• A phase I/II study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial

      Fox, C. P.; Ali, A. S.; McIlroy, G. W.; Thust, S. C.; Martinez-Calle, N.; Jackson, A. E.; Hopkins, L.; Thomas, C. M.; Kassam, S.; Wright, J.; et al. (2021)
      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 multicenter, phase I/II study 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+3 design investigated the recommended phase II dose of thiotepa for a single-stage phase II cohort, assessing activity of two cycles of TIER against rrPCNSL. The primary outcome was overall response rate. The dose-finding study demonstrated 50mg/m2 of thiotepa could be safely delivered within the TIER regimen. No dose-limiting toxicities were encountered in phase I, and TIER was well-tolerated by the 27 patients treated in phase II. The most common Grade 3/4 toxicities were neutropenia (56% of patients) and thrombocytopenia (39%). An overall response was confirmed in 14 (52%) patients, meeting the pre-specified threshold for clinically relevant activity. The median progression-free survival was 3 months (95% confidence interval 2 to 6 months) and overall survival 5 months (3 to 9 months). Exploratory analyses suggest a greater benefit for thiotepa-naïve patients. Six patients successfully completed autologous stem cell transplant consolidation (ASCT), with 4 experiencing durable remissions after median follow-up of 50 months. The TIER regimen can be safely delivered and is active against rrPCNSL, and followed by ASCT can provide durable remission and long-term survival. However, for the majority of patients, prognosis remains poor and novel treatment strategies are urgently needed.