程序性死亡受体1抑制剂联合利妥昔单抗方案治疗复发难治弥漫大B细胞淋巴瘤疗效和安全性的初步分析

Programmed cell death-1 inhibitor combined with rituximab in refractory or relapsed diffuse large B-cell lymphoma:a preliminary efficacy and safety analysis

目的:探讨程序性死亡受体1(PD-1)抑制剂联合利妥昔单抗方案治疗复发难治性弥漫大B细胞淋巴瘤(rrDLBCL)的疗效和安全性。方法:回顾性分析中国医学科学院肿瘤医院2018年10月至2020年1月初治采用R-CHOP方案(利妥昔单抗+环磷酰胺+阿霉素+长春新碱+强的松)治疗后进展复发、应用PD-1抑制剂联合利妥昔单抗作为解救治疗方案的22例rrDLBCL患者的疗效和安全性。患者至少接受过1次PD-1抑制剂联合利妥昔单抗方案治疗,且有疗效和安全性评价结果。结果:22例患者的中位年龄为51.5岁,中位既往治疗方案数为2个。初治R-CHOP方案的中位至治疗进展时间(TTP)为9.3个月,患者开始该研究方案治疗前中位距末次含利妥昔单抗方案治疗时间为5.5个月。生发中心(GCB)型8例,非GCB型9例,原发纵隔大B细胞淋巴瘤(PMBCL)5例。双表达型4例,三打击型1例。9例患者进行了程序性死亡受体配体1(PD-L1)免疫组织化学染色,8例肿瘤细胞表达比例为1%~90%,阴性1例。全组患者的客观有效率(ORR)为72.7%,完全缓解(CR)率为13.6%,中位无进展生存时间(PFS)为8.0个月(95% CI为7.0~14.5个月),中位生存时间(OS)未达到。17例非特指型DLBCL的ORR为64.7%,中位PFS为4.0个月(95% CI为0~8.8个月),1年无进展生存率和总生存率分别为39.2%(95% CI为19.4%~43.4%)和81.3%(95% CI为71.4%~91.1%)。5例PMBCL患者的ORR为100%,CR 1例,部分缓解(PR)4例,PFS分别为16.4、9.3、8.3、7.9和3.0个月。1例患者出现美国癌症研究所常见不良反应事件评价标准的3度垂体炎,1例患者出现3度间质性肺炎。 结论:对于既往应用过利妥昔单抗治疗的rrDLBCL患者,PD-1抑制剂联合利妥昔单抗方案具有良好的疗效和安全性,是值得继续探索的一个新的治疗方案。

Objective To investigate the efficacy and safety of programmed cell death protein-1(PD-1)inhibitor combined with rituximab in the treatment of refractory or relapsed diffuse large B-cell lymphoma(rrDLBCL)patients.Methods The efficacy and safety of rrDLBCL patients treated with PD-1 inhibitor combined with rituximab as salvage therapeutic regimen after initially treated with rituximab,cyclophosphamide,anthracycline,vincristine and prednisone(R-CHOP)regimen in Cancer Hospital,Chinese Academy of Medical Science&Peking Union Medical College from October 2018 to Janurary 2020 were retrospectively analyzed.Patient who received at least one dose of PD-1 inhibitor combined with rituximab treatment and obtained the efficacy and safety evaluation were included.Results A total of 22 patients were enrolled in this study.The median age was 51.5 years and the median number of prior treatment regimen was 2.The median time to progression(TTP)for the initial R-CHOP treatment was 9.3 months and the median interval time of rituximab administrations between the previous and the research regimen was 5.5 months.Patients were classified as germinal center B cell(GCB)origin(n=8),non-GCB origin(n=9)and primary mediastinal large B cell lymphoma(PMBCL,n=5).Four patients were double-expression lymphoma,one patient were triple-hit lymphoma.Nine patients had PD-L1 immunohistochemical staining and the proportion of PD-L1 positive tumor cells were 1%-90%for eight patients and negative for one patient.The objective response rate(ORR)and complete response rate(CR)were 72.7%(16/22)and 13.6%(3/22),respectively.The median progression free survival(PFS)was 8.0(95%CI:7.0-14.5)months,and overall survival(OS)was not reached.For the 17 patients of non-specific DLBCL,the ORR was 64.7%(11/17),the estimated median PFS was 4.0(95%CI:0-8.8)months,the 1-year PFS and OS rates were 39.2%(95%CI:19.4%-43.4%)and 81.3%(95%CI:71.4%-91.1%),respectively.All of 5 PMBCL cases achieved ORR,among them,one case was CR and 4 cases were partial responase(PR),and their PFS were 16.4,9.3,8.3,7.9and 3.0 months,respectively.One patient had National Cancer Institute Common Terminology Criteria for Adverse Events(NCI CTCAE)version 5.0 grade 3 hypophysitis and one patient had NCI CTCAE grade 3 interstitial pneumonia.Conclusion For rrDLBCL patients who have underwent rituximab treatment previously,PD-1 inhibitor combined with rituximab regimen shows a promising efficacy and tolerability,which can be a potential treatment option.