Patients with central nervous system (CNS) lymphoma are more likely to achieve complete remission when Rituxan (rituximab) and Tepidina (thiotepa) are added to conventional methotrexate-cytarabine therapy, according to the results of the first randomization of the Phase 2 IELSG32 trial. The four-drug regimen, called MATRix regimen, had increased but acceptable toxicity.
The trial results were published in The Lancet Hematology in a study titled “Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.”
Currently, patients with primary CNS lymphoma are treated in two phases: the induction phase, meant to induce remission, and the consolidation phase, given once remission is achieved. Although the most common treatment strategy is high-dose Trexall (methotrexate)-based chemotherapy followed by consolidative whole-brain radiotherapy, many patients relapse and die from lymphoma or have an increased risk of neurotoxicity.
Recently, the same group had observed Trexall plus Depocyt (cytarabine) to be superior to Trexall alone, but new studies are required to define the standard induction and consolidation therapies for CNS lymphoma patients.
To address this question, the team designed a two-stage randomization study. The first randomization was meant to evaluate whether adding Rituxan with or without Tepadina to Trexall with Depocyt could improve remission rates of CNS patients. Primary endpoint of this stage was complete remission rate.
Then, patients who achieved at least stable disease with the initial chemotherapy regimen underwent a second randomization to whole-brain radiotherapy versus high-dose chemotherapy. The researchers have now reported data from the first randomization.
The study enrolled 227 patients aged 18 to 70 with newly diagnosed primary CNS lymphoma and measurable disease. Among the participants, 75 patients were assigned Trexall-Depocyt therapy alone, 74 received the combination plus Rituxan, and 78 were included in the MATRix group.
All patients received four courses of Trexall (3.5g/m2) on day 1 and Depocyt (2g/m2) twice daily on days 2 and 3. Patients who received Rituxan (375mg/m2) received it on days -5 and 0, and those on Tepadina (30 mg/m2) received one dose at day 4. Patients repeated treatment within three weeks.
Results revealed that after a median follow-up of 30 months, patients treated with Rituxan had a complete remission rate of 30%, which was superior to the 23% complete remission rate seen in Trexall-Depocyt treated patients. However, Rituxan plus Tepadina (MATRix) was found to be the significantly better than the other treatment options, with a complete remission rate of 49%.
Overall response rate, two-year overall survival, and progression-free survival were also higher in the MATRix group, compared to the other two study arms.
MATRix regimen was associated with increased but manageable grade 3 and grade 4 adverse events. After the first stage of the study, 118 patients with at least stable disease moved on to the second randomization.
Although these results suggest that Rituxan and Tepadina should be added to standard of care therapy in CNS lymphoma patients, 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 believe that the study has major limitations that may impact data interpretation.
“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 his colleagues wrote in an accompanying editorial.