伴有或不伴有 TP53 突变的不良细胞遗传学患者接受 Venetoclax 和阿扎胞苷治疗的结局。

Outcomes in Patients with Poor-Risk Cytogenetics with or without TP53 Mutations Treated with Venetoclax and Azacitidine.

机构信息

Division of Hematology, School of Medicine, University of Colorado, Aurora, Colorado.

Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.

出版信息

Clin Cancer Res. 2022 Dec 15;28(24):5272-5279. doi: 10.1158/1078-0432.CCR-22-1183.

DOI:10.1158/1078-0432.CCR-22-1183

PMID:36007102

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9751752/

Abstract

PURPOSE

To evaluate efficacy and safety of venetoclax + azacitidine in treatment-naïve patients with acute myeloid leukemia harboring poor-risk cytogenetics and TP53mut or TP53wt.

PATIENTS AND METHODS

We analyzed data from a phase III study (NCT02993523) comparing venetoclax (400 mg orally days 1-28) + azacitidine (75 mg/m2 days 1-7) or placebo + azacitidine, and from a phase Ib study (NCT02203773) of venetoclax + azacitidine. Patients were ineligible for intensive therapy. TP53 status was analyzed centrally; cytogenetic studies were performed locally.

RESULTS

Patients (n = 127) with poor-risk cytogenetics receiving venetoclax + azacitidine (TP53wt = 50; TP53mut = 54) were compared with patients with poor-risk cytogenetics (n = 56) receiving azacitidine alone (TP53wt = 22; TP53mut = 18).For poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine versus azacitidine alone resulted in composite remission rates (CRc) of 70% versus 23%, median duration of remission (DoR) of 18.4 versus 8.5 months, and median overall survival (OS) of 23.4 versus 11.3 months, respectively. Outcomes with venetoclax + azacitidine were comparable with similarly treated patients with intermediate-risk cytogenetics and TP53wt.For poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine versus azacitidine alone resulted in CRc of 41% versus 17%, median DoR of 6.5 versus 6.7 months, and median OS of 5.2 versus 4.9 months, respectively.For poor-risk cytogenetics + TP53mut patients, predominant grade ≥3 adverse events (AE) for venetoclax + azacitidine versus azacitidine were febrile neutropenia (55%/39%), thrombocytopenia (28%/28%), neutropenia (26%/17%), anemia (13%/6%), and pneumonia (28%/33%). AEs were comparable between TP53mut and TP53wt patients.

CONCLUSIONS

In poor-risk cytogenetics + TP53mut patients, venetoclax + azacitidine improved remission rates but not DoR or OS compared with azacitidine alone. However, in poor-risk cytogenetics + TP53wt patients, venetoclax + azacitidine resulted in higher remission rates and longer DoR and OS than azacitidine alone, with outcomes comparable with similarly treated patients with intermediate-risk cytogenetics. Toxicities were similar in TP53mut and TP53wt patients. See related commentary by Green and Zeidner, p. 5235.

摘要

目的

评估 venetoclax + 阿扎胞苷治疗初治伴不良细胞遗传学和 TP53 突变或 TP53wt 的急性髓系白血病患者的疗效和安全性。

患者和方法

我们分析了一项比较 venetoclax（400 mg 口服，第 1-28 天）+ 阿扎胞苷（75 mg/m2，第 1-7 天）或安慰剂+阿扎胞苷的 III 期研究（NCT02993523）和 venetoclax + 阿扎胞苷的 Ib 期研究（NCT02203773）的数据。患者不符合强化治疗条件。TP53 状态由中心分析；细胞遗传学研究由当地进行。

结果

接受 venetoclax + 阿扎胞苷治疗的不良细胞遗传学患者（TP53wt = 50；TP53mut = 54）与接受阿扎胞苷单药治疗的不良细胞遗传学患者（TP53wt = 22；TP53mut = 18）进行比较。对于不良细胞遗传学+TP53wt 患者，venetoclax + 阿扎胞苷与阿扎胞苷单药治疗的复合缓解率（CRc）分别为 70%与 23%，缓解持续时间（DoR）中位数分别为 18.4 个月与 8.5 个月，总生存期（OS）中位数分别为 23.4 个月与 11.3 个月。venetoclax + 阿扎胞苷的治疗结果与具有中等风险细胞遗传学和 TP53wt 的相似患者相似。对于不良细胞遗传学+TP53mut 患者，venetoclax + 阿扎胞苷与阿扎胞苷单药治疗的 CRc 分别为 41%与 17%，DoR 中位数分别为 6.5 个月与 6.7 个月，OS 中位数分别为 5.2 个月与 4.9 个月。对于不良细胞遗传学+TP53mut 患者，venetoclax + 阿扎胞苷与阿扎胞苷单药治疗的主要不良事件（AE）发生率≥3 级分别为发热性中性粒细胞减少症（55%/39%）、血小板减少症（28%/28%）、中性粒细胞减少症（26%/17%）、贫血（13%/6%）和肺炎（28%/33%）。TP53mut 和 TP53wt 患者的 AE 相似。

结论

在不良细胞遗传学+TP53mut 患者中，venetoclax + 阿扎胞苷与阿扎胞苷单药治疗相比，缓解率提高，但无进展生存期（DoR）或总生存期（OS）无改善。然而，在不良细胞遗传学+TP53wt 患者中，venetoclax + 阿扎胞苷治疗与阿扎胞苷单药治疗相比，缓解率更高，无进展生存期和总生存期更长，且与具有中等风险细胞遗传学的相似患者的治疗结果相当。TP53mut 和 TP53wt 患者的毒性相似。详见 Green 和 Zeidner 的相关评论，第 5235 页。