Venetoclax Dose Research Articles

Venetoclax-Based Therapy before Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

Introduction The BCL-2 inhibitor venetoclax (VEN) is effective in older patients with untreated acute myeloid leukemia (AML). Few reports exist on the use of VEN as a bridging therapy for allogeneic hematopoietic cell transplantation (HCT) for AML. Previous studies have shown that NPM1 and IDH2 gene mutations are associated with high response rates to VEN therapy. We performed a retrospective cohort study to analyze the efficacy of VEN-based bridging therapy before HCT. Methods We included 46 patients who were eligible for HCT and received bridging therapy combined with VEN between April 2021 and June 2023 at our center. We evaluated response rates to VEN and HCT outcomes. None of the patients received VEN prior to the study. The response rate to VEN was evaluated using the 2022 European LeukemiaNet (ELN) criteria. We estimated overall survival (OS) using the Kaplan-Meier method, log-rank test, and Gray's test for univariate analysis of cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). We used the Cox proportional hazards model for a multivariate analysis of OS. We extracted DNA from the bone marrow or peripheral blood, and analyzed gene mutations using next-generation sequencing (NGS), targeting 70 genes known to be recurrently mutated in myeloid malignancies. Results Of the 46 patients, 32 had de novo AML, 7 had de novo MDS/AML, 5 had secondary AML, 1 had secondary MDS/AML, and 1 had myeloid sarcoma. The median age was 59 (21-70) years. Nineteen were women and 7 had a history of HCT. The regimens combined with VEN were azacitidine in 39 cases and low-dose cytarabine in 7. According to the 2022 ELN risk classification by genetics at diagnosis, 7 were favorable, 11 were intermediate, and 27 were at adverse risk. Nine patients were in hematological complete remission (CR) / CR with incomplete count recovery (CRi) while 37 were not, when VEN was initiated. The maximum response rates among the patients who started VEN treatment in the non-CR group were: 18 with CR/CRi (49%) and no response in 19 (51%). The median time from the first dose of VEN to HCT was 70 (27-315) days. Forty-one patients underwent HCT and 19 (43%) were in CR/CRi at HCT. The reasons for discontinuation of VEN were HCT in 34 cases, failure in 9, and adverse events in 4 (hematological toxicity in 3 cases and infection in 1). Sixteen patients died due to primary disease (n=9), infection (n=5), thrombotic microangiopathy (n=1), and multi-organ failure (n=1). The median post-HCT observation period of survivors was 156 (25-775) days, and at 1-year after HCT, OS was 49.6% (95% CI: 28.0-67.9), CIR was 40.6% (95% CI: 24.1-56.6) and NRM was 15.2% (95% CI: 5.5-29.5). At 1-year after HCT, outcomes of the patients who were in CR/CRi at HCT was better than that of those who were not (OS, 80.8% vs. 26.4%, p=0.002; CIR, 13.4% vs. 61.8%, p<0.01; NRM, 0% vs. 26.7%, p<0.05). In 35 of the patients who underwent the first HCT, the 1-year OS was 88.9% in those who were in CR and 36.5% in those who were not (p=0.015). Thirty cases were non-CR at the start of the VEN regimen prior to their first HCT. This group had a 1-year OS of 57.8% (95% CI, 27.4-79.3). In 11 patients who achieved CR before HCT and 18 others who did not, the 1-year OS rates were 83.3% and 39.9%, respectively (p=0.10). Genetic analysis was performed by NGS in 37 patients before starting VEN, revealing mutations in TP53 (n=9), RUNX1 (n=7), IDH1 (n=6), ASXL1 (n=6), and DNMT3A (n=6) (Fig. 1A). Alterations in MDS-related genes (n=20) and kinase-related genes ( KIT, PTPN11, FLT3, KRAS, n=11) were frequent. Among the patients receiving their first HCTs, the 1-year OS was 0% in the group with TP53 mutations, and 63.9% in the wild-type TP53 group (p=0.04). The OS was worse in patients with mutated TP53 or kinase-related genes (n=19) than those without either mutation (n=15) (Fig. 1B, 1-year OS 28.7% vs. 72.9%, p=0.029). A multivariate analysis of OS revealed that patients who were not in CR at HCT (HR, 25.01 [95% CI, 2.406-259.9], p=0.007), those who previously underwent HCT (HR, 36.81 [95% CI, 4.599-294.7], p=0.035), and those with TP53 or kinase-related gene mutations (HR, 6.311 [95% CI, 1.137-350.0], p=0.035) had significantly lower OS rates. There was no significant difference in OS between the different ELN risk categories. Conclusions Non-CR at the time of HCT, a history of HCT, and mutations in TP53 or kinase-related genes were found to be independent poor prognostic factors for OS after VEN-based bridging treatment followed by HCT.

Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results, Including MRD Data, from the BRUIN Phase 1b Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL). Recent clinical studies have evaluated the safety and efficacy of fixed-duration regimens with venetoclax and cBTKi. While these combinations are effective, their use may be limited by toxicity. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has shown promising safety and efficacy in heavily pretreated relapsed or refractory (R/R) CLL patients (pts). Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts with R/R CLL were eligible for pirtobrutinib combined with venetoclax ± rituximab in the phase 1b portion of the multicenter phase 1/2 BRUIN study (NCT03740529). Prior cBTKi therapy was allowed, but not prior venetoclax. Pts were enrolled into sequential cohorts, first in the pirtobrutinib + venetoclax (PV) cohort and then the PV + rituximab (PVR) cohort. Pirtobrutinib 200 mg QD was started on cycle 1 day 1, and venetoclax was started on cycle 2 day 1 with the standard 5-week dose ramp to 400 mg QD target dose. PV was given for up to 24 cycles; each cycle was 28 days. For the PVR cohort, rituximab was given at 375 mg/m 2 on cycle 1 day 1 and then 500 mg/m 2 on day 1 of cycles 2-6. The primary endpoint was safety as assessed by treatment-emergent adverse events (TEAEs) graded according to CTCAE v5.0. Other key endpoints included overall response rate (ORR), progression-free survival (PFS), and minimal residual disease (MRD). Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10,000 nucleated cells (<1x10 -4) in peripheral blood by ClonoSEQ® assay (Adaptive Biotechnologies, Seattle, WA). A data cut of May 5, 2023, was utilized. Results: Fifteen pts received PV, and 10 received PVR. Median age was 66 years (range, 49-77) for those who received PV and 69 (range, 39-78) for those who received PVR. Median prior lines of therapy was 1 (range, 1-2) for the PV cohort and 2 (range 1-4) for the PVR cohort. Most pts had received prior chemotherapy (PV=53%; PVR=60%), CD20 monoclonal antibody (73%; 70%), and cBTKi (73%; 60%). The majority of pts had IGHV unmutated CLL (PV=73%; PVR=89%). ORR was 93.3% (95% CI, 68.1-99.8) for the 15 pts receiving PV and 100% (95% CI, 69.2-100.0) for the 10 pts receiving PVR, with 10 complete responses (PV=7; PVR=3). Median duration of follow-up for PFS was 22.1 months (IQR, 20.1-25.7) for PV and 22.1 months (IQR, 20.7-22.1) for PVR; PFS at 18 months was 92.9% (95% CI, 59.1-99.0) for the 15 pts receiving PV and 80.0% (95% CI, 40.9-94.6) for the 10 pts receiving PVR. The overall uMRD rate at cycle 13 was 70.8% (PV=10; PVR=7) for the 24 evaluable pts, with 87.5% (PV=12; PVR=9) of pts achieving uMRD at some time during the trial and all but one pt sustaining uMRD during subsequent MRD assessments ( Figure). Twenty-two pts discontinued treatment (PV=14; PVR=8); of these, 14 completed all 24 cycles of therapy (PV=9; PVR=5) and 8 discontinued early because of progressive disease (PV=2), adverse events (PVR=2), protocol noncompliance (PV=1), death unrelated to treatment (PVR=1), or other reasons (PV=2). Three pts (PV=1; PVR=2) continue to receive treatment. The median relative dose intensity was similar in both cohorts (PV=97.9%; PVR=98.6%). The most common TEAE of any grade included nausea (PV=60.0%; PVR=40.0%), fatigue (53.3%; 50.0%), and diarrhea (46.7%; 60.0%). The most common grade ≥3 TEAE was neutropenia/neutrophil count decreased (PV=46.7%; PVR=60.0%). Grade ≥3 clinical tumor lysis syndrome occurred during venetoclax dose escalation (PV=2), including a grade 3 case that resolved spontaneously after 24 hours and a grade 4 case that resolved after short-term intravenous fluids. Treatment-related adverse events led to dose reductions in three pts (PV=1; PVR=2) and treatment discontinuation in two pts (PVR=2). Conclusions: Fixed-duration pirtobrutinib combined with venetoclax ± rituximab was well tolerated and demonstrated sufficiently promising efficacy to warrant further investigation in pts with R/R CLL. The BRUIN CLL-322 phase 3 trial comparing PVR vs VR in previously treated CLL is currently enrolling pts (NCT04965493).

A Phase 2 Study of the Fully Oral Combination of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax for Older and/or Unfit Patients with Acute Myeloid Leukemia

Background: The combination of a hypomethylating agent (HMA) plus venetoclax is the standard of care for patients (pts) with acute myeloid leukemia (AML) who are older (age ≥ 75 yrs) and/or unfit for intensive chemotherapy. ASTX727 (oral decitabine/cedazuridine) is an oral formulation of decitabine with pharmacokinetic AUC equivalent exposures to IV decitabine. We performed a phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax in the frontline (FL) and relapsed-refractory (R/R) settings. Methods: Pts ≥ 18 yrs with WHO 2016-defined AML were eligible. The FL cohort enrolled newly diagnosed pts with ECOG ≤ 3 who were either ≥ 75 yrs or ineligible for intensive chemotherapy due to comorbidities. Pts ≥ 18 yrs and ECOG ≤ 2 were eligible for the R/R cohort. Pts with a history of myelodysplastic syndrome (MDS), including previously treated MDS, were eligible. Treatment consisted of ASTX727 (decitabine/cedazuridine) 35/100 mg PO daily x 5 days and venetoclax 400 mg PO daily (adjusted for azoles) for 28 days during induction (held if blast clearance on day 21 bone marrow examination) and 21 days in consolidation. Dose reductions were permitted for toxicity/tolerability. Therapy was administered in 28-day cycles for up to 24 cycles. Risk stratification and responses were determined per ELN 2022. This study was registered on ClinicalTrials.gov (NCT04746235). Results: 52 pts have been enrolled (42 in the FL and 10 in the R/R cohorts). In the FL cohort, the median age was 79 yrs (range 50-92). 17/42 (40%) pts had antecedent MDS (including 8 [19%] with treated secondary AML) and 6/42 (14%) had therapy-related AML (t-AML). By ELN 2022, 6 (14%) were favorable, 3 (7%) were intermediate, and 33 (79%) were adverse. 9/42 (21%) had complex cytogenetics and 6 (14%) had TP53 mutations. In the R/R cohort (n=10), the median age was 71 yrs (46-75). 2 (20%) pts had antecedent MDS and 2 (20%) had t-AML. By ELN 2022, 3 (30%) were intermediate and 7 (70%) were adverse. 5/10 (50%) had complex cytogenetics and 2/10 (20%) had TP53 mutations. The median prior lines of therapy in the R/R cohort was 2 (1-4), with 5 (50%) pts with 2 or more prior lines of therapy. The median number of cycles given was 3 (1-12). In the FL cohort, the ORR was 67% (28/42 pts: 15 [36%] CR, 11 [26%] CRi, 2 [5%] MLFS). In responding FL pts, measurable residual disease (MRD) by flow cytometry became undetectable in 7/22 (32%) pts with adequate samples. In the R/R cohort, the ORR was 50% (5/10 pts: 3 [30%] CR, 2 [20%] CRi). The median number of cycles to first and best response were 1 (1-4) and 1 (1-7), respectively. At a median follow-up of 12.8 months, the median OS was 12.7 months in the FL cohort and 7.6 months in the R/R cohort (figure A). In pts achieving CR/CRi (n=26 FL and 5 RR), the median RFS was 9.8 months in the FL and 4.6 months in the R/R cohort (figure B). The median DOR was 13.2 and 4.6 months the FL and R/R settings, respectively. 2 (4%) pts (1 FL and 1 R/R) went off protocol to undergo stem cell transplantation. We then stratified the FL pts into 3 genetic groups (group 1: TP53 wt, K/NRAS wt, no FLT3-ITD; group 2: TP53 wt, K/NRAS mut or FLT3-ITD positive; group 3: TP53 mut) as previously described (Döhner, ASH 2022). The median OS in group 1 (n=24), group 2 (n=12), and group 3 (n=6) was 16.2, 9.1, and 1.4 months, respectively. In FL pts achieving CR/CRi, the median RFS in group 1 (n=17), group 2 (n=7), and group 3 (n=2) was 13.2, 8.1, and 9.8 months, respectively. OS in the FL cohort was similar between the pts under 80 yrs (n=21, median 12.7 months) vs those 80+ yrs (n=21, median 14.8 months), p=0.98. The most common grade 3/4 adverse events were neutropenic fever (23%), pneumonia (13%), bacteremia (8%), cellulitis (6%), sepsis (6%), and respiratory failure (6%). 4-wk and 8-wk mortality were 10% and 15%, respectively. The median time to cycle 2 was 38 days (26-70). In pts who experienced count recovery during cycle 1, the median time to platelets > 50 x 10 9/L and absolute neutrophil count > 1.0 x 10 9/L was 23 (18-55) and 42 (28-69) days, respectively. Cycle 2 dose reductions occurred in 27/42 (64%) pts (21 venetoclax dose reductions, 6 both drugs reduced). Of the 29 observed deaths, 15 (52%) occurred in non-responders, 11 (38%) following AML relapse, and only 3 (10%) in pts with ongoing response (1 sepsis, 1 GI hemorrhage, and 1 electing to pursue hospice). Conclusions: In this older and very high-risk population of pts with AML, an entirely oral regimen consisting of ASTX727 and venetoclax was effective and tolerable.

