Autologous hematopoietic cell transplantation for myeloma patients with hepatitis B virus or hepatitis C virus in the era of novel agents
Autologous hematopoietic cell transplantation for myeloma patients with hepatitis B virus or hepatitis C virus in the era of novel agents
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新药时代乙型肝炎病毒或丙型肝炎病毒骨髓瘤患者的自体造血细胞移植
DOI：
10.1038/s41409-022-01640-7
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发表时间：
2022
影响因子：
4.8
通讯作者：
Atsuta Yosh
中科院分区：
文献类型：
--
作者：
Mizuno Shohei;Takami Akiyoshi;Takamatsu Hiroyuki;Hanamura Ichiro;Shimazu Yutaka;Hangaishi Akira;Tsukada Nobuhiro;Kako Shinichi;Kikuchi Taku;Ota Shuichi;Shimizu Hiroaki;Iida Shinsuke;Yoshioka Satoshi;Sawa Masashi;Fukuda Takahiro;Kanda Yoshinobu;Atsuta Yosh
乙型肝炎病毒（HBV）和丙型肝炎病毒（HCV）是常见的血液传播感染。在新型药物时代，骨髓瘤患者HBV再激活的频率有所增加，因为硼替佐米可能被认为是HBV再激活的可能危险因素[1,2]。在同种异体造血细胞移植（allogeneic hematopoietic cell transplantation, alloo - hct）中，肝脏并发症在HCV感染患者中是公认的[3,4]。然而，关于HBV或HCV感染对骨髓瘤患者自体HCT （auto-HCT）结果的影响尚未达成共识。在这里，我们提出了第一个大型回顾性分析，证明HBV或HCV感染对接受自体hct的骨髓瘤患者预后的影响。共有4735名年龄≥16岁的患者在2007年至2018年期间接受了首次自体hct治疗外周血干细胞骨髓瘤。HBV阳性定义为存在HBV核心抗体或表面抗原。HCV阳性定义为存在抗HCV抗体。此外，没有详细的HBV和HCV病毒载量数据。我们从分析中排除了hbv -和hcv -合并感染的患者，因为他们的数量很少。荧光原位杂交分析的高危细胞遗传学异常部分在日本进行，因为保险范围的问题。因此，变量“细胞遗传风险”被排除在分析之外。总生存期（OS）采用Kaplan-Meier法估计，组间比较采用log-rank检验。使用累积发生率分析估计一年移植相关死亡率（TRM），并使用Gray检验比较两组之间的差异。采用Cox比例风险模型对OS进行多因素分析。所有p值均来自双侧检验；p值< 0.05为有统计学意义。所有的统计分析使用EZR（埼玉医学中心，Jichi医科大学，埼玉，日本），一个R（统计计算的R基础，版本2.7-0）[5]的图形用户界面进行。4735例符合条件的患者中，4546例（96.0%）同时为hbv和hcv阴性，143例（3.0%）为hbv阳性，46例（1.0%）为hcv阳性。患者中位年龄59岁（范围18-77岁），中位随访时间1085天（范围0-4547天）。该队列的特征总结于补充表1。除hct特异性合并症指数差异外，hbv和hcv阴性患者、hbv阳性患者和hcv阳性患者之间无显著差异（P= 0.012）。hbv阴性患者和hbv阳性患者5年移植后OS无显著差异(67.4%[95%可信区间（CI）： 65.5-69.1%]和63.6%[95% CI: 51.3-73.6%]；P = 0.43)(图1)。此外，移植后1年TRM也无显著差异（分别为1.2%[95% CI: 0.9-1.5%]和1.5%[95% CI: 0.3-4.8%]， P= 0.95）（图2）。1 b)。hbv和hcv阴性患者与hcv阳性患者移植后的OS差异显著（5年分别为67.4%[95% CI: 65.5-69.1%]和52.3%[95% CI: 32.8-68.6%]， P= 0.035）（图2）。1)。然而，移植后1年TRM无显著差异（分别为1.2%[95% CI: 0.9-1.5%]和2.4%[95% CI: 0.2-10.9%]， P= 0.44）（图2）。1 b)。多因素分析显示，HCV阳性是影响OS的显著不利因素（危险比[HR]， 1.74 [95% CI, 1.06-2.85]； P= 0.029），而HBV阳性则不是（危险比[HR]， 1.00 [95% CI, 0.68-1.48]， P= 0.99）(补充表2…
Hepatitis B virus (HBV) and hepatitis C virus (HCV) are common blood-borne infections. The frequency of HBV reactivation in myeloma patients has increased in the era of novel agents because bortezomib administration may be considered a possible risk factor for HBV reactivation [1, 2]. In allogeneic hematopoietic cell transplantation (allo-HCT), liver complications are well recognized in patients with HCV infection [3, 4]. However, no consensus has been reached concerning HBV or HCV infection influence on autologous HCT (auto-HCT) outcomes in myeloma patients. Here we present the first large retrospective analysis demonstrating the impact of HBV or HCV infection on outcomes in myeloma patients who have