (AZA) (Viale-A) or low-dose cytarabine (LDAC) (Viale-C). Methods: Viale-A and Viale-C included treatment-naïve pts with AML, ≥18 years of age, and ineligible to receive intensive chemotherapy. Pts were randomized 2:1 to receive VEN +AZA or placebo (PBO)+AZA in Viale-A, and VEN+ LDAC or PBO+LDAC in Viale-C. Pt-reported outcome (PRO) measures included the PROMIS Cancer Fatigue Short Form 7a, the EORTC QLQ-C30 global health status (GHS)/QoL and physical functioning [PF] subscales, and the EQ-5D-5L health status visual analog scale (VAS). PRO data were collected on Day 1 of every 28-day cycle throughout both trials. Time to deterioration (TTD) was assessed to quantify differences between treatment groups. TTD was defined as worsening from baseline in PRO-specific meaningful change thresholds of ≥10, 7, or 5 points for the EORTC-QLQ-C30, EQ-5D-5L VAS, and PROMIS Fatigue, respectively. TTD differences between treatment arms were analyzed using Kaplan-Meier curves, unadjusted log-rank tests, and Cox PH models adjusted for key covariates (age, baseline ECOG and PRO scores, AML type, and cytogenetic risk category). TTD analyses were conducted for all pts in the full dataset who survived up to a given assessment with available data on ≥1 PRO measures from baseline. Results: Viale-A included 431 pts (VEN+AZA: 286, PBO+AZA: 145), of whom 60% were male; median age was 76 years. Compared with PBO+AZA pts, VEN+AZA pts had a non-statistically significant trend to longer TTD in GHS/QoL (median in months [95% CI]: 16.5 [95% CI: 9.8, NE] vs. 9.3 [95% CI: 4.7, 16.6], P=0.066) and fatigue (9.3 [7.2, 16.6] vs. 8.6 [4.2, 16.6], P=0.189) (Figure 1A, B). VEN+AZA pts had significantly longer TTD in PF (9.7 [6.7, 16.0] vs. 6.2 [4.7, 9.5], P=0.028) and health status VAS (10.7 [7.5, 18.6] vs. 3.9 [2.4, 7.4], P Conclusions: Results showed a longer TTD in PRO measures of global health status, VAS, fatigue, and PF for pts receiving VEN combinations vs AZA or LDAC monotherapy, with significantly longer TTD observed for all PRO measures from the unadjusted and adjusted analyses in Viale-C, and for PF and health VAS in Viale-A. These results suggest that VEN conveys meaningful benefit in terms of HRQoL. Limitations included the small sample size beyond early cycles in these studies; however, the early separation of the TTD curves with the initial larger sample size, suggests that these results are not due to chance variability and are statistically valid. Overall the improvements in PROs with VEN are consistent with previous efficacy reports. In summary, VEN appears to have a positive impact on the HRQoL of pts with AML who are ineligible for intensive chemotherapy, leading to a longer preservation of functioning and overall health status. Disclosures Pratz: Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy. Panayiotidis:AbbVie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Genesis: Honoraria, Research Funding; Takeda: Honoraria; Phizer: Honoraria; ASH: Honoraria; Janssen: Honoraria; Gilead: Honoraria. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Daiichi Sankyo: Research Funding; Genentech/Roche: Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; LP Therapeutics: Research Funding; Forma: Research Funding; Pharmacyclics: Research Funding; Pfizer: Research Funding; Jazz: Consultancy, Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Hanmi: Research Funding; Takeda: Consultancy. Dinardo:Takeda: Honoraria; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Novak:Janssen: Other: Travel expenses; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy; Amgen: Consultancy, Other: Travel expenses; Takeda: Consultancy. Pejsa:Oktal Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alvogen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pliva: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stevens:Amgen, MorphoSys: Consultancy. Yeh:Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Kim:AbbVie: Other: Clinical trials investigator. Fracchiolla:Amgen: Honoraria, 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; Pfizer: Honoraria, 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; Gilead: Honoraria, 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; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Yamamoto:Takeda: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Zenyaku: Research Funding; SymBio: Research Funding; Solasia Pharma: Research Funding; Aichi Cancer Center: Current Employment; AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Bayer: Research Funding; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy; IQIVA/HUYA: Honoraria; HUYA: Consultancy; IQIVA/Incyte: Research Funding; Gilead Sciences: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Mochida: Honoraria; MSD: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Sanofi: Honoraria; Sumitomo Dainippon: Honoraria; Stemline Therapeutics: Consultancy. Ofran:AbbVie: Membership on an entity's Board of Directors or advisory committees. Wei:Astra Zeneca: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties: AW is eligible for royalty payments related to venetoclax; Novartis: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Macrogenics: Honoraria; Roche: Honoraria; Servier: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Janssen: Honoraria; Abbvie: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau. Bui:AbbVie: Current Employment, Current equity holder in publicly-traded company. Benjamin:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Mendes:AbbVie: Current Employment, Current equity holder in publicly-traded company. Devine:Genentech: Current Employment, Current equity holder in publicly-traded company. Fiedler:Daiichi Sankyo: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; Jazz Pharmaceuticals: Honoraria, Other: support for meeting attendance; Abbvie: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; ARIAD/Incyte: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: support for meeting attendance, Patents & Royalties, Research Funding.

