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Na Zhao,1,2,* Lijun Zhu,1,* Xing Hu,1,* Juan Tong,1 Hongfeng Ge,3 Li Ye,4 Xijun Zhu,5 Can Gai,6 Yuhu Feng,7 Lei Zhang,1 Li Wang,1 Guangyu Sun,1 Lei Xue,1 Xiaoyu Zhu,1 Changcheng Zheng1,8 1Department of Hematology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230000, People’s Republic of China; 2State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230000, People’s Republic of China; 3Department of Hematology, Bozhou People’s Hospital, Bozhou, Anhui, 233500, People’s Republic of China; 4Department of Hematology, Lu’an People’s Hospital, Lu’an, Anhui, 237000, People’s Republic of China; 5Department of Hematology, Xuancheng People’s Hospital, Xuancheng, Anhui, 242000, People’s Republic of China; 6Department of Hematology, Huaibei People’s Hospital, Huaibei, Anhui, 235000, People’s Republic of China; 7Department of Hematology, Fuyang People’s Hospital, Fuyang, Anhui, 236000, People’s Republic of China; 8Department of Hematology, Centre for Leading Medicine and Advanced Technologies of IHM, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Changcheng Zheng, Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China, Email zhengchch1123@ustc.edu.cnPurpose: Evidence supporting venetoclax combined with hypomethylating agents (HMAs) in treatment-naïve myelodysplastic syndromes with increased blasts (MDS-IB), a biologically aggressive subset with high risk of leukemic transformation, remains lacking. We conducted a prospective, multicenter cohort study to evaluate the efficacy and safety of venetoclax plus HMAs in newly diagnosed MDS-IB.Patients and Methods: In this prospective, multicenter, single-arm trial conducted at six hospitals in China (August 2022–September 2024), 43 newly diagnosed adults with MDS-IB received venetoclax (ramp-up to 400 mg on days 1– 14) plus azacitidine or decitabine in 28-day cycles. Dose adjustments were made for cytopenias, infections, or drug interactions. Primary endpoints were overall response rate (ORR), duration of response (DoR), and safety. Secondary endpoints included overall survival (OS) and transformation to acute myeloid leukemia. The study was registered in the Chinese Clinical Trial Registry (registration number: [ChiCTR2200055204]).Results: The ORR was 74.4% (95% CI, 58.8-86.5%), comprising 34.4% complete remission (CR), 59.4% marrow CR (mCR), and 6.3% partial response (PR). Among the thirty-two patients who got ORR, the median DoR was 8.1 months (range, 0.9– 29.0). The 6-, 12-, and 24-month DoR rates were 68.8% (95% CI, 49.7– 81.8%), 53.2% (95% CI, 33.7– 69.4%), and 47.7% (95% CI, 27.8– 65.1%), respectively. Median OS was 12.8 months, with 12- and 24-month OS rates of 62.4% (95% CI, 46.1– 75.1%) and 49.3% (95% CI, 32.2– 64.3%), respectively. Grade 3/4 neutropenia/febrile neutropenia occurred in 60% (26/43), and pneumonia in 16% (7/43). The median interval between cycles was 59 days (range 33– 113), mainly due to hematologic toxicity.Conclusion: Venetoclax plus HMAs demonstrated promising clinical activity with manageable toxicity in newly diagnosed MDS-IB, supporting further prospective evaluation of this combination in treatment-naïve patients with increased-blast MDS.Trial Registration: Chinese Clinical Trial Registry, ChiCTR2200055204, https://www.chictr.org.cn/index.html.Keywords: venetoclax, hypomethylating agents, myelodysplastic syndromes

Background/Objectives: Patients with chronic lymphocytic leukemia (CLL) are susceptible to infections that can affect their clinical outcomes. Aims: The aims of this study were to assess the following: (1) the incidence of pneumonia in CLL patients treated with venetoclax-based regimens in a real-world setting, (2) the risk factors for event-free survival (EFS), and (3) overall survival (OS). Methods: This multicenter study included 322 patients from eight centers. Univariable and multivariable analyses (MVA) were performed, with the development of pneumonia during venetoclax-based treatment and OS as outcomes. Results: The most common complication was neutropenia (59%). During treatment with venetoclax-based regimens, 66 (20%) patients developed pneumonia—50 (23%) patients in the rituximab-plus-venetoclax (R-VEN) group and 13 (16%) patients in the obinutuzumab-plus-venetoclax (O-VEN) group (p = 0.15). Chronic obstructive pulmonary disease (COPD)/asthma, splenomegaly, elevated creatinine, and anemia < 8 g/dL were the risk factors for EFS in MVA (HR = 2.08, 95%CI 1.16–3.74, p = 0.014; HR 1.73, 95%CI 1.08–2.78, p = 0.02; HR 2.13, 95%CI 1.10–4.11, p = 0.03, HR 3.58, 95%CI 2.18–5.89, p < 0.001, respectively). Relapsed/refractory (R/R) CLL patients treated with R-VEN with pneumonia had worse OS than those without (p < 0.001). In patients treated with O-VEN, median OS did not differ between patients with and without pneumonia (p = 0.45). Conclusions: Our real-world study showed that pneumonia during venetoclax treatment occurs more frequently than reported in registration trials and has a negative impact on OS, especially in patients with R/R CLL who are treated with R-VEN. Neutropenia is not a risk factor for pneumonia.

