On December 2, the U.S. Food and Drug Administration (FDA) approved rituximab (Rituxan) in combination with chemotherapy for pediatric patients (≥ 6 months to < 18 years old) with previously untreated, advanced-stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia.
Inter-B-NHL Ritux 2010
Efficacy was evaluated in Inter-B-NHL Ritux 2010 (ClinicalTrials.gov identifier NCT01516580), a global, multicenter, open-label, randomized trial of patients ≥ 6 months old with previously untreated, advanced-stage, CD20-positive DLBCL, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia. 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 non-Hodgkin lymphoma or B-cell acute leukemia.
Patients were randomly assigned 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, administered as six infusions of intravenous rituximab at 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, 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 CYVE (cytarabine, etoposide) course, whichever occurred first. A prespecified interim efficacy analysis at 53% information fraction was performed in 328 randomly assigned patients, with a median follow-up of 3.1 years.
There were 28 event-free survival events in the LMB group and 10 in the rituximab-LMB group (hazard ratio = 0.32, 90% confidence interval [CI] = 0.17–0.58, P = .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 hazard ratio of 0.36 (95% CI = 0.16–0.81). No formal statistical test was conducted for overall survival, and the overall survival result is considered descriptive. Random assignment 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 the LMB chemotherapy arm 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, six infusions of rituximab are given, two doses during each of the induction courses, COPDAM1 (cyclophosphamide, vincristine, prednisolone, doxorubicin, methotrexate) and COPDAM2, and one dose during each of the two consolidation courses of CYM (cytarabine, 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 also granted Priority Review.
