Population Pharmacokinetic Models of Venetoclax in Hematologic Malignancies: A Systematic Review.

Several population pharmacokinetic (PPK) models of B cell lymphoma-2 (BCL-2) venetoclax (VEN) have been developed and published to characterize the influencing factors of pharmacokinetics in hematologic malignancies. This review described PPK models of VEN examining the magnitude and types of covariate effects in PK parameters, as well as identified areas that require further investigation in order to facilitate their use. Currently, there are six analyses on PPK models of VEN summarized in this review. Most analyses described the pharmacokinetics of VEN with a two-compartment model and all covariates are categorical. The median estimated apparent clearance (CL/F) was 446 L/Day and apparent volume of distribution of the central compartment (V2/F) was 114.5 L. The median IIV of CL/F reported was 39.5% and V2/F was 46.7%. Most commonly, CYP3A inhibitors, OATP1B3 inhibitors and rituximab co-administration were found to be significant covariates on CL/F. In addition, sex and population were influential covariates on V2/F. A detailed description of the characteristics of PPK models of VEN is provided in this review, as well as the effects of covariates on the PK parameters. For future development of the VEN PPK model, CYP3A inhibitors, rituximab co-administration, OATP1B1 transporter inhibitors, sex, population, and food might be considered. Further research and comprehensive investigations should be undertaken to explore reference ranges for therapeutic drug monitoring, define the potential role of patients with cerebrospinal fluid complications, and assess new or potential covariates. These endeavors will facilitate the development of personalized VEN therapy.

Efficacy and safety of venetoclax-based combination therapy for previously untreated acute myeloid leukemia: a meta-analysis.

PURPOSE: To explore the efficacy and safety of venetoclax-based combination therapy for older patients with newly diagnosed acute myeloid leukemia (AML). METHODS: We performed a systematic review and meta-analysis of clinical trials comparing venetoclax plus hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) with mono-HMAs or LDAC. The random or fixed effects model was applied to the studies based on heterogeneity. Dichotomous data were summarized using the risk ratio (RR) and 95% confidence interval (CI). Continuous variable data were reported as weighted mean differences (WMDs). RESULTS: Nine studies, including a total of 1232 patients, were included in this meta-analysis. Thec complete remission (CR)/complete remission with incomplete hematological recovery (CRi) rate of the venetoclax (Ven) + azacytidine (Aza) group was significantly greater than that of the Aza monotherapy group (RR: 2.42; 95% CI: 1.85-3.15; P < 0.001). Similarly, the CR/CRi rate of the Ven + LDAC group was also significantly greater than that of the LDAC monotherapy group (RR: 2.57; 95% CI: 1.58-4.17; P = 0.00). The same results were observed for OS among these groups. However, the incidence of febrile neutropenia was greater in the Ven + Aza group than in the Ven + Decitabine (Dec) or monotherapy Aza group (RR: 0.69; 95% CI: 0.53-0.90; P = 0.006 and RR: 2.19; 95% CI: 1.58-3.03; P < 0.001, respectively). In addition, the Ven + LDAC group had significantly greater rates of constipation, diarrhea, nausea, and vomiting than the LDAC monotherapy group, with RRs and CIs of 0.61 (95% CI 0.44-0.83, P = 0.002), 1.81 (95% CI 1.22-2.67, P = 0.003), 1.39 (95% CI 1.06-1.82, P = 0.016), and 1.80 (95% CI 1.19-2.72, P = 0.005), respectively. CONCLUSION: Venetoclax combined with azacitidine, decitabine, or LDAC significantly improved the CR/CRi and OS of patients with previously untreated AML. However, venetoclax plus azacitidine or LDAC was more likely to lead to increased febrile neutropenia and gastrointestinal toxicity.

[Efficacy and safety of venetoclax combined with hypomethylating agents in the treatment of 83 patients with higher-risk myelodysplastic syndromes].

