提示: 手机请竖屏浏览!

阿扎胞苷联合维奈托克治疗未经治疗的急性髓系白血病
Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia


Courtney D. DiNardo ... 肿瘤 • 2020.08.13
NEJM 动画解读

急性髓系白血病的联合治疗
相关阅读
• gilteritinib治疗FLT3 突变型急性髓系白血病 • FLT3阳性急性髓系白血病的研究进展 • 米哚妥林联合化疗治疗FLT3基因突变急性髓系白血病的研究

摘要


背景

老年急性髓系白血病(AML)患者的预后极差,接受低甲基化药物(hypomethylating agent)治疗后也是如此。在之前的1b期研究中,维奈托克(venetoclax)联合阿扎胞苷表现出有前景的疗效。

 

方法

我们将因合并症、因年龄≥75岁或因同时有这两种情况而不适合接受标准诱导化疗,并且未经治疗的AML确诊患者随机分组,两组分别接受阿扎胞苷+维奈托克治疗或阿扎胞苷+安慰剂治疗。所有患者均接受了标准剂量的阿扎胞苷治疗(每28日一个周期,在每个周期的第1~7日接受皮下或静脉给药,每次75 mg/m2体表面积),并且以28日为一个周期接受了每日1次维奈托克(目标剂量,400 mg)或匹配安慰剂口服给药。主要终点是总生存期。

 

结果

意向治疗人群包括431例患者(阿扎胞苷-维奈托克组286例和阿扎胞苷-安慰剂[对照]组145例)。两组的中位年龄为76岁(范围,49~91)。在中位随访20.5个月时,阿扎胞苷-维奈托克组和对照组的中位总生存期分别为14.7个月和9.6个月(死亡的风险比,0.66;95% CI,0.52~0.85;P<0.001)。阿扎胞苷-维奈托克组的完全缓解率高于对照组(36.7% vs. 17.9%;P<0.001),复合完全缓解(完全缓解或伴有血液学非完全恢复的完全缓解)率也高于对照组(66.4% vs. 28.3%;P<0.001)。关键不良事件包括任何级别的恶心(阿扎胞苷-维奈托克组44%的患者和对照组35%的患者),以及3级或更高级别的血小板减少(分别为45%和38%)、中性粒细胞减少(42%和29%)和发热性中性粒细胞减少(42%和19%)。阿扎胞苷-维奈托克组85%的患者和对照组67%的患者发生了任何级别的感染,严重不良事件发生率分别为83%和73%。

 

结论

在不适合接受强化化疗的未经治疗患者中,阿扎胞苷+维奈托克组患者的总生存期和缓解率均超过阿扎胞苷单药治疗组。维奈托克-阿扎胞苷组的发热性中性粒细胞减少的发生率高于对照组(由艾伯维[AbbVie]和基因泰克[Genentech]资助,VIALE-A在ClinicalTrials.gov注册号为NCT02993523)。





作者信息

Courtney D. DiNardo, M.D., Brian A. Jonas, M.D., Ph.D., Vinod Pullarkat, M.D., Michael J. Thirman, M.D., Jacqueline S. Garcia, M.D., Andrew H. Wei, M.B., B.S., Ph.D., Marina Konopleva, M.D., Ph.D., Hartmut Döhner, M.D., Anthony Letai, M.D., Ph.D., Pierre Fenaux, M.D., Ph.D., Elizabeth Koller, M.D., Violaine Havelange, M.D., Ph.D., Brian Leber, M.D., Jordi Esteve, M.D., Ph.D., Jianxiang Wang, M.D., Vlatko Pejsa, M.D., Ph.D., Roman Hájek, M.D., Ph.D., Kimmo Porkka, M.D., Ph.D., Árpád Illés, M.D., D.Sci., David Lavie, M.D., Roberto M. Lemoli, M.D., Kazuhito Yamamoto, M.D., Ph.D., Sung-Soo Yoon, M.D., Ph.D., Jun-Ho Jang, M.D., Su-Peng Yeh, M.D., Mehmet Turgut, M.D., Wan-Jen Hong, M.D., Ying Zhou, Ph.D., Jalaja Potluri, M.D., and Keith W. Pratz, M.D.
From the Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (C.D.D., M.K.); the Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis School of Medicine, Sacramento (B.A.J.), the Department of Hematology and Hematopoietic Cell Transplantation and Gehr Family Center for Leukemia Research, City of Hope Comprehensive Cancer Center, Duarte (V. Pullarkat), and Genentech, South San Francisco (W.-J.H.) — all in California; the Section of Hematology and Oncology, Department of Medicine, University of Chicago Medicine, Chicago (M.J.T.), and AbbVie, North Chicago (Y.Z., J.P.) — both in Illinois; the Department of Medical Oncology, Dana–Farber Cancer Institute, Harvard Medical School, Boston (J.S.G., A.L.); the Australian Centre for Blood Diseases, Alfred Hospital and Monash University, Melbourne, VIC (A.H.W.); the Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany (H.D.); Hôpital St. Louis, Assistance Publique–Hôpitaux de Paris and Université de Paris, Paris (P.F.); the Third Medical Department for Hematology and Oncology, Hanusch Hospital, Vienna (E.K.); the Department of Hematology, Cliniques Universitaires Saint-Luc, Brussels (V.H.); the Department of Medicine, McMaster University, Hamilton, ON, Canada (B.L.); the Department of Hematology, Hospital Clinic, August Pi i Sunyer Biomedical Research Institute, Barcelona (J.E.); the Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences, Peking Union Medical College, Tianjin, China (J.W.); the Department of Hematology, University Hospital Dubrava, University of Zagreb School of Medicine, Zagreb, Croatia (V. Pejsa); the Department of Clinic Subjects, University Hospital Ostrava-Poruba, Ostrava, Czech Republic (R.H.); Helsinki University Hospital Comprehensive Cancer Center, University of Helsinki, Helsinki (K.P.); the Faculty of Medicine, Department of Hematology, University of Debrecen, Debrecen, Hungary (A.I.); Hadassah Medical Center, Jerusalem (D.L.); the Clinic of Hematology, Department of Internal Medicine, University of Genoa, and San Martino Hospital IRCCS — both in Genoa, Italy (R.M.L.); the Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan (K.Y.); the Department of Internal Medicine, Seoul National University College of Medicine (S.-S.Y.), and the Department of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine (J.-H.J.) — both in Seoul, South Korea; the Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan (S.-P.Y.); the Faculty of Medicine, Department of Internal Medicine, Division of Hematology, Ondokuz Mayıs University, Samsun, Turkey (M.T.); and Abramson Cancer Center, University of Pennsylvania, Philadelphia (K.W.P.). Address reprint requests to Dr. DiNardo at the University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 428, Houston, TX 77030, or at cdinardo@mdanderson.org.

