Summary: The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B‐cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28–78) and 2 (range 0–4). The overall response rate after MATRix was 79%. Nine (6%) treatment‐related deaths were recorded. After a median follow‐up of 27.4 months (95% confidence interval [CI] 24.4–31.9%), the two‐year progression‐free and overall survival were 56% (95% CI 48.4–64.9%) and 64.1% (95% CI 56.7–72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non‐trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.

Primary central nervous system lymphoma (PCNSL) is a highly aggressive Non-Hodgkin lymphoma (NHL) with rising incidence over the past 30 years in immunocompetent patients. Although outcomes have improved, PCNSL is still associated with inferior prognosis compared to systemic NHL. Many questions regarding the optimal therapeutic approach remain unanswered. This is a randomized, open-label, international phase III trial with two parallel arms. We will recruit 250 patients with newly diagnosed PCNSL from approximately 35 centers within the networks of the German Cooperative PCNSL study group and the International Extranodal Lymphoma Study Group. All enrolled patients will undergo induction chemotherapy consisting of 4 cycles of rituximab 375 mg/m2/d (days 0 & 5), methotrexate 3.5 g/m2 (d1), cytarabine 2 × 2 g/m2/d (d2-3), and thiotepa 30 mg/m2 (d4) every 21 days. All patients will undergo stem-cell harvest after the second cycle. After 4 cycles of induction chemotherapy, patients achieving partial or complete response will be centrally randomized to 2 different consolidation treatments: (A) conventional-dose immuno chemotherapy with rituximab 375 mg/m2 (d0), dexamethasone 40 mg/d (d1-3), etoposide 100 mg/m2/d (d1-3), ifosfamide 1500 mg/m2/d (d1-3) and carboplatin 300 mg/m2 (d1) (R-DeVIC) or (B) high-dose chemotherapy with BCNU (or busulfan) and thiotepa followed by autologous stem cell transplantation (HCT-ASCT). The objective is to demonstrate superiority of HCT-ASCT compared to R-DeVIC with respect to progression-free survival (PFS, primary endpoint). Secondary endpoints include overall survival (OS), treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 24 months. The rationale for consolidation treatment in PCNSL is to eliminate residual lymphoma cells and to decrease the risk for relapse. This can be achieved by agents crossing the blood brain barrier either applied at conventional doses or at high doses requiring autologous stem cell support. HCT-ASCT has been shown to be feasible and highly effective in patients with newly-diagnosed PCNSL. However, it is unclear whether HCT-ASCT is really superior compared to conventional-dose chemotherapy after an intensified antimetabolites-based immunochemotherapy in patients with newly-diagnosed PCNSL. To answer this question, we designed this investigator initiated randomized phase III trial. German clinical trials registry DRKS00005503 registered 22 April 2014 and ClinicalTrials.gov NCT02531841 registered 24 August 2015.

Key Points: Age-adapted high-dose chemotherapy and autologous stem cell transplantation is safe and highly effective in elderly patients with PCNSL.

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Primary central nervous system lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system (CNS) with rising incidence among patients > 65 years. Although elderly patients are able to tolerate aggressive systemic chemotherapy, previous studies have demonstrated inferior outcomes for patients who present with a poor performance status (PS) and older age. Usually, intensive treatment approaches including high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) are only offered to patients younger than 65–70 years of age. This is an open-label, multicentric, non-randomized, single arm phase II trial. We will recruit 51 immuno-competent patients with newly diagnosed PCNSL from 12 German centers. The objective is to investigate the efficacy of age-adapted induction treatment followed by HDT-ASCT. All enrolled patients will undergo induction chemotherapy consisting of 2 cycles of rituximab 375 mg/m2/d (days 0 & 4), methotrexate 3.5 g/m2 (d1), and cytarabine 2 × 2 g/m2/d (d2–3) every 21 days. After 2 cycles of induction chemotherapy, patients achieving at least stable disease will undergo HDT-ASCT with busulfan 3.2 mg/kg/d (days − 7-(− 6)) and thiotepa 5 mg/kg/d (days − 5-(− 4)) followed by autologous stem cell transplantation. The primary endpoint of this study is 1-year progression-free survival (PFS). Secondary endpoints include PFS, overall survival, treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 12 months. Current treatment options for PCNSL have improved over the last years, resulting in the potential to achieve durable remission or cure in patients < 70 years. Age alone may not be the only criterion to select patients for this effective treatment approach and probably many elderly patients are undertreated just because of advanced age. There have been no multicentre trials investigating this curative treatment concept in elderly and fit PCNSL patients so far. We aim to answer whether HDT-ASCT is feasible and effective in fit patients > 65 years with newly-diagnosed PCNSL. German clinical trials registry DRKS00011932 registered 18 August 2017.