Objective: This study aimed to evaluate the efficacy and safety of venetoclax (VEN) combined with hypomethylating agents (HMA) in the treatment of higher-risk myelodysplastic syndromes (HR-MDS) and analyze the factors influencing their therapeutic effect. Methods: The clinical data of 83 patients with HR-MDS who were diagnosed at the First Affiliated Hospital of Zhengzhou University between November 2019 and May 2023 were retrospectively analyzed. All patients were treated with VEN combined with HMA. The Kaplan-Meier method was used to depict the survival curves, and the log-rank test was used to compare survival between the groups. Results: The median age was 57 (15-82) years old, and 51 patients (61.4%) were male. Forty-five patients (54.2%) were initially treated with HMA, 23 (27.7%) received ≤4 cycles of HMA, and 15 (18.1%) demonstrated HMA failure. At the median follow-up of 10.3 (0.6-34.4) months, the overall response rate (ORR) was 62.7% (52/83), including 18 patients (21.7%) with a complete response (CR), 14 (16.9%) with a bone marrow CR (mCR) with hematological improvement, and 20 (24.1%) with a mCR. The ORR of patients with initial treatment, ≤4 HMA cycles, and HMA failure were 66.7%, 60.9%, and 53.3%, respectively (P=0.641). The median overall survival time was 14.6 (95% CI 7.2-22.0) months, and the median progression-free survival time was 8.9 (95% CI 6.7-11.1) months. The multivariate analysis showed that serum alkaline phosphatase (ALP) ≥90 U/L (OR=14.574, 95% CI 3.036-69.951, P=0.001), TP53 mutation (OR=13.052, 95% CI 1.982-85.932, P=0.008), and U2AF1 mutation (OR=7.720, 95% CI 1.540-38.698, P=0.013) were independent risk factors for poor efficacy of VEN combined with HMA. Hematological toxicity occurred in all patients, and the incidence of treatment-induced grade 3-4 leukopenia was 48.2% (40/83). Infection was the most common non-hematological adverse event, mainly pulmonary infection (31.3%) . Conclusion: VEN combined with HMA had a high response rate in patients with HR-MDS, both at initial treatment and with HMA failure. ALP ≥ 90 U/L, TP53 mutation, and U2AF1 mutation were independent risk factors for non-response to treatment.

Clinical pharmacokinetics and pharmacodynamics of venetoclax, a selective B-cell lymphoma-2 inhibitor.

Venetoclax, a highly potent BCL-2 inhibitor, is indicated for treatment of some hematologic malignancies as monotherapy, and/or in combination with other agents. Venetoclax pharmacokinetics has been extensively characterized in patients and healthy participants. After oral dosing, the median time to reach maximum plasma concentration ranged from 5 to 8 h and harmonic mean half-life ranged from 14 to 18 h. Food increases venetoclax bioavailability by 3-5-fold and venetoclax should be administered with food to ensure adequate and consistent bioavailability. Venetoclax is eliminated via cytochrome P450 (CYP)3A metabolism, and a negligible amount of unchanged drug is excreted in urine. Strong CYP3A/P-glycoprotein inhibitors increased venetoclax exposures (AUC) by 1.44- to 6.90-fold while a significant decrease (71%) has been observed when dosed with strong CYP3 inducers. Venetoclax does not inhibit or induce CYP enzymes or transporters. Venetoclax pharmacokinetics is not appreciably altered by age, weight, sex, but the exposure is up to twofold higher in participants from Asian countries. Mild-to-severe renal impairment or end-stage renal disease do not alter venetoclax exposures, and venetoclax is not cleared by dialysis. Although mild-to-moderate hepatic impairment does not affect venetoclax exposures, twofold higher exposure was observed in subjects with severe hepatic impairment. Venetoclax exposure is comparable across patients with different hematologic malignancies and healthy participants. Overall, venetoclax exposure is only affected by food and CYP3A modulators and is only higher in Asian subjects and subjects with severe hepatic impairment. Venetoclax exposure-response relationships are malignancy-dependent and can be different between monotherapy and combination therapy.

