利妥昔单抗治疗高危、成熟 B 细胞非霍奇金淋巴瘤患儿。
Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.
机构信息
From the Departments of Pediatric and Adolescent Oncology (V.M.-C., C.P.) and Clinical Research (G.V.), INSERM Unité 1015 (V.M.-C.), and the Unit of Biostatistics and Epidemiology and INSERM Unité 1018 (A.A.), Gustave Roussy, Université Paris-Saclay, Villejuif, France; the Department of Pediatric Hematology and Oncology, University of Padua, Padua, Italy (M.P.); the Department of Paediatric Haematology, Oncology, and Palliative Care, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge (G.A.A.B.), Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham (K.W.), and the Department of Histopathology, Royal Marsden NHS Foundation Trust, London (A.W.) - all in the United Kingdom; the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (D.A.B.); the Department of Pediatric Hematology and Oncology, University of Valencia, Valencia, Spain (R.F.D.); the Division of Haematology-Oncology, Hospital for Sick Children, Toronto (S.A.); the Department of Pediatric Hematology and Oncology, University Hospitals Leuven, Leuven, Belgium (A.U.); the Center for Cancer and Immunology Research, Children's National Health System and George Washington University, Washington, DC (C.M.B.); Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands (J.Z.); the Department of Pediatric Hematology and Oncology, Semmelweis University, Budapest, Hungary (M.C.); the Department of Pediatric Bone Marrow Transplantation, Oncology, and Hematology, Wroclaw Medical University, Wroclaw, Poland (B.K.); the Department of Pediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong (A.K.C.); the Department of Pathology, University of Utah, Salt Lake City (R.R.M.); Children's Hospital of Philadelphia, Philadelphia (P.C.A.); and the National Cancer Institute, Center for Global Health, Rockville, MD (T.G.G.).
出版信息
N Engl J Med. 2020 Jun 4;382(23):2207-2219. doi: 10.1056/NEJMoa1915315.
BACKGROUND
Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin's lymphoma are limited.
METHODS
We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin's lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed.
RESULTS
Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt's lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion.
CONCLUSIONS
Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin's lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).
背景
利妥昔单抗联合化疗可延长 B 细胞癌成人患者的生存时间。有关其在儿童高危成熟 B 细胞非霍奇金淋巴瘤中的疗效和安全性的数据有限。
方法
我们进行了一项开放标签、国际、随机、3 期临床试验，纳入了年龄小于 18 岁的高危成熟 B 细胞非霍奇金淋巴瘤（III 期乳酸脱氢酶升高或 IV 期）或急性白血病患者，比较了利妥昔单抗联合六剂标准 LMB 化疗与单纯标准 LMB 化疗。主要终点为无事件生存。还评估了总生存和毒性作用。
结果
根据 328 例接受随机分组的患者（每组 164 例）进行了分析；85.7%的患者为伯基特淋巴瘤。中位随访时间为 39.9 个月。利妥昔单抗化疗组中有 10 例患者发生事件，化疗组中有 28 例患者发生事件。利妥昔单抗化疗组 3 年无事件生存率为 93.9%（95%置信区间[CI]，89.1 至 96.7），化疗组为 82.3%（95%CI，75.7 至 87.5）（原发性难治性疾病或首次进展、缓解后复发、任何原因死亡或第二次癌症的主要进展风险比，0.32；95%CI，0.15 至 0.66；单侧 P=0.00096，达到本分析的显著性水平）。利妥昔单抗化疗组有 8 例患者死亡（4 例与疾病相关，3 例与治疗相关，1 例与第二癌症相关），化疗组有 20 例患者死亡（17 例与疾病相关，3 例与治疗相关）（风险比，0.36；95%CI，0.16 至 0.82）。利妥昔单抗化疗组预处理后发生 4 级或 4 级以上急性不良事件的发生率为 33.3%，化疗组为 24.2%（P=0.07）；事件主要与发热性中性粒细胞减少和感染有关。利妥昔单抗化疗组中有近两倍的患者在试验纳入后 1 年时 IgG 水平较低。
结论
在患有高危成熟 B 细胞非霍奇金淋巴瘤的儿童和青少年中，利妥昔单抗联合标准 LMB 化疗可显著延长无事件生存和总生存时间，并且与低丙种球蛋白血症的发生率较高有关，可能与感染次数增加有关。（由法国卫生部等临床研究医院计划资助；ClinicalTrials.gov 编号，NCT01516580。）
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