Chemoimmunotherapy combination ‘new standard’ for CNS lymphoma

The addition of rituximab to thiotepa and methotrexate–cytarabine increased the complete remission rate among patients with central nervous system lymphoma, according to results from the first randomization of the phase 2 IELSG32 trial.

However, the combination, also called the MATRix regimen, also caused more grade 3 to grade 4 adverse events.

“The IELSG32 trial provides a high level of evidence supporting the use of the MATRix combination as the new standard chemoimmunotherapy for patients younger than 70 years of age with newly diagnosed primary CNS lymphoma and as the control group for future randomized trials,” Andrés J.M. Ferreri, MD, of the unit of lymphoid malignancies in the department of onco-hematology at Ateneo Vita-Salute San Raffaele in Milano, Italy and colleagues wrote.

Because the standard treatment for patients with primary CNS lymphoma had not been defined, Ferreri and colleagues sought to evaluate the tolerability and efficacy of adding rituximab (Rituxan, Genentech) with or without thiotepa to methotrexate–cytarabine combination therapy. In a second randomization, researchers also are comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation.

The analysis included data from 227 HIV–negative patients aged 18 to 70 years with newly diagnosed primary CNS lymphoma and measurable disease.

All patients received four courses of 3.5g/m² of methotrexate on day 1 with 2g/m² of cytarabine twice daily on days 2 and 3.

Researchers randomly assigned patients to receive that combination alone (n = 75), with 375mg/m² rituximab on days –5 and 0 (n = 74), or with rituximab plus 30 mg/m² thiotepa on day 4 (n = 78). Each group repeated treatment every 3 weeks.

Patients with responsive or stable disease after the first stage moved on to the second randomization (n = 118).

The current analysis includes data from the first randomization. Completion remission rate served as the primary endpoint of the first randomization.

Median follow-up was 30 months (interquartile range, 22-38). Evaluable data were available from 219 patients.

Forty-nine percent (n = 37) of patients treated with MATRix achieved complete remission. By comparison, complete remission rates were 30% (n = 21) in the methotrexate–cytarabine plus rituximab arm (HR = 0.61, 95% CI 0.4-0.94), and 23% (n = 17) in the methotrexate–cytarabine-alone arm (HR = 0.46, 95% CI, 0.28-0.74).

Overall response rate also was higher in the MATRix arm (87%) compared with the methotrexate–cytarabine plus rituximab arm (74%, HR = 0.89, 95% CI, 0.76-1.03) and the methotrexate–cytarabine-alone arm (53%; HR = 0.61, 95% CI, 0.49-0.77).

More patients in the MATRix arm achieved 2-year OS (69%) and PFS (61%) than patients in the methotrexate–cytarabine plus rituximab arm (OS, 56%; PFS, 46%) and methotrexate–cytarabine-alone arm (OS, 42%; PFS, 36%).

Thrombocytopenia, neutropenia, anemia, and febrile neutropenia or infections were the most common grade 3 to grade 4 adverse events in all three treatment groups.

More patients treated with MATRix experienced grade 4 hematological toxicity. Seventy-three percent of patients experienced grade 4 thrombocytopenia in this group compared with 59% in the methotrexate–cytarabine plus rituximab arm and 52% in the methotrexate–cytarabine-alone group.

Toxicity caused the death of 13 patients (6%).

Ferreri and colleagues acknowledged limitations of their study, including a potential for assessment bias in efficacy due to the open-label design and that they changed the statistical parameters of the study after an unplanned preliminary analysis showed a lower complete remission rate and OS than what had been predicted.

Although these data provide evidence in support of including blood–brain barrier-penetrating alkylating agents and rituximab into the imitation management of this disease, the study limitations are important to consider, David Schiff, MD, Harrison distinguished professor of neurology, neurological surgery and medicine, as well as co-director of the Neuro-Oncology Center at University of Virginia School of Medicine, and colleagues wrote in an accompanying editorial.

“Limitations in the study design imposed from trying to answer two key questions with a relatively small population prevent us from accepting the report’s assertion that MATRix represents the new standard of care for this patient group,” Schiff and colleagues wrote.

These limitations include that the trial was not prospectively designed to test the benefit of adding rituximab or thiotepa to MATRix, that the primary analysis did not incorporate the International Extranodal Lymphoma Study Group risk group stratification, and that remission rate is not a proven surrogate for OS in primary CNS lymphoma. – by Nick Andrews

Disclosure: The researchers and editorial authors report no relevant financial disclosures.