First-line venetoclax combinations versus chemoimmunotherapy in fit patients with chronic lymphocytic leukaemia (GAIA/CLL13): 4-year follow-up from a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: In the primary analysis report of the GAIA/CLL13 trial, we found that venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib improved undetectable measurable residual disease (MRD) rates and progression-free survival compared with chemoimmunotherapy in patients with previously untreated chronic lymphocytic leukaemia. However, to our knowledge, no data on direct comparisons of different venetoclax-based combinations are available. METHODS: GAIA/CLL13 is an open-label, randomised, phase 3 study conducted at 159 sites in ten countries in Europe and the Middle East. Eligible patients were aged 18 years or older, with a life expectancy of at least 6 months, an Eastern Cooperative Oncology group performance status of 0-2, a cumulative illness rating scale score of 6 or lower or a single score of 4 or lower, and no TP53 aberrations. Patients were randomly assigned (1:1:1:1), with a computer-generated list stratified by age, Binet stage, and regional study group, to either chemoimmunotherapy, venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. All treatments were administered in 28-day cycles. Patients in the chemoimmunotherapy group received six cycles of treatment, with patients older than 65 years receiving intravenous bendamustine (90 mg/m2, days 1-2), whereas patients aged 65 years or younger received intravenous fludarabine (25 mg/m2, days 1-3) and intravenous cyclophosphamide (250 mg/m2, days 1-3). Intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added to chemotherapy. In the experimental groups, patients received daily venetoclax (400 mg orally) for ten cycles after a 5-week ramp-up phase starting on day 22 of cycle 1. In the venetoclax-rituximab group, intravenous rituximab (375 mg/m2, day 1 of cycle 1; 500 mg/m2, day 1 of cycles 2-6) was added. In the obinutuzumab-containing groups, obinutuzumab was added (cycle 1: 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15; cycles 2-6: 1000 mg on day 1). In the venetoclax-obinutuzumab-ibrutinib group, daily ibrutinib (420 mg orally, from day 1 of cycle 1) was added until undetectable MRD was reached in two consecutive measurements (3 months apart) or until cycle 36. The planned treatment duration was six cycles in the chemoimmunotherapy group, 12 cycles in the venetoclax-rituximab and the venetoclax-obinutuzumab group and between 12 and 36 cycles in the venetoclax-obinutuzumab-ibrutinib group. Coprimary endpoints were the undetectable MRD rate in peripheral blood at month 15 for the comparison of venetoclax-obinutuzumab versus standard chemoimmunotherapy and investigator-assessed progression-free survival for the comparison of venetoclax-obinutuzumab-ibrutinib versus standard chemoimmunotherapy, both analysed in the intention-to-treat population (ie, all patients randomly assigned to treatment) with a split α of 0·025 for each coprimary endpoint. Both coprimary endpoints have been reported elsewhere. Here we report a post-hoc exploratory analysis of updated progression-free survival results after a 4-year follow-up of our study population. Safety analyses included all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02950051, recruitment is complete, and all patients are off study treatment. FINDINGS: Between Dec 13, 2016, and Oct 13, 2019, 1080 patients were screened and 926 were randomly assigned to treatment (chemoimmunotherapy group n=229; venetoclax-rituximab group n=237; venetoclax-obinutuzumab group n=229; and venetoclax-obinutuzumab-ibrutinib group n=231); mean age 60·8 years (SD 10·2), 259 (28%) of 926 patients were female, and 667 (72%) were male (data on race and ethnicity are not reported). At data cutoff for this exploratory follow-up analysis (Jan 31, 2023; median follow-up 50·7 months [IQR 44·6-57·9]), patients in the venetoclax-obinutuzumab group had significantly longer progression-free survival than those in the chemoimmunotherapy group (hazard ratio [HR] 0·47 [97·5% CI 0·32-0·69], p<0·0001) and the venetoclax-rituximab group (0·57 [0·38-0·84], p=0·0011). The venetoclax-obinutuzumab-ibrutinib group also had a significantly longer progression-free survival than the chemoimmunotherapy group (0·30 [0·19-0·47]; p<0·0001) and the venetoclax-rituximab group (0·38 [0·24-0·59]; p<0·0001). There was no difference in progression-free survival between the venetoclax-obinutuzumab-ibrutinib and venetoclax-obinutuzumab groups (0·63 [0·39-1·02]; p=0·031), and the proportional hazards assumption was not met for the comparison between the venetoclax-rituximab group versus the chemoimmunotherapy group (log-rank p=0·10). The estimated 4-year progression-free survival rate was 85·5% (97·5% CI 79·9-91·1; 37 [16%] events) in the venetoclax-obinutuzumab-ibrutinib group, 81·8% (75·8-87·8; 55 [24%] events) in the venetoclax-obinutuzumab group, 70·1% (63·0-77·3; 84 [35%] events) in the venetoclax-rituximab group, and 62·0% (54·4-69·7; 90 [39%] events) in the chemoimmunotherapy group. The most common grade 3 or worse treatment-related adverse event was neutropenia (114 [53%] of 216 patients in the chemoimmunotherapy group, 109 [46%] of 237 in the venetoclax-rituximab group, 127 [56%] of 228 in the venetoclax-obinutuzumab group, and 112 [48%] of 231 in the venetoclax-obinutuzumab-ibrutinib group). Deaths determined to be associated with study treatment by the investigator occurred in three (1%) patients in the chemoimmunotherapy group (n=1 due to each of sepsis, metastatic squamous cell carcinoma, and Richter's syndrome), none in the venetoclax-rituximab and venetoclax-obinutuzumab groups, and four (2%) in the venetoclax-obinutuzumab-ibrutinib group (n=1 due to each of acute myeloid leukaemia, fungal encephalitis, small-cell lung cancer, and toxic leukoencephalopathy). INTERPRETATION: With more than 4 years of follow-up, venetoclax-obinutuzumab and venetoclax-obinutuzumab-ibrutinib significantly extended progression-free survival compared with both chemoimmunotherapy and venetoclax-rituximab in previously untreated, fit patients with chronic lymphocytic leukaemia, thereby supporting their use and further evaluation in this patient group, while still considering the higher toxicities observed with the triple combination. FUNDING: AbbVie, Janssen, and F Hoffmann-La Roche.

