Venetoclax Combination Therapy Research Articles

Venetoclax Combination Treatment of Acute Myeloid Leukemia in Adolescents and Young Adult Patients.

Over the past two decades, the prognosis in adolescents and young adults (AYAs) diagnosed with acute myeloid leukemia (AML) has significantly improved. The standard intensive cytotoxic treatment approach for AYAs with AML, consisting of induction chemotherapy with anthracycline/cytarabine combination followed by consolidation chemotherapy or stem cell transplantation, has lately been shifting toward novel targeted therapies, mostly in the fields of clinical trials. One of the most recent advances in treating AML is the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax with hypomethylating agents, which has been studied in elderly populations and was approved by the Food and Drug Administration (FDA) for patients over 75 years of age or patients excluded from intensive chemotherapy induction schemas due to comorbidities. Regarding the AYA population, venetoclax combination therapy could be a therapeutic option for patients with refractory/relapsed (R/R) AML, although data from real-world studies are currently limited. Venetoclax is frequently used by AYAs diagnosed with advanced hematologic malignancies, mainly acute lymphoblastic leukemia and myelodysplastic syndromes, as a salvage therapeutic option with considerable efficacy and safety. Herein, we aim to summarize the evidence obtained from clinical trials and observational studies on venetoclax use in AYAs with AML. Based on the available evidence, venetoclax is a safe and effective therapeutic option for R/R AML AYA patients. However, further research in larger cohorts is needed to confirm these data, establishing the benefits of a venetoclax-based regimen for this special population.

Abstract 5991: Improved venetoclax therapy by a novel conjugate with artemisinin by NOXA-mediated reduction of Mcl-1 and cyclin D1 protein in myeloid leukemia cells

Abstract Evasion of apoptosis is crucial for the growth, survival and chemoresistance of myeloid leukemia. The Bcl-2 selective inhibitor venetoclax is the only apoptosis inducer approved for clinical use. Venetoclax in combination with hypomethylating agents or low-dose cytarabine has now become the standard care for elderly AML patients. However, a sizeable fraction of patients are either refractory to venetoclax combination therapy or ultimately relapse. High or induced expression of Mcl-1 and Bcl-xL mediates venetoclax resistance. Previously we reported that artemisinin enhances venetoclax apoptosis induction by degrading Mcl-1 through NOXA induction. We designed a novel conjugate A1 of venetoclax with dihydroartemisinin. A1 shows dual functions of inhibiting Bcl-2 and inducing NOXA. A1 treatment releases Bim from both Bcl-2 and Mcl-1, further degrades Mcl-1 protein, and presents ten-fold stronger apoptotic induction ability in venetoclax insensitive cells. Acquired increase of Mcl-1 protein was observed in venetoclax resistant MOLM-13/VEN cells, which are sensitive to A1-induced apoptosis. In Bcl-xL expressing venetoclax refractory leukemia cells A1 obtains a new mechanism of inhibiting cell cycling by downregulating cyclin D1 through a new NOXA/cyclin D1 cascade, mediated through the endoperoxide moiety of artemisinin and intracellular iron, independent of Bcl-2 inhibition. We reveal a new compound A1 overcoming venetoclax resistance by NOXA-mediated degradation of Mcl-1 and cyclin D1 protein. Citation Format: Jingyi Zhang, Zhenwei Zhang, Samuel Waxman, Linxiang Zhao, Yongkui Jing. Improved venetoclax therapy by a novel conjugate with artemisinin by NOXA-mediated reduction of Mcl-1 and cyclin D1 protein in myeloid leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5991.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy

BackgroundWilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis.Methods33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed.ResultsThe median age was 73 years (range 39–87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210–482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse.ConclusionThis study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

[Analysis of the Efficacy and Prognosis Factors of Acute Myeloid Leukemia with a Combination Therapy of Venetoclax].

To explore the efficacy and prognosis factors of acute myeloid leukemia with a combination therapy of venetoclax. A retrospective analysis was performed on the clinical data of AML patients treated with a combination therapy of venetoclax from March 2020 to April 2023 in the First Hospital of Lanzhou University. The efficacy, adverse reactions and survival were observed, and the influencing factors were analyzed. A total of 74 AML patients were included in this study, including 43 initially treated AML and 31 relapsed or refractory AML (R/R AML). The median age of 43 initially treated AML patients was 65 years old, the composite complete remission (cCR) rate was 67.4% (29/43), the objective response rate (ORR) was 72.1% (31/43), and the median overall survival (OS) was 17.3 months. The median age of 31 R/R AML patients was 51 years old, with a cCR rate of 38.7% (12/31), an ORR of 58.1% (18/31), and a median OS of 7.1 months. Sex, the blood cell count before VEN, gene mutation and prognosis stratification were related to whether to obtain cCR. Failure to obtain cCR was an independent risk factor for adverse outcomes. A combination therapy of venetoclax is safe and efficacious for AML. Its efficacy and survival are affected by molecular biology, cytogenetics and other factors.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma

BackgroundDespite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL.MethodsPatients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC.ResultsThirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed.ConclusionIbrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Improved Survival with Venetoclax in Patients with Acute Myeloid Leukemia: A Retrospective Single-Center Cohort Study

