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

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    Authors
    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.
    Chaganti, S.
    Smith, J.
    Chau, I.
    Culligan, D.
    Linton, Kim M
    Collins, G. P.
    Ferreri, A. J. M.
    Lewis, D.
    Davies, A. J.
    Johnson, R. J.
    Auer, D. P.
    Cwynarski, K.
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    Affiliation
    Faculty of Medicine and Health Sciences, University of Nottingham, United Kingdom
    Issue Date
    2021
    
    Metadata
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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 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.
    Citation
    Fox CP, Ali AS, McIlroy GW, Thust SC, Martinez-Calle N, Jackson AE, et al. A phase I/II study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial. Blood Advances. 2021 Aug 31.
    Journal
    Blood Advances
    URI
    http://hdl.handle.net/10541/624646
    DOI
    10.1182/bloodadvances.2021004779
    PubMed ID
    34464973
    Additional Links
    https://dx.doi.org/10.1182/bloodadvances.2021004779
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1182/bloodadvances.2021004779
    Scopus Count
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    All Paterson Institute for Cancer Research

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