Background: In the Phase 3 randomized, placebo-controlled VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival (OS) and complete response (CR) rates vs Aza + placebo (Pbo; DiNardo et al. N Engl J Med. 2020. In Press). Neutropenia and related infections are common in acute myeloid leukemia (AML) and exacerbated by Ven combinations. Antimicrobial prophylaxis is used variably in patients (pts) with AML receiving low-intensity therapies. Ven dose modifications are required for concomitant use of commonly used antimicrobials that are strong or moderate cytochrome P450 3A inhibitors (CYP3Ai). A previous report's findings showed that Ven dose reductions with CYP3Ai do not affect Ven exposure (Wei et al. Blood. 2020;135:2137). This analysis evaluated the use of prophylactic anti-infective CYP3Ai and these agents' effects on infections and efficacy outcomes in the VIALE-A study (NCT02993523). Methods: Pts with newly diagnosed AML, aged ≥75 y or 18-75 yand ineligible for induction therapy were enrolled. Pts were randomized 2:1 to receive Ven (daily, orally) + Aza (75 mg/m2 d 1-7, subcutaneously/intravenously) or Pbo + Aza in 28-d cycles. Anti-infective prophylaxis was required for pts with absolute neutrophil count Results: In total, 286 pts were randomized to Ven + Aza and 145 to Pbo + Aza. Within the first 2 cycles of therapy, concomitant anti-infective prophylaxis agents considered moderate CYP3Ai were received by 41/286 pts (14%) in the Ven + Aza arm and 18/145 (12%) in the Pbo + Aza arm. Concomitant anti-infective prophylaxis agents considered strong CYP3Ai were received in the first 2 cycles by 22/286 pts (8%) treated with Ven + Aza and 13/145 pts (9%) treated with Pbo + Aza. The median duration of each prophylactic CYP3Ai agent use was 12.5 d (range, 1-614) in the Ven + Aza arm and 15 d (range, 1-731) in the Pbo + Aza arm. The rates of CR+CR with incomplete marrow recovery (CRi) as a best response during the study were similar with concomitant use of moderate (61%; CR, 24%; CRi, 37%) or strong (64%; CR, 27%; CRi, 36%) CYP3Ai with adjusted-dose Ven vs no use of CYP3Ai (67%; CR, 39%; CRi, 27%; Table 1). The relatively lower CR and higher CRi rates appear to be due to delay in recovery of peripheral blood counts in pts who received strong CYP3Ai during the first 2 cycles (Table 2). The median time to first CR+CRi was 1.2 mo (range, 0.6-9.9), 1.4 mo (range 1.0-5.5), and 1.4 mo (range, 0.9-5.4) in those receiving no, moderate, and strong CYP3Ai agents, respectively, in the Ven + Aza arm. Median OS was not statistically different regardless of use of moderate or strong CYP3Ai in both arms, as noted by overlapping CIs (Table 1). The 24-month estimated OS was 26.2% (95% CI, 8.1-48.9) for pts receiving strong CYP3Ai vs 37.9% (95% CI, 30.2-45.6) for those receiving no CYP3Ai. Rates of any-grade or Grade 3/4 infections within the first 2 cycles varied between those with or without use of moderate CYP3Ai reported as being given as prophylaxis in both treatment arms (Table 1). Rates of invasive fungal infections were 3%, 12%, and 9% with Ven + Aza and 0%, 0%, and 15% with Pbo + Aza in pts receiving no, moderate, and strong CYP3Ai agents, respectively. Rates of discontinuation from infections were similar in both arms regardless of CYP3Ai use. Conclusions:Antimicrobial prophylaxis with moderate or strong CYP3Ai was used in neutropenic pts in the VIALE-A study, with overall similar composite remission rates with Ven dose reductions. The use of CYP3Ai did not increase rates of discontinuation from infections. Analysis of differences in baseline characteristics, rates of infections, and efficacy outcomes for pts who began anti-infective prophylaxis at the initiation of therapy is ongoing. Disclosures Jonas: Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Genentech/Roche: Research Funding; Sigma Tau: Research Funding; Hanmi: Research Funding; Pfizer: Research Funding; LP Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding. Dinardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Calithera: Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Fracchiolla:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria, 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; Pfizer: Honoraria, 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; Amgen: Honoraria, 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. Pristupa:Beigene: Honoraria, Research Funding; State Institution of Health of the Ryazan Regional Clinical Hospital: Current Employment; Pfizer: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; Daiichi Sankyo: Honoraria, Research Funding; Paraxel: Honoraria, Research Funding; Acerta: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Geron: Honoraria, Research Funding. Ishizawa:Takeda: Honoraria; Ono: Honoraria; Chugai: Honoraria; Eizai: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; SymBio: Research Funding; Bayer: Research Funding; AbbVie: Research Funding. Jin:The First Affiliated Hospital of Zhejiang University: Current Employment. Konopleva:Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Calithera: Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy; Ascentage: Research Funding; 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; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding. Ofran:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Rambam Health Care: Current Employment; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy. Kovacsovics:Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria; Astella: Honoraria; Agios: Honoraria. Kantarjian:Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Jazz: Research Funding; Abbvie: Honoraria, Research Funding; Sanofi: Research Funding; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; Ascentage: Research Funding. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Pratz:Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Celgene: Other: Scientific Advisory Board; Boston BioMedical: Consultancy; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding.

