Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial.
Effect of rituximab on immune status in children with mature B-cell non-Hodgkin lymphoma: a prespecified secondary analysis of the Inter-B-NHL Ritux 2010 trial.
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利妥昔单抗对成熟 B 细胞非霍奇金淋巴瘤儿童免疫状态的影响：Inter-B-NHL Ritux 2010 试验的预先指定二次分析。
DOI：
10.1016/s2352-3026(23)00062-5
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发表时间：
2023
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通讯作者：
Alexander S
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作者：
Alexander S
研究背景：在化疗基础上加用利妥昔单抗可提高儿童和青少年高危、成熟B细胞非霍奇金淋巴瘤患者的生存率。利妥昔单抗对治疗后免疫重建的影响尚未得到很好的描述。在此，我们评估了在强化化疗中加入利妥昔单抗的免疫效果，这是Inter-B-NHL Ritux 2010 trial.MethodsThe Inter-B-NHL Ritux 2010 trial. MethodsThe的一项国际性、开放标签、随机、3期儿童试验（年龄6个月至18岁）与高风险，成熟的B细胞非霍奇金淋巴瘤，比较化疗单独或化疗与利妥昔单抗。在基线、治疗结束后1个月和治疗开始后1年完成免疫状态的测量，此后每年测量一次，直至恢复正常。对于该次要分析，我们报告了这些时间点淋巴细胞计数和免疫球蛋白浓度低的患者比例，总淋巴细胞计数、B细胞计数和IgG浓度作为主要终点。其他关注的终点包括暴露于免疫球蛋白替代治疗和疫苗血清。评估免疫终点的人群是在一个时间点具有至少一个免疫参数的合格符合方案人群。比较了随机化治疗组之间的免疫状态。在治疗结束后至少随访3个月且无癌症相关事件的符合免疫研究条件的人群中评估治疗后阶段的安全性。Inter-B-NHL Ritux 2010研究注册于ClinicalTrials.gov，NCT 01516580;状态已完成，次要目标分析正在进行中。结果从2011年12月19日至2017年6月13日，421例患者（344例[82%]男孩和77例[18%]女孩;平均年龄为8.8岁[SD 4.1]）入组，并在随访期间或两者均具有基线免疫数据。研究人群包括随机分配的患者（n=289）和计划中期分析后入组的非随机队列（n=132）。基线时，290例有可用数据的患者中有99例（34%）（不包括伴有外周原始细胞的骨髓疾病患者）发生淋巴细胞减少症，368例患者中有178例（48%）发生低丙种球蛋白血症。治疗结束后1个月，接受利妥昔单抗化疗的患者比仅接受化疗的患者更容易发生淋巴细胞减少症（86/106 [81%] vs 53/89（60%），比值比[OR] 2.92 [95%CI 1.53 - 5.57]，p= 0.0011），B细胞淋巴细胞减少症（72/75 [96%] vs 36/56 [64%]，OR 13.33 [3.71 - 47.84]，p<0.0001）和低丙种球蛋白血症（67/95 [71%] vs 37/79 [47%]，OR 2.72 [1.45 - 5.07]，p= 0.0017）。仅低丙种球蛋白血症在1年时仍存在差异（52/94 [55%] vs 16/63 [25%]，OR 3.64 [1.81 - 7.31]，p= 0.0003）。利妥昔单抗化疗组患者比化疗组患者更可能接受免疫球蛋白替代治疗（26例[16%] 164 vsnine [7%] 158，风险比[HR] 2.63 [95%CI 1.23 - 5.62]，p= 0.010），主要是由于免疫球蛋白浓度低。在联合治疗组中，包括非随机分配的患者，由于疫苗可预防的感染而失去保护性血清的患者比例从47例脊髓灰质炎患者中的4例（9%）到50例肺炎链球菌（肺炎球菌）患者中的21例（42%）不等。1例患者（利妥昔单抗化疗组）在最后一次化疗后2个月报告了危及生命的多微生物细菌性脓毒症感染事件。
BackgroundSurvival of children and adolescents with high-risk, mature B-cell non-Hodgkin lymphoma is improved by the addition of rituximab to chemotherapy. The effect of rituximab on immune reconstitution after therapy has not been well described. Herein, we evaluate the immune effects of the addition of rituximab to intensive chemotherapy, a prespecified secondary aim of the Inter-B-NHL Ritux 2010 trial.MethodsThe Inter-B-NHL Ritux 2010 trial was an international, open-label, randomised, phase 3 trial in children (age 6 months to 18 years) with high-risk, mature B-cell non-Hodgkin lymphoma, comparing chemotherapy alone or chemotherapy with rituximab. Measures of immune status were completed at baseline, 1 month from the end of treatment, and 1 year from the start of therapy, and yearly thereafter until normalised. For this secondary analysis, we report on the proportions of patients with low lymphocyte counts and immunoglobulin concentrations at these timepoints with total lymphocyte count, B-cell count, and IgG concentration as the main endpoints. Other endpoints of interest included exposure to immunoglobulin replacement therapy and vaccine serologies. The population assessed for immune endpoints was the eligible per-protocol population with at least one immune parameter at one timepoint. Comparisons of immune status were made between the randomised treatment groups. Safety in the post-therapy period was assessed in the population eligible for the immunity study who were followed up at least 3 months after the end of treatment and without cancer-related events. The Inter-B-NHL Ritux 2010 study was registered with ClinicalTrials.gov, NCT01516580; status completed, with analyses of secondary aims ongoing.FindingsFrom Dec 19, 2011, to June 13, 2017, 421 patients (344 [82%] boys and 77 [18%] girls; mean age was 8·8 years [SD 4·1]) were enrolled and had immune data at baseline during follow-up, or both. The study population included randomly assigned patients (n=289) and a non-randomised cohort enrolled after the planned interim analysis (n=132). At baseline, 99 (34%) of 290 patients with available data (excluding patients with bone marrow disease with peripheral blast cells) had lymphopenia, and 178 (48%) of 368 had hypogammaglobulinemia. 1 month from the end of therapy, patients who received chemotherapy with rituximab were more likely than those who received chemotherapy alone to have lymphopenia (86 [81%] of 106vs53 (60%) of 89, odds ratio [OR] 2·92 [95% CI 1·53–5·57], p=0·0011), B-cell lymphopenia (72 [96%] of 75vs36 [64%] of 56, OR 13·33 [3·71–47·84], p<0·0001), and hypogammaglobulinemia (67 [71%] of 95vs37 [47%] of 79, OR 2·72 [1·45–5·07], p=0·0017). Differences remained at 1 year for hypogammaglobulinemia only (52 [55%] of 94vs16 [25%] of 63, OR 3·64 [1·81–7·31], p=0·0003). Patients in the chemotherapy with rituximab group were more likely than those in the chemotherapy group to receive immunoglobulin replacement (26 [16%] 164vsnine [7%] of 158, hazard ratio [HR] 2·63 [95% CI 1·23–5·62], p=0·010), mainly due to low immunoglobulin concentration. In the combined treatment groups, including non-randomly assigned patients, the proportion of patients who had loss of protective serologies to a vaccine preventable infection varied from four (9%) of 47 for polio to 21 (42%) of 50 forStreptococcus pneumoniae(pneumococcus). One patient (chemotherapy with rituximab group) had a life-threatening infectious event of polymicrobial bacterial sepsis reported 2 months after the final chemotherapy administration.InterpretationChildren with high-risk mature B-cell non …