undergone auto-HCT. A total of 4735 patients aged≥ 16 years, who received first auto-HCT for myeloma with peripheral blood stem cells performed between 2007 and 2018. HBV positivity was defined as the presence of either the HBV core antibody or surface antigen. HCV positivity was defined as the presence of anti-HCV antibodies. Moreover, detailed viral load data were unavailable for both HBV and HCV. We excluded HBV-and HCV-coinfected patients from the analyses because of their small number. High-risk cytogenetic abnormalities of fluorescence in situ hybridization analyses are partially performed in Japan because of issues with insurance coverage. Thus, the variable “cytogenetic risk” was excluded from the analysis. Overall survival (OS) was estimated using the Kaplan–Meier method and compared between groups using the log-rank test. One-year transplant-related mortality (TRM) was estimated using a cumulative incidence analysis and compared between groups using Gray’s test. Multivariate analysis was conducted using the Cox proportional hazards model for OS. All p-values were from two-tailed tests; p-values< 0.05 indicated statistical significance. All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), a graphical user interface for the R (The R Foundation for Statistical Computing, version 2.7–0)[5]. Of 4735 eligible patients, 4546 (96.0%) were both HBV-and HCV-negative, 143 (3.0%) were HBV-positive, and 46 (1.0%) were HCV-positive. The median age of the patients was 59 (range, 18–77) years, and the median follow-up time was 1085 (range, 0–4547) days. The characteristics of the cohort are summarized in Supplementary Table 1. There were not significant differences among the HBV-and HCV-negative patients, HBV-positive patients, and HCV-positive patients, except for the HCT-specific comorbidity index (P= 0.012). The OS after transplantation between HBV-and HCV-negative patients and HBV-positive patients did not differ significantly (67.4%[95% confidence interval (CI): 65.5–69.1%] and 63.6%[95% CI: 51.3–73.6%] at 5 years, respectively; P= 0.43)(Fig. 1 a). Further, 1-year TRM after transplantation also did not differ significantly (1.2%[95% CI: 0.9–1.5%] and 1.5%[95% CI: 0.3–4.8%], respectively; P= 0.95)(Fig. 1 b). The OS after transplantation between HBV-and HCV-negative patients and HCV-positive patients differed significantly (67.4%[95% CI: 65.5–69.1%] and 52.3%[95% CI: 32.8–68.6%] at 5 years, respectively; P= 0.035)(Fig. 1 a). However, 1-year TRM after transplantation did not differ significantly (1.2%[95% CI: 0.9–1.5%] and 2.4%[95% CI: 0.2–10.9%], respectively; P= 0.44)(Fig. 1 b). Multivariate analysis revealed that HCV positivity was a significant adverse factor with respect to OS (hazard ratio [HR], 1.74 [95% CI, 1.06–2.85]; P= 0.029) but HBV positivity was not (HR, 1.00 [95% CI, 0.68–1.48], P= 0.99)(Supplementary Table 2 …