维奈克拉在急性髓系白血病中的研究进展
Progress of Venetoclax in Acute Myeloid Leukemia
DOI: 10.12677/ACM.2024.142556, PDF,   
作者: 李 贺, 陈智超*：华中科技大学同济医学院附属协和医院血液科，湖北 武汉
关键词: 维奈克拉；急性髓系白血病；Venetoclax； Acute Myeloid Leukemia
摘要: 维奈克拉(venetoclax, VEN)是一种靶向B细胞淋巴瘤-2 (B-cell lymphoma-2, BCL-2)的特异性抑制剂。在急性髓系白血病(acute myeloid leukemia, AML)中，VEN单药表现出良好的耐受性，但是疗效有限。VEN联合低甲基化药物或低剂量阿糖胞苷在AML中取得了显著的疗效，为老年或无法耐受强化化疗的AML患者带来了新的治疗选择。VEN联合强化化疗、靶向治疗和免疫治疗等临床试验的初步结果也表现出良好的疗效，为AML患者提供更多治疗可能。同时，使用VEN引发的不良反应和治疗过程中可能产生的耐药问题也需要关注。本文对VEN在AML中的最新研究进展以及其不良反应和耐药机制进行综述，以期为AML治疗提供更多可行方案。
Abstract: Venetoclax (VEN) is a specific inhibitor that targets B-cell lymphoma-2 (BCL-2). In acute myeloid leukemia (AML), VEN monotherapy shows good tolerability, but its efficacy is limited. However, when combined with hypomethylating agents or low-dose cytarabine, VEN has shown high effec-tiveness in AML treatment. This combination therapy provides a new opportunity for patients with AML, especially the elderly or those who cannot tolerate intensive chemotherapy. Preliminary re-sults from clinical trials combining VEN with intensive chemotherapy, targeted therapy, and im-munotherapy have also demonstrated good efficacy. These findings offer more treatment options for patients with AML. It is also important to note that adverse reactions and drug resistance may occur due to the use of VEN. This review reports the latest research progress of VEN in AML as well as its adverse reactions and drug resistance mechanisms, aiming to present more viable therapeu-tic options for AML.
文章引用：李贺, 陈智超. 维奈克拉在急性髓系白血病中的研究进展[J]. 临床医学进展, 2024, 14(2): 4004-4011. https://doi.org/10.12677/ACM.2024.142556

参考文献

[1] Döhner, H., Wei, A.H., Appelbaum, F.R., et al. (2022) Diagnosis and Management of AML in Adults: 2022 Recom-mendations from an International Expert Panel on Behalf of the ELN. Blood, 140, 1345-1377. [Google Scholar] [CrossRef] [PubMed]
[2] Czabotar, P.E. and Garcia-Saez, A.J. (2023) Mechanisms of BCL-2 Family Proteins in Mitochondrial Apoptosis. Nature Reviews Molecular Cell Biology, 24, 732-748. [Google Scholar] [CrossRef] [PubMed]
[3] Diepstraten, S.T., Anderson, M.A., Czabotar, P.E., et al. (2022) The Manipulation of Apoptosis for Cancer Therapy Using BH3-Mimetic Drugs. Nature Reviews Cancer, 22, 45-64. [Google Scholar] [CrossRef] [PubMed]
[4] 中国临床肿瘤学会白血病专家委员会. 维奈克拉治疗恶性血液病临床应用指导原则(2021年版) [J]. 白血病∙淋巴瘤, 2021, 30(12): 710-718.
[5] 中华医学会血液学分会白血病淋巴瘤学组. 成人急性髓系白血病(非急性早幼粒细胞白血病)中国诊疗指南(2023年版) [J]. 中华血液学杂志, 2023, 44(9): 705-712.
