阿扎胞苷和维奈托克治疗未经治急性髓系白血病。

Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia.

机构信息

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.).

出版信息

N Engl J Med. 2020 Aug 13;383(7):617-629. doi: 10.1056/NEJMoa2012971.

DOI:10.1056/NEJMoa2012971

PMID:32786187

Abstract

BACKGROUND

Older patients with acute myeloid leukemia (AML) have a dismal prognosis, even after treatment with a hypomethylating agent. Azacitidine added to venetoclax had promising efficacy in a previous phase 1b study.

METHODS

We randomly assigned previously untreated patients with confirmed AML who were ineligible for standard induction therapy because of coexisting conditions, because they were 75 years of age or older, or both to azacitidine plus either venetoclax or placebo. All patients received a standard dose of azacitidine (75 mg per square meter of body-surface area subcutaneously or intravenously on days 1 through 7 every 28-day cycle); venetoclax (target dose, 400 mg) or matching placebo was administered orally, once daily, in 28-day cycles. The primary end point was overall survival.

RESULTS

The intention-to-treat population included 431 patients (286 in the azacitidine-venetoclax group and 145 in the azacitidine-placebo [control] group). The median age was 76 years in both groups (range, 49 to 91). At a median follow-up of 20.5 months, the median overall survival was 14.7 months in the azacitidine-venetoclax group and 9.6 months in the control group (hazard ratio for death, 0.66; 95% confidence interval, 0.52 to 0.85; P<0.001). The incidence of complete remission was higher with azacitidine-venetoclax than with the control regimen (36.7% vs. 17.9%; P<0.001), as was the composite complete remission (complete remission or complete remission with incomplete hematologic recovery) (66.4% vs. 28.3%; P<0.001). Key adverse events included nausea of any grade (in 44% of the patients in the azacitidine-venetoclax group and 35% of those in the control group) and grade 3 or higher thrombocytopenia (in 45% and 38%, respectively), neutropenia (in 42% and 28%), and febrile neutropenia (in 42% and 19%). Infections of any grade occurred in 85% of the patients in the azacitidine-venetoclax group and 67% of those in the control group, and serious adverse events occurred in 83% and 73%, respectively.

CONCLUSIONS

In previously untreated patients who were ineligible for intensive chemotherapy, overall survival was longer and the incidence of remission was higher among patients who received azacitidine plus venetoclax than among those who received azacitidine alone. The incidence of febrile neutropenia was higher in the venetoclax-azacitidine group than in the control group. (Funded by AbbVie and Genentech; VIALE-A ClinicalTrials.gov number, NCT02993523.).

摘要

背景

即使接受低甲基化药物治疗，年龄较大的急性髓系白血病（AML）患者预后仍较差。阿扎胞苷联合 venetoclax 在之前的 1b 期研究中显示出有前景的疗效。

方法

我们随机分配了未经治疗的 AML 患者，这些患者因共存疾病或年龄在 75 岁及以上而不适合标准诱导治疗，将其分配至阿扎胞苷加 venetoclax 或安慰剂组。所有患者均接受标准剂量阿扎胞苷（每平方米体表面积皮下或静脉注射 75 mg，每 28 天周期第 1 至 7 天）；venetoclax（目标剂量 400 mg）或匹配的安慰剂每天口服一次，28 天为一个周期。主要终点为总生存期。

结果

意向治疗人群包括 431 名患者（阿扎胞苷-venetoclax 组 286 名，阿扎胞苷-安慰剂[对照组]组 145 名）。两组的中位年龄均为 76 岁（范围 49 至 91 岁）。中位随访 20.5 个月时，阿扎胞苷-venetoclax 组的中位总生存期为 14.7 个月，对照组为 9.6 个月（死亡风险比，0.66；95%置信区间，0.52 至 0.85；P<0.001）。阿扎胞苷-venetoclax 组的完全缓解率高于对照组（36.7% vs. 17.9%；P<0.001），完全缓解（完全缓解或完全缓解伴不完全血液学恢复）率也高于对照组（66.4% vs. 28.3%；P<0.001）。主要不良事件包括任何等级的恶心（阿扎胞苷-venetoclax 组 44%，对照组 35%）和 3 级或以上血小板减少症（分别为 45%和 38%）、中性粒细胞减少症（分别为 42%和 28%）和发热性中性粒细胞减少症（分别为 42%和 19%）。阿扎胞苷-venetoclax 组 85%的患者发生任何等级的感染，对照组为 67%，严重不良事件分别为 83%和 73%。

结论

在不适合强化化疗的未经治疗的患者中，与接受阿扎胞苷单药治疗的患者相比，接受阿扎胞苷加 venetoclax 治疗的患者总生存期更长，缓解率更高。venetoclax-azacitidine 组发热性中性粒细胞减少症的发生率高于对照组。（由 AbbVie 和 Genentech 资助；VIALE-A ClinicalTrials.gov 编号，NCT02993523）。