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Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial


219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

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Fig. 1: Consort diagram.
Fig. 2: Progression-free and overall survival curves.

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We are indebted to our patients and their families. The IELSG32 academic trial was sponsored by the IELSG and was conducted without commercial funding. We thank the investigators, research nurses, and study coordinators at each study center. We particularly thank hematologists, oncologists, neuroradiologists, radiation oncologists, pathologists, and psychologists from all centers for their generous commitment and sustained scientific collaboration. We appreciate the excellent technical assistance of the clinical trial offices of the Fondazione Italiana Linfomi (Modena and Alessandria, Italy), of Cancer Research UK (Southampton, UK), Universitätsklinikum Freiburg (Freiburg, Germany), Universitetshospital Aarhus (Aarhus, Denmark), as well as the administrative support in data collection and study conduction from the clinical project manager and central study team at the IELSG Coordinating Center (Bellinzona, Switzerland). We also express gratitude to the members of the independent data monitoring board of the study. The IELSG32 study was supported in part by grants from the Agenzia Italiana del Farmaco (Ricerca Indipendente FARM99FS3Y), Cancer Research UK (C36711/A12115; CRUK/10/023), Oncosuisse (KLS 02399-02-2009), and the Swiss National Science Foundation (31003B_132924).

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AJMF, KC, EP, JF, FC, EZ, and GI were responsible for designing the review protocol, writing the protocol and report, analysing data, interpreting results, and writing the manuscript. CC and MF was responsible for revision and analysis of neuropsychological tests and results interpretation. AN performed statistical analysis. CPF, ES, PLR, MB, AF, FI, MK, AR, CH, PWJ, KML, TP, JSG, MB, GH, UK, SS, JP, AT, LO, FP, MZ, SWK, HJS, BH, MR, JS, LT, GC, and EP registered and treated patients, and provided clinical data. MP and MD performed central pathology review. LSP performed central radiology review. AF, KeC, EB, and NI acted as data managers and study coordinators, contributed to data extraction and provided feedback on the report. All the authors approved manuscript and submission.

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Correspondence to Andrés J. M. Ferreri.

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Ferreri, A.J.M., Cwynarski, K., Pulczynski, E. et al. Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial. Leukemia 36, 1870–1878 (2022).

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