Outpatient Low-Dose Venetoclax Plus Azacitidine Vs. Intensive Chemotherapy for Newly Diagnosed Fit Patients with Acute Myeloid Leukemia in a Limited Resource Setting

Introduction: venetoclax plus azacitidine (Ven/Aza) is the standard-of-care in patients with newly diagnosed acute myeloid leukemia (AML) who are unsuitable candidates for intensive chemotherapy (IC), prompting questions related to whether it should be used for candidates fit for IC (FIT). Access to novel agents in low- and middle-income countries (LMIC) is limited, however, in a previous phase 2 study (NCT05048615), we demonstrated that using venetoclax concomitantly with strong CYP3A4 inhibitors like itraconazole could be a practical approach to reduce the venetoclax dose and diminish treatment-related costs without compromising treatment response. We sought to compare FIT patients for IC with newly diagnosed AML who received either low-dose Ven/Aza or traditional IC as first-line treatment to evaluate survival outcomes in LMIC. Methods: we retrospectively included all newly diagnosed adult patients with AML suitable for IC treated in our center from August 2016 to March 2023. Since the COVID-19 pandemic, we have used Ven/Aza as a standard first-line therapy in an effort to reduce early mortality and to allow outpatient induction for all patients with AML. Low-dose Ven/Aza was administered as follows: venetoclax 100 mg QD fixed dose plus itraconazole 100 mg BID for 21 days per cycle, and azacitidine 100 mg SC fixed dose QD or 7 days, 1-2 cycles. IC patients received 7+3 or intermediate dose cytarabine plus 3 days of mitoxantrone. Consolidation with intermediate dose cytarabine was given following remission in both groups. Baseline characteristics were registered and compared. We evaluated induction complications, complete response (CR/CRi), 30 and 60-day early death (ED), allogeneic hematopoietic stem cell transplantation (HCT), event-free survival (EFS), and overall survival (OS). Multivariate Cox regression for OS was performed. Results: 83 patients were included, the median age at diagnosis was 44 years (IQR, 32-56), 27 received Ven/Aza (56% received 2 cycles), and 56 IC. Patients who received Ven/Aza were older, had a higher risk disease, and had a longer time between diagnosis and treatment. Patients who received Ven/Aza had a lower incidence of febrile neutropenia, need for transfusions, and less than half required hospitalization during induction; 30- and 60-day mortality was reduced 2.4 and 3-fold in Ven/Aza vs IC although statistical significance was not reached. There were no differences in the rate of CR/CRi between groups (Table 1). After achieving CR/CRi, the IC group had a higher incidence of being relapsed however the median EFS was not different with 7.7 months (95% CI 5.9-9.6) for Ven/Aza vs. 8.5 months (95% CI 6.6-10.5) for IC (p=0.53). Median OS was 10 months (95% CI 5.8-14.1) for Ven/Aza vs 9 months for IC (95% CI 6.6-11.3) (p=0.33) (Figure 1). Patients who received Ven/Aza followed by HCT had the best outcomes with a 2-year OS of 80% vs. 35.5% of those who received IC plus HCT. An OS landmark analysis for patients alive at or beyond 5 months (median time from diagnosis to HCT) showed prolonged survival in HCT vs. not transplanted patients (16 vs 11 months, p=0.035), irrespective of their induction arm. In the multivariate analysis, HCT (HR 0.05, 95% CI 0.007-0.5) and a need for cytoreduction (HR 8.7, 95% CI 1.2-59.6) were the only predictors of OS. Conclusion: in this single-center study, AML patients treated in a limited resource setting with low-dose Ven/Aza had similar complete response and survival to IC with reduced complications and shorter hospital stay, despite being older with higher risk disease. This induction treatment is a low-cost but effective option in a LMIC environment and could be considered an alternative option, even in suitable candidates for IC, especially with access to HCT.

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study

Data concerning venetoclax and azacitidine (Ven/Aza) as first-line therapy for newly diagnosed acute myeloid leukemia (ND-AML) in candidates for intensive chemotherapy are limited, and outpatient induction regimens in ND-AML have been poorly explored. The enzyme CYP3A4 metabolizes Venetoclax. Conversely, itraconazole is a strong CYP3A4 inhibitor; thus, it produces a 75 % reduction in the dose and cost of venetoclax. This phase 2 trial assessed the feasibility, safety, and efficacy of outpatient induction with venetoclax 100 mg daily from days 1–21, itraconazole 100 mg twice daily from days 1–21, and azacytidine 100 mg subcutaneously, once daily from days 1–7. Fifteen adults with ND-AML were enrolled. The median age was 53 (range 25–73) and twelve (80 %) were considered candidates for intensive chemotherapy. Nine (60 %) subjects started treatment as outpatients,. The first treatment cycle completion in the outpatient setting was achieved in 77.7 %. Early 14-day, 30-day, and 60-day mortality rates were 6.7 %, 13.3 %, and 13.3 %, respectively. Composite CR/CRi after the first and second treatment cycles were 53.9 % and 85.7 %, respectively. Common adverse events included hematological and gastrointestinal toxicities. Outpatient induction with low-dose venetoclax plus itraconazole is feasible, safe, and has acceptable preliminary efficacy in ND-AML patients. This trial was registered in www.clinicaltrials.gov as #NCT05048615.

Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/μL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.

Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer.

Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.

