A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation
A multicenter phase 1 study of nivolumab for relapsed hematologic malignancies after allogeneic transplantation
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DOI：
10.1182/blood.2019004710
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发表时间：
2020-06-11
期刊：
影响因子：
20.3
通讯作者：
Armand, Philippe
中科院分区：
文献类型：
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作者：
Davids, Matthew S.;Kim, Haesook T.;Armand, Philippe
程序性细胞死亡-1(PD-1)/程序性死亡配体-1阻断可能会增强异基因造血细胞移植(AllHCT)后的移植物抗肿瘤效应，但抗PD-1治疗的回顾性研究报告了移植物抗宿主病(GVHD)的显著毒性。在这里，我们报告PD-1阻断治疗异基因HCT后复发恶性血液病(HMS)的前瞻性临床试验结果(NCT01822509)。这项由研究人员发起的第一阶段多中心研究的主要目标是确定最大耐受量和安全性。次要目标是评估疗效和免疫活性。异体血细胞移植后复发的HMS患者符合条件。尼伏卢单抗每两周给药一次，直到病情进展或出现不可接受的毒性，从1毫克/公斤的队列开始，根据毒性计划降级到0.5毫克/公斤的队列。治疗28例(髓系19例，淋巴系9例)。中位年龄57岁(范围27-76岁)，从异基因HCT到登记的中位时间为21个月(范围5.6-108.5)。剂量为1 mg/kg的6名患者中有2名出现了免疫相关不良事件(IrAEs)的剂量限制性毒性(DLT)。22例患者接受0.5 mg/kg的治疗，发生DLT 4例，其中2例发生irAEs，2例发生致死性移植物抗宿主病。可评价疗效的患者总有效率为32%(8/25)。随访11个月，1年无进展生存率和总生存率分别为23%和56%。在这项针对异基因红细胞移植后复发的抗PD-1抗体的首次前瞻性临床试验中，发生了移植物抗宿主病和irAEs，需要降低剂量，只有适度的抗肿瘤活性。同种异体血细胞移植后抗PD-1治疗的进一步研究可能需要特定的毒性缓解策略。
Programmed cell death-1 (PD-1)/programmed death ligand-1 blockade may potentially augment graft-vs-tumor effects following allogeneic hematopoietic cell transplantation (alloHCT), but retrospective studies of anti-PD-1 therapy reported substantial toxicity from graft-versus-host-disease (GVHD). Here, we report the results of a prospective clinical trial of PD-1 blockade for relapsed hematologic malignancies (HMs) after alloHCT (NCT01822509). The primary objective in this phase 1 multicenter, investigator-initiated study was to determine maximum tolerated dose and safety. Secondary objectives were to assess efficacy and immunologic activity. Patients with relapsed HMs following alloHCT were eligible. Nivolumab was administered every 2 weeks until progression or unacceptable toxicity, starting with a 1-mg/kg cohort, with planned deescalation based on toxicity to a 0.5-mg/kg cohort. Twenty-eight patients were treated (n = 19 myeloid, n = 9 lymphoid). Median age was 57 years (range 27-76), and median time from alloHCT to enrollment was 21 months (range 5.6-108.5). Two of 6 patients treated at 1 mg/kg experienced dose-limiting toxicity (DLT) from immune-related adverse events (irAEs). Twenty-two patients were treated at 0.5 mg/kg, and 4 DLTs occurred, including 2 irAEs and 2 with fatal GVHD. The overall response rate in efficacy-evaluable patientswas 32% (8/25). With amedian follow-up of 11months, the 1-year progression-free survival and overall survival were 23% and 56%, respectively. In this first prospective clinical trial of an anti-PD-1 antibody for post-alloHCT relapse, GVHD and irAEs occurred, requiring dose deescalation, with only modest antitumor activity. Further studies of anti-PD-1 therapy post-alloHCT may require specific toxicity mitigation strategies.