Beyond the Guidelines in the Treatment of Peripheral T-Cell Lymphoma: New Drug Development

Authors: Andy I. Chen MD, PhD 1 and Ranjana H. Advani MD 1
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  • 1 From the Division of Oncology, Stanford University Medical Center, Stanford, California.
  • 2 Medical/Scientific Editor, Journal of the National Comprehensive Cancer Network
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  • 1 From the Division of Oncology, Stanford University Medical Center, Stanford, California.
  • 2 Medical/Scientific Editor, Journal of the National Comprehensive Cancer Network
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Peripheral T-cell lymphomas (PTCLs) are a rare and diverse group of neoplasms with a poor prognosis. Management of these disorders has been largely extrapolated from the treatment of aggressive B-cell lymphomas; however, therapeutic responses to this approach are neither adequate nor durable for most patients with PTCL. Given the rarity of PTCL, much of the literature consists of studies with small sample size and anecdotal case reports. Therefore, no consensus exists on the best therapeutic strategy for either newly diagnosed or relapsed/refractory PTCL. This article reviews promising novel approaches in the treatment of PTCL and its subtypes. Investigation into the pathogenesis of PTCL has also identified new targets for treatment. These emerging therapies include new uses of existing agents and the development of novel agents specifically targeted against T-cell lymphoma. Results using antimetabolites, immunotherapies, and histone deacetylase inhibitors have been particularly encouraging. These novel therapies are being tested as single agents and in combination with conventional lymphoma regimens in the frontline and salvage settings. Because of the rarity and heterogeneity of PTCL, national and international cooperation is needed to conduct the clinical studies required for the development of more effective treatment paradigms. These efforts are ongoing and will hopefully guide new strategies to improve the historically poor outcome of PTCL.

Correspondence: Ranjana H. Advani, MD, Stanford University Medical Center, Division of Oncology, 875 Blake Wilbur Drive, Stanford, CA 94305. E-mail: radvani@stanford.edu

Disclosure: Kerrin G. Robinson, MA, has disclosed no relevant financial relationships.

  • 1.

    Jaffe ES, Harris NL, Stein H, Vardiman JW. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Haematopoietic and Lymphoid Tissues. Lyon: IARC Press; 2001.

    • Search Google Scholar
    • Export Citation
  • 2.

    Savage KJ, Chhanabhai M, Gascoyne RD, Connors JM. Characterization of peripheral T-cell lymphomas in a single North American institution by the WHO classification. Ann Oncol 2004;15:14671475.

    • Search Google Scholar
    • Export Citation
  • 3.

    Vose JM. International Peripheral T-Cell Lymphoma (PTCL) Clinical and Pathologic Review Project: poor outcome by prognostic indices and lack of efficacy with anthracyclines [abstract]. Blood 2005;106: Abstract 811.

    • Search Google Scholar
    • Export Citation
  • 4.

    Gisselbrecht C, Gaulard P, Lepage E. Prognostic significance of T-cell phenotype in aggressive non-Hodgkin's lymphomas. Groupe d'Etudes des Lymphomes de l'Adulte (GELA). Blood 1998;92:7682.

    • Search Google Scholar
    • Export Citation
  • 5.

    Lopez-Guillermo A, Cid J, Salar A. Peripheral T-cell lymphomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. Classification. Ann Oncol 1998;9:849855.

    • Search Google Scholar
    • Export Citation
  • 6.

    Gallamini A, Stelitano C, Calvi R. Peripheral T-cell lymphoma unspecified (PTCL-U): a new prognostic model from a retrospective multicentric clinical study. Blood 2004;103:24742479.

    • Search Google Scholar
    • Export Citation
  • 7.

    Went P, Agostinelli C, Gallamini A. Marker expression in peripheral T-cell lymphoma: a proposed clinical-pathologic prognostic score. J Clin Oncol 2006;24:24722479.

    • Search Google Scholar
    • Export Citation
  • 8.

    Escalon MP, Liu NS, Yang Y. Prognostic factors and treatment of patients with T-cell non-Hodgkin lymphoma: the M. D. Anderson Cancer Center experience. Cancer 2005;103:20912098.

    • Search Google Scholar
    • Export Citation
  • 9.