Introduction The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in ~20% of patients (pts) with AML ≥70 years (Schneider et al, 2012). Both FLT3-ITD and FLT3-TKD mutations (mut) are associated with AML proliferation and potentially targetable with small molecule inhibitors. The presence of a FLT3mut, particularly FLT3-ITD, often correlates with high leukemic burden and risk of relapse despite high response rates (Gale et. al, 2008). There is limited evidence of the effect of currently available therapies on treatment-naïve AML pts unfit for intensive treatment with FLT3mut. We evaluated the efficacy and safety of venetoclax (Ven) and Azacitidine (Aza) combination among treatment-naïve AML pts with co-morbidities and/or age ≥ 75 years, unfit for intensive treatment, and with FLT3mut. Methods Data were pooled from pts enrolled in a phase 3 study (NCT02993523, data cut-off: 04Jan2020) that compared pts treated with Ven+Aza or placebo (Pbo)+Aza, and a prior phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per the modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for FLT3; [Leukostrate FLT3 CDx for phase 3 study or MyAML panel (Invivoscribe) for Phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were not included in the analyses. Results In this pooled analysis, FLT3mut was detected in 40 pts treated with Ven+Aza and 22 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), the median age was 75 (range: 49-91)/75 (65-85) years. Cytogenetic risks were: intermediate: 88%/96% and poor: 13%/5%, Eastern Co-operative Oncology Group performance scores were: 0-1: 40%/50% and 2-3: 60%/50%. 78%/86% had de novo AML, while 23%/14% had secondary AML. FLT3-ITD was detected in 28/13 and FLT3-TKD in 13/10 pts, respectively. FLT3-ITD allelic ratios were: Complete response (CR)+CR with partial hematologic recovery (CRh) rates in FLT3mut pts (Ven+Aza/Pbo+Aza) were 65% (95% CI:48%-79%)/18% (5%-40%) (Table) with a median duration of response (mDoR) 18.3 [95% CI: 10.1- not reached (NR)]/15.1 (13.9-NR) mos. Median time to first CR/CRh response was 1.0/3.2 months (mos). 43%/0% achieved CR+CRh by initiation of cycle (C) 2. Median overall survival (mOS) was 13.3 (95% CI: 8.4-23.5)/8.6 (5.9-14.7) mos, respectively. Among pts with FLT3-ITD, CR+CRh rates (Ven+Aza/Pbo+Aza) were 61% (95% CI: 41%-79%)/23% (5%-54%) with mDoR 17.4 (95% CI: 3.7-NR)/14.5 (13.9-15.1) mos. The median time to first CR/CRh response was 1.0/3.5 mos and 39%/0% pts achieved CR+CRh by initiation of C2. The mOS was 11.5 (95% CI: 6.4-23.5)/8.5 (6.1-20.3) mos, respectively. CR+CRh rates in pts with FLT3-TKD were 69% (95% CI: 39%-91%)/20% (3%-56%) with mDoR 18.3 (95% CI: 3.0-NR)/NR (15.1-NR) mos. The median time to first CR/CRh response was 1.0/2.7 mos and 46%/0% achieved a response by initiation of C2. The mOS was 19.2 (95% CI:1.8-NR/10.0 (0.2-14.7) mos, respectively. In pts treated with Ven+Aza, CR+CRh rates among pts with FLT3 detected/FLT3 not detected were 65% (95% CI: 48%-79%)/63% (56%-69%) with mDoR 18.3 (95% CI: 10.1-NE)/18.1 (15.3-NR) mos. The mOS was 13.3 (95%CI: 8.4-23.5)/14.1 (10.6-18.7) mos, respectively (Figure). Among pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) in pts with FLT3 detected/FLT3 not detected was 67%/77%, and included anemia (33%/25%), neutropenia (36%/33%), thrombocytopenia (39%/36%), and febrile neutropenia (36%/43%). Grade 3/4 hematologic AEs among pts with FLT3-ITD/FLT3-TKD treated with Ven+Aza was 67%/69%. Conclusion Ven+Aza compared to Aza monotherapy resulted in significantly higher CR+CRh rates among treatment-naïve pts with FLT3mut ineligible for intensive chemotherapy. In this unselected AML population, insufficient pt numbers in various subgroups limit the ability to draw conclusions regarding DoR and mOS for FLT3-ITD and TKD subgroups. There were no unexpected toxicities in the Ven+Aza arm. Future studies with larger sample sizes are warranted. Disclosures Konopleva: Ascentage: Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Kisoji: Consultancy; Agios: Research Funding; Calithera: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; 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; AstraZeneca: Research Funding; AbbVie: Consultancy, Research Funding; Sanofi: Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Ablynx: Research Funding. Thirman:AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Research Funding; TG Therapeutics: Research Funding; Tolero: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Gilead