Rituximab combined with chemotherapy approved in the United States for pediatric patients with specific malignant tumors

On December 2, 2021, the Food and Drug Administration approved rituximab (rituximab) in combination with chemotherapy for the treatment of pediatric patients (≥6 months to <18 years) with previously untreated advanced 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 in patients ≥ 6 months old with untreated advanced, CD20-positive DLBCL/BL/BLL/B-AL. Advanced stage is defined as stage III with elevated lactose dehydrogenase (LDH) levels (LDH greater than twice the institutional upper limit of normal) or stage IV B-cell NHL or B-AL.

Patients were randomized to receive 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, according to the LMB protocol, at 375 Rituximab was administered intravenously for 6 times at a dose of mg/m2 (2 times in each of the 2 induction phases and 1 time in each of the 2 consolidation phases).

The primary efficacy indicator is event-free survival (EFS), defined as disease progression, recurrence, secondary malignancy, death from any cause, or non-response proven by residual viable cell testing after the second course of CYVE (cytarabine, VP16), whichever occurs first.

A prespecified interim efficacy analysis was performed with an informative score of 53% among 328 randomized patients, with a median follow-up of 3.1 years.

There were 28 EFS events in the LMB group and 10 EFS events 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 group and 8 deaths in the rituximab plus LMB chemotherapy group, with an estimated overall survival HR of 0.36 (95% CI: 0.16, 0.81). No formal statistical test of overall survival (OS) was performed, and OS results were considered descriptive. After the interim analysis, randomization was stopped, and an additional 122 patients received rituximab plus LMB chemotherapy and participated in the safety analysis.

Adverse reactions (Grade 3 or higher, >15%) that occurred in pediatric patients receiving rituximab and chemotherapy were febrile neutropenia, stomatitis, enteritis, sepsis, increased alanine aminotransferase, and hypokalemia. Grade 3 or higher adverse reactions that occurred more frequently in the rituximab plus LMB chemotherapy group compared with the LMB chemotherapy group included sepsis, stomatitis, and enteritis. Fatal adverse reactions occurred in <2% of patients in the rituximab plus LMB chemotherapy group and the LMB chemotherapy group.

The recommended dose of rituximab is 375 mg/m² as an intravenous infusion in combination with systemic LMB chemotherapy. A total of 6 injections of rituximab were performed, 2 injections each during each induction process, namely COPDAM₁ (cyclophosphamide, vincristine, prednisone, doxorubicin, methotrexate) and COPDAM₂, and 1 injection each during the 2 consolidation processes of CYM (cytarabine, methotrexate) and CYVE.