Section of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.
Department of Pharmacy, Texas Children's Hospital, Houston.
JAMA Netw Open. 2021 Feb 1;4(2):e2036321. doi: 10.1001/jamanetworkopen.2020.36321.
Rituximab is among the most frequently used immunotherapies in pediatrics. Few studies have reported long-term adverse events associated with its use for children.
To describe the use of rituximab and to assess whether its use is associated with short- or long-term adverse events, infections, or time to immune reconstitution in a diverse group of young people.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included 468 patients aged younger than 21 years who received rituximab for diverse indications between October 1, 2010, and December 31, 2017, at Texas Children's Hospital, a large pediatric referral hospital. Patterns of adverse events, infections, and immune recovery are described. Data analyses were conducted from December 2019 to June 2020.
One or more doses of rituximab.
Adverse drug events (eg, anaphylaxis), incidence of mild and severe infections, and time to recovery of B lymphocyte subset counts and immunoglobulin levels. Survival models and logistic regression analyses and were used to identify associated risk factors of infectious and noninfectious adverse drug events.
We identified 468 patients receiving at least 1 dose of rituximab. The total follow-up time was 11 713 person-months. Of the 468 patients, 293 (62.6%) were female, the median (interquartile range) age at receipt of dose was 14.3 (9.9-16.8) years, and 209 (44.7%) were self-reported White Hispanic. Adverse events associated with rituximab infusion occurred in 72 patients (15.4%), and anaphylaxis occurred in 17 patients (3.6%). Long-term adverse events, such as prolonged neutropenia and leukoencephalopathy, were absent. Infections occurred in 224 patients (47.9%); 84 patients (17.9%) had severe infections, and 3 patients (0.6%) had lethal infections. Concurrent use of intravenous chemotherapy, treatment of systemic lupus erythematosus, neutropenia, and use of intravenous immunoglobulin were associated with increased risk of infection. Among 135 patients (28.8%) followed up to B cell count recovery, CD19+ or CD20+ cell numbers normalized in a median of 9.0 months (interquartile range, 5.9-14.4 months) following rituximab use; 48 of 95 patients (51%) evaluated beyond a year had low-for-age B cell counts. Recovery of CD27+ memory B cell number occurred in a median of 15.7 months (interquartile range, 6.0-22.7 months). Among patients with normal baseline values, low immunoglobulin G (IgG) levels developed in 67 of 289 patients (23.2%) and low IgM levels in 118 of 255 patients (40.8%); of these patients evaluated beyond 12 months from rituximab, 16 of 117 (13.7%) had persistently low IgG and 37 (33.9%) of 109 had persistently low IgM.
Rituximab is well tolerated among young people and is associated with few serious adverse events, but infections are common, corresponding to a prolonged period of B cell count recovery often lasting for longer than a year. Further examination of strategies to prevent infections following rituximab should be pursued.
重要性：利妥昔单抗是儿科最常用的免疫疗法之一。很少有研究报告其在儿童中的使用与长期不良事件相关。
目的：描述利妥昔单抗的使用情况，并评估其在不同人群中的使用是否与短期或长期不良事件、感染或免疫重建时间有关。
设计、地点和参与者：本回顾性队列研究纳入了 2010 年 10 月 1 日至 2017 年 12 月 31 日期间，在一家大型儿科转诊医院——德克萨斯儿童医院接受利妥昔单抗治疗的 468 名年龄小于 21 岁的患者。描述了不良事件、感染和免疫恢复的模式。数据分析于 2019 年 12 月至 2020 年 6 月进行。
暴露：一种或多种剂量的利妥昔单抗。
主要结果和测量：药物不良事件（如过敏反应）、轻度和重度感染的发生率，以及 B 淋巴细胞亚群计数和免疫球蛋白水平恢复的时间。使用生存模型和逻辑回归分析来确定感染和非感染性药物不良事件的相关危险因素。
结果：我们确定了 468 名至少接受了 1 剂利妥昔单抗的患者。总随访时间为 11713 人月。在这 468 名患者中，293 名（62.6%）为女性，接受剂量时的中位（四分位间距）年龄为 14.3（9.9-16.8）岁，209 名（44.7%）为自报的西班牙裔白人。与利妥昔单抗输注相关的不良事件发生在 72 名患者（15.4%）中，17 名患者（3.6%）发生过敏反应。没有出现长期不良事件，如长期中性粒细胞减少和白质脑病。224 名患者（47.9%）发生感染；84 名患者（17.9%）发生严重感染，3 名患者（0.6%）发生致死性感染。同时使用静脉内化疗、系统性红斑狼疮治疗、中性粒细胞减少症和静脉内免疫球蛋白与感染风险增加有关。在 135 名（28.8%）随访至 B 细胞计数恢复的患者中，在使用利妥昔单抗后 9.0 个月（中位数，5.9-14.4 个月）内，CD19+或 CD20+细胞数量恢复正常；95 名患者中有 48 名（51%）评估时间超过 1 年的患者，其 B 细胞计数低于年龄正常值。CD27+记忆 B 细胞数量中位数在 15.7 个月（中位数，6.0-22.7 个月）恢复。在基线免疫球蛋白 G（IgG）水平正常的患者中，289 名患者中有 67 名（23.2%）出现低 IgG 水平，255 名患者中有 118 名（40.8%）出现低 IgM 水平；在接受利妥昔单抗治疗 12 个月以上的患者中，117 名患者中有 16 名（13.7%）持续存在低 IgG，109 名患者中有 37 名（33.9%）持续存在低 IgM。
结论和相关性：利妥昔单抗在年轻人中耐受性良好，与严重不良事件相关的不良事件很少，但感染很常见，这对应于 B 细胞计数恢复的时间很长，通常持续 1 年以上。应进一步研究预防利妥昔单抗治疗后感染的策略。
