复发弥漫性大 B 细胞淋巴瘤的联合靶向治疗。
Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma.
机构信息
From the Lymphoid Malignancies Branch (C. Melani, R.L., J.D.P., D.W.H., J.S., J.M., Y.Y., W.X., A.P., C. Morrison, A.T., A.M.J., M.R., L.M.S., W.H.W.), the Clinical Pharmacology Program (C.J.P., O.A., W.D.F.), the Molecular Imaging Branch (E.M., L.L., E.B.), and the Biostatistics and Data Management Section (S.M.S.), Center for Cancer Research, the Laboratory of Pathology, Clinical Center (S.P., T.D.-H., S.D.P., E.S.J.), and the Biometric Research Program, Division of Cancer Treatment and Diagnosis (G.W.), National Cancer Institute, the Division of Pre-Clinical Innovation Chemistry Technologies, National Center for Advancing Translational Sciences (C.J.T., M.C., F.A.T.), and the Clinical Center Pharmacy Department (C.L.), National Institutes of Health, Bethesda, and Greenebaum Comprehensive Cancer Center, University of Maryland Medical Center, Baltimore (S.T.L.) - all in Maryland; the Division of Hematology and Oncology, University of Virginia, Charlottesville (C.A.P.); Mario Lemieux Center for Blood Cancers, University of Pittsburgh School of Medicine, Pittsburgh (R.J.F.); and Adaptive Biotechnologies, Seattle (A.J., H.S.).
出版信息
N Engl J Med. 2024 Jun 20;390(23):2143-2155. doi: 10.1056/NEJMoa2401532.
BACKGROUND
The identification of oncogenic mutations in diffuse large B-cell lymphoma (DLBCL) has led to the development of drugs that target essential survival pathways, but whether targeting multiple survival pathways may be curative in DLBCL is unknown.
METHODS
We performed a single-center, phase 1b-2 study of a regimen of venetoclax, ibrutinib, prednisone, obinutuzumab, and lenalidomide (ViPOR) in relapsed or refractory DLBCL. In phase 1b, which included patients with DLBCL and indolent lymphomas, four dose levels of venetoclax were evaluated to identify the recommended phase 2 dose, with fixed doses of the other four drugs. A phase 2 expansion in patients with germinal-center B-cell (GCB) and non-GCB DLBCL was performed. ViPOR was administered every 21 days for six cycles.
RESULTS
In phase 1b of the study, involving 20 patients (10 with DLBCL), a single dose-limiting toxic effect of grade 3 intracranial hemorrhage occurred, a result that established venetoclax at a dose of 800 mg as the recommended phase 2 dose. Phase 2 included 40 patients with DLBCL. Toxic effects that were observed among all the patients included grade 3 or 4 neutropenia (in 24% of the cycles), thrombocytopenia (in 23%), anemia (in 7%), and febrile neutropenia (in 1%). Objective responses occurred in 54% of 48 evaluable patients with DLBCL, and complete responses occurred in 38%; complete responses were exclusively in patients with non-GCB DLBCL and high-grade B-cell lymphoma with rearrangements of and or (or both). Circulating tumor DNA was undetectable in 33% of the patients at the end of ViPOR therapy. With a median follow-up of 40 months, 2-year progression-free survival and overall survival were 34% (95% confidence interval [CI], 21 to 47) and 36% (95% CI, 23 to 49), respectively.
CONCLUSIONS
Treatment with ViPOR was associated with durable remissions in patients with specific molecular DLBCL subtypes and was associated with mainly reversible adverse events. (Funded by the Intramural Research Program of the National Cancer Institute and the National Center for Advancing Translational Sciences of the National Institutes of Health and others; ClinicalTrials.gov number, NCT03223610.).
背景
弥漫性大 B 细胞淋巴瘤（DLBCL）中致癌突变的鉴定导致了靶向关键生存途径的药物的发展，但靶向多个生存途径是否能治愈 DLBCL 尚不清楚。
方法
我们进行了一项单中心、1b-2 期研究，评估了维奈托克、依鲁替尼、泼尼松、奥滨尤妥珠单抗和来那度胺（ViPOR）方案在复发或难治性 DLBCL 中的疗效。在 1b 期，该方案包括 DLBCL 和惰性淋巴瘤患者，评估了 4 个维奈托克剂量水平以确定 2 期推荐剂量，同时固定其他 4 种药物的剂量。在生发中心 B 细胞（GCB）和非 GCB DLBCL 患者中进行了 2 期扩展。ViPOR 每 21 天给药 6 个周期。
结果
在研究的 1b 期，包括 20 例患者（10 例 DLBCL），1 例患者出现 3 级颅内出血的剂量限制毒性反应，这一结果确定维奈托克 800mg 为 2 期推荐剂量。2 期包括 40 例 DLBCL 患者。所有患者观察到的毒性反应包括 3 或 4 级中性粒细胞减少症（24%的周期）、血小板减少症（23%）、贫血（7%）和发热性中性粒细胞减少症（1%）。48 例可评估的 DLBCL 患者中有 54%的患者出现客观缓解，38%的患者完全缓解；完全缓解仅见于非 GCB DLBCL 和伴有 或 或 （或两者）重排的高级别 B 细胞淋巴瘤患者。ViPOR 治疗结束时，33%的患者循环肿瘤 DNA 检测不到。中位随访 40 个月后，2 年无进展生存率和总生存率分别为 34%（95%CI，21%47%）和 36%（95%CI，23%49%）。
结论
ViPOR 治疗与特定分子 DLBCL 亚型患者的持久缓解相关，与主要可逆的不良事件相关。（由美国国立癌症研究所和美国国立卫生研究院转化科学推进中心等的内部研究计划以及其他机构资助；ClinicalTrials.gov 编号，NCT03223610。）
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