    Gressin R, Peoch M, Deconinck E. The VIP-ABVD regimen is not superior to the CHOP 21 for the treatment of non epidermotropic peripheral T cell lymphoma. Final results of the ``LTP95'' protocol of the GOELAMS [abstract]. Blood 2006;108:Abstract 2464.

    • Search Google Scholar
    • Export Citation
  • 10.

    Rodriguez J, Conde E, Gutierrez A. Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group. Eur J Haematol 2007;79:338.

    • Search Google Scholar
    • Export Citation
  • 11.

    Corradini P, Tarella C, Zallio F. Long-term follow-up of patients with peripheral T-cell lymphomas treated up-front with high-dose chemotherapy followed by autologous stem cell transplantation. Leukemia 2006;20:15331538.

    • Search Google Scholar
    • Export Citation
  • 12.

    Kewalramani T, Zelenetz AD, Teruya-Feldstein J. Autologous transplantation for relapsed or primary refractory peripheral T-cell lymphoma. Br J Haematol 2006;134:202207.

    • Search Google Scholar
    • Export Citation
  • 13.

    Chen AI, McMillan A, Negrin RS. Long term results of autologous hematopoietic cell transplantation (AHCT) for peripheral T cell lymphoma: the Stanford experience [abstract]. Blood 2007;110: Abstract 1906.

    • Search Google Scholar
    • Export Citation
  • 14.

    Corradini P, Dodero A, Zallio F. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol 2004;22:21722176.

    • Search Google Scholar
    • Export Citation
  • 15.

    Feyler S, Prince HM, Pearce R. The role of high-dose therapy and stem cell rescue in the management of T-cell malignant lymphomas: a BSBMT and ABMTRR study. Bone Marrow Transplant 2007;40:443450.

    • Search Google Scholar
    • Export Citation
  • 16.

    Zelenetz AD, Advani RH, Bociek RG. The NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin's Lymphomas, version 3, 2007. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed December 24, 2007.

    • Search Google Scholar
    • Export Citation
  • 17.

    Dang NH, Pro B, Hagemeister FB. Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. Br J Haematol 2007;136:439447.

    • Search Google Scholar
    • Export Citation
  • 18.

    Foss F, Sjak-Shie N, Goy A. Denileukin diftitox (ONTAK) plus CHOP chemotherapy in patients with peripheral T-cell lymphomas (PTCL), the CONCEPT trial [abstract]. Blood 2007;110: Abstract 3449.

    • Search Google Scholar
    • Export Citation
  • 19.

    Lundin J, Hagberg H, Repp R. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003;101:42674272.

    • Search Google Scholar
    • Export Citation
  • 20.

    Dearden CE, Matutes E, Cazin B. High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H. Blood 2001;98:17211726.

  • 21.

    Enblad G, Hagberg H, Erlanson M. A pilot study of alemtuzumab (anti-CD52 monoclonal antibody) therapy for patients with relapsed or chemotherapy-refractory peripheral T-cell lymphomas. Blood 2004;103:29202924.

    • Search Google Scholar
    • Export Citation
  • 22.

    Zinzani PL, Alinari L, Tani M. Preliminary observations of a phase II study of reduced-dose alemtuzumab treatment in patients with pretreated T-cell lymphoma. Haematologica 2005;90:702703.

    • Search Google Scholar
    • Export Citation
  • 23.

    Gallamini A, Zaja F, Patti C. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood 2007;110:23162323.

    • Search Google Scholar
    • Export Citation
  • 24.

    Kim JG, Sohn SK, Chae YS. Alemtuzumab plus CHOP as front-line chemotherapy for patients with peripheral T-cell lymphomas: a phase II study. Cancer Chemother Pharmacol 2007;60:129134.

    • Search Google Scholar
    • Export Citation
  • 25.

    Weidmann E, Hess G, Krause SW. A phase II immunochemotherapy study with alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin (Campath-FCD) in peripheral T-cell lymphomas [abstract]. Blood 2006;108:Abstract 2721.

    • Search Google Scholar
    • Export Citation
  • 26.

    Kim YH, Duvic M, Obitz E. Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma. Blood 2007;109:46554662.

    • Search Google Scholar
    • Export Citation
  • 27.

    d'Amore F, Radford J, Jerkeman M. Zanolimumab (HuMax-CD4TM), a fully human monoclonal antibody: efficacy and safety in patients with relapsed or treatment-refractory non-cutaneous CD4+ T-cell lymphoma [abstract]. Blood 2007;110:Abstract 3409.