Venetoclax pharmacokinetics in subjects with end-stage renal disease undergoing hemodialysis.

e19042 Background: Venetoclax is a first-in-class Bcl-2 inhibitor approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia(AML) and is currently being investigated as a treatment for t(11;14)-positive relapsed/refractory multiple myeloma (MM). Renal insufficiency is a common comorbidity in patients with hematologic malignancies, and no clinical study has been conducted to assess how end stage renal disease might affect venetoclax pharmacokinetics. This study aimed to assess the pharmacokinetics of venetoclax after oral administration of a single 100 mg dose of venetoclax in subjects with normal renal function and end-stage renal disease, including those undergoing hemodialysis. Methods: Venetoclax was administered as a single 100 mg dose to 7 healthy female subjects with normal renal function (eGFR &gt; 90 ml/min) and 6 female subjects with end-stage renal disease (ESRD) (eGFR &lt; 15 ml/min) both prior to hemodialysis (Period 1) and between hemodialysis days (Period 2). Intensive PK and protein binding samples were collected from all subjects. Arterial and venous samples were collected from ESRD subjects during hemodialysis to assess the effect of hemodialysis on the pharmacokinetics of venetoclax. Pharmacokinetic parameters were estimated using non-compartmental methods. Results: There was no difference in plasma venetoclax concentrations between arterial and venous samples, suggesting that hemodialysis did not affect the PK of venetoclax. The fraction unbound (fu) of venetoclax increased approximately 2-fold for subjects with ESRD compared to subjects with normal renal function.The unbound Cmax and AUC0-48 of ESRD subjects, between dialysis days were comparable to unbound Cmax and AUC0-48 observed in the normal renal function subjects. The harmonic mean t1/2 between groups (normal renal function vs. ESRD) ranged from 11 and 12.2 hours, demonstrating that end-stage renal disease did not affect the half-life of venetoclax. Conclusions: End-stage renal disease does not alter unbound venetoclax plasma concentrations and no dose adjustment is neededfor patients with renal insufficiency based on pharmacokinetics. Clinical trial information: NCT04810598 .

Phase 1 study of ziftomenib (KO-539) in combination with venetoclax or venetoclax/azacitidine or standard induction cytarabine/daunorubicin (7+3) chemotherapy for the treatment of patients with acute myeloid leukemia.

TPS7079 Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) represent a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin-mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A) interaction driving leukemogenesis in these subtypes. An ongoing Phase 1/2 study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in KMT2A-r and NPM1-m human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2A-r AML xenografts. Therefore, administration of ziftomenib in combination with standard-of-care (SOC) therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1-m and KMT2A-r menin-dependent AML. Methods: KOMET-007 (KO-MEN-007, NCT# ) is a 2-part dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy (NIC) and intensive chemotherapy (IC) in patients with NPM1-m and KMT2A-r AML. During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts ( NPM1-m and KMT2A-r) using a rule-based approach (n = 6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. The Phase 1b portion will also evaluate zifto/ven/aza in newly diagnosed AML ( KMT2A-r and NPM1-m) and zifto/ven in R/R AML ( NPM1-m only). The overall primary objectives are to establish the minimum biologically effective, dose limiting toxicities, and recommended Phase 2 dose of ziftomenib combined with NIC and IC backbones in each genetically defined cohort. Additional secondary endpoints include preliminary antileukemic efficacy (including MRD-negative responses and number of patients able to transition to subsequent allogeneic stem cell transplant), pharmacokinetic, and pharmacodynamic data. Exploratory end points include biomarkers for efficacy and resistance, pharmacodynamic biomarkers and activity in isolated myeloid sarcoma. Clinical trial information: NCT04067336 .

Higher-dose venetoclax with measurable residual disease-guided azacitidine discontinuation in newly diagnosed acute myeloid leukemia.

Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: 1)Higher doses of venetoclax are tolerable and more effective, and 2)Azacitidine can be discontinued after deep remissions. Forty-two newly-diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine + Venetoclax (HiDDAV) Study. Patients received 1-3 "induction" cycles of venetoclax 600mg daily with azacitidine. Responders received MRD-positive or negative "maintenance" arms: azacitidine with 400mg venetoclax or 400mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD-negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital PCR. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD-negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.

Venetoclax in combination with chemotherapy as treatment for pediatric advanced hematologic malignancies.

Venetoclax is frequently used as salvage treatment in pediatric, adolescent, and young adult (AYA) patients with advanced hematologic malignancies. However, more data are needed from real-world studies to guide the safe and appropriate use of venetoclax in this population. We retrospectively reviewed the medical records of all patients diagnosed with hematologic malignancies less than 30 years of age treated with venetoclax outside of clinical trials at the University of California San Francisco Benioff Children's Hospitals from 2016 to 2022. We identified 13 patients (acute myeloid leukemia, n=8; B-acute lymphoblastic leukemia, n=3; myelodysplastic syndrome, n=2) aged 4 months to 27 years. A median of 3 prior lines of therapy weregiven (range 0-5). All patients received venetoclax in combination with either a hypomethylating agent or conventional chemotherapy. Three (23%) patients achieved complete remission (CR); two (15%) achieved partial remission (PR); 3 (23%) had stable disease (SD), and five (42%) had progressive disease. Median survival and time to progression from venetoclax initiation was 9 months (range 2.5-52 months) and 3 months (range 2weeks to 7.5 months), respectively. Six patients (46%) developed grade 3 or higher infections while receiving venetoclax, including bacteremia due to atypical organisms, invasive pulmonary infections with Aspergillus, cytomegalovirus (CMV) viremia, skin infections, and encephalitis with bacterial brain abscesses. Venetoclax in combination with hypomethylating agents or cytotoxic chemotherapy was effective in a subset of pediatric/AYA patients with advanced hematologic malignancies, but multiple severe infections were observed, particularly among patients who received venetoclax in combination with chemotherapy. Prospective studies will be required to determine the optimal dose and duration of venetoclax in this population.

