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    A phase 1/2 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.
    Thust, S.
    Martinez-Calle, N.
    Jackson, A. E.
    Hopkins, L. M.
    Thomas, C. M.
    Kassam, S.
    Wright, J.
    Chaganti, S.
    Smith, J.
    Chau, I.
    Culligan, D.
    Linton, K. M.
    Collins, G. P.
    Ferreri, A. J. M.
    Lewis, D.
    Davies, A. J.
    Johnson, R.
    Auer, D. P.
    Cwynarski, K.
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    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 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.
    Citation
    Fox CP, Ali AS, McIlroy G, Thust S, Martinez-Calle N, Jackson AE, et al. A phase 1/2 study of thiotepa-based immunochemotherapy in relapsed/refractory primary CNS lymphoma: the TIER trial [Internet]. Vol. 5, Blood Advances. American Society of Hematology; 2021. p. 4073–82.
    Journal
    Blood Advances
    URI
    http://hdl.handle.net/10541/625092
    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
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