[6] Konopleva, M., Pollyea, D.A., Potluri, J., et al. (2016) Efficacy and Biological Correlates of Response in a Phase II Study of Venetoclax Monotherapy in Patients with Acute Myelogenous Leukemia. Cancer Dis-covery, 6, 1106-1117. [Google Scholar] [CrossRef] 
[7] DiNardo, C.D., Jonas, B.A., Pullarkat, V., et al. (2020) Aza-citidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. New England Journal of Medicine, 383, 617-629. [Google Scholar] [CrossRef] 
[8] Kwag, D., Cho, B.S., Bang, S.Y., et al. (2022) Venetoclax with Decitabine versus Decitabine Monotherapy in Elderly Acute Myeloid Leukemia: A Propensity Score-Matched Analysis. Blood Cancer Journal, 12, Article No. 169. [Google Scholar] [CrossRef] [PubMed]
[9] Wei, A.H., Montesinos, P., Ivanov, V., et al. (2020) Venetoclax plus LDAC for Newly Diagnosed AML Ineligible for Intensive Chemotherapy: A Phase 3 Randomized Place-bo-Controlled Trial. Blood, 135, 2137-2145. [Google Scholar] [CrossRef] [PubMed]
[10] Kadia, T.M., Reville, P.K., Wang, X., et al. (2022) Phase II Study of Venetoclax Added to Cladribine plus Low-Dose Cytarabine Alternating with 5-Azacitidine in Older Patients with Newly Diagnosed Acute Myeloid Leukemia. Journal of Clinical Oncology, 40, 3848-3857. [Google Scholar] [CrossRef] 
[11] Stahl, M., Menghrajani, K., Derkach, A., et al. (2021) Clinical and Molecular Predictors of Response and Survival Following Venetoclax Therapy in Relapsed/Refractory AML. Blood Ad-vances, 5, 1552-1564. [Google Scholar] [CrossRef] [PubMed]
[12] Weng, G., Zhang, Y., Yu, G., et al. (2023) Genetic Char-acteristics Predict Response to Venetoclax plus Hypomethylating Agents in Relapsed or Refractory Acute Myeloid Leu-kemia. Journal of Internal Medicine, 293, 329-339. [Google Scholar] [CrossRef] [PubMed]
[13] Todisco, E., Papayannidis, C., Fracchiolla, N., et al. (2023) AVALON: The Italian Cohort Study on Real‐Life Efficacy of Hypomethylating Agents plus Venetoclax in Newly Diagnosed or Re-lapsed/Refractory Patients with Acute Myeloid Leukemia. Cancer, 129, 992-1004. [Google Scholar] [CrossRef] [PubMed]
[14] Jin, H., Zhang, Y., Yu, S., et al. (2023) Venetoclax Combined with Aza-citidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial. Journal of Hematology & Oncology, 16, Article No. 42. [Google Scholar] [CrossRef] [PubMed]
[15] Wang, H., Mao, L., Yang, M., et al. (2022) Venetoclax plus 3 + 7 Daunorubicin and Cytarabine Chemotherapy as First-Line Treatment for Adults with Acute Myeloid Leukaemia: A Multicentre, Single-Arm, Phase 2 Trial. The Lancet. Haematology, 9, E415-E424. [Google Scholar] [CrossRef] 
[16] Di Nardo, C.D., Lachowiez, C.A., Takahashi, K., et al. (2022) Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed Acute Myeloid Leukemia. American Journal of Hematology, 97, 1035-1043. [Google Scholar] [CrossRef] [PubMed]
[17] Di Nardo, C.D., Lachowiez, C.A., Takahashi, K., et al. (2021) Venetoclax Combined with FLAG-IDA Induction and Consolidation in Newly Diagnosed and Relapsed or Refractory Acute Mye-loid Leukemia. Journal of Clinical Oncology, 39, 2768-2778. [Google Scholar] [CrossRef] 
[18] Kadia, T.M., Reville, P.K., Borthakur, G., et al. (2021) Venetoclax plus Intensive Chemotherapy with Cladribine, Idarubicin, and Cytarabine in Patients with Newly Diagnosed Acute Myeloid Leukaemia or High-Risk Myelodysplastic Syndrome: A Cohort from a Single-Centre, Single-Arm, Phase 2 Trial. The Lancet. Haematology, 8, E552-E561. [Google Scholar] [CrossRef] 