A phase 3b study of venetoclax and azacitidine or decitabine in an outpatient setting in patients with acute myeloid leukemia.

Venetoclax, a highly selective BCL-2 inhibitor, combined with hypomethylating agents (HMAs) azacitidine or decitabine, is approved for the treatment of newly diagnosed acute myeloid leukemia (ND AML) in patients who are ineligible to receive intensive chemotherapy. Previous clinical studies initiated venetoclax plus HMA in an inpatient setting owing to concerns of tumor lysis syndrome (TLS). This study (NCT03941964) evaluated the efficacy and safety of venetoclax plus HMA in a United States community-based outpatient setting in patients with ND AML (N = 60) who were treatment naïve for AML, ineligible to receive intensive chemotherapy, had no evidence of spontaneous TLS at screening, and were deemed as appropriate candidates for outpatient initiation of venetoclax plus HMA by the investigator. Patients received venetoclax in combination with azacitidine (75 mg/m2) or decitabine (20 mg/m2) for up to 6 cycles during the study. With a median time on study of 18.3 weeks, the best response rate of composite complete remission was 66.7%, and the overall post-baseline red blood cell (RBC) and platelet transfusion independence rate was 55.0%, consistent with results of studies in which treatment was initiated in an inpatient setting. Key adverse events included nausea, anemia, thrombocytopenia, neutropenia, and white blood cell count decrease of any grade (≥50% of patients). The observed safety profile was generally consistent with that of venetoclax plus HMA observed in inpatient AML studies. With close monitoring, 2 cases of TLS were identified, appropriately managed, and the patients were able to continue study treatment. CLINICAL TRIALS REGISTRATION: This study is registered at ClinicalTrials.gov. The registration identification number is NCT03941964.

Combination of venetoclax and azacitidine in relapsed/refractory acute B-cell lymphoblastic leukemia: a case series from a single center.

OBJECTIVES: Relapsed/refractory acute B-cell lymphoblastic leukemia (R/R B-ALL) often responds poorly to induction chemotherapy. However, recent research has shown a novel and effective drug treatment for R/R B-ALL. METHODS: A total of eight patients with R/R B-ALL were enrolled in the study from November 2021 to August 2022. All patients received chemotherapy based on a combination regimen of venetoclax and azacitidine. The regimen was as follows venetoclax 100 mg d1, 200 mg d2, 400 mg d3-14, azacitidine 75 mg/m2 d1-7. RESULTS: Five of eight patients achieved very deep and complete remission (CR) with minimal residual disease (MRD) less than 0.1%. One patient achieved partial remission. Two patients did not achieve remission. There were no serious adverse events and all patients were well tolerated. Three patients were eligible for consolidation chemotherapy and were bridged to CAR-T therapy. CONCLUSIONS: The combined regimen of venetoclax and azacitidine may be beneficial for patients with R/R B-ALL.

Efficacy of Venetoclax and Azacitidine in Acute Myeloid Leukemia Compared to Azacitidine Monotherapy: Real-World Experience.

