A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial

Fox, Christopher P.; Ali, Ayesha S.; McIlroy, Graham; Thust, Steffi; Martinez-Calle, Nicolás; Jackson, Aimee E.; Hopkins, Louise M.; Thomas, Catherine M.; Kassam, Shireen; Wright, Josh; Chaganti, Sridhar; Smith, Jeffery; Chau, Ian; Culligan, Dominic; Linton, Kim M.; Collins, Graham P.; Ferreri, Andrés J. M.; Lewis, David; Davies, Andrew J.; Johnson, Rod; Auer, Dorothee P.; Cwynarski, Kate

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.

• Journal Article Type: Article
• Acceptance Date: May 7, 2021
• Online Publication Date: Oct 20, 2021
• Publication Date: Oct 26, 2021
• Deposit Date: Feb 8, 2023
• Publicly Available Date: Feb 8, 2023
• Journal: Blood Advances
• Electronic ISSN: 2473-9529
• Publisher: American Society of Hematology
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 20
• Pages: 4073-4082
• DOI: https://doi.org/10.1182/bloodadvances.2021004779
• Keywords: Hematology
• Public URL: https://nottingham-repository.worktribe.com/output/7356845
• Publisher URL: https://ashpublications.org/bloodadvances/article/5/20/4073/476729/A-phase-1-2-study-of-thiotepa-based