On December 2, 2021, the Food and Drug Administration approved rituximab (Rituxan, Genentech, Inc.) in combination with chemotherapy for pediatric patients (≥6 months to <18 years) with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature B-cell acute leukemia (B-AL).
Efficacy was evaluated in Inter-B-NHL Ritux 2010 (NCT01516580), a global multicenter, open-label, randomized (1:1) trial of patients ≥ 6 months in age with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL. Advanced stage was defined as Stage III with elevated lactose dehydrogenase (LDH) level (LDH greater than twice the institutional upper limit of normal values) or stage IV B-cell NHL or B-AL. Patients were randomized to Lymphome Malin B (LMB) chemotherapy (corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide, and triple drug [methotrexate/cytarabine/corticosteroid] intrathecal therapy) alone or in combination with rituximab or non-U.S. licensed rituximab, administered as 6 infusions of rituximab IV 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) as per the LMB scheme.
The main efficacy outcome measure was event-free survival (EFS), defined as progressive disease, relapse, second malignancy, death from any cause, or non-response as evidenced by detection of viable cells in residue after the second CYVE (Cytarabine [Aracytine, Ara-C], Veposide [VP16]) course, whichever occurs first. A prespecified interim efficacy analysis at 53% information fraction was performed in 328 randomized patients with a median follow-up of 3.1 years. There were 28 EFS events in the LMB group and 10 in the rituximab-LMB group (HR 0.32; 90% CI: 0.17, 0.58; p=0.0012). At the time of the interim analysis, there were 20 deaths in the LMB chemotherapy arm compared to 8 deaths in the rituximab plus LMB chemotherapy arm, with an estimated overall survival HR of 0.36 (95% CI: 0.16, 0.81). No formal statistical test was conducted for overall survival (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 contributed to the safety analysis.
Adverse reactions (grade 3 or higher, >15%) occurring in pediatric patients treated with rituximab and chemotherapy were febrile neutropenia, stomatitis, enteritis, sepsis, increased alanine aminotransferase, and hypokalemia. Grade 3 or higher adverse reactions that occurred more often in the rituximab plus LMB chemotherapy arm compared to LMB chemotherapy included sepsis, stomatitis, and enteritis. Fatal adverse reactions occurred in <2% of patients in both the rituximab plus LMB chemotherapy and LMB chemotherapy arms.
The recommended rituximab dose is 375 mg/m2 as an intravenous infusion given in combination with systemic LMB chemotherapy. In total, 6 infusions of rituximab are given, 2 doses during each of the induction courses, COPDAM1 [cyclophosphamide, Oncovin (vincristine), prednisolone, Adriamycin (doxorubicin), methotrexate] and COPDAM2, and 1 dose during each of the 2 consolidation courses of CYM (Cytarabine [Aracytine, Ara-C], methotrexate) and CYVE.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment, and Streamlined Review.
This application was granted priority review. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.
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