Nivolumab Plus ICE As First Salvage Therapy in High-Risk Relapsed/Refractory Hodgkin Lymphoma

Introduction: Nivolumab (nivo) is an anti-PD-1 antibody that restores effective anti-tumor immune responses and is tolerable and effective in patients (pts) with relapsed/refractory (RR) classic Hodgkin lymphoma (cHL). We previously reported results of PET-adapted sequential nivo +/- ICE (ifosfamide, carboplatin, etoposide) chemotherapy as first salvage tx in RR cHL, which was a safe and effective bridge to autologous stem cell transplant (ASCT). Here we present preliminary results of cohort B (non PET-adapted) of this trial, in which high-risk cHL patients all received nivo+ICE (NICE). Methods: In cohort B of this prospective, multicenter trial, pts with biopsy-proven high-risk RR cHL after frontline treatment received 240mg nivo, and then starting 2 weeks later received 2-3 cycles of NICE (240mg nivo day 1, standard doses of ICE, administered inpatient or outpatient). High-risk RR cHL was defined as having one of the following: primary refractory cHL, relapse within 1 year of completing frontline therapy, B symptoms at relapse, extranodal disease at relapse, received brentuximab vedotin as part of initial therapy. PET-CT was performed after Nivo x 1 and NICE x 2; a third cycle of NICE was administered per discretion of the treating physician. Responding patients (complete response (CR) or partial response (PR)) were intended to proceed to ASCT. The primary endpoint was CR rate according to 2014 Lugano classification. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan Meier method. Results: 35 patients were enrolled, of whom 32 have completed the study treatment (3 remain in treatment). 34 patients were evaluable for toxicity; 32 were evaluable for response. Baseline characteristics are shown in Table 1. Of patients completing the study treatment, 25 received 3 cycles in total (NICE x 2) and 7 received 4 cycles (NICE x 3). The overall response rate (ORR) was 100% with a CR rate of 88% (28/32). 29/32 patients who completed therapy have undergone ASCT. There were no stem cell mobilization/collection failures. The median time to neutrophil engraftment after ASCT was 11 days (range, 9-14) and median time to platelet engraftment was 11 days (range, 9-14). Of the 29 patients who have undergone ASCT to date, 7 (24%) have received post-ASCT consolidation (4 BV, 2 Nivolumab, 1 lenalidomide/ipilimumab) and 22 (76%) did not receive consolidation. Median follow-up was 12.8 months (range:0.5-29) and median post-ASCT follow-up was 12.5 months (range:0.3-25.6). 1-year PFS and OS for the entire cohort (n=34) was 90% (95% CI: 66-98) and 100% (95% CI: N/A), respectively (Figure 1). In patients who underwent ASCT directly after protocol therapy (n=22 with available data), 1-year PFS and OS were both 100% (95% CI:N/A for both). The most common AEs (all grades) observed after the first nivo dose were hypertension (24%), fatigue (21%), and pruritis (15%), all of which were grade (gr) 1-2; no gr 3-4 events after nivo monotherapy were observed. The most common AEs (all grades) after NICE were anemia (65%), nausea (65%), fatigue (59%), hypertension (50%), sinus tachycardia (44%), and constipation (38%). The only non-hematologic gr 3-4 AE was gr 3 vomiting in one patient. Conclusion: NICE is a well-tolerated and highly effective first salvage approach in pts with RR HL. In our cohort of high-risk patients, we observed high CR rates with excellent PFS after ASCT.

引言：纳武利尤单抗（nivo）是一种抗PD - 1抗体，可恢复有效的抗肿瘤免疫反应，对复发/难治性（RR）经典霍奇金淋巴瘤（cHL）患者具有耐受性且有效。我们之前报道了在RR cHL中以PET适应性序贯纳武利尤单抗±ICE（异环磷酰胺、卡铂、依托泊苷）化疗作为首次挽救治疗的结果，它是通向自体干细胞移植（ASCT）的一种安全有效的桥梁。在此我们展示了该试验B队列（非PET适应性）的初步结果，其中高危cHL患者均接受纳武利尤单抗 + ICE（NICE方案）。 方法：在这项前瞻性、多中心试验的B队列中，经活检证实的一线治疗后高危RR cHL患者接受240mg纳武利尤单抗，然后从2周后开始接受2 - 3个周期的NICE方案（第1天给予240mg纳武利尤单抗，标准剂量的ICE，住院或门诊给药）。高危RR cHL定义为具有以下情况之一：原发性难治性cHL、在完成一线治疗1年内复发、复发时有B症状、复发时有结外病变、在初始治疗中接受过本妥昔单抗。在纳武利尤单抗使用1次和NICE方案使用2次后进行PET - CT检查；第三个周期的NICE方案由治疗医师酌情使用。有反应的患者（完全缓解（CR）或部分缓解（PR））拟进行ASCT。主要终点是根据2014年卢加诺分类的完全缓解率。无进展生存期（PFS）和总生存期（OS）采用卡普兰 - 迈耶方法计算。 结果：共纳入35例患者，其中32例已完成研究治疗（3例仍在治疗中）。34例患者可评估毒性；32例患者可评估疗效。基线特征见表1。在完成研究治疗的患者中，25例总共接受了3个周期（NICE方案×2），7例接受了4个周期（NICE方案×3）。总缓解率（ORR）为100%，完全缓解率为88%（28/32）。完成治疗的32例患者中有29例已进行了ASCT。没有干细胞动员/采集失败的情况。ASCT后中性粒细胞植入的中位时间为11天（范围，9 - 14天），血小板植入的中位时间为11天（范围，9 - 14天）。到目前为止已进行ASCT的29例患者中，7例（24%）接受了ASCT后的巩固治疗（4例本妥昔单抗，2例纳武利尤单抗，1例来那度胺/伊匹木单抗），22例（76%）未接受巩固治疗。中位随访时间为12.8个月（范围：0.5 - 29个月），ASCT后的中位随访时间为12.5个月（范围：0.3 - 25.6个月）。整个队列（n = 34）的1年PFS和OS分别为90%（95%置信区间：66 - 98）和100%（95%置信区间：不适用）（图1）。在按照方案治疗后直接进行ASCT的患者中（n = 22，有可用数据），1年PFS和OS均为100%（95%置信区间：两者均不适用）。首次给予纳武利尤单抗剂量后观察到的最常见不良事件（所有级别）为高血压（24%）、疲劳（21%）和瘙痒（15%），均为1 - 2级；未观察到纳武利尤单抗单药治疗后的3 - 4级事件。NICE方案后最常见的不良事件（所有级别）为贫血（65%）、恶心（65%）、疲劳（59%）、高血压（50%）、窦性心动过速（44%）和便秘（38%）。唯一的非血液学3 - 4级不良事件是1例患者的3级呕吐。 结论：NICE方案是RR HL患者中一种耐受性良好且高效的首次挽救治疗方法。在我们的高危患者队列中，我们观察到较高的完全缓解率以及ASCT后良好的无进展生存期。