    • Search Google Scholar
    • Export Citation
  • 28.

    Casale DA, Bartlett NL, Hurd DD. A phase I open label dose escalation study to evaluate MEDI-507 in patients with CD2-positive T-cell lymphoma/leukemia [abstract]. Blood 2006;108:Abstract 2727.

    • Search Google Scholar
    • Export Citation
  • 29.

    Uike N, Tsukasaki K, Utsunomiya A. Phase I study of KW-0761, a humanized anti-CCR4 antibody, in patients (pts) with relapsed or refractory adult T-cell leukemia-lymphoma (ATLL) and peripheral T-cell lymphoma (PTCL): preliminary results [abstract]. Blood 2007;110:Abstract 4492.

    • Search Google Scholar
    • Export Citation
  • 30.

    Sallah S, Wan JY, Nguyen NP. Treatment of refractory T-cell malignancies using gemcitabine. Br J Haematol 2001;113:185187.

  • 31.

    Zinzani PL, Magagnoli M, Bendandi M. Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 1998;9:13511353.

  • 32.

    Tsimberidou AM, Giles F, Duvic M. Phase II study of pentostatin in advanced T-cell lymphoid malignancies: update of an M. D. Anderson Cancer Center series. Cancer 2004;100:342349.

    • Search Google Scholar
    • Export Citation
  • 33.

    Czuczman MS, Porcu P, Johnson J. Results of a phase II study of 506U78 in cutaneous T-cell lymphoma and peripheral T-cell lymphoma: CALGB 59901. Leuk Lymphoma 2007;48:97103.

    • Search Google Scholar
    • Export Citation
  • 34.

    Duvic M, Forero-Torres A, Foss F. Response to oral forodesine in refractory cutaneous T-cell lymphoma: interim results of a phase I/II study [abstract]. Blood 2007;110:Abstract 122.

    • Search Google Scholar
    • Export Citation
  • 35.

    O'Connor OA, Hamlin PA, Gerecitano J. Pralatrexate (PDX) produces durable complete remissions in patients with chemotherapy resistant precursor and peripheral T-cell lymphomas: results of the MSKCC phase I/II experience [abstract]. Blood 2006;108:Abstract 400.

    • Search Google Scholar
    • Export Citation
  • 36.

    Duvic M, Talpur R, Ni X. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109:3139.

    • Search Google Scholar
    • Export Citation
  • 37.

    Olsen EA, Kim YH, Kuzel TM. Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:31093115.

    • Search Google Scholar
    • Export Citation
  • 38.

    Kim YH, Reddy S, Kim EJ. Romidepsin (depsipeptide) induces clinically significant responses in treatment-refractory CTCL: an international, multicenter study [abstract]. Blood 2007;110:Abstract 123.

    • Search Google Scholar
    • Export Citation
  • 39.

    Piekarz RL, Frye R, Turner M. Responses and molecular markers in patients with peripheral T-cell lymphoma treated on a phase II trial of depsipeptide, FK228 [abstract]. J Clin Oncol 2005;23: Abstract 3061.

    • Search Google Scholar
    • Export Citation
  • 40.

    Advani R, Hymes K, Pohlman B. Belinostat (PXD101) in patients with recurrent or refractory peripheral or cutaneous T-cell lymphoma: results of a phase II study [abstract]. Blood 2007;110: Abstract 3453.

    • Search Google Scholar
    • Export Citation
  • 41.

    Zinzani PL, Musuraca G, Tani M. Phase II trial of proteasome inhibitor bortezomib in patients with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:42934297.

    • Search Google Scholar
    • Export Citation
  • 42.

    Feldman AL, Sun DX, Law ME. Syk tyrosine kinase is overexpressed in the majority of peripheral T- and NK-cell lymphomas, and represents a potential therapeutic target [abstract]. Blood 2007;110:Abstract 690.

    • Search Google Scholar
    • Export Citation
  • 43.

    Streubel B, Vinatzer U, Willheim M. Novel t(5;9)(q33;q22) fuses ITK to SYK in unspecified peripheral T-cell lymphoma. Leukemia 2006;20:313318.

    • Search Google Scholar
    • Export Citation
  • 44.

