双重 PI3K-δ、γ 抑制剂度维利塞治疗复发或难治性淋巴肿瘤患者的安全性和疗效：前瞻性临床试验的系统评价和荟萃分析。

BACKGROUND: Duvelisib is the first FDA-approved oral dual inhibitor of phosphatidylinositol-3-kinase PI3K-delta (PI3K-δ) and PI3K-gamma (PI3K-γ). Although many clinical studies support the efficacy of duvelisib, the safety of duvelisib remains with great attention. This systematic review and meta-analysis aimed to evaluate the safety and efficacy of duvelisib in treating different relapsed or refractory (RR) lymphoid neoplasm types. METHODS: We searched prospective clinical trials from PUBMED, EMBASE, Cochrane Library, and ClinicalTrials.gov. For efficacy analysis, Overall response rate (ORR), complete response rate (CR), partial response rate (PR), rate of stable disease (SDR), rate of progressive disease (PDR), median progression-free survival (mPFS), 12-/24-month PFS, and 12-month overall survival (OS) were assessed. For safety analysis, the incidences of any grade and grade ≥3 adverse events (AEs), serious AEs, and treatment-related discontinuation and death were evaluated. Subgroup analysis based on the disease type was performed. RESULTS: We included 11 studies and 683 patients, including 305 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 187 B-cell indolent non-Hodgkin lymphoma (iNHL), 39 B-cell aggressive non-Hodgkin lymphoma (aNHL), and 152 T-cell non-Hodgkin lymphoma (T-NHL) patients. The pooled ORR in CLL/SLL, iNHL, aNHL and T-NHL was 70%, 70%, 28% and 47%, respectively. Additionally, the pooled ORR in CLL/SLL patients with or without TP53 mutation/17p-deletion (62% vs. 74%, p=0.45) and in follicular lymphoma (FL) or other iNHL (69% vs. 57%, p=0.38) had no significant differences. Mantle cell lymphoma (MCL) patients had higher pooled ORR than other aNHL (68% vs. 17%, p=0.04). Angioimmunoblastic TCL (AITL) patients had higher pooled ORR than other PTCL patients (67% vs. 42%, p=0.01). The pooled incidence of any grade, grade ≥3, serious AEs, treatment-related discontinuation and death was 99%, 79%, 63%, 33% and 3%, respectively. The most frequent any-grade AEs were diarrhea (47%), ALT/AST increase (39%), and neutropenia (38%). The most frequent grade ≥3 AEs were neutropenia (25%), ALT/AST increased (16%), diarrhea (12%), and anemia (12%). CONCLUSION: Generally, duvelisib could offer favorable efficacy in patients with RR CLL/SLL, iNHL, MCL, and AITL. Risk and severity in duvelisib treatment may be mitigated through proper identification and management.

背景：杜韦利昔布是 FDA 批准的首个口服双重磷脂酰肌醇-3-激酶 PI3K-δ（PI3K-δ）和 PI3K-γ（PI3K-γ）抑制剂。尽管许多临床研究支持杜韦利昔布的疗效，但仍需要密切关注其安全性。本系统评价和荟萃分析旨在评估杜韦利昔布治疗不同复发或难治性（RR）淋巴肿瘤类型的安全性和疗效。

方法：我们从 PUBMED、EMBASE、Cochrane 图书馆和 ClinicalTrials.gov 中搜索了前瞻性临床试验。对于疗效分析，评估总缓解率（ORR）、完全缓解率（CR）、部分缓解率（PR）、疾病稳定率（SDR）、疾病进展率（PDR）、中位无进展生存期（mPFS）、12/24 个月 PFS 和 12 个月总生存期（OS）。对于安全性分析，评估了任何级别和≥3 级不良事件（AE）、严重 AE、与治疗相关的停药和死亡的发生率。根据疾病类型进行了亚组分析。

结果：我们纳入了 11 项研究和 683 名患者，包括 305 例慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）、187 例 B 细胞惰性非霍奇金淋巴瘤（iNHL）、39 例 B 细胞侵袭性非霍奇金淋巴瘤（aNHL）和 152 例 T 细胞非霍奇金淋巴瘤（T-NHL）患者。CLL/SLL、iNHL、aNHL 和 T-NHL 患者的汇总 ORR 分别为 70%、70%、28%和 47%。此外，CLL/SLL 患者中伴有或不伴有 TP53 突变/17p 缺失（62% vs. 74%，p=0.45）和滤泡性淋巴瘤（FL）或其他 iNHL（69% vs. 57%，p=0.38）的 ORR 无显著差异。套细胞淋巴瘤（MCL）患者的汇总 ORR 高于其他 aNHL（68% vs. 17%，p=0.04）。血管免疫母细胞性 T 细胞淋巴瘤（AITL）患者的汇总 ORR 高于其他 PTCL 患者（67% vs. 42%，p=0.01）。任何级别、≥3 级、严重 AE、与治疗相关的停药和死亡的发生率分别为 99%、79%、63%、33%和 3%。最常见的任何级别 AE 为腹泻（47%）、ALT/AST 升高（39%）和中性粒细胞减少（38%）。最常见的≥3 级 AE 为中性粒细胞减少（25%）、ALT/AST 升高（16%）、腹泻（12%）和贫血（12%）。

结论：一般来说，杜韦利昔布在 RR CLL/SLL、iNHL、MCL 和 AITL 患者中具有良好的疗效。通过正确识别和管理，可能会减轻杜韦利昔布治疗的风险和严重程度。