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

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 + 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. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/search as EudraCT 2014-000227-24 and ISRCTN 12857473.

• Authors: Christopher P Fox, Ayesha S Ali, Graham McIlroy, Steffi Thust, Nicolás Martinez-Calle, Aimee E Jackson, Louise M Hopkins, Catherine M Thomas, Shireen Kassam, Josh Wright, Sridhar Chaganti, Jeffery Smith, Ian Chau, Dominic Culligan, Kim M Linton, Graham P Collins, Andrés J M Ferreri, David Lewis, Andrew J Davies, Rod Johnson, Dorothee P Auer, Kate Cwynarski
• Journal: Blood advances (Blood Adv) Vol. 5 Issue 20 Pg. 4073-4082 (10 26 2021) ISSN: 2473-9537 [Electronic] United States
• PMID: 34464973 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Thiotepa

Topics

• Antineoplastic Combined Chemotherapy Protocols (adverse effects)
• Combined Modality Therapy
• Hematopoietic Stem Cell Transplantation
• Humans
• Lymphoma, Non-Hodgkin (drug therapy)
• Prospective Studies
• Thiotepa (therapeutic use)
• Transplantation, Autologous