 

参考文献

1. Howlader N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2016. Bethesda, MD: National Cancer Institute, 2019.

2. Song X, Peng Y, Wang X, et al. Incidence, survival, and risk factors for adults with acute myeloid leukemia not otherwise specified and acute myeloid leukemia with recurrent genetic abnormalities: analysis of the Surveillance, Epidemiology, and End Results (SEER) database, 2001-2013. Acta Haematol 2018;139:115-127.

3. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424-447.

4. Richard-Carpentier G, DiNardo CD. Venetoclax for the treatment of newly diagnosed acute myeloid leukemia in patients who are ineligible for intensive chemotherapy. Ther Adv Hematol 2019;10:2040620719882822-2040620719882822.

5. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood 2019;133:7-17.

6. Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126:291-299.

7. Adams CM, Clark-Garvey S, Porcu P, Eischen CM. Targeting the Bcl-2 family in B cell lymphoma. Front Oncol 2019;8:636-636.

8. Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov 2014;4:362-375.

9. Lagadinou ED, Sach A, Callahan K, et al. BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 2013;12:329-341.

10. Campos L, Rouault JP, Sabido O, et al. High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 1993;81:3091-3096.

11. Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell 2006;10:375-388.

12. Karakas T, Miething CC, Maurer U, et al. The coexpression of the apoptosis-related genes bcl-2 and wt1 in predicting survival in adult acute myeloid leukemia. Leukemia 2002;16:846-854.

13. Mehta SV, Shukla SN, Vora HH. Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: its correlation with FLT3. Neoplasma 2013;60:666-675.

14. Souers AJ, Leverson JD, Boghaert ER, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med 2013;19:202-208.

15. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov 2016;6:1106-1117.

16. Jin S, Cojocari D, Purkal JJ, et al. 5-Azacitidine induces NOXA to prime AML cells for venetoclax-mediated apoptosis. Clin Cancer Res 2020;26:3371-3383.

17. Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma 2015;56:226-229.

18. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol 2018;19:216-228.

19. Pollyea DA, Parts KW, Jonas BA, et al. Venetoclax in combination with hypomethylating agents induces rapid, deep, and durable responses in patients with AML ineligible for intensive therapy. Blood 2018;132:Suppl 1:285-285. abstract.

20. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol 2003;21:4642-4649.

21. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 2018;131:1275-1291.

22. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. opens in new tab).

23. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562-569.

24. Cortes JE, Heidel FH, Hellmann A, et al. Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. Leukemia 2019;33:379-389.

25. Krauss AC, Gao X, Li L, et al. FDA approval summary: (daunorubicin and cytarabine) liposome for injection for the treatment of adults with high-risk acute myeloid leukemia. Clin Cancer Res 2019;25:2685-2690.

26. Leverson JD, Phillips DC, Mitten MJ, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med 2015;7:279ra40-279ra40.

27. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood 2020;135:85-96.

28. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia 2019;33:2795-2804.

服务条款 | 隐私政策 | 联系我们