Sciences: Research Funding. Pratz:Millennium: Research Funding; Celgene: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Agios: Other: Scientific Advisory Board, Research Funding; Daiichi Sankyo: Research Funding; Jazz Pharmaceutical: Consultancy. Letai:Flash Therapeutics: Membership on an entity's Board of Directors or advisory committees; Dialectic: Membership on an entity's Board of Directors or advisory committees; Chugai: Other: Lecture Fees; Novartis: Research Funding; AbbVie: Consultancy; Zentalis: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy. Pullarkat:AbbVie, Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dova: Consultancy, Honoraria; Genetech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kantarjian:Immunogen: Research Funding; Janssen: Honoraria; Sanofi: Research Funding; BioAscend: Honoraria; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aptitute Health: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Delta Fly: Honoraria; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; Jazz: Research Funding. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Miller:AbbVie: Current Employment, Current equity holder in publicly-traded company. Dinardo:Takeda: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Celgene: Research Funding; Agios: Consultancy, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria. Wei:AbbVie: Honoraria, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria; Amgen: Honoraria, Research Funding; Walter and Eliza Hall Institute of Medical Research: Patents & Royalties; Genetech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction Isocitrate dehydrogenase (IDH) mutations occur in ~20% of acute myeloid leukemia (AML) patients (pts) and are frequently identified in older pts. Pre-clinical data showed that cells with IDH1/2 mutation (mut) were susceptible to Venetoclax (Ven) therapy (Chan et.al., 2015). Clinical studies have demonstrated that pts with IDH1/2mut treated with Ven and azacitidine (Aza) achieved high response rates that were durable, and had longer median overall survival (mOS) (DiNardo et. al., 2020; DiNardo et. al., 2019). Herein, we further evaluated the efficacy and safety of Ven+Aza among treatment-naïve AML pts with IDH1/2 mut unfit for intensive treatment either due to comorbidities and/or age ≥ 75 yrs. Methods Data were pooled from pts enrolled in an ongoing phase 3 study (NCT02993523, data cut-off: 04Jan2020) comparing pts treated with Ven+Aza or placebo (Pbo)+Aza, and a phase 1b study (NCT02203773, data cut-off: 19Jun2019) where pts were treated with Ven+Aza. Pts on Ven+Aza received Ven 400 mg daily orally (days 1-28) and Aza (75 mg/m2; days 1-7/28-day cycle). Disease assessments were performed per modified International Working Group response criteria for AML. DNA was isolated from bone marrow aspirates collected from pts prior to the first dose of study drug and analyzed centrally. Pts with positive test results for IDH1 and 2 [RealTime IDH1 or IDH2 assay (Abbott) for phase 3 study, MyAML panel (Invivoscribe) for phase 1b study] were counted as mutation "detected"; pts with a negative test result were counted as mutation "not detected." Pts without a result either due to an inconclusive test or missing specimen were excluded from the analyses. Results IDH1/2 mut was detected in 79 pts treated with Ven+Aza and 28 pts treated with Pbo+Aza. At baseline (Ven+Aza/Pbo+Aza), median age was 76 (range: 64-90)/78 (62-90) yrs. Cytogenetic risks were intermediate: 79%/68%, and poor:21%/32%. ECOG scores were: 0-1: 56%/68% and 2-3: 44%/32%. 73%/86% had de novo AML, and 27%/14% had secondary AML. IDH1 was detected in 32/11, IDH2 in 49/18, IDH2R140 in 36/15, and IDH2R172 were detected in 13/3 pts, respectively. The median number of treatment cycles received (Ven+Aza/Pbo+Aza) by IDH1/2 pts was 8 (range: 1-37)/2.5 (1-18). Complete response (CR)+CR with partial hematologic recovery (CRh) in Ven+Aza/Pbo+Aza were 72% (95% CI: 61%-82%)/7% (1%-24%) (Table). Median time to first CR/CRh response was 1.0/2.6 months (mos), and 51%/0% achieved CR+CRh by initiation of cycle (C) 2. Median duration of response (mDoR) was 29.5 [95% CI: 16.7-not reached(NR)]/15.5 (NR-NR) mos and mOS was 24.5 [15.2- NR/6.2 (2.3-12.7) mos. The separation of 95% CIs for mOS indicate superior treatment effect of Ven+Aza (Figure). In pts with IDH1, CR+CRh (Ven+Aza/Pbo+Aza) was 59%/9%. Median time to first CR/CRh response was 2.3/3.1 mos, and 25%/0% achieved CR+CRh by initiation