Background: Venetoclax in combination with azacitidine or low-dose cytarabine has become standard treatment for newly diagnosed elderly or unfit patients with acute myeloid leukemia (AML). Since approval of venetoclax in 2020 in Japan, venetoclax combination therapy have been also used for relapsed or refractory patients although its role in relapsed or refractory disease is not well defined. The survival impact of chemotherapy with venetoclax combination therapy compared with that without venetoclax combination therapy on AML patients in a real-life setting is scarcely reported. Objective: The aim of this retrospective study was to evaluate chemotherapy with or without venetoclax combination therapy in patients with newly diagnosed AML in our institution. Patients and Methods: This study included 234 non-M3 newly diagnosed AML patients who were treated with or without venetoclax combination therapy between February 2008 and July 2023 in our hospital. We evaluated overall survival and composite complete remission (complete remission or complete remission with incomplete hematologic recovery). Overall survival was compared with the use of a cox proportional-hazards regression model adjusted for age (1-year increase) and cytogenetic risk (favorable or intermediate vs. adverse). Composite complete remission was compared between the treatment groups with the use of a logistic regression model adjusted for the same prognostic factors. Subgroup analyses of overall survival was performed according to variables based on disease characteristics at baseline to assess whether the beneficial effect of venetoclax combination therapy varied among specific patient subgroups. Results: We identified 41 patients who were treated with venetoclax as first-line or later treatment and 193 patients who were treated without venetoclax. In the venetoclax group, 26 (63.4%) received venetoclax combination therapy as first-line and 15 (36.6%) as second- or later-line treatement. Twenty (48.8%) were treated with venetoclax combined with azacitidine, 12 (29.3%) with low-dose cytarabine and 9 (22.0%) with both in their course of treatment. Patients in the venetoclax group was older than those in the non-venetoclax group (median age, 76 years vs. 67 years, respectively; P<0.001). FLT3, NPM1, TP53 and IDH1/2 mutational status was comparable between groups. The percentage of patients classified as poor cytogenetic risk category according to the NCCN guidelines for AML, 2021 was higher in the venetoclax group than that in the non-venetoclax group (51.2% vs. 28.0%, respectively; P=0.005). The percentage of patients who umderwent allogeneic hematopoietic stem cell transplantation was lower in the venetoclax group than that in the non-venetoclax group (2.4% vs. 16.6%, respectively; P=0.014). Composite complete remission was achieved in 46.3% (95% CI, 30.7 to 62.6) of the patients in the venetoclax group and 54.4% (95% CI, 47.1 to 61.6) of the patients in the non-venetoclax group (P=0.199). In a Cox model adjusting for age and cytogenetic risk, the 1-year overall survival rate was 79.4% (95% confidence interval [CI], 66.5 to 87.8) in the venetoclax group, as compared with 68.0% (95% CI, 59.6 to 75.0) in the non-venetoclax group (adjusted hazard ratio, 0.64; 95% CI, 0.41 to 1.00; P=0.049). Subgroup analysis of overall survival showed a greater survival benefit in the venetoclax group than in the non-venetoclax group in patients who were 70 years of age or older (P=0.003 for interaction) and in patients with de novo AML (P=0.022 for interaction) after adjustment for age and cytogenetic risk. Conclusions: These real-world data suggested that incorporation of venetoclax combination therapy into existing therapies improved survival in patients with AML. The survival benefit of venetoclax combination therapy was greater in elderly patient and in de novo AML patients than secondary AML patients. Interpretation of the results must be careful because the sample size in the venetoclax group was small. To confirm our findings, further investigation in a larger patient population is required.

Targeting Venetoclax Resistance in TP53-Mutated Acute Myeloid Leukemia

Introduction: The combination therapy of Venetoclax (Ven) and Azacitidine (Aza) has shown remarkable improvements in the treatment of acute myeloid leukemia (AML) patients not eligible for chemotherapy. Nevertheless, patients with TP53-mutated AML are more prone to have a refractory disease or develop rapid resistance. A recent study indicated that a combined expression ratio of BCL-2, BCL-XL and MCL-1 proteins in leukemic stem cells predicts clinical response to Ven+Aza (Waclawiczek et al. 2023). Furthermore, our previous work has demonstrated that erythroid and megakaryoblastic leukemia blasts are more dependent on BCL-XL than BCL-2 (Kuusanmäki et al. 2023). Emerging evidence suggests that the erythroid-biased differentiation and gene signature is enhanced in many TP53-mutated patients (Rodriquez-Meira et al. 2022). Here we hypothesized that in TP53 -mutated AML, leukemic blasts correspond more closely to megakaryocyte-erythroid progenitors (MEPs) leading to an unfavorable BCL-2 family expression ratio, which can be associated with poor responses to Ven. Consequently, we aimed to identify novel compounds targeting this specific patient subgroup. Methods: We utilized flow cytometry to analyze the mean fluorescent intensity (MFI) of BCL-2 family proteins (BCL-2, BCL-XL, MCL-1) in the CD34+ blast cells of 16 bone marrow-derived AML samples taken before Ven+Aza therapy ( TP53mut n=8, TP53wt n=8). Ex vivo drug testing was performed with eight compounds and blast-specific drug responses were analyzed after 48 hours with flow cytometry. RNA sequencing was performed on CD34+ or CD117+ cells enriched from 35 pre-Ven+Aza treatment samples. To assess erythroid signature scores, we calculated the mean expression of six different erythroid genes ( GATA1, KLF1, ZFPM1, GATA2, GYPA, TFRC) for each patient, following the approach by Rodriquez-Meira et al. 2022. The expression levels of 19 intracellular proteins, including BCL-2, BCL-XL, MCL-1, were quantified from the corresponding cell population of the samples by mass cytometry (CyTOF). Results: In the comparison of BCL-2 family protein expression and treatment responses, BCL-XL levels were significantly higher (p=0.03) in the treatment-resistant group, while no differences were found in BCL-2 or MCL-1 ( Figure 1A). In the TP53-mutated blasts, a trend of decreased BCL-2 was identified compared to the TP53 wild-typeblasts (p=0.08), but no difference in BCL-XL or MCL-1 levels was noted. However, all three Ven+Aza-refractory TP53-mutants exhibited high BCL-XL expression compared to the treatment-responsive TP53-mutated patients. Next, we assessed whether an erythroid-like phenotype was associated with TP53 mutation status by computing the erythroid gene signature scores from the RNAseq data of enriched blasts. Erythroid scores were increased among TP53-mutated samples (p=0.04), and interestingly, a higher erythroid score was linked to lower BCL-2 protein expression, regardless of TP53 mutation status ( Figure 1B). Finally, we assessed the drug efficacy of eight pre-selected compounds, including BCL-2 family inhibitors. As expected, Ven was ineffective in the TP53-mutated samples. In contrast, the TP53-mutated blasts showed higher ex vivo sensitivity to Navitoclax (BCL-2/BCL-XL inhibitor) (Nav IC50=90nM, Ven IC50>1000nM). Additionally, LCL-161 (IAPs inhibitor) demonstrated notable efficacy in the TP53-mutants and was significantly more effective compared to the wild-type controls (LCL-161 IC50=300nM, Ven IC50>1000nM). Discussion: Here, we show that increased BCL-XL protein expression is associated with clinical resistance to Ven+Aza. Furthermore, the link between erythroid gene signature and BCL-2 expression suggests that especially those AML blasts harboring TP53 mutations might have impaired BCL-2 expression due to a closer resemblance to MEPs. The increased sensitivity of TP53-mutated AML cells to LCL-161 demonstrated in the study, highlights the potential of targeting extrinsic apoptosis pathway via inhibiting the inhibitors of apoptosis proteins (IAPs). Furthermore, co-targeting of BCL-2/BCL-XL might provide alternative therapeutic approach in Ven resistant TP53-mutated patients. These findings are currently being validated with a larger patient cohort.

