Division of Lymphoma, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.
Division of Biostatistics, City of Hope National Medical Center, Duarte, CA, USA.
Lancet Haematol. 2023 Jan;10(1):e14-e23. doi: 10.1016/S2352-3026(22)00318-0. Epub 2022 Nov 17.
After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma.
We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795.
Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed.
Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted.
Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.
自体造血干细胞移植（HSCT）后，采用 Brentuximab vedotin 巩固治疗高危复发或难治性经典霍奇金淋巴瘤（cHL），可改善无进展生存期（PFS），优于安慰剂。Brentuximab vedotin 联合nivolumab 是一种安全有效的复发或难治性经典霍奇金淋巴瘤治疗方法；因此，我们旨在评估高危复发或难治性经典霍奇金淋巴瘤患者自体 HSCT 巩固治疗后，该药物联合方案的安全性和疗效。
我们在美国五家中心进行了一项多中心 2 期试验。符合条件的患者为年龄 18 岁及以上、高危复发或难治性经典霍奇金淋巴瘤、ECOG 体能状态 0-2 分、有足够的器官和骨髓功能的患者。入组患者在自体 HSCT 后 30-60 天（第 1 周期第 1 天）开始接受 brentuximab vedotin（1.8mg/kg）和 nivolumab（3mg/kg）静脉输注，每 21 天为一个周期，最多 8 个周期。nivolumab 剂量不得减少。允许 brentuximab vedotin 剂量减少至 1.2mg/kg。如果一种药物因毒性作用而停药，则另一种药物可以继续使用。主要终点为所有治疗患者的 18 个月无进展生存期（PFS）。本研究在 ClinicalTrials.gov 上注册，编号为 NCT03057795。
2017 年 5 月 3 日至 2019 年 7 月 13 日，共 59 例患者入组并接受了研究治疗。患者在自体 HSCT 后中位 54 天（IQR 46-58）开始接受 Brentuximab vedotin 联合 nivolumab 治疗，中位接受 8 个周期（8-8）。59 例患者中，34 例（58%）为男性，29 例（49%）完成了 8 个周期的 Brentuximab vedotin 联合 nivolumab 治疗，45 例（76%）完成了至少 8 个周期的至少一种药物治疗。中位随访时间为 29.9 个月（IQR 24.6-34.8）。59 例患者的 18 个月 PFS 为 94%（95%CI 84-98）。最常见的不良反应为感觉周围神经病（59 例中有 31 例[53%]）和中性粒细胞减少症（25 例[42%]），17 例（29%）患者发生需要皮质类固醇治疗的免疫相关不良反应。未观察到治疗相关死亡。
Brentuximab vedotin 联合 nivolumab 是高危复发或难治性经典霍奇金淋巴瘤患者自体 HSCT 巩固治疗后的一种高度有效治疗方法，其中大多数患者既往接受过 Brentuximab vedotin 或 PD-1 阻断剂治疗。在这种情况下，联合免疫疗法应在经典霍奇金淋巴瘤患者中进一步研究，并进一步调整方案以减轻毒性作用，特别是在高危患者中，更需要强化治疗以预防复发。
百时美施贵宝、白血病和淋巴瘤协会、淋巴瘤研究基金会和美国国立卫生研究院国家癌症研究所。