BACKGROUND/AIM: The combination of venetoclax (VEN) and azacitidine (AZA) (VEN+AZA) leads to higher complete remission rates and longer overall survival (OS) in patients with untreated acute myeloid leukemia (AML) who are ineligible for intensive combination chemotherapy. In practice, the doses of VEN and AZA are reduced at the attending physician's discretion to avoid adverse events; however, the impact of dose and duration reductions has not been fully clarified. We analyzed whether the efficacy was maintained with reduced VEN+AZA compared to AZA monotherapy in the real world. PATIENTS AND METHODS: A total of 33 patients were included; 17 (10 newly diagnosed, 7 primary refractory or relapsed) received VEN+AZA, and 16 (7 newly diagnosed, 9 primary refractory or relapsed) received AZA. We analyzed complete remission (CR) and CR with incomplete hematologic recovery (CRi) rates, OS, and the incidence of adverse events. RESULTS: CR/CRi were achieved in 7/17 (41.2%) and 11/17 (64.7%) patients in the VEN+AZA group and 0/15 (0%) and 2/15 (6.7%) patients in the AZA group, respectively. The CR/CRi rate was higher in the VEN+AZA group than in the AZA group (p=0.001). OS was longer in the VEN+AZA group than in the AZA group (p=0.03), with a median of 506 days [95% confidence interval (CI)=234-585 days] and 208 days (95% CI=52-343 days), respectively. CONCLUSION: The doses of the VEN+AZA combination were reduced at the attending physician's discretion, resulting in a higher CR/CRi rate and longer OS than AZA monotherapy and is considered useful for AML in the real world.

[The Efficacy and Safety of Venetoclax Combined with Azacitidine in the Treatment of Adult Patients with Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy].

OBJECTIVE: To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. METHODS: The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively. RESULTS: After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred. CONCLUSION: VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.

Poor prognosis of SRSF2 gene mutations in patients treated with VEN-AZA for newly diagnosed acute myeloid leukemia.

Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.

Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disease, which is prone to transform into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). TP53 mutation is a driving factor involved in the transformation of SDS into MDS/AML, and in the evolution of MDS to AML. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable approach, however, challenge remains regarding the balance between efficacy and the high risk from treatment-related toxicity and mortality to achieve temporary disease control before transplantation to gain time and opportunities for transplantation. At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case.

Proteomics for optimizing therapy in acute myeloid leukemia: venetoclax plus hypomethylating agents versus conventional chemotherapy.

The use of Hypomethylating agents combined with Venetoclax (VH) for the treatment of Acute Myeloid Leukemia (AML) has greatly improved outcomes in recent years. However not all patients benefit from the VH regimen and a way to rationally select between VH and Conventional Chemotherapy (CC) for individual AML patients is needed. Here, we developed a proteomic-based triaging strategy using Reverse-phase Protein Arrays (RPPA) to optimize therapy selection. We evaluated the expression of 411 proteins in 810 newly diagnosed adult AML patients, identifying 109 prognostic proteins, that divided into five patient expression profiles, which are useful for optimizing therapy selection. Furthermore, using machine learning algorithms, we determined a set of 14 proteins, among those 109, that were able to accurately recommend therapy, making it feasible for clinical application. Next, we identified a group of patients who did not benefit from either VH or CC and proposed target-based approaches to improve outcomes. Finally, we calculated that the clinical use of our proteomic strategy would have led to a change in therapy for 30% of patients, resulting in a 43% improvement in OS, resulting in around 2600 more cures from AML per year in the United States.

Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

Low incidence of tumor lysis syndrome in elderly patients with chronic lymphocytic leukemia treated with venetoclax under real-world conditions: results from the prospective observational VeRVe study.

