Addition of Rituximab to High-Dose Chemotherapy Does Not Improve Response in Patients With Central Nervous System Lymphoma

According to results of an international, randomized, phase III trial, combining rituximab with high-dose, methotrexate-based chemotherapy did not improve response rates or survival for patients with primary central nervous system lymphoma (PCNSL). Jacoline Bromberg, MD, of the Department of Neuro-Oncology at the Daniel den Hoed Cancer Center in Rotterdam, the Netherlands, and colleagues presented the findings at the 2017 ASH Annual Meeting.

Patients (aged 18-70 years) with newly diagnosed, non-immunocompromised PCNSL were included in the trial if they had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-3. Participants were randomized to receive induction with two cycles of MBVP (high-dose methotrexate, carmustine, teniposide, prednisone) alone (arm A) or in combination with rituximab 375 mg/m2 (arm B).

Rituximab was administered weekly during cycle one of MBVP (on days 0 and 14) and every other week during cycle two for a total of six administrations. Patients with cerebrospinal fluid (CSF) that tested persistently positive for lymphoma after the first MBVP cycle received intrathecal methotrexate, and those who achieved at least a partial response received consolidation with high-dose cytarabine.

Patients were stratified based on age (≤60 vs. ≥61 years) and ECOG score (0-1 vs. 2-3).

Patients 60 years or younger were treated with 30 Gray (Gy) whole-brain radiotherapy (WBRT) with an additional 10 Gy in case of partial remission. Patients 61 years or older were not to be irradiated. Magnetic resonance imaging (MRI) was evaluated after two cycles of MBVP, after high-dose cytarabine, and four weeks after WBRT, when applicable.

During follow-up, patients underwent MRI every three months for the first two years, every six months in years three through five, and annually thereafter.

Two-hundred patients (median age = 61 years; range = 26-70 years) were enrolled from 24 centers in the Netherlands, Australia, and New Zealand between August 2010 and June 2016: 100 patients were randomized to arm A and 99 to arm B. One patient was not eligible and was excluded from all analyses. Most (72%) had an ECOG score of ≤1, 29 percent had elevated lactate dehydrogenase, and 30 percent had positive CSF.

All patients received cycle one of planned treatment, 90 percent received cycle two, and 81 percent received high-dose cytarabine. Eight patients in each arm received intrathecal treatment. Irradiation occurred in 70 patients (35%): 34 percent in arm A and 36 percent in arm B.

At the time of analysis, 79 patients had died, with treatment-related deaths reported in 7 percent in arm A and 3 percent in arm B. Most of the deaths were attributable to PCNSL (71% in arm A and 76% in arm B). A total of four patients died of treatment complications (3 and 1, respectively).

Grade 3 or 4 adverse events (AEs) occurred in 59 percent of patients in arm A and 63 percent in arm B. Infections were the most frequent AE, occurring in 23 percent and 21 percent, respectively.

After a median follow-up of 32.9 months (range = 3.6-79.2 months), response rates and event-free survival (EFS; primary endpoint) were similar in both treatment arms:

  • overall response rate: 87% in both groups
  • complete response (CR)/CR unconfirmed (CRu) rate: 66% in arm A and 68% in arm B
  • one-year EFS: 49% in arm A and 52% in arm B

An exploratory multivariate analysis revealed a possible effect of rituximab in younger patients, but not patients older than 60 (hazard ratio [HR] = 0.54; 95% CI 0.30-0.98).

Overall survival (OS) data were not evaluable at the time of reporting, but among the 120 patients who were alive at last follow-up, there was no apparent difference (HR=0.93; 95% CI 0.59-1.44; p=0.74).

Although these results suggest that there is no value in adding rituximab to high-dose chemotherapy in this patient population, the authors noted that “longer follow-up is needed to evaluate the effect on OS.”

The authors report financial relationships with Janssen, Celgene, Takeda, Amgen, and Novartis.


Bromberg J, Issa S, Bukanina K, et al. Effect of rituximab in primary central nervous system lymphoma –  results of the randomized phase III HOVON 105/ALLG NHL 24 study. Abstract #582. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.