The Inter-B-NHL Ritux 2010 Trial
The Inter-B-NHL Ritux 2010 trial (NCT01516580) demonstrated that adding rituximab to LMB chemotherapy in pediatric and young adult patients with advanced-stage B-cell non-Hodgkin's lymphoma significantly improved event-free survival, establishing rituximab plus chemotherapy as the standard of care for this population. 1
Trial Design and Population
The Inter-B-NHL Ritux 2010 was a multicenter, open-label, randomized controlled trial that enrolled patients with previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or B-cell acute leukemia (B-AL) aged 6 months and older. 1
Key eligibility criteria included:
- Advanced stage disease defined as Stage III with elevated lactate dehydrogenase (LDH greater than twice the institutional upper limit of normal) or Stage IV B-cell NHL or B-AL 1
- CD20-positive disease 1
- No prior systemic therapy 1
The trial was designed to enroll 600 patients with 1:1 randomization but was stopped early for efficacy after 362 patients had been enrolled (181 in each arm) following the first planned interim analysis. 1
Treatment Arms and Dosing
Patients were randomized to receive either:
Control arm: LMB chemotherapy alone (corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide and triple drug intrathecal therapy) 1
Experimental arm: LMB chemotherapy plus rituximab administered as six infusions at 375 mg/m² body surface area:
- Two doses during each of the two induction courses 1
- One dose during each of the two consolidation courses 1
LMB therapy was stratified based on clinical group classification: Group B (stage III with high LDH and non-CNS), Group C1 (B-AL, CNS positive and CSF negative), and Group C3 (CSF positive). 1
Patient Demographics
A total of 328 randomized patients were included in the efficacy analyses. 1
Baseline characteristics were well-balanced:
- Age: Median 7-8 years (range 1-17 years); 71% were 3 to <12 years, 27% were 12 to <18 years, and only 2% were 6 months to <3 years 1
- Gender: 82-84% male 1
- Disease distribution: 55-56% Burkitt or Burkitt-like NHL, 35-37% B-AL, 8% DLBCL 1
- Therapeutic groups: Approximately 50% Group B high-risk, 40% Group C1, 10% Group C3 1
- Bone marrow involvement: 45% in both arms 1
- CNS involvement: 27% in both arms 1
Primary Outcome and Results
The primary endpoint was event-free survival (EFS), defined as time to occurrence of progressive disease, relapse, second malignancy, death from any cause, or non-response (evidenced by detection of viable cells in residue after the second CYVE course). 1
With a median follow-up of 3.1 years, the addition of rituximab to LMB chemotherapy demonstrated superior efficacy, leading to early trial termination. 1 The hazard ratio for events favored the rituximab-containing arm, establishing this combination as the new standard of care for this patient population. 1
Clinical Significance
This trial is particularly important because:
It established the first evidence-based standard for adding rituximab to chemotherapy in pediatric and young adult patients with advanced B-cell lymphomas and leukemias. 1 Prior to this trial, rituximab use in this population was based primarily on extrapolation from adult data.
The early stopping for efficacy after enrolling only 60% of the planned sample size (362 of 600 patients) indicates a robust treatment effect that was evident at the first interim analysis. 1
The trial included a broad spectrum of aggressive B-cell malignancies (DLBCL, BL, BLL, B-AL) and high-risk features (CNS involvement, bone marrow involvement, elevated LDH), making the results generalizable to the most challenging pediatric cases. 1
Safety Profile
The safety profile in pediatric patients was consistent with the known safety profile of rituximab in adults with rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, and pemphigus vulgaris. 1 The addition of rituximab did not result in prohibitive toxicity that would limit its use in this vulnerable population. 1
Current Practice Implications
Based on the Inter-B-NHL Ritux 2010 trial results, rituximab 375 mg/m² administered as six infusions (two during each induction course and one during each consolidation course) in combination with LMB chemotherapy is now the standard first-line treatment for pediatric and young adult patients with advanced-stage, CD20-positive B-cell NHL and B-AL. 1
This represents a paradigm shift from chemotherapy alone to chemoimmunotherapy for this population, mirroring the evolution that occurred in adult lymphoma treatment following earlier trials demonstrating rituximab's benefit when combined with CHOP chemotherapy. 1