Adding venetoclax to lenalidomide and rituximab is safe and effective in patients with untreated mantle cell lymphoma

AbstractMantle cell lymphoma (MCL) is a rare, incurable hematological malignancy with a heterogeneous presentation and clinical course. A wide variety of chemotherapy-based regimens are currently used in patients who are untreated. Over the last several years, several targeted or small-molecule therapies have shown efficacy in the relapsed/refractory setting and have since been explored in the frontline setting. Lenalidomide plus rituximab was explored in a phase 2 study of 38 patients with MCL who were untreated and ineligible to receive transplantation, in which the combination produced durable remissions. We looked to build upon this regimen by adding venetoclax to the combination. We conducted a multicenter, open-label, nonrandomized, single-arm study to evaluate this combination. We enrolled 28 unselected patients with untreated disease irrespective of age, fitness, or risk factors. Lenalidomide was dosed at 20 mg daily from days 1 to 21 of each 28-day cycle. The dose of venetoclax was determined using the time-to-event continual reassessment method. Rituximab was dosed at 375 mg/m2 weekly, starting on cycle 1, day 1 until cycle 2, day 1. No dose-limiting toxicities were noted. All patients were treated with venetoclax at the maximum tolerated dose of 400 mg daily. The most common adverse events were neutropenia and thrombocytopenia. The overall and complete response rates were 96% and 86%, respectively. In total, 86% of patients achieved minimal residual disease undetectability via next-generation sequencing. The median overall and progression-free survivals were not reached. The combination of lenalidomide, rituximab, and venetoclax is a safe and effective regimen in patients with untreated MCL. This trial was registered at www.clinicaltrials.gov as #NCT03523975.

Abstract 2677: ROCK inhibitors synergize with the BCL2 inhibitor venetoclax for treatment of AML

Abstract Acute Myeloid Leukemia (AML) is a rare but catastrophic hematological cancer with a poor prognosis, high mortality, and relapse rates. Several new agents targeting specific genes or cell survival pathways have been recently approved by the FDA. AML treatment with single agents often results in resistance; therefore, combination therapies may provide more durable and effective responses. Rho kinases (ROCK1/2) are aberrantly expressed in AML patient cells, and ROCK1 has emerged lately as a potential therapeutic target for AML treatment. Previously, our group developed a new ROCK inhibitor DJ4 as an effective inducer of AML cell death. Our initial screening of DJ4 with AML standard therapy (cytarabine, daunorubicin, azacytidine, venetoclax) showed promising synergy between DJ4 and the BCL2 (B-cell lymphoma-2) inhibitor venetoclax (VEN). Enrichment of ROCK pathway in recent CRISPR drop-out screening after VEN treatment in MOLM-13 cells further validates the synergistic cooperation between ROCK and BCL2 pathways. Though VEN is widely used in hematological malignancies, its clinical efficacy is limited due to the development of resistance. Thus, we sought to investigate the novel strategy of combining VEN with ROCK inhibitors (ROCKi) for AML treatment. The combination of VEN with ROCKi (Fasudil, Y-27632, GSK269962A, DJ4) exhibited synergetic cytotoxicity in naïve (MOLM-13, MV4-11) and VEN-resistant (MV4-11/VENR, HL-60, OCI-AML3, U937) human AML cell lines. Flow cytometric analysis of Annexin V and cellular ROS levels in MV4-11 (naïve and VENR) cells upon co-treatment with sub-lethal doses of VEN and ROCKi demonstrated a significant (p&amp;lt;0.05) increase in the apoptosis and oxidative stress compared to single agents. Treatment of MV4-11 cells with VEN+ROCKi enhanced the activity of several caspases in the MultiCaspase assay. Furthermore, the colony-forming ability of AML cell lines and primary AML patient cells was significantly reduced with the combination treatment, while single agents exhibited minimal effects. MV4-11 (naïve and VENR) cells displayed alterations in the levels of critical apoptosis regulators (Bcl2, Bax, Mcl1, cleaved caspase-3) upon co-treatment in immunoblotting analysis. Additionally, MV4-11-Luc xenograft mice exhibited a significant reduction in the average leukemic burden after combination therapy relative to single agents (p&amp;lt;0.05). Altogether, our in vitro and in vivo findings established a synergetic interaction between VEN and ROCKi to effectively inhibit AML cell progression and overcome the VEN resistance (inherent or acquired). These results indicate that therapy co-targeting BCL2 and ROCK pathways exerted antileukemic activity by inducing apoptosis and may be particularly effective for AML treatment. Further studies are ongoing to explore the precise molecular mechanism of action of the VEN+ROCKi combination and its efficacy in pre-clinical animal models. Citation Format: Upendarrao Golla, Satyam Patel, Diwakar B. Tukaramrao, Jeremy Hengst, Juliana Restrepo, Shantu Amin, Dhimant Desai, Sinisa Dovat, David Claxton, Arati Sharma. ROCK inhibitors synergize with the BCL2 inhibitor venetoclax for treatment of AML [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 2677.

Practical aspects of the use of ventoclax in combination with azacitidine for the treatment of newly diagnosed acute myeloid leukaemia in patients ineligible for intensive chemotherapy

The aim of treating elderly patients with acute myeloid leukaemia (AML) ineligible for intensive chemotherapy is to extend survival, but treatment results are often unsatisfactory. Therapy with venetoclax combined with azacitidine allowed remission in two-thirds of patients and significantly prolong the median overall survival. The treatment is increasingly used in clinical practice and establishes a new medical standard. The use of venetoclax in treating AML requires knowledge of drug use rules and their individualization. This review summarizes critical elements of the clinical practice of venetoclax use in combination with azacitidine regarding the dosing regimen, management of cytopenias during therapy and treatment adjustments to prevent drug-to-drug interactions. Treatment with venetoclax can cause the risk of tumor lysis syndrome (TLS), and therefore step-wise dose ramp-up is required with the prophylaxis of TLS and reduction in leucocyte count. Cytopenias that occur during the therapy affect most of the patients; nevertheless, it is not recommended to modify the treatment until the remission of the disease. In haematologic toxicity after disease remission, it is recommended to delay the next cycle and shorten the treatment while maintaining the dose. Knowledge about venetoclax drug-to-drug interactions is necessary for an efficacious and safe therapy. It is essential to reconsider the rationale behind using some agents, e.g., azole derivatives commonly used in the prophylaxis of invasive fungal infections, as well as to be aware of the rules of venetoclax dosing. Detailed knowledge of the above aspects of therapy is essential to ensure the continuity, safety, and efficacy of venetoclax with azacitidine.

Concomitant Venetoclax and Imatinib for Comanaging Chronic Lymphocytic Leukemia and Chronic Myeloid Leukemia: A Case Report

Patients with synchronous malignancies can be problematic to diagnose and manage because workup and therapeutic targeting for each individual malignancy must be coordinated carefully. This report presents a patient with concurrent chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) managed with concomitant venetoclax and imatinib. Because imatinib is a moderate cytochrome P450 3A4 inhibitor, close monitoring is required when using with a substrate of 3A4 such as venetoclax. Although the target dose of venetoclax is 400 mg, it was capped at 100 mg due to the interaction. Despite the interaction and possible enhancement of toxicities, the patient has tolerated therapy well, and both diseases have responded to this novel approach. In addition, because aberrant BCL-2 activity has been implicated in CML, the use of venetoclax may contribute to success in the management of this patient's CML. This case report represents the safe concomitant use of venetoclax and imatinib in a patient with synchronous CML and CLL.