of C2. Median DoR and OS were 21.9 (7.8-29.5)/NR and 17.5 (6.3-32.7)/2.2(1.1-5.6) mos. In pts with IDH2, CR+CRh rates were 80%/6%. Median time to first CR/CRh response was 1.0/2.1 mos and 67%/0% achieved CR+CRh by initiation of C2. Median DoR was NR (16.7-NR)/15.5 (NR-NR), and mOS was NR (17.6-NR)/13.0 (95% CI: 3.8-15.8) mos. In pts with IDH2R140, CR+CRh were 75%/7%. Median time to first CR/CRh response was 1.0/2.1 mos, and 58%/0% achieved CR+CRh by initiation of C2. Median DoR and mOS were NR (17.8-NR)/15.5 (NR-NR) and NR (15.0-NR)/12.7 (1.7-15.8) mos, respectively. Response rates in pts with IDH2R172 were 92%/0%. Median time to first CR/CRh response was 1.0/NR mos, and 92%/0% achieved response by initiation of C2. Median DoR and mOS were 16.7 (7.5-NR)/3.5 (NR-NR) and NR (12.2-NR)/13.7 (10.6-NR) mos. IDH1/2 mut pts achieved higher CR+CRh rates with Ven+Aza treatment as compared to pts with IDH not detected (72%/60%). Median DoR and mOS were 29.5 (16.7-NR)/17.5 (10.6-23.5) and 24.5 (15.2-NR)/12.3 (9.7-14.8) mos, respectively. In pts treated with Ven+Aza, grade 3/4 hematologic adverse events (AEs) among pts with IDH1/2 detected/IDH not detected were similar (81%/74%) and included grade 3/4 thrombocytopenia (46%/34%), febrile neutropenia (43%/41%), neutropenia (35%/33%) and anemia (29%/24%). Conclusion Ven+Aza compared to Aza monotherapy resulted in higher response rates, longer DoR, and mOS among treatment-naïve pts with IDH1/2mut ineligible for intensive chemotherapy. The safety profile was acceptable. No unexpected toxicities were noted with Ven+Aza combination. Disclosures Pollyea: Pfizer: Consultancy; Glycomimetics: Other; Takeda: Consultancy; Daiichi Sankyo: Consultancy; Abbvie: Consultancy, Research Funding; Syros: Consultancy; Syndax: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Genentech: Consultancy; Amgen: Consultancy; Janssen: Consultancy; 47: Consultancy, Research Funding; Agios: Consultancy; Celgene/BMS: Consultancy. Dinardo:Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Agios: Consultancy, Research Funding; Celgene: Research Funding; Calithera: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; AbbVie: Consultancy, Research Funding; ImmuneOnc: Honoraria. Arellano:Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding; Cephalon Oncology: Research Funding. Fiedler:Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Gilead: Honoraria; BMS: Honoraria; BerGenBio ASA: Research Funding; Servier: Honoraria, Other; Ariad/Incyte: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Daiichi Sankyo Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations; Morphosys: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: support in medical writing; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accomodations, support in medical writing, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Konopleva: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; Calithera: Research Funding; AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; AstraZeneca: Research Funding; Eli Lilly: Research Funding; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Ascentage: Research Funding; Ablynx: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Amgen: Consultancy; Genentech: Consultancy, Research Funding; Kisoji: Consultancy; Rafael Pharmaceutical: Research Funding; Forty-Seven: Consultancy, Research Funding. Rizzieri:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; abbvie: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Acrobiotech: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Honoraria, Speakers Bureau; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Celltrion: Membership on an entity's Board of Directors or advisory committees; Mustang: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Smith:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Shinagawa:AbbVie: Research Funding. Lemoli:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio ASA: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Chyla:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Ridgeway:AbbVie: Current Employment, Current equity holder in publicly-traded company. Kantarjian:Janssen: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Oxford Biomedical: Honoraria; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Delta Fly: Honoraria; BMS: Research Funding; Aptitute Health: Honoraria; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Jazz: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding.

