Among some patients with relapsed or refractory primary central nervous system (PCNS) lymphoma, adding thiotepa to an immunochemotherapy regimen may improve overall survival outcomes, according to research published in Blood Advances.

PCNS lymphoma is a rare, aggressive subset of diffuse large B cell lymphoma, which is associated with disease-specific morbidities and treatment complications. Although responses are common with first-line treatments, relapse after systemic therapy and autologous stem cell transplantation (ASCT) is common, and most patients with relapsed or refractory disease are at a high risk of death.

No standard of care has been defined in the relapsed/refractory setting, necessitating therapeutic advancement. For this prospective phase 1/2 study, researchers evaluated the safety and efficacy of thiotepa—a polyfunctional alkylator effective at CNS penetration that has previously been used as an ASCT conditioning agent—as part of an immunochemotherapy regimen among patients with relapsed or refractory PCNS lymphoma.

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The researchers aimed to establish the recommended phase 2 dose of thiotepa in a combination that included ifosfamide, etoposide, and rituximab (the TIER regimen). All included patients had relapsed after or were refractory to methotrexate-based therapy.

Overall, 36 patients were enrolled and treated using the TIER regimen. The median age was 62 years, 39% of patients were female, 53% of patients had a performance status of 0 or 1, and 6% of patients had received prior ASCT consolidation therapy.

A total of 5 patients received thiotepa 30 mg/m2, 4 were allocated to receive 40 mg/m2, and 27 were allocated to receive 50 mg/m2. No patients in the 50 mg/m2 group experienced any dose-limiting toxicities. Grade 3 to 4 neutropenia (56%) and thrombocytopenia (39%) were the most frequently noted adverse events.

Among patients who received thiotepa 50 mg/m2, the overall response rate was 52% and the median progression-free survival was 3 months (95% CI: 2-6). Median overall survival was 5 months (95% CI: 3-9).

A total of 6 patients subsequently received ASCT consolidation, and 4 remissions were noted at a median follow-up of 50 months.

“The TIER regimen is an immunochemotherapy option that is not cross-resistant for sufficiently fit patients whose PCNS [lymphoma] has relapsed after treatment with high-dose methotrexate,” the authors wrote. “In meeting its prespecified end point, this trial demonstrates that thiotepa can be safely incorporated into a multidrug regimen and can produce a meaningful response rate worthy of further clinical development.”

Disclosure: The study author(s) declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Fox CP, Ali AS, McIlroy G, et al. A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial. Blood Adv. 2021;5(20):4073-4082. doi:10.1182/bloodadvances.2021004779