[19] Suo, X., Zheng, F., Wang, D., et al. (2023) Venetoclax Combined with Daunorubicin and Cytarabine (2 + 6) as Induction Treatment in Adults with Newly Diagnosed Acute Myeloid Leukemia: A Phase 2, Multicenter, Single-Arm Trial. Experimental Hematology & Oncology, 12, Article No. 45. [Google Scholar] [CrossRef] [PubMed]
[20] Wang, H., Yao, Y., Mao, L., et al. (2023) Venetoclax plus “2 + 5” Modified Intensive Chemotherapy with Daunorubicin and Cytarabine in Fit Elderly Patients with Untreated De Novo Acute Myeloid Leukaemia: A Single-Centre Retrospective Analysis. British Journal of Haematology, 201, 568-572. [Google Scholar] [CrossRef] [PubMed]
[21] Janssen, M., et al. (2022) Venetoclax Synergizes with Gilteritinib in FLT3 Wild-Type High-Risk Acute Myeloid Leukemia By Suppressing MCL-1. Blood, 140, 2594-2610. [Google Scholar] [CrossRef] [PubMed]
[22] Daver, N., Perl, A.E., Maly, J., et al. (2022) Venetoclax plus Gilteritinib for FLT3-Mutated Relapsed/Refractory Acute Myeloid Leukemia. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 40, 4048-4059. [Google Scholar] [CrossRef] 
[23] Issa, G.C. and Di Nardo, C.D. (2021) Acute Myeloid Leukemia with IDH1 and IDH2 Mutations: 2021 Treatment Algorithm. Blood Cancer Journal, 11, Article No. 107. [Google Scholar] [CrossRef] [PubMed]
[24] Pollyea, D.A., Di Nardo, C.D., Arellano, M.L., et al. (2022) Impact of Venetoclax and Azacitidine in Treatment-Naïve Patients with Acute Myeloid Leukemia and IDH1/2 Mutations. Clinical Cancer Research, 28, 2753-2761. [Google Scholar] [CrossRef] 
[25] Cathelin, S., Sharon, D., Subedi, A., et al. (2022) Enasidenib-Induced Differentiation Promotes Sensitivity to Venetoclax in IDH2-Mutated Acute Myeloid Leukemia. Leukemia, 36, 869-872. [Google Scholar] [CrossRef] [PubMed]
[26] Jasra, S., Kazemi, M., Shah, N., et al. (2021) Case Report of Combination Therapy with Azacytidine, Enasidenib and Venetoclax in Primary Refractory AML. Experimental Hematology & Oncology, 10, Article No. 1. [Google Scholar] [CrossRef] [PubMed]
[27] Molica, M., Perrone, S., Mazzone, C., et al. (2021) CD33 Ex-pression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin. Cancers, 13, Article No. 3214. [Google Scholar] [CrossRef] [PubMed]
[28] Morse, J.W., Rios, M., Ye, J., et al. (2023) Antibody Therapies for the Treatment of Acute Myeloid Leukemia: Exploring Current and Emerging Therapeutic Targets. Expert Opinion on Investigational Drugs, 32, 107-125. [Google Scholar] [CrossRef] [PubMed]
[29] Daver, N.G., Vyas, P., Kambhampati, S., et al. (2023) Tol-erability and Efficacy of the Anticluster of Differentiation 47 Antibody Magrolimab Combined with Azacitidine in Pa-tients with Previously Untreated AML: Phase Ib Results. Journal of Clinical Oncology, 41, 4893-4904. [Google Scholar] [CrossRef] 
[30] Lane, A.A., Garcia, J.S., Raulston, E.G., et al. (2023) Phase 1b Trial of Tagraxofusp in Combination with Azacitidine with or without Venetoclax in Acute Myeloid Leukemia. Blood Advances, 8, 591-602. [Google Scholar] [CrossRef] [PubMed]