A Phase Ib Study of the Safety and Efficacy of Venetoclax When Combined with Escalating Doses of Omacetaxine in Patients with Relapsed/Refractory Acute Myeloid Leukemia Failing Treatment with Venetoclax-Containing Regimens (VEN-OM)

Background: Venetoclax (VEN) combined with hypomethylating agents (HMA) are increasingly used as first line (1L) treatment in AML patients (pt) intolerant of intensive chemotherapy, due to the high complete remission (CR) rate (66.4%), tolerance of therapy and a median duration CR of 17.5 months. However, >60% of pts discontinued VEN/HMA (n=286) during the VIALE-A trial, mostly due to disease progression (DiNardo et al.N Engl J Med2020; 383:617-29). Outcomes for such pts receiving 2L and 3L therapies for relapsed/refractory (R/R) AML are poor and may be due to development of resistance to BCL-2 inhibition through mechanisms including the upregulation of the anti-apoptotic proteins BCL-XL or MCL1. In vitro studies demonstrate that VEN-resistant leukemia stem cells (LSC) are re-sensitized to BCL-2 inhibition when MCL-1 is also inhibited (Ramsey et al. Cancer Discov 2018; 8:1566-81). Novel MCL-1 inhibitors are thus in phase 1 clinical trials in R/R AML (e.g. NCT02675452), however there have been concerns for cardiotoxicity. Metabolic studies (Stevens et al. Nat Commun 2018: 9, 3694) indicate that the CD123+ malignant stem cell compartment of pts with high-grade MDS rely on upregulation of the protein synthesis machinery and mitochondrial oxidative phosphorylation (OxPhos). Omacetaxine (OM), a protein translation inhibitor both inhibits OxPhos and down-regulates (other) proteins with a short half-life such as MCL1. Treatment of a xenograft AML model with a combination of OM and VEN indicates in vivo synergistic effects in impairing mitochondrial respiration, ATP production, BCL-2 inhibition and MCL-1 downregulation (Fig 1A). We hypothesize this combination will prove effective in pts with R/R AML including those resistant to VEN-containing regimens. A similar drug combination is being studied by Dinardo et al. in R/R AML and MDS pts with RUNX1 mutations. Methods: VEN-OM is a single arm, open-label, phase Ib dose-escalation study in R/R AML pts (18-75y). The trial utilizes an innovative Bayesian Optimal Interval (BOIN) adaptive design (Yuan et al. Clin Cancer Res 2016)to determine the maximum tolerated dose (MTD), with a target dose-limiting toxicity (DLT) rate of 2%, and 4 pre-specified dose levels of OM, involving 24-30 pts. Major eligibility: ECOG 0-2, adequate organ function, R/R AML having progressed on ≥ 1L of therapy, which must have included a VEN-containing regimen. Exclusion criteria: Prior use of OM, peripheral blast count > 25 × 109/L, unresolved ≥ grade 2 clinically significant nonhematologic toxicities from prior anticancer therapy, unresolved ≥ grade 2 disseminated intravascular coagulation (DIC), other active malignancy within 1 year before study entry, or active infections. Induction Phase: Beginning with the first pt treated at the lowest dose of OM (0.625 mg/m2 q12h), OM dose escalation and de-escalation will involve comparison of the observed DLT rate at the current dose with a pair of fixed, pre-specified boundary rates. After a VEN ramp-up phase (days 1-3), the VEN dose is fixed at 400mg daily on days 4-28. OM doses are given days 1-7. OM dose will be escalated for each subsequent pt until the first DLT occurs, whereupon the current dose cohort is expanded to 3. In simulations of these conditions with a target DLT rate of 20%, the percentage correct selection of the MTD is between 60% with enrollment of 20 pts and 70% with 24 pts. Consolidation Phase: OM dose will be as per induction dose for days 1-7 of each cycle. VEN dose is 400mg days 1-21. Regimen comprises 3 cycles: Induction cycle x 1 and Consolidation cycles x 2 (Fig 1B). Primary endpoint is MTD of the combination of VEN and OM. Secondary endpoints include overall response rate after 3 cycles, characterization of adverse effects, and estimates of EFS and OS at 12 months. Exploratory objectives include measurement of validated markers of early renal injury including urine TIMP-2 x IGFBP7 and KIM-1 to identify pts susceptible to OM-induced nephrotoxicity and potential correlation with OM efficacy. Our previous experience with OM added to 7+3 ("AML-02", ASH 2022 abstract submitted) suggests that quantification of BM leukemia blast protein synthesis rates (Walker et al. Clin Cancer Res 2021, 27:819-30) and 'BH3 profiling' at presentation predicts outcomes, and these correlative studies will also be performed. The study recently opened, with the first patient completing induction without complications. Trial registered as (NCT04926285). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Exposure-Response Analysis Supports a Lower Dose of Venetoclax in t(11;14)-Positive Relapsed/Refractory Multiple Myeloma Patients When Combined with Daratumumab and Dexamethasone

Introduction: Venetoclax is a first in class BCL2 inhibitor approved for treatment of CLL and AML and is currently under investigation in other hematological malignancies including multiple myeloma (MM). This analysis aimed to select the optimal venetoclax dose in combination with daratumumab and dexamethasone (VenDd) in t(11;14)-positive relapsed/refractory MM patients using data from Study M15-654 (NCI: NCT03314181) which evaluated VenDd versus bortezomib in combination with daratumumab and dexamethasone (DVd). Methods: 66 subjects (47 receiving VenDd and 19 in the control arm receiving DVd) enrolled in Study NCI: NCT03314181 were included in the analysis. A population pharmacokinetic model was developed and individual subject venetoclax exposures (average area under the concentration time curve [AUCavg] and steady state AUC [AUCss] were determined using the individual post hoc empirical Bayes parameter estimates. The effect of the following covariates on the relationships for the efficacy and safety endpoints were evaluated: number of prior therapies, cytogenetic risk, international staging system (ISS) stage, t(11;14) status, bortezomib co-administration, and daratumumab route of administration. Kaplan-Meier curves and Cox proportional hazards models were used to describe the relationship between venetoclax exposures (AUCavg or AUCss) and progression free survival (PFS). Quartile plots and logistic regression models were used to describe the relationship between venetoclax exposure (AUCavg or AUCss) and the other efficacy and safety endpoints. Results: Exposure-response analysis demonstrated that compared to the control arm, venetoclax resulted in higher response rates (very good partial response or better [≥VGPR] and complete response or better [≥CR]) and longer PFS (PFS data not mature at time of analysis). Within the VenDd treatment arms, evaluating the exposure-response relationships over the venetoclax exposure range in patients receiving 400 mg or 800 mg venetoclax demonstrated that higher venetoclax exposures were not associated with an improved efficacy profile (PFS or ≥VGPR and ≥CR rates) compared to subjects with lower venetoclax exposures. While both 400 mg and 800 mg venetoclax were generally tolerated, higher venetoclax exposures (AUCavg and AUCss) trended with higher rates of treatment-emergent serious adverse events (any grade), and Grade ≥3 treatment-emergent adverse events (AUCss only). Higher venetoclax exposures were not associated with higher rates of Grade ≥2 infections, Grade ≥3 infections or Grade ≥3 neutropenia. Additionally, no other significant covariates were identified for any of the efficacy or safety endpoints evaluated. Conclusion: Exposure-response analyses support the selection and evaluation of the 400 mg QD dosing of venetoclax in combination with daratumumab and dexamethasone in t(11;14)-positive relapsed/refractory MM subjects in future studies. This is a lower dose than that selected for venetoclax when combined only with dexamethasone in t(11;14)-positive relapsed/refractory MM patients.

