NEWS & PERSPECTIVE
Rituximab added to LMB chemotherapy prolongs survival in children with high-risk mature b-cell non-Hodgkin’s lymphoma
Since its introduction in 1997, rituximab has been central to the treatment of high-grade B-cell lymphomas which account for 85% of all non-Hodgkin’s lymphoma (NHL) diagnoses in adults.1 However, evidence of rituximab’s efficacy in children is limited and that chemotherapy alone has demonstrated a better outcome in children with high-grade B-cell lymphomas. In 2010, the European Intergroup for Childhood Non-Hodgkin Lymphoma (EICNHL) and the Children’s Oncology Group (COG) collaborated in a phase 3 trial to assess the improvement of event-free survival (EFS) in children and adolescents carrying high-risk mature B-cell NHL with the addition of rituximab to a modified lymphomes malins B (LMB) chemotherapy regimen.2 The results were published in June 2020 in the New England Journal of Medicine (NEJM).
Rituximab is a monoclonal antibody that targets B-lymphocyte antigen CD20 and, upon binding, triggers a multifactorial cellular response that eventually leads to a global depletion of B-cells.3 The drug has greatly altered the treatment landscape of adult-onset NHL, and it has seen widespread use as both a single-agent therapy for relapsed/refractory (R/R) indolent lymphomas and as an addition to the standard chemotherapy regimens.1 On the other hand, the cure rates for youths with high-grade, mature B-cell NHL, including Burkitt’s lymphoma and diffuse large B-cell lymphoma, have improved drastically over the last 30 years even when treated with standard chemotherapy. Nonetheless, no large-scale study has been conducted to confirm the effects of rituximab in youths.
Previously, rituximab was demonstrated to be active as a single-agent therapy in youths and safe as an added agent to the LMB regimen in the phase 2 COG ANHL01P1 trial and the French-American-British(FAB)/LMB 96 study, respectively.4 Concurrent to the COG ANHL01P1 trial, the EICNHL and COG collaborated in the international, multicentre, randomized phase 3 Inter-B-NHL Ritux 2010 trial to confirm rituximab’s efficacy in youths.2
In the Inter-B-NHL Ritux 2010 trial, 328 patients between 6 months to 18 years of age from 12 countries including Hong Kong were analyzed. All patients were newly diagnosed of high-grade, mature B-cell neoplasms and were advanced on the St. Jude system of stages. 85.7% of patients carried Burkitt’s lymphoma while the rest either suffered from diffuse large B-cell lymphoma or other unspecified NHL subtypes. Patients were randomized 1:1 to receive either standard LMB chemotherapy or the modified protocol with rituximab added. The primary endpoint was EFS. Overall survival (OS) and toxic effects were also evaluated.2
The overall median follow-up period was 39.9 months. At 3 years, the rituximab-chemotherapy group demonstrated a significantly improved EFS when compared to the chemotherapy alone group at 93.9% vs. 82.3%, respectively (HR=0.32; 95% CI: 0.15-0.66). This efficacy was echoed by the OS at 3 years which was significantly improved in the rituximab-chemotherapy group when compared to the chemotherapy alone group at 95.1% vs. 87.3% , respectively (HR=0.36, 95% CI: 0.16-0.82). 95% of patients receiving rituximab-chemotherapy also has complete remission at 3 years. The results were similar regardless of age, histologic features, and therapeutic subgroups.2
While not statistically significant, the results also suggested a higher incidence of adverse effects (AEs) of grade 4 or above, particularly febrile neutropenia and infection, with rituximab when compared to chemotherapy at 37.7% versus 32.7%, respectively (p=0.36). After prephase treatment, the difference in AEs of grade 4 or above remained statistically insignificant (33.3% vs. 24.2%; p=0.07). No other toxic effects were observed in the trial.2
To summarize, the Inter-B-NHL Ritux 2010 trial confirmed the efficacy of rituximab in combination with the LMB chemotherapy regimen with a marked increase in both 3-year EFS and OS in children and adolescents with high-risk mature B-cell NHL. However, while the addition of rituximab could potentially reduce cytotoxic chemotherapy, the survival rate of chemotherapy alone in patients with standard-risk mature B-cell NHL is already very high at 97-98%. More data would be required to evaluate the long-term safety of rituximab and to confirm the efficacy of rituximab across all NHL risk groups.2
- Dotan E et al. Impact of Rituximab (Rituxan) on the Treatment of B-Cell Non-Hodgkin's Lymphoma. P T. 2010;35(3):148-157.
- Minard-Colin V et al. Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children. N Engl J Med. 2020;382(23):2207-2219.
- Smith M. Rituximab (Monoclonal anti-CD20 antibody): Mechanisms of action and resistance. Oncogene 2003;22(47):7359-7368.
- Goldman S et al. Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children's Oncology Group report. Leukemia. 2013;27(5):1174-1177.