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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/m 2 (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 consoli-
dation 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, Aus-
tralia, 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 treat-
ment. 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 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.
REFERENCE
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.
SCENES FROM THE 2017 ASH ANNUAL MEETING
March 2018
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