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

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 JohnsonDorothee P Auer, Kate Cwynarski

Research output: Contribution to journalArticlepeer-review


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/m 2 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.

Original languageEnglish
Pages (from-to)4073-4082
Number of pages10
JournalBlood Advances
Issue number20
Publication statusPublished - 26 Oct 2021


  • 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

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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