No Benefit in Adding Rituximab to MBVP in CNS Lymphoma

Results from a phase III trial suggest there is no survival benefit of adding the anti-CD20 monoclonal antibody rituximab to a standard methotrexate-based chemotherapy regimen for patients with primary central nervous system (CNS) lymphoma. The findings were published in Lancet Oncology.

In this open-label, multicenter, randomized trial, an international team of researchers from 23 hospitals in the Netherlands, Australia, and New Zealand recruited non-immunocompromised adult patients with newly diagnosed CNS lymphoma. Based on earlier phase II and single-arm studies that suggested that rituximab improved response rates in patients with primary CNS lymphomas – the majority of which are CD20-positive – they hypothesized that rituximab plus a high-dose methotrexate combination would improve survival rates, compared with chemotherapy alone.

A total of 199 patients were stratified according to treatment center, age, and Eastern Cooperative Oncology Group–WHO performance status. Participants were then randomized to receive either:

  • MBVP: two 28-day treatment cycles of methotrexate 3 g/m2 on days 1 and 15, teniposide 100 mg/m2 on days 2 and 3, carmustine 100 mg/m2 on day 4, and prednisolone 60 mg/m2 on days 1-5 (n=100)
  • R-MBVP: MBVP plus rituximab 375 mg/m2 on days 0, 7, 14, and 21 in cycle 1 and days 0 and 14 in cycle 2 (n=99)

At the end of induction, patients who responded to therapy received high-dose cytarabine; responders age 60 or younger also received low-dose whole-brain radiotherapy. Median age for all patients was 61 years (interquartile range [IQR] = 55-67 years).

The study’s primary endpoint was event-free survival (EFS). Events were defined as absence of complete response (CR) or unconfirmed CR at the end of all protocol treatment, or relapse or death after previous CR or unconfirmed CR.

Most patients (n=180/199; 90%) received both cycles of MBVP or R-MBVP. A total of 161 patients (81%) went on to receive high-dose cytarabine consolidation per study protocol, and 70 (35%) received whole-brain radiotherapy (34 in the MBVP group and 36 in the R-MBVP group).

The median follow-up in the study was 32.9 months (IQR = 23.9-51.5 months). After one year, 98 patients experienced an event: 51 in the MBVP group and 47 in the R-MBVP group. Of those patients, 79 died: 41 in the MBVP group and 38 in the R-MBVP group.

This translated to one-year EFS rates of 49% in the MBVP group and 52% in the R-MBVP group (hazard ratio = 1.00; 95% CI 0.70-1.43; p=0.99). The authors found no significant difference in one-year EFS rates after adjusting for age and performance status.

Median EFS was 10.8 months (range = 5.9-26.3 months) in the MBVP group and 14.9 months (range = 7.0-41.4 months) in the R-MBVP group. As seen in TABLE, one-year progression-free and overall survival rates were similar between the two groups.

Table 1: Progression-Free and Overall Survival Rates

Response rates also appeared similar in the MBVP and R-MBVP groups: 36% and 30%, respectively, achieved a CR or unconfirmed CR following induction chemotherapy, and this rate improved to 53% and 45% after consolidation with high-dose cytarabine (p value not provided). Radiotherapy further improved CR and unconfirmed CR rates in patients aged 60 or younger (66% for MBVP and 68% for R-MBVP).

According to the authors, there was “no evidence that treatment with R-MBVP increased the number of CRs or unconfirmed CRs compared with MBVP (odds ratio = 1.08; 95% CI 0.59-1.98; p=0.81).”

Toxicity also was similar between the two regimens, with 64% of MBVP-treated patients and 58% of R-MBVP–treated patients experiencing a grade 3 or 4 adverse event (AE). The most common AEs in both groups included:

  • infections (24% [MBVP] vs. 21% [R-MBVP])
  • hematologic toxicity (15% [MBVP] vs. 12% [R-MBVP])
  • CNS disorders (10% [MBVP] vs. 15% [R-MBVP]; p values not reported)

Similar proportions of patients in both groups experienced life-threatening or fatal serious AEs (12% in MBVP and 10% in R-MBVP). Treatment-related death was observed in five patients in the MBVP group and three patients in the R-MBVP group. The authors added that more patients receiving R-MBVP stopped treatment due to excessive toxicity (5 in the MBVP group and 11 in the R-MBVP group).

A possible explanation for the lack of improvement with additional rituximab is its inability to cross the blood-brain barrier. The researchers hypothesized that rituximab would be able to penetrate this barrier while it was disrupted due to whole-brain radiotherapy, but that did not appear to be the case. Results from a post hoc subgroup analyses showed no differences in survival according to patient sex or age, but the authors found a statistically significant difference in EFS favoring R-MBVP in patients younger than age 60 (p=0.015). However, they noted, the study was not powered for this comparison. Other limitations include the study’s open-label design.

The authors report relationships with Roche.

References

Bromberg JEC, Issa S, Bakunina K, et al. Rituximab in patients with primary CNS lymphoma (HOVON 105/ALLG NHL 24): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2019;20:216-28.

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