Is There a Benefit to Adding Rituximab to Methotrexate-Based Chemotherapy in Primary CNS Lymphoma?


Key Points

  • The addition of rituximab to high-dose methotrexate-based treatment did not significantly improve event-free survival.
  • No significant improvement was observed in progression-free or overall survival.

In a phase III trial (HOVON 105/ALLG NHL 24) reported in The Lancet Oncology, Bromberg et al found no significant benefit of the addition of rituximab to high-dose methotrexate-based chemotherapy in patients with newly diagnosed primary central nervous system (CNS) lymphoma.

Study Details

In the open-label intergroup trial, performed at 23 sites in the Netherlands, Australia, and New Zealand, 199 patients were randomly assigned between August 2010 and May 2016 to receive two 28-day cycles of induction chemotherapy with intravenous (IV) methotrexate (3 g/m² on days 1 and 15), IV carmustine (100 mg/m² on day 4), IV teniposide (100 mg/m² on days 2 and 3), and oral prednisone (60 mg/m² on days 1–5), with (R-MBVP, n = 99) or without (MBVP, n = 100) IV rituximab at 375 mg/m² on days 0, 7, 14, and 21 in cycle 1 and days 0 and 14 in cycle 2. Patients with a response at the end of induction therapy received high-dose cytarabine and, in patients aged ≤ 60 years, low-dose whole-brain radiotherapy.

The primary endpoint was event-free survival, with events defined as not reaching complete response or complete response unconfirmed at the end of treatment or disease progression or death after response.

Treatment Outcomes and Adverse Events

Median follow-up was 32.9 months. Events occurred in 47 patients in the R-MBVP group and 51 patients in the MBVP group, including death in 38 and 41 patients. Event-free survival at 1 year was 52% vs 49% (hazard ratio [HR] = 1.00, P = .99). Median event-free survival was 14.9 months vs 10.8 months. Progression-free survival at 1 year was 65% vs 58% (HR = 0.77, P = .18). Median overall survival was not reached vs 56.7 months (HR = 0.93, P = .74).

Grade 3 or 4 adverse events occurred in 64% of patients in the R-MBVP group and 58% of patients in the MBVP group, with the most common being infections (21% vs 24%), hematologic toxicity (12% vs 15%), and nervous system disorders (15% vs 10%). Life-threatening or fatal adverse events occurred in 10% vs 12% of patients, with death from treatment-related adverse events occurring in 3% vs 5%.

The investigators concluded, “We found no clear benefit of addition of rituximab to methotrexate, carmustine, teniposide, and prednisone chemotherapy in primary CNS lymphoma. Therefore, the results of this study do not support the use of rituximab as a component of standard treatment in primary CNS lymphoma.”

Jacoline E.C. Bromberg, MD, of the Department of Neuro-Oncology, Erasmus MC Cancer Institute, Rotterdam, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Roche, the Dutch Cancer Society, and Stichting STOPhersentumoren. The study authors’ full disclosures can be found at

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