Berubicin Substituted for Cytarabine in a MATRix-Based Regimen for Isolated Central Nervous System Lymphoma: A Five-Patient Case Series from the BER-PUM Study

Primary and isolated secondary central nervous system lymphomas are aggressive malignancies requiring effective central nervous system–directed therapy. Intensive high-dose methotrexate–based regimens may be difficult to deliver, particularly in older or functionally impaired patients. Berubicin is a doxorubicin analog developed to cross the blood–brain barrier. We report a prospective case series of five adults with primary or isolated secondary CNS lymphoma treated within the BER-PUM phase Ib/II study (EudraCT 2021-006028-41), evaluating berubicin as part of the investigational MBTRIX regimen. Patients received up to four 21-day cycles of rituximab, high-dose methotrexate, berubicin, and thiotepa, with between-patient and intrapatient berubicin dose escalation. Four out of five patients completed all planned cycles, even though most of the patients had an ECOG score of 2. After two cycles, four achieved partial response, and one had progressive disease. Two patients underwent autologous stem-cell transplantation; one achieved complete response maintained at 12 months, whereas the other died from severe infectious and multiorgan complications. All patients experienced at least one grade ≥ 3 adverse event, predominantly hematologic. No protocol-defined dose-limiting toxicity or berubicin dose reduction occurred. Recruitment ended prematurely because berubicin became unavailable. This case series demonstrates the feasibility of MBTRIX, although the small sample and incomplete dose escalation preclude definitive conclusions regarding safety and efficacy.