Results of a Phase 1 Trial Testing the Novel Combination Therapy of Venetoclax and Ruxolitinib in Relapsed/Refractory Acute Myeloid Leukemia Patients

Introduction : A functional small molecule screen on a large cohort of primary AML patient samples revealed that the combination of Ruxolitinib (Rux) and Venetoclax (Ven) exhibited ex vivo efficacy and synergy in both newly diagnosed and R/R AML. This observation motivated a Phase I multi-center trial to evaluate Rux+Ven in R/R AML, for which we now report complete toxicity and efficacy data for 30 subjects. Methods: This study was designed to identify a maximum tolerated or recommended Phase II dose (RP2D) and evaluate the overall safety and preliminary efficacy of Rux+Ven therapy. Eligible subjects were ≥18 years old with R/R AML. There was no restriction on the number of previous therapies or prior exposure to Ven or Rux. We included subjects with prior allogeneic transplant if GVHD was controlled and prior MDS (≥75 years old or having poor cardiac or kidney function) who progressed on a hypomethylating agent (HMA) but had no primary AML therapy. In cohorts of 3 to 4, subjects were assigned to receive Rux+Ven at 1 of 6 dose levels according to the “keyboard” Bayesian toxicity probability interval design applied to a target dose-limiting toxicity (DLT) rate of 30%. DLTs were defined as non-disease-related, Grade ≥3 non-hematologic toxicities, with exceptions for nausea, vomiting, infections, febrile neutropenia episodes, and electrolyte abnormalities that resolved within 48 hours. Hematologic DLT was specified as Grade 4 neutropenia after 42 days in the absence of disease. The DLT evaluation period covered the first cycle. Subjects could continue study therapy after two 28-day cycles if they had a response (ie, CR/CRi or MLFS) or were otherwise deriving clinical benefit. Results : This Phase 1 study has completed enrollment (n=30), with all but one patient off-treatment as of June 2023. Baseline patient characteristics are summarized in Table 1. Median age was 69 (range 29-84), 40% of subjects had ≥3 prior therapies, and 43% had prior Ven. At enrollment, 30% had prior MDS, 24% had mutated TP53 (of 25 patients with available data), and 47% had CD56+ blasts. The numbers of patients treated by dose level (DL) were: 3 on DL0 (200 mg qd Ven; 10 mg bid Rux), 4 on DL1 (400 mg qd Ven; 10 mg bid Rux), 3 on DL2 (400 mg qd Ven; 20 mg bid Rux), and 20 on DL3 (400 mg qd Ven; 30 mg bid Rux), the highest dose level of the study. Per prescribing guidelines, the cycle 1 Rux doses of 15 subjects and Ven doses of 20 subjects were reduced because of a concomitant CYP3A inhibitor. The regimen was well-tolerated. As no DLTs were observed, DL3 is the RP2D. The median (interquartile range) duration of therapy was 55 (36-93) days. The most common grade ≥3 hematologic AEs, regardless of attribution, were thrombocytopenia (50%; which was 30% at study enrollment), anemia (40%; 40% at enrollment), neutropenia (37%; 10% at enrollment), febrile neutropenia (33%), and leukopenia (33%; 7% at enrollment). Six subjects had a Grade 5 AE: 4 were unrelated to study drug (2 death NOS, 1 lung infection, 1 respiratory failure) and 2 were potentially related to Ven (1 sepsis, 1 neutropenic pneumonia). Over the first 2 cycles of study therapy, the Clinical Benefit Rate (CBR; defined as the proportion of subjects obtaining at least stable disease) was 63% (95% CI: 44%-80%). Morphologic leukemia-free state (MLFS) was achieved in 20% (95% CI: 8%-39%) and Composite Complete Remission in 10% (95% CI: 2%-27%). Median overall survival (OS) was 3.7 months (95% CI: 2.3-6.5), with 23% (95% CI: 10%-39%) alive 1 year after commencing Rux+Ven. Two participants were exceptional responders: the first achieving MLFS and receiving 16 cycles of study therapy and the second having a complete remission and remaining on-treatment after 31 cycles. Pre-Rux+Ven CD56 expression on blasts correlated with worse response (all 6 ≥MLFS patients were CD56-; Fig 1) and overall survival (HR=2.37, p=0.044; Table 1). Correlative studies such as ex vivo drug assessment, genomic analysis, CyTOF, and single-cell imaging will be presented to enhance this finding. Conclusion: The novel, all-oral combination of Rux+Ven in R/R AML patients was well-tolerated with no DLTs and an encouraging 63% CBR over cycles 1-2. Negative CD56 was a biomarker of response, although additional work is required to determine if this is a broad association with Ven-based therapies or unique to the Rux+Ven combination. The tolerable toxicity profile of Rux+Ven makes it a promising combination to test with HMAs in high-risk AML patients.