High Response and Prolonged Treatment-Free Remission after a Short-Course of Modified Intensive Chemotherapy and Venetoclax in Elderly AML: An Updated Analysis of the Caveat Trial

Background Venetoclax (VEN) plus azacitidine has an established role in the management of older patients (pts) with AML (DiNardo, NEJM 2020). To explore the feasibility of intensive chemotherapy combined with VEN in older pts with newly diagnosed AML, we conducted the CAVEAT trial (Chua et al, JCO 2020). We now present an updated analysis of this trial (with >3 years median follow-up), reporting on the optimal dose of VEN with chemotherapy, with and without posaconazole (POSA), the deliverability of consolidation therapy, characteristics of treatment failure and observation of substantial treatment-free remission in subsets of pts using this time-limited, short-course regimen. Methods The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy. Five VEN dose escalation cohorts (50-100-200-400-600 mg) were explored initially. Two additional cohorts examined the safety of adjusted dosing of VEN (50 or 100 mg) during anti-fungal prophylaxis with the strong CYP3A4 inhibitor POSA. For induction, VEN was administered over 14 days, commencing with a 7-day pre-chemo dose ramp-up, followed by a 7-day overlap with 5+2 chemotherapy (cytarabine 100mg/m2/d IVI d1-5 and idarubicin 12mg/m2 IV d2-3). Consolidation (CONS) with 2+1 chemotherapy (below), followed by up to 7 cycles of VEN monotherapy maintenance was planned. Results Data cut-off: 31MAR2022. A total of 69 pts are included in this analysis (first pt 17JUL2016, last pt 15MAY2020). Median age was 71 years (range 63-80). Poor risk features included sAML (42%), adverse karyotype (28%) and prior HMA (23%). From the dose escalation phase, the VEN 600 mg cohort was well tolerated (30-day mortality 6%). Induction with VEN-POSA (n=18) was also well tolerated (30-day mortality 0%) with 3 DLTs observed: 2 hematologic (1 in each cohort) and 1 due to pulmonary infiltrates occurring on d2 induction (suspected to be allopurinol hypersensitivity). No clinical TLS was observed. Although hematologic recovery was satisfactory after VEN-POSA induction, recovery was considerably longer in the VEN (100mg)-POSA cohort after CONS1 compared to VEN (50mg)-POSA for both neutrophils (median 64 vs 44d to 0.5 x109/L) and platelets (median not reached vs 26d to 50 x109/L). Therefore, if POSA is used concurrently, VEN 50 mg is recommended. Alternatively, if VEN 600 mg is used, POSA should commence only after completion of VEN. In the VEN 600 mg cohort, significant delays in hematological recovery were also observed after multiple rounds of attenuated CONS (VEN d1-14, bolus doses of cytarabine 100 mg/m2 d1-2, idarubicin 12 mg/m2 on d1), limiting deliverability (median CONS cycles 1; range 1-3). By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively. With a median follow-up of 37 months (m), the median overall survival (OS) was 15.4m. Median OS was 31.3m in de novo AML (40% alive at 36m) and 30.3m in intermediate karyotype AML (38% alive at 36m). In the VEN 600 mg cohort, median OS was 24.1m (36% alive at 36m). As CAVEAT delivered just one intensive cycle of therapy, followed by limited post remission therapy (median time on therapy 7.7m), we next assessed the duration of treatment-free remission (TFR) among responders. Among pts achieving CR/CRi, 20/51 (39%) experienced TFR (Fig 1). The median TFR was 22.1m (range 4.6-48.3m). At data cut-off, 12 (24%) have ongoing TFR. Notably, 15/20 (75%) with TFR had an NPM1 or IDH2 mutation at diagnosis. 11 out of 14 evaluable pts with NPM1 mutation had mutation clearance by RT-qPCR, including 3 with NPM1 negative disease at time of failure (1 refractory, 2 relapse). Two pts with persistently mutated NPM1 at relapse had a concomitant FLT3-ITD or KIT mutation. The mutation landscape at relapse is shown (Fig 1) Conclusion VEN combined with modified intensive chemotherapy achieved high response rates in older pts with newly diagnosed AML. With long-term follow-up, the time-limited CAVEAT schedule enabled pts, especially with mutated NPM1 or IDH2, to experience a durable treatment-free remission. Cumulative hematological toxicity is limiting, prompting us to now explore non-anthracycline CONS (low dose cytarabine 20mg/m2 SC d1-10 + VEN 400mg d1-7, for up to 4 cycles), followed by VEN monotherapy (400mg D1-14 q28d cycle x7). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Treatment Response and Impact Factor of Venetoclax Based Regimens in the Frontline Treatment of Newly Diagnosed Unfit Acute Myeloid Leukemia in the Real World of China

