In a European Intergroup for Childhood Non-Hodgkin Lymphoma/Children’s Oncology Group phase III trial reported in The New England Journal of Medicine, Véronique Minard‑Colin, MD, PhD, of Gustave Roussy, Université Paris-Saclay, Villejuif, France, and colleagues found that the addition of rituximab to standard Lymphomes Malin de Burkitt (LMB) chemotherapy significantly improved event-free and overall survival in children with high-risk, mature B-cell non-Hodgkin lymphoma.¹ Rituximab/chemotherapy was associated with numerically higher rates of severe febrile neutropenia and infection and a significantly higher rate of low immunoglobulin G (IgG) levels.

Véronique Minard‑Colin, MD, PhD

As stated by the investigators, “Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin lymphoma are limited.”

Study Details

In the open-label trial, 328 patients (main analysis population) from 12 countries, aged 6 months to 18 years, with newly diagnosed high-risk, mature B-cell non-Hodgkin lymphoma (stage III with elevated lactate dehydrogenase [LDH] or stage IV) or acute leukemia were randomly assigned between December 2011 and November 2015 to receive rituximab plus standard LMB chemotherapy (n = 164) or LMB chemotherapy alone (n = 164). Rituximab was given at 375 mg/m² on day −2 (ie, 2 days before) and day 1 of the two induction chemotherapy courses and on day 1 of the two consolidation courses (six total doses). All patients received prephase treatment with low-dose cyclophosphamide, vincristine, and prednisone. The primary endpoint was event-free survival.

In the rituximab/chemotherapy vs chemotherapy groups, 84% vs 82% were male. The mean age was 9 years in both groups (27% vs 34% < 6 years, 45% vs 41% between 6 and 12 years, 18% vs 13% between 12 and 15 years, and 10% vs 12% ≥ 15 years). Overall, 85% vs 87% had Burkitt lymphoma and 12% vs 7% had diffuse large B-cell lymphoma. The prognosis group was high-risk group B (stage III disease and LDH more than twice the upper limit of the normal range or non–central nervous system [CNS] stage IV disease with bone marrow involvement < 25%) in 49% vs 50%, group C1 (cerebrospinal fluid [CSF]-negative stage IV disease with bone marrow involvement ≥ 25%, CNS-positive disease, or both) in 40% vs 39%, and group C3 (CSF-positive stage IV disease) in 11% vs 10%. The primary site was abdomen or retroperitoneum in 59% vs 58%, and clinical presentation of leukemia was noted in 18% vs 21%.

Event-Free Survival

Median follow-up was at 39.9 months. Event-free survival events occurred in 10 patients in the rituximab/chemotherapy group vs 28 in the chemotherapy group, with the greatest difference between groups being the occurrence of relapse or disease progression in 3 vs 23 patients. Event-free survival at 3 years was 93.9% (95% confidence interval [CI] = 89.1%–96.7%) in the rituximab/chemotherapy group vs 82.3% (95% CI = 75.7%–87.5%) in the chemotherapy group (hazard ratio [HR] = 0.32, P = .00096).

The event-free survival benefit of rituximab/chemotherapy was observed across subgroups of patients, including among group B patients (HR = 0.33, 95% CI = 0.12–0.91), group C1 patients (HR = 0.37, 95% CI = 0.12–1.18), and group C3 patients (HR = 0.19, 95% CI = 0.02–1.73) and among patients with Burkitt lymphoma (HR = 0.36, 95% CI = 0.16–0.77). By age group, hazard ratios were 0.26 (95% CI = 0.06–1.22) for those up to age 6, 0.13 (95% CI = 0.03–0.59) for those between 6 and 12 years, and 0.72 (95% CI = 0.24–2.14) for those 12 years and older.

Mortality occurred in eight patients in the rituximab/chemotherapy group, with four deaths being disease-related, three treatment-related, and one due to a second cancer. Death occurred in 20 patients in the chemotherapy group, with 17 being disease-related and 3 treatment-related. Overall survival at 3 years was 95.1% (95% CI = 90.5%–97.5%) vs 87.3% (95% CI = 81.2%–91.6%), with a hazard ratio of 0.36 (95% CI = 0.16–0.82).

Adverse Events

Grade ≥ 4 adverse events occurred in 33.3% of the rituximab/chemotherapy group vs 24.2% of the chemotherapy group (P = .07). Grade ≥ 4 febrile neutropenia occurred in 11.7% vs 6.5% of patients (P = .11), and grade ≥ 4 infection occurred in 18.5% vs 11.1% (P = .07).

A greater proportion of patients in the rituximab/chemotherapy group had IgG levels below the limit of normal range at the end of therapy (70.3% vs 46.8%, P = .002) and at 1 year (55.9% vs 25.4%, P < .001). A greater proportion also received intravenous immune globulin (15.8% vs 7.0%), with the primary reason being low immunoglobulin levels without infection; seven vs three patients continued to receive immune globulin at 1 year after enrollment. As stated by the investigators, “Complete and longer follow-up with regard to immune status and late infections have not been evaluated.”

The investigators concluded: “Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection.” 

DISCLOSURE: The study was funded by the Clinical Research Hospital Program of the French Ministry of Health, Cancer Research UK, National Institute for Health Research Clinical Research Network, Children’s Cancer Foundation Hong Kong, National Cancer Institute, and F. Hoffmann–La Roche–Genentech. Dr. Minard‑Colin has received institutional research support from F. Hoffmann–La Roche. For full disclosures of the other study authors, visit www.nejm.org.

REFERENCE

1. Minard‑Colin V, Aupérin A, Pillon M, et al: Rituximab for high-risk, mature B-cell non-Hodgkin’s lymphoma in children. N Engl J Med 382:2207-2219, 2020.