March 26, 2019
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Rituximab added to chemotherapy confers no EFS benefit in CNS lymphoma

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Patients with primary central nervous system lymphoma did not benefit from the addition of rituximab to methotrexate-based chemotherapy , according to results of a randomized phase 3 study published in Journal of Clinical Oncology.

“Histologically, more than 90% of primary CNS lymphomas are CD20-positive diffuse large B-cell lymphomas,” Jacoline E.C. Bromberg, MD, of the department of neuro-oncology at Erasmus MC Cancer Institute in the Netherlands, and colleagues wrote. “Rituximab, a chimeric monoclonal antibody that targets the CD20 cell surface protein, has substantial activity in systemic CD20-positive diffuse large B-cell lymphoma ... but its efficacy in primary CNS lymphoma is unknown, and low penetration of the large rituximab molecule through the blood-brain barrier could limit its effect.”

For the open-label, randomized phase 3 study, Bromberg and colleagues recruited 200 nonimmunocompromised adults (median age, 61 years; interquartile range [IQR] = 55-67; 109 men) with newly diagnosed CNS lymphoma from 23 centers in the Netherlands, Australia and New Zealand between Aug. 3, 2010, and May 27, 2016. They excluded one patient due to incorrect diagnosis.

Researchers randomly assigned patients at a 1:1 ratio to methotrexate-based chemotherapy with or without IV rituximab (Rituxan, Genentech). The web-based randomization system stratified patients by center, age, ECOG-WHO performance status and a minimization procedure.

All patients underwent two 28-day cycles of induction MBVP chemotherapy, which included 3 g/m2 IV methotrexate on days 1 and 15, 100 mg/m2 IV carmustine on day 4, 100 mg/m2 IV teniposide on days 2 and 3, and 60 mg/m2 oral prednisone on days 1 to 5.

Ninety-nine patients also received 375 mg IV rituximab (R-MBVP) on days 0, 7, 14 and 21 in cycle one and days 0 and 14 in cycle two. Patients showing response at the end of induction therapy received high-dose cytarabine, and for those aged 60 years or younger, low-dose whole-brain radiotherapy.

EFS served as the study’s primary endpoint. Events included failure to achieve or unconfirmed complete response at the end of treatment or progression or death after response.

Secondary endpoints included OS, toxicity, and the proportion of patients achieving a response after induction chemotherapy with MBVP or R-MBVP, after high-dose cytarabine and after completion of radiotherapy.

At median follow-up of 32.9 months (IQR, 23.9-51.5), events occurred in 98 patients — including 51 in the MBVP group and 47 in the R-MBVP group — and 79 of these patients died (41 vs.38).

One-year EFS was 49% (95% CI, 39-58) in the MBVP group vs. 52% (95% CI, 42-61) in the R-MBVP group (HR = 1; 95% CI, 0.7-1.43).

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In each group, 86% of patients achieved a response after induction chemotherapy. The number of complete responses increased following high-dose cytarabine and, in patients aged 60 years and younger, radiotherapy, reaching 66% in the MBVP group and 68% in the R-MBVP group.

OS with MBVP vs. R-MBVP was 79% for both cohorts at 1 year, 65% vs. 71% at 2 years, and 61% vs. 58% at 3 years. Median OS was 56.7 months with MBVP and not reached with R-MBVP (adjusted HR = 0.93; 95% CI, 0.59-1.44).

An unplanned subgroup analysis by age among patients aged 18 to 60 years showed a median EFS of 19.7 months (95% CI, 6.5-not reached) in the MBVP group vs. 59.9 months (41.4-not reached) among those in the R-MBVP group (HR = 0.56; 95% CI, 0.31-1.01).

Among patients older than 60 years, median EFS was 8.3 months (95% CI, 4.2-24.8) with MBVP vs. 4.2 months (95% CI, 3.5-10.5) with R-MBVP (HR =1.42; 95% CI, 0.9-2.23). Similar proportions of patients in each age group achieved complete response after induction and cytarabine consolidation.

Fifty-eight percent of patients (n = 58) in the MBVP group experienced grade 3 or grade 4 adverse events vs. 64% of patients (n = 63) in the R-MBVP group. The most common of these were infections (24% vs. 21%), hematological toxicity (15% vs. 12%) and nervous system disorders (10% vs. 15%).

Twelve percent of patients in the MBVP group and 10% of patients in the R-MBVP group experienced life-threatening or fatal serious adverse events. Five patients in the MBVP group and three in the R-MBVP group died of causes associated with treatment.

The researchers acknowledged limitations to their study, including potential bias associated with the unblinded treatment design and the possible drawbacks of EFS as a primary endpoint.

The differences in EFS in the subanalysis by age warrants further investigation, according to an editorial by Benjamin Kasenda, MD, and Gerald Illerhaus, MD, of the department of hematology/oncology and palliative care at Klinikum Stuttgart’s Stuttgart Cancer Center in Germany.

“Do we really believe that an arbitrary age cutoff at 60 years drives this difference? Or is it rather an interaction with the treatment protocol (whole-brain radiotherapy vs. observation) of the trial?” the editorial authors wrote. “This ultimately remains unclear. To address these uncertainties and inform clinical decision-making, all available evidence from randomized trials must be considered.” – by Jennifer Byrne

Disclosures: Bromberg reports grants, personal fees and nonfinancial support from Roche during the conduct of the study. Please see the study for all other authors’ relevant financial disclosures. Kasenda and Illerhaus report no relevant financial disclosures.