Background: Patients with acute myeloid leukemia (AML) who are older or ineligible for intensive induction chemotherapy have limited treatment options and poor survival. In the VIALE-A study, venetoclax (Ven) + azacitidine (Aza) improved overall survival and response rates compared with placebo (Pbo) + Aza in older or unfit patients with newly diagnosed AML (DiNardo et al. N Engl J Med. 2020). Although cytopenia is common in AML, Ven+Aza was associated with hematologic adverse events in 83% of patients in the VIALE-A study (vs 69% in the Pbo+Aza arm). Here, the frequency and management of cytopenia are analyzed in patients achieving a best response of complete remission (CR) or CR with partial hematologic recovery (CRh) in the VIALE-A study. Methods: This double-blind, Pbo-controlled, multicenter Phase 3 study (NCT02993523) enrolled patients with newly diagnosed AML who were ineligible for intensive chemotherapy due to age ≥75 years or comorbidities. Patients were randomized 2:1 to receive 75 mg/m2 Aza (Days 1-7 of each 28-day cycle) plus either daily 400 mg Ven (Ven+Aza) or Pbo (Pbo+Aza). Disease response was assessed via bone marrow aspirate and biopsy at the end of Cycle 1 and at least every 3 cycles thereafter. After patients achieved blast clearance (bone marrow blasts Results: In total, 186 of 283 (66%) Ven+Aza-treated patients and 33 of 144 (23%) Pbo+Aza-treated patients achieved a best response of CR or CRh (CR/CRh). Of patients with a best response of CR/CRh in the Ven+Aza arm, 77% achieved blast clearance by the end of Cycle 1, 88% by the end of Cycle 2, 92% by the end of Cycle 3, and 98% by the end of Cycle 4. Of patients with a best response of CR/CRh in the Pbo+Aza arm, 33% achieved blast clearance by the end of Cycle 1, 55% by the end of Cycle 2, 76% by the end of Cycle 3, and 91% by the end of Cycle 4. After achieving blast clearance, 75% and 67% of patients in the Ven+Aza and Pbo+Aza arms, respectively, had a delay of the next cycle, with a median duration per cycle delay post-blast clearance (range) of 9.0 (1-39) and 5.5 (1-21) days. Among CR/CRh patients, more patients receiving Ven+Aza versus Pbo+Aza had post-remission cytopenia (87% vs 45%; Table 2). A similar percentage of CR/CRh patients in both arms (Ven+Aza, 26%; Pbo+Aza, 24%) had in-cycle dose interruptions (ie, days without Ven/Pbo exposure between a cycle's first and last Ven/Pbo dose), with a median duration (range) of 2.0 days (1-20) for Ven+Aza and 1.0 (1-13) for Pbo+Aza. A greater proportion of CR/CRh patients experienced post-remission cycle delays due to cytopenia in the Ven+Aza arm (77%) than in the Pbo+Aza arm (30%). Furthermore, a higher percentage of CR/CRh patients had post-remission cycles with a reduction in Ven/Pbo dosing days and/or cycle delays totaling ≥7 days due to cytopenia in the Ven+Aza arm (75%) than in the Pbo+Aza arm (27%). Among these patients, the median percentage of days without Ven/Pbo administration while in remission (out of the total number of days in remission) was 18% (range, 1-69) in the Ven+Aza arm and 13% (3-44) in the Pbo+Aza arm. Ultimately, 129 CR/CRh patients (69%) in the Ven+Aza arm and 10 (30%) in the Pbo+Aza arm received ≤21-day Ven/Pbo dosing post-remission, with a median time from remission to first ≤21-day cycle (range) of 92.0 days (1-480) for Ven+Aza and 74.0 days (6-405) for Pbo+Aza. Conclusion: In the VIALE-A study of older or unfit patients with newly diagnosed AML, the majority of responding patients in the Ven+Aza arm required dosing modifications to manage cytopenia, of which delays between cycles or within-cycle reductions of Ven dosing days were most common. Post-remission cytopenia and dosing modifications were more frequent with Ven+Aza versus Pbo+Aza treatment. The impact of cytopenia and dosing modifications on patient outcomes with Ven+Aza is currently being analyzed and will be reported at a future date. Disclosures Pratz: AbbVie: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Astellas: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding; Agios: Other: Scientific Advisory Board, Research Funding; Celgene: Other: Scientific Advisory Board. DiNardo:MedImmune: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Takeda: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; Novartis: Consultancy; Calithera: Research Funding. Selleslag:Amgen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy, Honoraria, Speakers Bureau; Belgian College: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Teva: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau. Yamamoto:AbbVie: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Zenyaku: Research Funding; Sumitomo Dainippon: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Research Funding; Mochida: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Janssen: Honoraria; Gilead Sciences: Research Funding; IQIVA/Incyte: Research Funding; HUYA: Consultancy; IQIVA/HUYA: Honoraria; Daiichi Sankyo: