Memorial Sloan Kettering Cancer Center, New York, NY.
Hospices Civils de Lyon, Lyon, France.
Blood. 2019 May 2;133(18):1964-1976. doi: 10.1182/blood-2018-11-880526. Epub 2019 Mar 8.
Novel strategies, such as chemosensitization with targeted agents, that build on the success of standard immunochemotherapy show promise for the treatment of non-Hodgkin lymphoma (NHL). Here, we report a phase 1b study investigating dose escalation of the BCL2 inhibitor, venetoclax, in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-/G-CHOP) chemotherapy in B-cell NHL. Objectives included safety assessment and determination of a recommended phase 2 dose (RP2D). Fifty-six patients were enrolled, most with follicular lymphoma (43%) or diffuse large B-cell lymphoma (DLBCL; 32%). Dose-limiting toxicities were reported in 3/14 patients at the first venetoclax dose (200 mg/d), after which dosing was changed from daily to 10 days per cycle and escalated to 800 mg. A further reduction to 5 days per cycle occurred at the 800-mg dose level in the G-CHOP arm. Cytopenias were predominant among grade 3/4 events and reported at a higher rate than expected, particularly in the G-CHOP arm; however, safety was manageable. Overall response rates were 87.5% (R-CHOP and G-CHOP combinations); complete response (CR) rates were 79.2% and 78.1%, respectively. Most double-expressor (BCL2 and MYC) DLBCL patients (87.5%; n = 7/8) achieved CR. Although the maximum tolerated dose was not reached, the RP2D for venetoclax with R-CHOP was established at 800 mg days 4 to 10 of cycle 1 and days 1 to 10 of cycles 2 to 8; higher doses were not explored, and this dosing schedule demonstrated an acceptable safety profile. This regimen is subsequently being evaluated in first-line DLBCL in the phase 2 portion of the study. This trial was registered at www.clinicaltrials.gov as #NCT02055820.
新型策略，如靶向药物增敏，在标准免疫化疗成功的基础上显示出治疗非霍奇金淋巴瘤（NHL）的希望。在这里，我们报告了一项 1b 期研究，该研究调查了 BCL2 抑制剂 venetoclax 与利妥昔单抗或奥滨尤妥珠单抗联合环磷酰胺、多柔比星、长春新碱和泼尼松（R-/G-CHOP）化疗在 B 细胞 NHL 中的剂量递增。目的包括安全性评估和确定推荐的 2 期剂量（RP2D）。56 名患者入组，大多数为滤泡性淋巴瘤（43%）或弥漫性大 B 细胞淋巴瘤（DLBCL；32%）。在首次 venetoclax 剂量（200mg/d）时，14 名患者中有 3 名出现剂量限制毒性，此后，剂量从每日改为每周期 10 天，并递增至 800mg。在 G-CHOP 臂中，在 800mg 剂量水平时进一步减少到每周期 5 天。在 3/4 级事件中，细胞减少症是主要的，报告的发生率高于预期，尤其是在 G-CHOP 臂中；然而，安全性是可控的。总缓解率为 87.5%（R-CHOP 和 G-CHOP 联合治疗）；完全缓解（CR）率分别为 79.2%和 78.1%。大多数双表达（BCL2 和 MYC）DLBCL 患者（87.5%；n=7/8）达到 CR。尽管未达到最大耐受剂量，但 venetoclax 联合 R-CHOP 的 RP2D 确定为第 1 周期的第 4 至 10 天和第 2 至 8 周期的第 1 至 10 天；未探索更高剂量，且该剂量方案显示出可接受的安全性特征。该方案随后在该研究的 2 期部分中作为一线 DLBCL 进行评估。该试验在 www.clinicaltrials.gov 上注册为 #NCT02055820。