NGS Profile and the Mathematical Prediction Model for Venetoclax Combination Therapy in HM-Screen-Japan 02 Study

[Introduction] Azacitidine and venetoclax combination therapy (Aza/Ven) is a novel strategy for acute myeloid leukemia (AML). Although this regimen is widely used as a first line treatment not only for unfit/elderly patients but also for fit/young patients in the real-world situation, appropriate patient selection is an important issue. HM-SCREEN-Japan 02 (UMIN-CTR UMIN000046371) is a Japanese multicenter prospective observational study to evaluate the clinical utility of targeted sequencing. In this study, we performed the sub-analysis of newly diagnosed AML patients who received Aza/Ven as a 1 st line treatment to elucidate the genetic background of AML. Furthermore, we proposed a novel mathematical model to predict the response of Aza/Ven. [Methods] AmoyDx® Myeloid Blood Cancer Panel for acute myeloid leukemia was used for the targeted sequencing. We performed linear discriminant analysis to predict complete response patients by Aza/Ven based on clinical information before treatment. We utilized three clinical quantities for the analysis: Wilms Tumor-1 (WT1) mRNA expression level, the number of “favorable mutations”, and that of “unfavorable mutations”. Favorable and unfavorable mutations were defined as IDH1, IDH2, NPM1, and CEBPA mutations, and ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and TP53 mutations, respectively, based on the previous reports (NEJM 2019, Blood 2022). The data were standardized and utilized for the linear discriminant analysis. Statistical analyses were performed using R version 4.2.3 software (R Foundation for Statistical Computation, Vienna, Austria). [Results] Total 158 patients were enrolled in our study. Among 48 patients who received Aza/Ven as a 1 st line therapy, NGS analyses were performed prior to treatment in 38 patients. Their median age was 70.5 (39-92) years old. AML with myelodysplasia-related changes was the major subtype (71%) and 37 percent of the cases had high risk cytogenetic abnormalities at diagnosis. After 1 st line Aza/Ven treatment, complete remission (CR)/ CR with incomplete blood count recovery (CRi) was achieved in 63% of the cases while the remaining 37% were non-CR. There was a trend that patients with NPM1 and IDH1/2 mutations achieved CR/CRi, while patients with RUNX1 mutation were not tended to achieve CR (Figure 1). Next, we performed linear discriminant analysis of treatment response using three pretreatment clinical factors. Linear discriminant analysis found a linear combination of prognostic factors that best separates two classes in the group of patients. Thirty-seven patients were employed to determine the discriminant function D, given by D = 0.638 × x − 0.76 × y + 0.68 × z + 0.145. Here x, y, and z represented the WT1 quantity in peripheral blood, the number of “favorable mutations”, and that of “unfavorable mutations” after standardization, respectively. Using this model, 81.1% of cases were correctly classified, and so were 75.7% of cases with leave-one-out cross validation method (Table 1). [Discussions] As previously reported (NEJM 2019, Blood adv 2020), IDH1/2 and NPM1 mutations tended to be sensitive to Aza/Ven in our cohort. However, it would be hard to predict the response of Aza/Ven by a single gene mutation because multiple gene mutations were co-existed in most of the cases (Figure 1) and clinical factors including tumor markers might also affect the outcome. Our mathematical model, involving gene mutations and WT1, could efficiently predict the response of Aza/Ven, which may support the selection of 1 st line treatment. In conclusion, our study revealed the genetic landscape of real-world Aza/Ven therapy and provided a potential prognostic model.

Clinical Outcomes and Cardiovascular Adverse Events of Patients with Acute Myeloid Leukemia Treated with Venetoclax Plus a Hypomethylating Agent or Low-Dose Cytarabine in the Veterans Health Administration: A National Retrospective Cohort Study

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a median age at diagnosis of 68 years. Standard curative treatment consists of intensive induction chemotherapy followed by consolidation, allogeneic stem-cell transplantation, or both. However, older patients may be ineligible for intensive chemotherapy due to impaired performance status or significant comorbidities. For those medically unfit, the combination of venetoclax plus a hypomethylating agent (VEN + HMA) can be used based on the results of the phase 3 VIALE-A clinical trial (PMID: 32786187). With a median follow-up of 20.5 months, azacitidine-venetoclax achieved superior OS than azacitidine monotherapy (14.7 versus 9.6 months; HR 0.66; 95% CI 0.52-0.85; P<0.001). The only cardiac event reported was atrial fibrillation in 5% of patients. Our retrospective study explores real-world clinical outcomes and new cardiovascular adverse events of patients treated with venetoclax plus either azacitidine, decitabine, or LDAC (VEN + LDAC) in the Veterans Health Administration (VHA). Methods Medical records of 198 veterans who were patients in the VHA and treated with VEN + HMA or VEN + LDAC between January 1, 2016, and December 31, 2021, were randomly selected and reviewed. Patients with a diagnosis of AML who received front-line therapy were included. Patients with acute promyelocytic leukemia were excluded. Overall survival (OS) was defined as the period between the date of diagnosis and the date of death from any cause and was estimated using the Kaplan-Meier method. Cardiovascular adverse events were characterized as those that occurred from the first dose until 30 days after discontinuation of treatment. Results A total of 101 patients were included. The median age at diagnosis was 74 years, 98% were male, 48% presented with de novo AML, 64% had an Eastern Cooperative Oncology Group performance-status score ≤ 1, and 52% had poor cytogenetic risk according to the European LeukemiaNet (ELN) 2017 stratification. Azacitidine was used in 62% of patients, decitabine in 34%, and LDAC in 4%. Based on the common terminology criteria for adverse events (CTCAE) version 5, 28% of the cohort had grade ≥3 (≥G3) anemia, 36% ≥G3 thrombocytopenia, and 62% ≥G3 neutropenia. The median OS was 8.5 months (95% CI:6.4-12.3). Those who received azacitidine had an OS of 7.7 months (95% CI: 5.6 - 12.4) versus 10.7 with decitabine (5.3 - 19.9), however the difference was not significant (p=0.29). Twenty-five percent of patients experienced at least one new cardiovascular adverse event. Of those, 11% already had a cardiovascular comorbidity at baseline. The most common adverse events were atrial fibrillation in 9%, non-ST elevation myocardial infarction in 4%, cardiopulmonary arrest in 3%, cardiogenic pulmonary edema in 2%, and LVEF decrease in 2%. Conclusion This is the first study to analyze the OS and the array of new cardiovascular events of patients with AML treated with VEN + HMA or VEN + LDAC in the VHA. Our national retrospective cohort study showed an inferior median OS and more new adverse cardiovascular events in patients treated with VEN + HMA than what was seen in the VIALE-A study. This is likely due to the clinical design of the phase 3 trial. Furthermore, we had a higher percentage of patients with secondary AML and poor cytogenetic risk which are known adverse prognostic factors. The limitations of this study include its retrospective and observational nature with data that was created for patient care, not research, and might contain missing information. Besides, the VHA sites are exclusively located in the United States and the cohort is mainly composed of male patients which is not fully applicable to the general population. Further studies are needed to determine the real-world OS and profile of cardiovascular adverse events of venetoclax combination therapy.

