On December 2, 2021, the U.S. Food and Drug Administration (FDA) approved rituximab (Rituxan®) in combination with chemotherapy for pediatric patients aged at least 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 at least 6 months old with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL. Advanced stage was defined as stage III with elevated lactose dehydrogenase greater than twice the institutional upper limit of normal values or stage IV B-cell NHL or B-AL.
Patients were randomized to receive Lymphome Malin de Burkitt (LMB) chemotherapy (i.e., 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 six IV infusions at a dose of 375 mg/m2 (two doses during each of the two induction courses and one during each of the two 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 nonresponse as evidenced by detection of viable cells in residue after the second course of cytarabine and veposide, whichever occurred 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. Twenty-eight EFS events occurred 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, 20 deaths had occurred 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 and the 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.
Grade 3 or higher adverse reactions occurring in more than 15% of 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 less than 2% of patients in both the rituximab plus LMB chemotherapy and LMB chemotherapy arms.
The recommended rituximab dose is 375 mg/m2 as an IV infusion given in combination with systemic LMB chemotherapy. In total, six rituximab infusions are given: two doses during each of the induction courses (both courses with cyclophosphamide, vincristine, prednisolone, doxorubicin, and methotrexate) and one dose during each of the two consolidation courses of cytarabine and methotrexate and cytarabine and veposide.
The review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment, and Streamlined Review.
The 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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