In the largest randomized trial in untreated primary central nervous system lymphoma to date, high-dose chemotherapy followed by autologous stem-cell transplantation improved progression-free and overall survival compared with nonmyeloablative consolidation in patients who responded to MATRix induction therapy. The phase III MATRix/IELSG43 trial was reported in The Lancet by Illerhaus et al.
Study Details
The open-label, randomized trial was conducted at 56 university and academic non-university hospitals with established transplantation facilities in Germany, Italy, Denmark, Norway, and Switzerland. It enrolled untreated, immunocompetent patients with B-cell primary central nervous system lymphoma.
Eligible patients were aged 18 to 65 years, regardless of Eastern Cooperative Oncology Group (ECOG) performance status, or 66 to 70 years with an ECOG performance status of 0 to 2. Patients with lymphoma outside the central nervous system or congenital or acquired immunodeficiency were excluded.
All patients received four cycles of MATRix induction, consisting of rituximab, high-dose methotrexate, high-dose cytarabine, and thiotepa. Patients who achieved at least a partial response and had sufficient stem-cell harvest were randomly assigned 1:1 to receive either two cycles of R-DeVIC consolidation or high-dose chemotherapy followed by autologous stem-cell transplantation. R-DeVIC consisted of rituximab plus dexamethasone, etoposide, ifosfamide, and carboplatin.
The primary endpoint was progression-free survival. Secondary endpoints included complete response rate, overall survival, duration of response, quality of life, safety, toxicity, and neurotoxicity.
Between July 2014 and August 2019, 368 patients were enrolled, 346 started induction therapy, and 230 were randomly assigned after induction. The full analysis set included 229 patients: 115 in the R-DeVIC group and 114 in the transplant group. Baseline characteristics were balanced between groups. The median age was 60 years in the R-DeVIC group and 58 years in the transplant group.
Key Findings
After a median follow-up of 45.3 months, progression-free survival was significantly better with transplant consolidation. The 3-year progression-free survival rate was 78% in the transplant group compared with 51% in the R-DeVIC group (hazard ratio [HR] = 0.43, P = .0003). Median progression-free survival was not reached in the transplant group and was 39 months in the R-DeVIC group.
Overall survival also favored transplant consolidation. Median overall survival was not reached in either group, but the 3-year overall survival rate was 86% with transplant consolidation vs 71% with R-DeVIC (HR = 0.46, P = .0075).
Complete response rates at day 60 after randomization were similar between groups: 69% in the transplant group and 65% in the R-DeVIC group, but relapse was less frequent after transplant consolidation, with a 3-year cumulative incidence of 19% vs 45%.
The findings apply only to patients who responded to induction therapy and proceeded to randomization. Of the 346 patients who started induction, 116 did not reach randomization, most commonly because of adverse events, treatment-related toxicity, or progressive or stable disease. The investigators noted that this highly intensive treatment approach is not universally applicable.
Adverse events were frequent with both consolidation strategies, but the overall adverse-event burden was higher with transplant consolidation. The mean number of adverse events per patient was 14.6 in the transplant group and 9.3 in the R-DeVIC group. During consolidation, febrile neutropenia, stomatitis, and diarrhea were reported more often with transplant consolidation than with R-DeVIC.
Fatal events after consolidation occurred in five patients in the transplant group and two patients in the R-DeVIC group. In the transplant group, these consisted serious infectious complications in four patients and pulmonary embolism in one patient. In the R-DeVIC group, both fatal events occurred in patients who developed acute myeloid leukemia. All fatal events except the pulmonary embolism were judged by investigators to be possibly treatment related.
The investigators concluded: “In the largest randomised trial in untreated [primary central nervous system lymphoma] to date, HCT–ASCT significantly improved progression-free and overall survival compared with non-myeloablative consolidation in patients who had completed induction treatment, establishing it as the preferred consolidation strategy in fit patients.”
Gerald Illerhaus, MD, of the Department of Haematology, Oncology, Stem-Cell Transplantation and Palliative Care, Tumorzentrum Eva Mayr-Stihl, Klinikum Stuttgart, Germany, is the corresponding author for The Lancet article.
DISCLOSURE: The study was funded by the German Federal Ministry of Research, Technology and Space; the Swiss Cancer Research Foundation; and Riemser Pharma. For full disclosures of the study authors, visit thelancet.com.