Consultancy; Eisai: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Yakult: Research Funding; Stemline Therapeutics: Consultancy; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Bayer: Research Funding; Aichi Cancer Center: Current Employment. Konopleva:AbbVie: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Sanofi: Research Funding; Amgen: 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; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Ablynx: Research Funding; Rafael Pharmaceutical: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding. McDonald:venetoclax advisory board in South Africa (in CLL context): Consultancy; Alberts Cellular Therapy: Current Employment. Babu:Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; Novartis: Research Funding; Janssen Oncology: Research Funding; Syndax: Research Funding; Nektar: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Alexion Pharmaceuticals: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding, Speakers Bureau; Lilly: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Bayer: Honoraria; AstraZeneca: Consultancy, Honoraria; AstraZeneca/MedImmune: Research Funding; Argenx: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy; Merck: Research Funding; AbbVie: Research Funding; TG Therapeutics: Research Funding; Amgen: Research Funding; Lutheran Hospital: Other; Fort Wayne Medical Oncology & Hematology: Current Employment, Current equity holder in publicly-traded company; Sanofi: Research Funding. Stevens:Amgen, MorphoSys: Consultancy. Kantarjian:BioAscend: Honoraria; Delta Fly: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; Janssen: Honoraria; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; Oxford Biomedical: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Traina:University of São Paulo at Ribeirão Preto Medical School: Current Employment; AbbVie: Other: Principal Investigator for Protocol Number M15-656 . Venditti:Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ramsingh:Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Genentech: Current Employment, Current equity holder in publicly-traded company. Jin:Genentech: Current Employment. Ainsworth:AbbVie: Current Employment, Current equity holder in publicly-traded company. Duan:AbbVie: Current Employment, Other: may hold stock or options. Svensson:AbbVie: Current Employment, Current equity holder in publicly-traded company. Werner:AbbVie: Current Employment, Current equity holder in publicly-traded company. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Jonas:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Amgen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; GlycoMimetics: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Celgene: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Forty Seven: Research Funding; Accelerated Medical Diagnostics: Research Funding; AROG: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Genentech/Roche: Research Funding; Hanmi: Research Funding; Incyte: Research Funding; LP Therapeutics: Research Funding; Pfizer: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding.

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

To define the efficacy of venetoclax with extended follow-up and identify clinical or biological treatment effect modifiers, updated data for previously treated patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) enrolled in 4 early-phase trials were pooled. Rates of response, complete remission (CR/CRi), and undetectable minimal residual disease (U-MRD) were analyzed for all patients (n = 436) and for those patients who were planned to receive 400 mg/day monotherapy (n = 347). Univariate and multiple regression analyses were performed to identify the pretreatment factors associated with response rates and duration of response (DoR). Objective responses were documented in 75% of all patients, including 22% CR/CRi. Overall, 27% and 16% of the patients achieved U-MRD in blood and marrow, respectively. Estimated median progression-free survival (PFS), DoR, and time to progression were 30.2, 38.4, and 36.9 months, respectively. Similar efficacy outcomes were observed within the 400 mg/day monotherapy subset. For those who achieved CR/CRi, the 3-year PFS estimate was 83%. DoR was superior for patients achieving CR/CRi or U-MRD in landmark analyses. In multiple regression analyses, bulky lymphadenopathy (≥5 cm) and refractoriness to B-cell receptor inhibitor (BCRi) therapy were significantly associated with lower CR rate and shorter DoR. Fewer prior therapies were associated with higher CR rate, but not DoR. Chromosome 17p deletion and/or TP53 mutation and NOTCH1 mutation were consistently associated with shorter DoR, but not probability of response. Thus, both pretreatment factors and depth of response correlated with DoR with venetoclax. Patients without bulky lymphadenopathy, BCRi-refractory CLL, or an adverse mutation profile had the most durable benefit.