Trial in Progress: Venetoclax in Combination with ASTX727, an All-Oral Therapy for Chronic Myelomonocytic Leukemia and Other MDS/MPN with Excess Blasts (VICTORY MDS/MPN): A Randomized, Phase 2 Trial

Background and Significance: The rare nature and diagnostic difficulty associated with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) has limited the inclusion of patients (pts) with these diseases, other than chronic myelomonocytic leukemia (CMML), in relevant clinical trials. This has resulted in the complete lack of approved agents for the treatment of pts with non-CMML MDS/MPN. Moreover, ASTX727 (oral decitabine-cedazuridine) was approved for CMML based on a study of only 16 pts with CMML. A larger study of CMML and non-CMML MDS/MPN is needed. MDS/MPNs appear to be BCL2-dependent (Bogenberger et al., 2015; Jilg et al., 2016), but data for venetoclax combination therapy are derived from retrospective analyses of relapsed/refractory disease (Cortes et al. 2019; Hammond et al., 2020) or single-arm studies not dedicated to MDS/MPN (NCT04655755, Venugopal et al. 2021). Venetoclax exposures are not affected by coadministration of ASTX727 and predict responses similar to historical data (Mannis et al. 2021). Based on these promising early data and the critical need, we proposed a randomized study of ASTX727 alone or in combination with venetoclax for pts with MDS/MPN and >5% blasts. Study Design and Methods: This is a National Cancer Institute-sponsored, multi-center, international, randomized phase 2 study (NCT05600894, NCI 10538) designed to evaluate the efficacy of ASTX727 alone or in combination with venetoclax in pts with newly diagnosed MDS/MPN with >5% marrow blasts. Key eligibility criteria include allowing hydroxyurea cytoreduction to a WBC <10,000/mm 3 for proliferative disease and excluding pts with need for emergent disease-directed therapy as well as prior therapy for myeloid malignancy other than hydroxyurea or thrombopoietic/erythropoietin stimulating agents. Pts will be randomized 1:1 to receive either ASTX727 alone (Days 1-5) or in combination with venetoclax, initially administered with a 3-day dosing ramp-up and given for 14 days per 28-day cycle (Figure 1). Pts are stratified by disease subtype, specifically CMML and non-CMML MDS/MPN. The primary endpoint is the rate of complete remission (adapted from the MDS/MPN-specific response criteria developed by Savona et al. 2015). Secondary endpoints include the overall response rate, overall survival, progression-free survival, allogeneic hematopoietic stem cell transplantation rate, clonality at time of hematologic remission, number of red cell and platelet transfusions required and toxicity of ASTX727 versus ASTX727 + venetoclax. Pts randomized to the ASTX727 monotherapy arm and without response after 4 cycles of therapy, or with progressive disease after an initial response, cross over to the ASTX727 + venetoclax arm. A futility analysis is planned for each cohort (first 18 and 13 pts in each treatment arm for the CMML and non-CMML cohorts, respectively). We assume that 85% and 90% of pts in the CMML and non-CMML MDS/MPN cohorts, respectively, randomized to the ASTX727 monotherapy arm will not achieve the primary endpoint and will cross over to the ASTX727 + venetoclax combination arm. The estimated accrual time of a total of 70 pts with CMML and 50 pts with non-CMML MDS/MPN will require about 2.9 and 2.1 years, respectively. Planned integrated studies include the use of an apoptosis multiplex immunoassay to evaluate how the addition of a BCL-2 inhibitor will influence the ability of ASTX727 to induce apoptosis and if particular thresholds of apoptosis are predictive of clinical response. Planned exploratory studies include the use of: 1) RNA-seq to evaluate if differences in baseline transcriptional programs appear to be predictive of response to ASTX727 and ASTX727+venetoclax, 2) next generation (Oncomine Comprehensive Assay (OCAv3)/whole exome sequencing to uncover biomarkers predictive of response/outcome, validate risk modeling to stratify these pts and detect/monitor measurable residual disease (MRD) on serial marrow samples that can predict depth of response with translation in improvement in event-based endpoints, and 3) circulating tumor DNA as a non-invasive means (i.e., without need for a marrow evaluation) of prospective MRD detection for prognostic use. This ongoing, randomized study may inform frontline therapeutic options, provide prospective data for venetoclax combination after HMA failure, and generate striking correlative science for pts with “high risk” MDS/MPN.