Venetoclax is active in both frontline and relapsed/refractory settings for the treatment of chronic lymphocytic leukemia (CLL). Although the prevalence and severity of tumor lysis syndrome (TLS) are well characterized in clinical trials, laboratory and clinical TLS remain relatively unexplored in real-world clinical practice.In this prospective, real-world observational study, we aimed to determine the incidence and outcomes of TLS in patients with CLL receiving venetoclax outside a clinical trial. The study (VeRVe) was conducted in centers in Austria, Germany, and Switzerland.Two hundred and thirty-nine patients were treated according to local label with at least one dose of venetoclax. Patient demographics, baseline characteristics, and blood chemistry at baseline were documented, and descriptive statistical analyses were conducted.Seventy eight patients (33%) were treated with venetoclax monotherapy, 101 (42%) with venetoclax in combination with rituximab and 60 (25%) with venetoclax in combination with obinutuzumab. In all cases, the TLS risk mitigation strategy adhered to the ramp-up protocol. Median age was 73 years and 66% of patients were male. The majority of patients (75%) had relapsed/refractory CLL, 63/192 (32.8%) patients tested had a del(17p) and 93/134 (69.4%) patients tested had unmutated immunoglobulin heavy chain variable region gene (IGHV). Clinical TLS occurred in 5 patients (2.1%) and laboratory TLS occurred in 15 patients (6.3%). Ten patients received specific treatment, of which 6 were hospitalized. There were no deaths due to a TLS event and venetoclax was well-tolerated. Of the 5 clinical TLS events reported, none were fatal or resulted in renal failure (NCT03342144, registered on Nov 10, 2017).

Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.

PURPOSE: Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. METHODS: This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). RESULTS: Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. CONCLUSION: The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.

Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1-6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5-94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL.

Management and use of healthcare resources in patients with chronic lymphocytic leukemia initiating venetoclax in routine clinical practice.

Venetoclax is a first-in-class B-cell lymphoma-2 (BCL-2) inhibitor approved as continuous monotherapy and in combination with rituximab as fixed-treatment duration for relapsed and refractory chronic lymphocytic leukemia (R/R CLL). DEVOTE was a 24-week, multicenter observational study (NCT03310190) evaluating the safety, healthcare resource utilization (HCRU) and health-related quality of life (HRQoL) of patients initiating venetoclax for R/R CLL in Canada. Overall, 89 patients received 1 dose of venetoclax; 80% had prior exposure (42% resistant) to ibrutinib. Biochemical tumor lysis syndrome (TLS) occurred in five patients. We observed differences in hospitalization across Canadian provinces including in patients at low risk for TLS with no clear impact on TLS incidence. Additionally, a rapid and sustained improvement in several domains of HRQoL was observed during venetoclax initiation. Early adoption of venetoclax was mainly for R/R CLL patients with few treatment options; nonetheless, acceptable toxicity and a positive impact on HRQoL were observed.

Chronic Lymphocytic Leukemia Therapy Guided by Measurable Residual Disease.

BACKGROUND: The combination of ibrutinib and venetoclax has been shown to improve outcomes in patients with chronic lymphocytic leukemia (CLL) as compared with chemoimmunotherapy. Whether ibrutinib-venetoclax and personalization of treatment duration according to measurable residual disease (MRD) is more effective than fludarabine-cyclophosphamide-rituximab (FCR) is unclear. METHODS: In this phase 3, multicenter, randomized, controlled, open-label platform trial involving patients with untreated CLL, we compared ibrutinib-venetoclax and ibrutinib monotherapy with FCR. In the ibrutinib-venetoclax group, after 2 months of ibrutinib, venetoclax was added for up to 6 years of therapy. The duration of ibrutinib-venetoclax therapy was defined by MRD assessed in peripheral blood and bone marrow and was double the time taken to achieve undetectable MRD. The primary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group, results that are reported here. Key secondary end points were overall survival, response, MRD, and safety. RESULTS: A total of 523 patients were randomly assigned to the ibrutinib-venetoclax group or the FCR group. At a median of 43.7 months, disease progression or death had occurred in 12 patients in the ibrutinib-venetoclax group and 75 patients in the FCR group (hazard ratio, 0.13; 95% confidence interval [CI], 0.07 to 0.24; P<0.001). Death occurred in 9 patients in the ibrutinib-venetoclax group and 25 patients in the FCR group (hazard ratio, 0.31; 95% CI, 0.15 to 0.67). At 3 years, 58.0% of the patients in the ibrutinib-venetoclax group had stopped therapy owing to undetectable MRD. After 5 years of ibrutinib-venetoclax therapy, 65.9% of the patients had undetectable MRD in the bone marrow and 92.7% had undetectable MRD in the peripheral blood. The risk of infection was similar in the ibrutinib-venetoclax group and the FCR group. The percentage of patients with cardiac serious adverse events was higher in the ibrutinib-venetoclax group than in the FCR group (10.7% vs. 0.4%). CONCLUSIONS: MRD-directed ibrutinib-venetoclax improved progression-free survival as compared with FCR, and results for overall survival also favored ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).