[31] DiNardo, C.D., Rausch, C.R., Benton, C., et al. (2018) Clinical Experience with the BCL2-Inhibitor Venetoclax in Combination Therapy for Relapsed and Refractory Acute Myeloid Leukemia and Related Myeloid Malignancies. American Journal of Hematology, 93, 401-407. [Google Scholar] [CrossRef] [PubMed]
[32] Dhakal, P., Bates, M., Tomasson, M.H., et al. (2023) Acute Myeloid Leu-kemia Resistant to Venetoclax-Based Therapy: What Does the Future Hold? Blood Reviews, 59, Article ID: 101036. [Google Scholar] [CrossRef] [PubMed]
[33] Carter, B.Z., Mak, P.Y., Tao, W., et al. (2022) Targeting MCL-1 Dysregulates Cell Metabolism and Leukemia-Stroma Interactions and Resensitizes Acute Myeloid Leukemia to BCL-2 Inhibition. Haematologica, 107, 58-76. [Google Scholar] [CrossRef] [PubMed]
[34] Moujalled, D.M., Brown, F.C., Chua, C.C., et al. (2023) Ac-quired Mutations in BAX Confer Resistance to BH3-Mi- metic Therapy in Acute Myeloid Leukemia. Blood, 141, 634-644. [Google Scholar] [CrossRef] [PubMed]
[35] DiNardo, C.D., Tiong, I.S., Quaglieri, A., et al. (2020) Molecular Patterns of Response and Treatment Failure after Frontline Venetoclax Combinations in Older Patients with AML. Blood, 135, 791-803. [Google Scholar] [CrossRef] [PubMed]
[36] Zhang, Q., Riley-Gillis, B., Han, L., et al. (2022) Activation of RAS/MAPK Pathway Confers MCL-1 Mediated Acquired Resistance to BCL-2 Inhibitor Venetoclax in Acute Myeloid Leukemia. Signal Transduction and Targeted Therapy, 7, Article No. 51. [Google Scholar] [CrossRef] [PubMed]
[37] Nechiporuk, T., Kurtz, S.E., Nikolova, O., et al. (2019) The TP53 Apoptotic Network Is a Primary Mediator of Resistance to BCL2 Inhibition in AML Cells. Cancer Discovery, 9, 910-925. [Google Scholar] [CrossRef] 
[38] Chen, X., Glytsou, C., Zhou, H., et al. (2019) Targeting Mi-tochondrial Structure Sensitizes Acute Myeloid Leukemia to Venetoclax Treatment. Cancer Discovery, 9, 890-909. [Google Scholar] [CrossRef] 
[39] Pollyea, D.A., Stevens, B.M., Jones, C.L., et al. (2018) Ve-netoclax with Azacitidine Disrupts Energy Metabolism and Targets Leukemia Stem Cells in Acute Myeloid Leukemia Pa-tients. Nature Medicine, 24, 1859-1866. [Google Scholar] [CrossRef] [PubMed]
[40] Stevens, B.M., Jones, C.L., Pollyea, D.A., et al. (2020) Fatty Ac-id Metabolism Underlies Venetoclax Resistance in Acute Myeloid Leukemia Stem Cells. Nature Cancer, 1, 1176-1187. [Google Scholar] [CrossRef] [PubMed]
[41] Jones, C.L., Stevens, B.M., Pollyea, D.A., et al. (2020) Nico-tinamide Metabolism Mediates Resistance to Venetoclax in Relapsed Acute Myeloid Leukemia Stem Cells. Cell Stem Cell, 27, 748-764.E4. [Google Scholar] [CrossRef] [PubMed]
[42] Kuusanmäki, H., Leppä, A.M., Pölönen, P., et al. (2020) Pheno-type-Based Drug Screening Reveals Association between Venetoclax Response and Differentiation Stage in Acute Mye-loid Leukemia. Haematologica, 105, 708-720. [Google Scholar] [CrossRef] [PubMed]
[43] Pei, S., Pollyea, D.A., Gustafson, A., et al. (2020) Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Patients with Acute Myeloid Leukemia. Cancer Discovery, 10, 536-551. [Google Scholar] [CrossRef] 
[44] White, B.S., Khan, S.A., Mason, M.J., et al. (2021) Bayesian Multi-Source Regression and Monocyte-Associated Gene Expression Predict BCL-2 Inhibitor Resistance in Acute Mye-loid Leukemia. NPJ Precision Oncology, 5, Article No. 71. [Google Scholar] [CrossRef] [PubMed]

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