Venetoclax with decitabine or azacitidine in previously untreated TP53mut acute myeloid leukemia.

e19051 Background: Patients with del17p or TP53mut AML have a dismal prognosis marked by high relapse rates and short survival. The addition of venetoclax to a hypomethylating agent (HMA; decitabine or azacitidine) improved overall survival in AML compared to HMA monotherapy for non-induction candidates. However, data on the relative efficacy of venetoclax combination therapy in adverse-risk molecular groups remains sparse outside of clinical trials. The purpose of this study was to determine the efficacy of venetoclax combination therapy in patients with del17p or TP53mut AML, using HMA monotherapy as a comparison. Methods: We retrospectively analyzed 35 patients with del17p or TP53mut AML treated with venetoclax + HMA or HMA alone from January 1, 2013 to January 1, 2022 at VCU Massey Cancer Center. Patients were treated in the front-line setting and separated into two cohorts: those treated with venetoclax + HMA or HMA monotherapy. To reduce confounding effects, patients that received venetoclax following initiation of HMA monotherapy were excluded from the monotherapy arm. We recorded baseline patient and disease characteristics, cytogenetic risk, response, and survival. We used Fisher’s exact test for nominal data and Mann-Whitney for ordinal data. We analyzed survival by the Kaplan-Meier method and compared groups with the log-rank test. Results: We identified 35 patients with del17p or TP53mut AML treated with venetoclax + HMA or HMA monotherapy in the first line. Twenty-one (60.0%) patients were in the venetoclax combination arm, and 14 (40.0%) were in the monotherapy arm. There were no significant between-group differences in age (72 vs 74, p = 0.303), ECOG score (2 vs 1, p = 0.292), or Charlson Comorbidity Index score (6 vs 7, p = 0.211) between the combination and monotherapy arms, respectively. The median TP53mut variant allele frequency (VAF) was 35.5% in the venetoclax cohort and 42.2% in the HMA cohort ( p = 0.479). The composite complete remission (CCR) rate significantly favored the venetoclax arm at 40.0% (95% CI, 21.9 - 61.3), compared to 0% (95% CI, 0 - 27.8) in the monotherapy arm ( p = 0.029). Furthermore, the median overall survival significantly favored the venetoclax cohort at 6.0 months compared to 3.4 months in the HMA cohort ( p = 0.026). Strikingly, in the venetoclax combination arm, we identified that a TP53mut VAF threshold of less than 35.0% predicted superior survival at 11.8 months compared to 2.8 months for VAF of greater than 35% ( p = 0.035). The identification of a similar VAF threshold was limited in the monotherapy arm due to the availability of NGS data. Conclusions: The addition of venetoclax offers significantly superior response and survival compared to HMA monotherapy in patients with del17p or TP53mut AML. We identified a novel TP53mut VAF threshold of 35.0% that predicts superior survival with combination therapy. The clinical use of this threshold requires prospective validation.

Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience.

The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions' experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6-21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.

Venetoclax and Azacytidine Therapy in High-Risk Myelodysplastic Syndromes: A Retrospective Evaluation of a Real-World Experience. Latin-American MDS Group - Glam

Background: Venetoclax, a selective, potent, orally bioavailable BCL2 inhibitor, has shown synergistic activity with hypomethylating agents in preclinical and clinical studies in high-risk MDS and AML. The primary objective of this study was to describe the safety, effectiveness, and management of this therapy in a real-world scenario. Methods: High-risk MDS patients receiving 400 mg of oral venetoclax daily for the first 14 days of each 28-day cycle, combined with azacytidine (AZA) at 75 mg/m2 from days 1 to 7 of the 28-day cycle were reported, and retrospectively analyzed. The response rates were evaluated according to IWG-2016. A Log-Rank test (Mantel Cox) and Kaplan-Meier were performed to compare the OS of responders and non-responders. Results: From September 2017 to July 2022, 18 high-risk MDS patients under venetoclax and azacytidine were retrospectively reported. This Latin-American multicenter study showed a median age of 63 (R 37-81); 61% male; 16% median blasts at diagnosis (R 0-19); an MDS subtype of MDS_EB (72%); therapy-related MDS (11%); IPSS-R > 4.5 (83%); and high, and very high-risk cytogenetic subgroups (53%) at diagnosis. Fifteen patients (83%) were naïve for hypomethylating agents. With a median cycle of 4.5 (R 1-39), the overall response rate was 78% (Complete Remission 33%, Partial Remission 17%, medular Complete Remission 17%, and Hematology Improvement 11%) and 22% for non-responders (Stable Disease and Progressive Disease). A total of 7 (39%) patients underwent transplantation, and the median number of cycles to reach the transplant was 1 (R 1-5). The estimated median overall survival (months) for responders versus non-responders was 39.1 vs 4.5 respectively (p=0.024). Five patients (28%) progressed to AML, and there was no correlation with the type and depth of the response achieved (Graphic). The most common treatment-emergent adverse events were neutropenia and infectious diseases (22%). Dose reductions or adjustments to azoles were necessary in 10 patients (56%). There were 7 deaths, 6 of which were related to MDS: infections (3), hemorrhage (1), and AML (2). One patient in Complete Remission died because of Covid-19. Conclusion: Combination therapy of venetoclax and azacytidine in high-risk MDS patients demonstrated a tolerable safety profile, a frequent need of dose adjustments, a high overall response rate (78%), a statistically significant longer overall survival of responders (p=0.024) and a high efficacy as bridge-therapy to transplant. Further experiences are warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Throughput Pre-Clinical Models to Determine a Synergistic Molar Ratio of 5-Azacitidine to Venetoclax and Uncover Resistance Mechanisms to 5-Azacitidine and Venetoclax Combination Therapy in Acute Myeloid Leukemia

High Throughput Pre-Clinical Models to Determine a Synergistic Molar Ratio of 5-Azacitidine to Venetoclax and Uncover Resistance Mechanisms to 5-Azacitidine and Venetoclax Combination Therapy in Acute Myeloid Leukemia

Evaluation of Infection in Patients with Acute Myeloid Leukemia Treated with Hypomethylating Agents: A Systematic Review

