Fox, CP; Ali, AS; McIlroy, G; Thust, S; Martinez-Calle, N; Jackson, AE; Hopkins, LM; ... Cwynarski, K; + view all Fox, CP; Ali, AS; McIlroy, G; Thust, S; Martinez-Calle, N; Jackson, AE; Hopkins, LM; Thomas, CM; Kassam, S; Wright, J; Chaganti, S; Smith, J; Chau, I; Culligan, D; Linton, KM; Collins, GP; Ferreri, AJM; Lewis, D; Davies, AJ; Johnson, R; Auer, DP; Cwynarski, K; - view fewer (2021) A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: The TIER trial. Blood Advances , 5 (20) pp. 4073-4082. 10.1182/bloodadvances.2021004779.

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Abstract

Relapsed or refractory primary central nervous system lymphoma (rrPCNSL) confers a poor prognosis with no accepted standard of care. Very few prospective studies have been conducted in this patient group. This study was a multicenter phase 1/2 study that investigated thiotepa in combination with ifosfamide, etoposide, and rituximab (TIER) for the treatment of PCNSL relapsed or refractory to high-dose methotrexate-based chemotherapy. A 3 1 3 design investigated the recommended phase 2 dose of thiotepa for a single-stage phase 2 cohort by assessing the activity of 2 cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated that 50 mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase 1, and TIER was well-tolerated by the 27 patients treated in phase 2. The most common grade 3 to 4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 patients (52%), which met the prespecified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval [CI], 2 to 6 months) and overall survival 5 months (95% CI, 3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplantation (ASCT) consolidation, with 4 experiencing durable remissions after a median follow-up of 50 months. The TIER regimen can be delivered safely and is active against rrPCNSL. When it is followed by ASCT, it can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor, and novel treatment strategies are urgently needed.

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