Romidepsin in peripheral and cutaneous T-cell lymphoma: Mechanistic implications from clinical and correlative data

S.E. Bates, R. Eisch, A. Ling, D. Rosing, M. Turner, S. Pittaluga, H.M. Prince, M.H. Kirschbaum, S.L. Allen, J. Zain, L.J. Geskin, David Joske, L. Popplewell, E.W. Cowen, E.S. Jaffe, J. Nichols, S. Kennedy, S.M. Steinberg, D.J. Liewehr, L.C. Showe & 5 others C. Steakley, J. Wright, T. Fojo, T. Litman, R.L. Piekarz

    Research output: Contribution to journalArticle

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    Abstract

    © 2015 John Wiley & Sons Ltd. Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.
    Original languageEnglish
    Pages (from-to)96-109
    JournalBritish Journal of Haematology
    Volume170
    Issue number1
    DOIs
    Publication statusPublished - 2015

    Fingerprint

    Peripheral T-Cell Lymphoma
    Cutaneous T-Cell Lymphoma
    Epigenomics
    Therapeutics
    Safety
    Aptitude
    National Cancer Institute (U.S.)
    romidepsin
    T-Cell Lymphoma
    Oligonucleotide Array Sequence Analysis
    Nuclear Family
    Transcriptome
    Cell Death
    Gene Expression
    Skin

    Cite this

    Bates, S. E., Eisch, R., Ling, A., Rosing, D., Turner, M., Pittaluga, S., ... Piekarz, R. L. (2015). Romidepsin in peripheral and cutaneous T-cell lymphoma: Mechanistic implications from clinical and correlative data. British Journal of Haematology, 170(1), 96-109. https://doi.org/10.1111/bjh.13400
    Bates, S.E. ; Eisch, R. ; Ling, A. ; Rosing, D. ; Turner, M. ; Pittaluga, S. ; Prince, H.M. ; Kirschbaum, M.H. ; Allen, S.L. ; Zain, J. ; Geskin, L.J. ; Joske, David ; Popplewell, L. ; Cowen, E.W. ; Jaffe, E.S. ; Nichols, J. ; Kennedy, S. ; Steinberg, S.M. ; Liewehr, D.J. ; Showe, L.C. ; Steakley, C. ; Wright, J. ; Fojo, T. ; Litman, T. ; Piekarz, R.L. / Romidepsin in peripheral and cutaneous T-cell lymphoma: Mechanistic implications from clinical and correlative data. In: British Journal of Haematology. 2015 ; Vol. 170, No. 1. pp. 96-109.
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    author = "S.E. Bates and R. Eisch and A. Ling and D. Rosing and M. Turner and S. Pittaluga and H.M. Prince and M.H. Kirschbaum and S.L. Allen and J. Zain and L.J. Geskin and David Joske and L. Popplewell and E.W. Cowen and E.S. Jaffe and J. Nichols and S. Kennedy and S.M. Steinberg and D.J. Liewehr and L.C. Showe and C. Steakley and J. Wright and T. Fojo and T. Litman and R.L. Piekarz",
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    Bates, SE, Eisch, R, Ling, A, Rosing, D, Turner, M, Pittaluga, S, Prince, HM, Kirschbaum, MH, Allen, SL, Zain, J, Geskin, LJ, Joske, D, Popplewell, L, Cowen, EW, Jaffe, ES, Nichols, J, Kennedy, S, Steinberg, SM, Liewehr, DJ, Showe, LC, Steakley, C, Wright, J, Fojo, T, Litman, T & Piekarz, RL 2015, 'Romidepsin in peripheral and cutaneous T-cell lymphoma: Mechanistic implications from clinical and correlative data' British Journal of Haematology, vol. 170, no. 1, pp. 96-109. https://doi.org/10.1111/bjh.13400

    Romidepsin in peripheral and cutaneous T-cell lymphoma: Mechanistic implications from clinical and correlative data. / Bates, S.E.; Eisch, R.; Ling, A.; Rosing, D.; Turner, M.; Pittaluga, S.; Prince, H.M.; Kirschbaum, M.H.; Allen, S.L.; Zain, J.; Geskin, L.J.; Joske, David; Popplewell, L.; Cowen, E.W.; Jaffe, E.S.; Nichols, J.; Kennedy, S.; Steinberg, S.M.; Liewehr, D.J.; Showe, L.C.; Steakley, C.; Wright, J.; Fojo, T.; Litman, T.; Piekarz, R.L.

    In: British Journal of Haematology, Vol. 170, No. 1, 2015, p. 96-109.

    Research output: Contribution to journalArticle

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    AU - Bates, S.E.

    AU - Eisch, R.

    AU - Ling, A.

    AU - Rosing, D.

    AU - Turner, M.

    AU - Pittaluga, S.

    AU - Prince, H.M.

    AU - Kirschbaum, M.H.

    AU - Allen, S.L.

    AU - Zain, J.

    AU - Geskin, L.J.

    AU - Joske, David

    AU - Popplewell, L.

    AU - Cowen, E.W.

    AU - Jaffe, E.S.

    AU - Nichols, J.

    AU - Kennedy, S.

    AU - Steinberg, S.M.

    AU - Liewehr, D.J.

    AU - Showe, L.C.

    AU - Steakley, C.

    AU - Wright, J.

    AU - Fojo, T.

    AU - Litman, T.

    AU - Piekarz, R.L.

    PY - 2015

    Y1 - 2015

    N2 - © 2015 John Wiley & Sons Ltd. Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

    AB - © 2015 John Wiley & Sons Ltd. Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re-initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

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