While venetoclax‐based combinations have shown promising results in acute myeloid leukemia (AML), the remission duration is generally short, warranting strategies to further improve efficacy and overcome resistance. Here, we show that the natural quassinoid brusatol induces cell‐cycle arrest and apoptosis in multiple AML cell lines while enhancing venetoclax efficacy irrespective of inherent or acquired resistance. Mechanistically, brusatol increased p53 protein expression, leading to upregulation of its target genes/proteins, including CDKN1A (p21) and BBC3 (PUMA). Genetic deletion of TP53 attenuated brusatol‐induced apoptosis and its synergy with venetoclax, supporting p53 activation as a central mechanism underlying the anti‐leukemia response. Furthermore, the combination synergistically decreased mitochondrial membrane potential and respiratory activity, causing accumulation of reactive oxygen species in AML cells. Although brusatol and venetoclax exhibited limited effects individually, their combination markedly reduced leukemia burden and significantly prolonged survival in three independent cell line‐derived xenograft models, including venetoclax‐resistant and ‐refractory models. Notably, brusatol increased normal leukocyte and platelet counts while reducing leukemic infiltration in both bone marrow and extramedullary sites. These findings provide mechanistic insight into the synergistic effects of the brusatol‐venetoclax combination, supporting further evaluation of this therapeutic strategy in myeloid leukemias.

Yinyu Zhao,1,2,* Xuchen Song,1,3,* Lin Zhang,4 Yidan Zhu,1,2 Jiali Chen,1,3 Yiru Gong,1,2 Xingxian Luo,1 Huan He,5 Xiaohong Zhang,1 Lin Huang1 1Department of Pharmacy, Peking University People’s Hospital, Beijing, People’s Republic of China; 2School of Pharmaceutical Sciences, Peking University, Beijing, People’s Republic of China; 3School of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 4Department of Pediatrics, Peking University People’s Hospital, Beijing, People’s Republic of China; 5Department of Pharmacy, Beijing Children’s Hospital of Capital Medical University, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lin Huang, Department of Pharmacy, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, People’s Republic of China, Email huanglin@pkuph.edu.cnBackground: Venetoclax (VEN), a selective B-cell lymphoma 2 (BCL-2) inhibitor, is used in pediatric hematologic malignancies. Research on individualized VEN therapy in Chinese pediatric patients remains limited. This study aimed to develop a population pharmacokinetic (PPK) model in Chinese pediatric patients, identify covariates influencing pharmacokinetics, support personalized dosing, and explore exposure-efficacy relationships in pediatric acute myeloid leukemia (AML).Methods: PPK modeling was based on 225 plasma concentrations from 96 patients using nonlinear mixed-effects (NLME) modeling in Phoenix NLME software. A retrospective cohort of 52 AML patients receiving VEN with hypomethylating agents was analyzed, grouped as newly diagnosed or relapsed/refractory (R/R). Minimal residual disease (MRD) negativity was the primary endpoint. Mann–Whitney U-tests and logistic regression assessed associations between trough concentration (C0) and 6-hour post-dose concentration (C6) levels and MRD status.Results: A one-compartment model best described the pharmacokinetics of VEN. Body surface area (BSA) and the use of triazole drugs significantly influenced apparent clearance (CL/F), while total protein (TP) had a significant impact on apparent volume of distribution (V/F). The final model estimates were: ka = 0.15 h− 1 (fixed), V/F = 124.7 L, CL/F = 4.8 L⋅h− 1. In both newly diagnosed and R/R AML patients, C0 and C6 concentrations were significantly higher in the MRD-negative group than in the MRD-positive group (all p < 0.05). Exposure–response analyses demonstrated a consistent positive association between higher VEN exposure and MRD negativity. Logistic regression further confirmed that both C0 and C6 were independent predictors of achieving MRD negativity. Notably, in the R/R cohort, higher C6 exposure quartiles were significantly associated with increased MRD-negative rates.Conclusion: This study establishes the first real-world population pharmacokinetic model of venetoclax in Chinese pediatric patients and demonstrates a clinically meaningful exposure–response relationship. The positive association between VEN exposure and MRD negativity supports the use of therapeutic drug monitoring and PPK-guided dosing to optimize treatment in pediatric AML.Keywords: venetoclax, pediatric, hematological malignancy, population pharmacokinetics