BACKGROUND: Acute myeloid leukemia (AML) is characterized by bone marrow failure, cytopenias, and complications related to bleeding and infection. In many adults with AML, hypomethylating agents (e.g., azacitidine, decitabine) comprise the backbone of outpatient chemotherapy. Due to underlying disease and/or treatments, patients with AML frequently have severe and prolonged neutropenia, which increases risk of infectious complications. The frequency and severity of infectious complications have not been well defined for patients receiving treatment with hypomethylating agents, either alone or in combination with venetoclax. OBJECTIVE: To inform optimal supportive care therapy to minimize infection risk, we evaluated the incidence and severity of neutropenia, febrile neutropenia, and infections among patients with AML treated with hypomethylating therapy. We also aimed to study the incremental risk with combination hypomethylating therapy, and the reported use of antimicrobial prophylaxis (CRD42022339158). POPULATION: Adult patients (age ≥ 18 years) with AML (≥80% of the study population) treated with hypomethylating agents. OUTCOMES: Our primary outcome was febrile neutropenia, as per the National Cancer Institute's Common Toxicity Criteria for Adverse Events (NCI-CTCAE). Secondary outcomes included infection of any grade, grade 3 or 4 infections, death due to infection, microbial and clinical infection subtype, frequency of grade 3 or 4 neutropenia, duration of neutropenia, and use of antimicrobial prophylaxis. METHODS: We searched Medline, Embase, CENTRAL and CINAHL from inception to April 2021. We included randomized controlled trials if they evaluated hypomethylating therapy in patients with AML and reported at least one outcome of interest. We used Freeman-Tukey transformation to calculate the weighted summary proportion using a random effects model. RESULTS: From 13,225 citations, we included 18 unique trials (published between 2010 and 2021), enrolling 2,788 patients. Azacitidine was evaluated in 8/18 trials (n = 984 patients) while 6/18 trials (n = 877 patients) evaluated decitabine, and 4/18 trials (n = 927 patients) evaluated combination therapy with hypomethylating agents and venetoclax. The median patient age was 74 years (interquartile range 72 to 76 years); males represented 53% of the population. 31% of patients had grade 3 or 4 neutropenia (95% confidence interval (CI) 21% to 41%; n = 9 trials; 1,407 patients). Febrile neutropenia affected 31% patients receiving single agent hypomethylating therapy (95% CI 26% to 37%; n = 11 trials; 1,382 patients), with increased risk among patients treated with the combination of hypomethylating therapy and venetoclax (46%; 95% CI 35% to 57%; n = 2 trials; 398 patients). 45% of AML patients reported infection (95% CI 33% to 57%; n = 11 trials; 1,232 patients). The most frequent infections were respiratory infections (31%), bacteremias (24%), skin and soft tissue infections (18%), and urinary tract infections (11%). Infection-related death occurred in 8% of patients with AML (95% CI 6% to 11%; n = 9 studies; 898 patients). Microbial subtype of infection and duration of neutropenia were not reported. Antimicrobial prophylaxis was reported in only one trial. CONCLUSION: Neutropenia and infection occur commonly in patients with AML treated with hypomethylating agents, with increased risk with venetoclax combination therapy. Reported risks were heterogenous among trials, and limited data was available to evaluate the relationship between neutropenia and infection. Antimicrobial prophylaxis was rarely reported. Clinical trials are needed to inform optimal supportive care interventions to decrease infection risk in this high-risk patient population.

Preclinical Studies and Phase II Trial of Venetoclax in Combination with Chidamide and Azacitidine in Relapsed/Refractory Acute Myeloid Leukemia

Background: The treatment for relapsed and refractory acute myeloid leukemia (R/R AML) remains challenging and leukemia stem cells (LSCs) play a causal role in R/R AML. Recent progress in genomics and molecular biology has uncovered a spectrum of mutations in AML suggesting that translational research combined with targeted therapy for LSCs has greater guiding significance to improve outcome in R/R AML. Therefore, we used a high-throughput screening platform to identify a novel and effective therapeutic combination, which is venetoclax, chidamide, and azacitidine (VCA). Next, to assess the efficacy of VCA, we performed preclinical studies on LSCs-like cell lines and patient-derived xenograft (PDX) mouse model. In addition, a subsequent phase II study was conducted to test the safety and preliminary efficacy of this combination. Methods:Preclinical: We performed an automated drug screen to evaluate the drug sensitivity in CD34+CD38- KG-1α and Kasumi-1 cells simultaneously. Ultimately select the optimal combination therapy of venetoclax, chidamide, and azacitidine (VCA) by using a high-throughput platform. To validate the efficacy of the combination in vivo, we used primary CD34+ AML PDX model. Mice were treated with single, dual, or triple of venetoclax (VEN, 30 mg/kg, oral gavage), chidamide (CS055, 7.5 mg/kg, oral gavage), and azacitidine (5-AZA, 2 mg/kg, intraperitoneal injection) every 3 days for 12 days consecutively. Phase II: In a multi-center, single-arm, open-labeled phase II study, patients aged ≥18 years with R/R AML were treated with VEN at 200 mg orally daily for 14 days, CS055 at 30 mg orally twice per week for 14 days, and 5-AZA at 100 mg by continuous hypodermic injection (IH) daily for 7 days for up to two 28-day cycles. The primary objective was to assess the safety and efficacy of VCA. The primary efficacy measurement was overall response rate (ORR), which was the combined complete remission (CR), CR with incomplete hematologic recovery (CRi) and partial remission (PR). ResultsPreclinical: VCA exhibited synergistic effects on attenuating cell viability and inducing apoptosis in CD34+CD38- KG-1α and Kasumi-1 cells. Importantly, triple therapy intensively reduced leukemia burden and improved prognosis in a primary CD34+ AML derived PDX model without significant adverse effects versus single or double combination. Mechanistically, co-exposure to three agents led to the inhibition of anti-apoptotic BCL-2 family proteins (including BCL2, BCL-XL and MCL-1), associating with enhanced ubiquitination. Moreover, CS055-mediated HDAC inhibition increased F-box and WD repeat domain-containing protein 7 (FBW7) acetylation, thus resulting in FBW7 stabilization, which further enhanced the MCL-1 protein degradation. Phase II: As of July 30th, 2022, 29 patients were enrolled in the study. Patients had a median age of 51 years (range: 35-64). The median time on study was 31 (range: 4-not reached [NR]) days. 25 patients (86.2%) had confirmed responses. The ORR was 75% (12/16: 2 CR, 7 CRi and 3PR) with one complete and 88.9% (8/9: 5 CR, 2 CRi and 1 PR) with two completes. The most common non-hematologic adverse events (AE) were nausea (75%) and vomiting (25%), and no grade III or IV non-hematologic AE was observed. There was no tumor lysis syndrome (TLS) or treatment-discontinuation due to therapy. Conclusions: This novel combination strategy of VEN, CS055 and 5-AZA has shown synergy in AML LSCs-like cells and PDX model. The phase II data suggests that VCA as a chemo-free therapy exhibits promising efficacy and is safe and well-tolerated in patients with R/R AML.

