On December 2, 2021, the FDA approved the use of rituximab (Rituxan; Genentech), a CD20-directed cytolytic antibody, in combination with chemotherapy, for the treatment of treatment-naïve pediatric patients (aged ≥6 months to <18 years) with advanced-stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia. Rituximab was previously approved for adults with non-Hodgkin lymphoma (NHL) or with chronic lymphocytic leukemia, as well as for several nonmalignant indications.
This approval was based on the Inter-B-NHL Ritux 2010 clinical trial, a global, multicenter, open-label, randomized (1:1) study of treatment-naïve pediatric patients aged ≥6 months to <18 years with advanced stage, CD20-positive DLBCL, Burkitt lymphoma, Burkitt-like lymphoma, or B-cell acute leukemia. Advanced stage was defined as stage III with elevated lactose dehydrogenase (LDH) level (LDH more than twice the institutional upper limit of normal values) or stage IV B-cell NHL or B-cell acute leukemia.
Patients were randomized to Lymphome Malin de Burkitt (LMB) chemotherapy (including corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and the triple-drug—methotrexate, cytarabine, and corticosteroid—intrathecal therapy) alone or in combination with rituximab, which was administered as 6 intravenous (IV) infusions of rituximab, at a dose of 375 mg/m2 (2 doses during each of the 2 induction courses and 1 during each of the 2 consolidation courses), per the LMB chemotherapy.
The primary end point was event-free survival (EFS), defined as progressive disease, disease relapse, second malignancy, death from any cause, or nonresponse as evidenced by detection of viable cells in residue after the second course of cytarabine and veposide, whichever occurs first.
A prespecified interim efficacy analysis included 328 patients, with a median follow-up of 3.1 years. A total 28 EFS events occurred in the LMB arm and 10 in the rituximab plus LMB arm (hazard ratio [HR], 0.32; 90% confidence interval [CI], 0.17-0.58; P = .0012). At the time of the interim analysis, 20 deaths occurred in the LMB chemotherapy arm versus 8 deaths in the rituximab plus LMB chemotherapy arm, with an estimated overall survival (OS) HR of 0.36 (95% CI, 0.16-0.81).
No statistical test was conducted for OS, and the OS result is considered descriptive. Randomization was discontinued after the interim analysis, and an additional 122 patients received rituximab plus LMB chemotherapy and were included in the safety analysis.
Adverse reactions (grade ≥3, >15%) reported with rituximab plus chemotherapy were febrile neutropenia, stomatitis, enteritis, sepsis, increased alanine aminotransferase, and hypokalemia. Grade ≥3 adverse reactions occurring more often in the rituximab plus LMB chemotherapy arm versus LMB chemotherapy alone included sepsis, stomatitis, and enteritis. Fatal adverse reactions occurred in <2% of patients in both arms.
The recommended rituximab dose is 375 mg/m2 as an IV infusion given in combination with systemic LMB chemotherapy.