The major form of cell death in normal as well as malignant cells is apoptosis, which is a programmed process highly regulated by the BCL-2 family of proteins. This includes the antiapoptotic proteins (BCL-2, BCL-XL, MCL-1, BCLW, and BFL-1) and the proapoptotic proteins, which can be divided into two groups: the effectors (BAX, BAK, and BOK) and the BH3-only proteins (BIM, BAD, NOXA, PUMA, BID, BIK, HRK). Notably, the BCL-2 antiapoptotic proteins are often overexpressed in malignant cells. While this offers survival advantages to malignant cells and strengthens their drug resistance capacity, it also offers opportunities for novel targeted therapies that selectively kill such cells. This review provides a comprehensive overview of the extensive preclinical and clinical studies targeting BCL-2 proteins with various BCL-2 proteins inhibitors with emphasis on venetoclax as a single agent, as well as in combination with other therapeutic agents. This review also discusses recent advances, challenges focusing on drug resistance, and future perspectives for effective targeting the Bcl-2 family of proteins in cancer.

Disruption of the physiologic balance between cell proliferation and cell death is an important step of cancer development. Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias. Among the different strategies that have been developed to inhibit BCL-2, BH3-mimetics have emerged as a novel class of compounds with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL). In April 2016, the first inhibitor of BCL-2, venetoclax, was approved by the US Food and Drug Administration for the treatment of patients with CLL who have 17p deletion and had received at least one prior therapy. This review focuses on the relevance of BCL-2 for apoptosis modulation at the mitochondrial level, its potential as therapeutic target for hematological malignancies, and the results obtained with selective inhibitors belonging to the BH3-mimetics, especially venetoclax used in monotherapy or in combination with other agents.

Previous studies have shown that small-molecule BCL-2 inhibitors can have a synergistic interaction with ABCG2 substrates in chemotherapy. Venetoclax is a potent and selective BCL-2 inhibitor, approved by the FDA in 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL). This study showed that, at a non-toxic concentration, venetoclax at 10 µM significantly reversed multidrug resistance (MDR) mediated by wild-type ABCG2, without significantly affecting MDR mediated by mutated ABCG2 (R482G and R482T) and ABCB1, while moderate or no reversal effects were observed at lower concentrations (0.5 to 1 µM). The results showed that venetoclax increased the intracellular accumulation of chemotherapeutic agents, which was the result of directly blocking the wild-type ABCG2 efflux function and inhibiting the ATPase activity of ABCG2. Our study demonstrated that venetoclax potentiates the efficacy of wild-type ABCG2 substrate drugs. These findings may provide useful guidance in combination therapy against wild-type ABCG2-mediated MDR cancer in clinical practice.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse 1 – 5 . In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes. Targeting of mitochondrial metabolism in combination with BCL-2 inhibition eradicates leukemia stem cells and induces long-lasting responses in patients with acute myeloid leukemia.

Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40–50% of younger and the great majority of elderly patients. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (IDH) 1/2–mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pre-treated patients with response rates of 30–40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with IDH1/2 mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (FLT3) mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for IDH1/2- and FLT3-mutated AML if available. In order to improve outcome in relapsed AML, it will be important to intelligently combine novel substances with each other as well as chemotherapy in prospective clinical trials. The development of therapies with bispecific antibodies or chimeric antigen receptor T cells (CAR-T) are still in early development.

Patients with acute myeloid leukemia (AML) who progress after exposure to hypomethylating agents (HMA) have a dismal prognosis. We hypothesized that the addition of venetoclax, a BCL-2 inhibitor, to AML patients who previously failed HMA might overcome resistance. Adult patients (≥ 18 years) with AML were eligible if leukemia relapsed after, or was refractory to HMA. In general, in addition to venetoclax, patients continued HMA or other low-intensity therapies. Patients who previously underwent allogeneic hematopoietic cell transplantation (HCT) were also eligible. Data were analyzed in November 2018. Twenty-three patients were treated between October 2016 and October 2018 and were eligible for this study. Median age was 76 years and 6 patients had leukemia that relapsed post allogeneic HCT. None of the patients experienced tumor lysis syndrome and toxicities were as expected and manageable. Febrile neutropenia was the most common toxicity (78% of patients). Median hospitalization time was 13 days. Forty-three percent of the patients achieved CR/CRi. Overall survival (OS) was 74% at 6 months and median OS in patients who achieved remission was 10.8 months. Higher number of blasts in both bone marrow and peripheral blood was associated with lower chances of CR, while higher WBC, LDH, and bone marrow or peripheral blasts were associated with increased mortality rate. The addition of venetoclax to patients with HMA-refractory AML may result in a substantial anti-leukemic activity, specifically in those achieving complete remission. This should be further tested in a well-designed prospective trial.