Purpose: Aim to assess the efficacy and safety of venetoclax (VEN) based regimens in the frontline treatment of newly diagnosed (ND) unfit acute myeloid leukemia (AML), and then explore the impact factors of the efficacy in the real world of China. Method: All patients with ND-unfit-AML being frontline treated with VEN-based regimens from July 2019 to February 2022 in Nanfang Hospital were included and analyzed their treatment response, safety and the impact factors of efficacy. Results: Totally 73 patients with a median age of 64(13-84) years old (54(74.0%) patients with Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0-2 and 19(26.0%) with ECOG PS of 3-4) were frontline treated with a median of 2(1-8) cycles of VEN-based therapy, including 68(93.2%) with VEN+azacytidine and 5(6.8%) with VEN+decitabine. 32(43.8%) patients terminated VEN-based therapy, including 26(35.6%) cases were adjusted their treatment strategy, and 20(27.4%) patients were bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). With a median follow-up of 8.0(1.0-31.0) months, a total of 56(76.7%) patients acquired treatment response, including 48(65.8%) with complete remission (CR)/CR with incomplete count recovery (CRi) and 30/71(42.3%) with measurable residual disease (MRD) negative. The median time of acquiring CR/CRi was 1(1-5) cycle of therapy. The rate of CR/CRi and MRD negative were increasing with rising cycles of therapy. Patients with low risk (vs intermediate risk and high risk) according to European Leukemia Net stratification, mutation of IDH1/2, NPM1 and FLT3-ITD/TKD, and 28 days of VEN (vs 14-21 days) had better response to VEN-based therapy. There were not significantly different in the rate CR/CRi and MRD negative between the patients with de novo versus secondary/treatment-related AML, the dose of VEN with 400mg/d versus 100-200mg/d (co-administered with posaconazoleorvoriconazole). The median overall survival (mOS) was 20.3±1.8 months. The rate of one year OS was 62.5%±7.5%. The patients with acquiring CR/CRi (P<0.001) or MRD negative (P=0.001 had significantly better mOS than those without. The patients with treatment strategy adjustment had much longer mOS (P=0.011) and lower rate of relapse (p=0,020) than those with continuous VEN-based therapy, especially remarkably in the patients with the age <60 years old or high risk. Bridging to allo-HSCT further improved mOS versus those without (P=0.010). The safety of VEN-based therapy was well tolerated and the incidence of ≥3 grade adverse events was low. Conclusion: VEN-based therapy as the frontline treatment of ND-unfit-AML in the real world was effective and safe. Molecular abnormalities, treatment strategy and whether standardized use of VEN or not could significantly impact the efficacy of VEN-based therapy. Key words: Venetoclax, unfit, acute myeloid leukemia, efficacy, safety

Updated Analyses: Safety and Efficacy of Gemtuzumab Ozogamicin and Venetoclax in Patients with Relapsed or Refractory CD33+ Acute Myeloid Leukemia: A Phase Ib/II Study

Background: Results of therapy for relapsed/refractory (R/R) AML patients (pts) remain poor, with few surviving >2 years. Refractoriness to treatment may be due to the resistance of quiescent leukemia stem cells (LSCs) to conventional chemotherapy. Gemtuzumab Ozogamicin (GO), a monoclonal antibody linked to the cytotoxin calicheamicin, targets CD33, an antigen with variable expression on LSC. However, decreased blast CD33 expression, p-glycoprotein upregulation and decreased mitochondrial apoptosis are recognized mechanism of resistance to GO (Linenberger et al Leukemia 2005; 19:176-82). GO-induced apoptosis requires Bax and Bak effectors and is opposed by the anti-apoptotic proteins BCL-2 and BCL-XL. Thus, Venetoclax (VEN), a BH3 mimetic with high affinity for BCL-2 should facilitate GO-mediated LSC apoptosis. In addition, LSC, due to their reliance on oxidative phosphorylation (Lagadinou, Cell Stem Cell 2013, 12:329-41) are also uniquely sensitive to BCL-2 inhibition. Thus, we hypothesized a potential synergy between these drugs in targeting LSC in R/R AML. Study design: Big Ten Cancer Research Consortium (BTCRC)-AML17-113 is a single arm, open-label, multi-center, dose-escalation phase Ib/II study of the combination of GO and escalating doses of VEN in R/R AML pts (18-75y), using a 3+3 design. Correlative studies include pre-treatment AML blast CD33 expression and BH3 profiling, minimal residual disease (MRD) measurements at post-therapy time points using digital drop PCR technology, and quality of life (QOL) assessments (EORTC QLQ-C30, FACT-Fatigue). Methods: The primary endpoint is to determine the maximum tolerated dose (MTD) of VEN with GO. Secondary endpoints include overall response rate (ORR), anti-leukemic activity, characterization of treatment emergent adverse events (TEAEs), and estimates of relapse free survival (RFS), event free survival (EFS), and overall survival (OS). Eligibility: ECOG 0-2, adequate organ function, CD33+ in ≥20% AML blasts, ≤2 lines of prior therapy, no prior use of GO, no history of veno-occlusive disease (VOD), no BMT within 2 months, no CNS disease or HIV. Induction: 3-day VEN ramp-up to the target dose of 200 (cohort #1), 400 (#2), or 600 (#3) mg daily x 28d, with GO 3mg/m2 infused d1, 4, and 7. Consolidation/Maintenance: If CR/CRi achieved, pts proceed to BMT if applicable. If no BMT, or if partial response (PR), pts are consolidated with VEN at the prescribed dose x 28d with GO 3mg/m2 given d1 and 4 (Cycle 2). If BMT not applicable, and in CR/CRi, VEN alone is then given as maintenance in cycles 3+ until disease progression or toxicity. Updated Analysis: Trial design was previously described by Arain, S et al. JCO 2020, 15:suppl. TPS7566. Cohort#3 is completing accrual with the last of 6 patients currently undergoing induction treatment. Enrollment n=12 pts. Barriers to accrual have been the COVID-19 pandemic and widespread use of VEN/HMA by referring community oncologists. The study has been amended to allow for prior use of VEN containing regimens. SAE: Respiratory failure gr 3 (n=1), febrile neutropenia (FN) gr 3/4 (n=3), Anemia/rectal pain gr 3/4 (n=1). TEAE:(%;max grade (gr)): thrombocytopenia and anemia (both 60%;gr 4); neutropenia (40%;gr 4); pruritus (30%;gr 3); FN (20%;gr 4), weight loss, diarrhea , headache, constipation (all 20%;gr 1-2). Outcomes: None of the 6 pts in cohorts #1 and #2 responded to treatment. One pt developed VOD gr 4, related to the use of total marrow irradiation conditioning regimen post-induction with GO/VEN. In cohort #3, 3 patients are in CR (one post-HSCT), 2 are undergoing induction and 1 has progressed. Conclusion: The updated analysis of this study reveals a well tolerated drug combination with low toxicities, demonstrating responses in cohort#3 (VEN 600 mg). We plan to expand accrual to this cohort adding 6-12 pts. This trial is registered at clinicaltrials.gov as NCT040768.