Real-World Experience of Venetoclax Combination Therapy in Patients with Acute Myeloid Leukemia (AML): A Single-Institution Retrospective Study in a Middle-Income Country

Introduction Venetoclax (VEN) combined with hypomethylating (HMA) agents or intensive chemotherapy (IC) has demonstrated high remission rates, good disease control, and high allogeneic stem cell transplantation (allo-SCT) rates in patients with acute myeloid leukemia (AML) compared to chemotherapy alone. Real-world data are required to confirm findings from phase 3 studies, particularly efficacy in middle-income countries. We describe the survival and response rates in patients with de novo AML and AML secondary to myeloproliferative neoplasms (MPN), and myelodysplastic syndromes (MDS) treated with VEN in combination with HMA or IC in a real-world setting in Santiago, Chile. Methods This is a retrospective study of medically fit and unfit patients with AML who received VEN in combination with HMA or IC as first or second-line therapy between October 2018 and August 2022. We included patients with AML (>20% blasts in bone marrow), MDS with increased blasts, or transformed MPN (>10% blasts in the bone marrow or >5% blasts in peripheral blood). Demographic characteristics, cytogenetic abnormalities, molecular information, and treatment including allo-SCT were recorded and included. The Kaplan Meier Method was used for survival analysis and log-rank test for survival comparisons. Results This study included 20 consecutive patients from Clínica Alemana in Santiago, Chile. The average age was 71 (range 22-85). Fourteen patients, 14/20 (70%), were older than 65 years. Eleven patients (55%) were ineligible for IC. Secondary AML affected 9 patients (45%). Nineteen patients (95%) had an intermediate or complex karyotype. Next-Generation Sequencing was available in 11 pts. Intermediate or high-risk mutations (FLT3-ITD, ASXL1, BCOR, RUNX1, SRSF2, STAG2 ,U2AF1,BCR/ABL1) were present in 8/20 (40%) of patients. Of the 20 patients, 12 (60%) were treated with curative intent and 8 (40%) with palliative intent. VEN was given to all patients at some point during treatment, with 14 (70%) as first-line and 6 (30%) as second-line. Decitabine or azacytidine with VEN were the most used regimens in first-line (13/20, 65%). FLAG-IDA combined with VEN was the most used second-line regimen (5/9, 55%). One patient died during induction before bone marrow evaluation on day 30. In 19 evaluable patients, the complete response rate (CR+CRi) with VEN was 57% in first line and 44% in second-line. According to flow cytometry, 60% of patients achieved negative measurable residual disease (<10-3). Overall, eleven patients (55%) were able to proceed to allo-SCT, with a transplant rate of 11/12 patients (92%) in the curative intention group. The 2 year Event-Free Survival and Overall Survival for the whole group was 56% and 66% respectively with a statistically significant difference in survival between the curative and palliative intention group (Figure 1). Conclusions Real-world data from a middle-income country institution confirms that VEN combined either with HMA or IC provides high remission rates and adequate disease control in this elderly group of patients with AML treated with curative intention. VEN is useful as a bridge for transplant and should be incorporated early during induction treatment in patients with AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Targeting of G3BP2 Refines Prognosis and Synergizes with Venetoclax in Acute Myeloid Leukemia

Background: Identifying the molecular alterations that drive acute myeloid leukemia (AML) progression is critical for developing effective therapies. Currently, the B-cell lymphoma-2 (BCL2) selective inhibitor venetoclax revealed puissant survival benefits in the naive and refractory/relapse (R/R) acute myeloid leukemia (AML) patients during combination therapy. However, there are complex factors that limit the therapeutic efficacy of using venetoclax. Our study aimed to unravel the role and regulatory mechanisms of Ras-GTPase-activating protein SH3-domainbinding protein 2 (G3BP2) in AML, and to explore its potential interaction with venetoclax. Method: The mRNA levels of G3BP2 were detected in patients with AML and healthy donors using quantitative reverse transcription-PCR (RT-qPCR). Functional assays were performed to examine the effects of G3BP2 on cell proliferation and apoptosis in vitro. Gene set enrichment analysis (GSEA) was carried out to explore aberrantly activated pathways as G3BP2 increased. A Pearson correlation test was conducted to identify a correlation between G3BP2 and anti-apoptotic BCL-2 family proteins (BCL-2 and MCL-1). A small molecule (C108) that interfered with G3BP2 was used in combination with venetoclax to assess whether it yielded synergistic effects. We applied bioinformatics analysis, JASPAR database, western blot analysis, and actinomycin D-dependent mRNA stability assay to identify the transcription factor for MLC1. Results: G3BP2 was upregulated in AML patients, and its expression was negatively correlated with overall survival (OS). Knockdown of G3BP2 significantly inhibited cell proliferation and enhanced apoptosis in vitro. GSEA revealed the mTOR signaling was activated when G3BP2 was upregulated, and knockdown of G3BP2 abrogated the redundancy of pmTOR and pS6. Targeting G3BP2 with C108 synergized with venetoclax to induce apoptosis in primary AML cells and cell lines. Mechanistically, down-regulated G3BP2 led to increased ELF1 mRNA decay, thus impacting the decreased expression of MCL1 to overcome the inadequate venetoclax activity in AML cells. Conclusion: Our findings demonstrated that elevated G3BP2 might be responsible for the progress of AML. Moreover, G3BP2 could promote MCL1 transcription via ELF1, thus resulting in poor response to venetoclax in AML cells. These results provided a potential therapeutic target for venetoclax combination therapy. Keywords: Acute myeloid leukemia, G3BP2, Venetoclax, MCL1, ELF1 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Investigational venetoclax combination therapy in acute myeloid leukemia - a systematic review and meta-analysis.

Not available.