The utility of positron emission tomography-computed tomography (PET-CT) in distinguishing Richter's transformation versus chronic lymphocytic leukemia (CLL) progression after ibrutinib and/or idelalisib was assessed in a post hoc analysis of a phase II study of venetoclax. Patients underwent PET-CT at screening and were not enrolled/treated if Richter's transformation was confirmed pathologically. Of 167 patients screened, 57 met criteria for biopsy after PET-CT. Of 35 patients who underwent biopsy, eight had Richter's transformation, two had another malignancy, and 25 had CLL. A PET-CT maximum standardized uptake value (SUVmax) ≥10 had 71% sensitivity and 50% specificity for detecting Richter's transformation [Odds Ratio (OR): 2.5, 95%CI: 0.4-15; P=0.318]. Response rate to venetoclax was similar for screening SUVmax

Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

Although ruxolitinib (RUX) is effective in alleviating splenomegaly and constitutional symptoms for patients with myelofibrosis (MF), it does not appear to modify underlying disease biology. RUX discontinuation rate within 5 years is approximately 40%, and patients have poor prognosis after discontinuing RUX [1]. The definition of disease modification in MF is evolving. Reversal of bone marrow fibrosis (BMF) and reduction in driver gene variant allele frequency (VAF) have been suggested as evidence of disease modification; however, clinical benefits derived from achieving these responses have not been fully elucidated. Ultimately, benefits in patient survival are requisite to claim true clinically meaningful disease modification. There is also an unmet need of effective therapies for patients with MF with high molecular risk (HMR) mutations (ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1 Q157). REFINE (NCT03222609) is a phase 2 trial evaluating navitoclax (NAV), a BCL-XL/BCL-2 inhibitor, combined with RUX, in patients with MF who progressed on or had a suboptimal response to RUX monotherapy. Here, we report the exploratory analyses assessing BMF, VAF, and HMR with respect to outcomes. As BMF improvements were often observed in patients who achieved ≥35% reduction in spleen volume (SVR35), we explored if the survival benefit observed was due to this potentially disease modification-related response. All statistics were descriptive. As of May 6, 2021, 34 patients were enrolled in Cohort 1a and received ≥1 dose of NAV plus RUX. Of these, 32 were evaluable for BMF and 12 (38%) had ≥1 grade improvement during anytime on study, 4 of whom improved by 2 grades. For driver gene VAF reductions, 26 patients (JAK2, n=19; CALR, n=7) were evaluable and 6 (23%) achieved ≥20% reduction at Week 24. Five patients achieved both BMF and VAF responses. Median overall survival (OS) for patients who had ≥1 grade improvement in BMF was not reached compared with 28.5 months for those without improvement (P Reference 1. Palandri F, Breccia M, Bonifacio M, et al. Life after ruxolitinib: Reasons for discontinuation, impact of disease phase, and outcomes in 218 patients with myelofibrosis. Cancer 2020; 126(6): 1243-52 Citation Format: Naveen Pemmaraju, Jacqueline Garcia, Jalaja Potluri, Yan Sun, Jason Harb, Srinivas K. Tantravahi, Srdan Verstovsek, Claire Harrison. Addition of navitoclax to ruxolitinib mediates responses suggestive of disease modification in patients with myelofibrosis previously treated with ruxolitinib monotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB108.

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-XL 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 × 109/L or >150 × 109/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% (SVR35) from BL at wk 24. Key secondary endpoints were ≥50% reduction in total symptom score (TSS50), 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 cm3 (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. SVR35 was achieved by 52% of evaluable pts at wk 24 (SVR35 in INT-2, 50%; HR, 33%) and by 76% at any time on treatment (Table). Median time to first SVR35 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. SVR35, TSS50, and BM fibrosis improved over time. Clinical trial information: NCT03222609. [Table: see text]

Background Venetoclax plus azacitidine is indicated in the USA for the treatment of newly diagnosed acute myeloid leukaemia in older patients (≥75 years) or those ineligible for induction chemotherapy due to co-morbidities. Methods In this phase 1/2 study (NCT02265731), Japanese patients (≥60 years) with untreated (ineligible for induction chemotherapy) or relapsed/refractory acute myeloid leukaemia received oral venetoclax 400 mg/day (3-day ramp up in cycle 1) plus subcutaneous or intravenous azacitidine 75 mg/m2 on days 1–7 per 28-day cycle until disease progression or unacceptable toxicity. Results As of 10 December 2019, six patients were enrolled (median age: 75 years; untreated: n = 5; relapsed/refractory: n = 1); median treatment duration: 10.3 months (range, 0.7–29.4). Most common grade ≥ 3 adverse events were lymphopaenia and febrile neutropaenia (n = 4 each). Four patients reported serious adverse events; only an event of grade 3 fungal pneumonia was considered possibly related to both study drugs, requiring dose interruption of venetoclax and delay of azacitidine. Five (83%) patients had responses (complete remission: n = 3). Median time to first response of complete remission/complete remission with incomplete count recovery was 1.0 month (range, 0.8–5.5); median overall survival: 15.7 months (95% confidence interval: 6.2, not reached). Conclusions Venetoclax plus azacitidine was well tolerated and showed high response rates in Japanese patients with acute myeloid leukaemia.

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/m2 ; days 1-7) or decitabine (DEC; 20 mg/m2 ; 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.

BACKGROUND: Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study. METHODS: We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival. RESULTS: The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P