    Wiernik PH, Lossos IS, Tuscano J. Preliminary results from a phase II study of lenalidomide oral monotherapy in relapsed/refractory aggressive non-Hodgkin lymphoma [abstract]. J Clin Oncol 2007;25:Abtract 8052.

    • Search Google Scholar
    • Export Citation
  • 45.

    Querfeld C, Kuzel TM, Guitart J, Rosen ST. Preliminary results of a phase II study of CC-5013 (Lenalidomide, Revlimid) in patients with cutaneous T-cell lymphoma [abstract]. Blood 2005;106:Abstract 3351.

    • Search Google Scholar
    • Export Citation
  • 46.

    de Leval L, Rickman DS, Thielen C. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 2007;109:49524963.

    • Search Google Scholar
    • Export Citation
  • 47.

    Dupuis J, Boye K, Martin N. Expression of CXCL13 by neoplastic cells in angioimmunoblastic T-cell lymphoma (AITL): a new diagnostic marker providing evidence that AITL derives from follicular helper T cells. Am J Surg Pathol 2006;30:490494.

    • Search Google Scholar
    • Export Citation
  • 48.

    Grogg KL, Attygalle AD, Macon WR. Expression of CXCL13, a chemokine highly upregulated in germinal center T-helper cells, distinguishes angioimmunoblastic T-cell lymphoma from peripheral T-cell lymphoma, unspecified. Mod Pathol 2006;19:11011107.

    • Search Google Scholar
    • Export Citation
  • 49.

    Tan BT, Warnke RA, Arber DA. The frequency of B- and T-cell gene rearrangements and Epstein-Barr virus in T-cell lymphomas: a comparison between angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, unspecified with and without associated B-cell proliferations. J Mol Diagn 2006;8:466475.

    • Search Google Scholar
    • Export Citation
  • 50.

    Zhao WL, Mourah S, Mounier N. Vascular endothelial growth factor-A is expressed both on lymphoma cells and endothelial cells in angioimmunoblastic T-cell lymphoma and related to lymphoma progression. Lab Invest 2004;84:15121519.

    • Search Google Scholar
    • Export Citation
  • 51.

    Dunleavy K, Wilson WH, Jaffe ES. Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications. Curr Opin Hematol 2007;14:348353.

    • Search Google Scholar
    • Export Citation
  • 52.

    Advani R, Horwitz S, Zelenetz A, Horning SJ. Angioimmunoblastic T cell lymphoma: treatment experience with cyclosporine. Leuk Lymphoma 2007;48:521525.

    • Search Google Scholar
    • Export Citation
  • 53.

    Joly B, Frenkel V, Gaulard P. Rituximab in combination with CHOP regimen in angioimmunoblastic T-cell lymphoma (AITL). Preliminary results in 9 patients treated in a single institution [abstract]. Blood 2005;106:Abstract 2686.

    • Search Google Scholar
    • Export Citation
  • 54.

    Jorgensen JM, Sorensen FB, Bendix K. Expression pattern and prognostic impact of vascular endothelial growth factors VEGF and VEGF-C and their receptors Flt-1, KDR and Flt-4 in peripheral T-cell lymphomas [abstract]. Blood 2007;110:Abstract 689.

    • Search Google Scholar
    • Export Citation
  • 55.

    Bruns I, Fox F, Reinecke P. Complete remission in a patient with relapsed angioimmunoblastic T-cell lymphoma following treatment with bevacizumab. Leukemia 2005;19:19931995.

    • Search Google Scholar
    • Export Citation
  • 56.

    Nagafuji K, Fujisaki T, Arima F, Ohshima K. L-asparaginase induced durable remission of relapsed nasal NK/T-cell lymphoma after autologous peripheral blood stem cell transplantation. Int J Hematol 2001;74:447450.

    • Search Google Scholar
    • Export Citation
  • 57.

    Yong W, Zheng W, Zhu J. Midline NK/T-cell lymphoma nasal-type: treatment outcome, the effect of L-asparaginase based regimen, and prognostic factors. Hematol Oncol 2006;24:2832.

    • Search Google Scholar
    • Export Citation
  • 58.

    Forero-Torres A, Bernstein SH, Gopal A. SGN-30 (Anti-CD30 mAb) has a single-agent response rate of 21% in patients with refractory or recurrent systemic anaplastic large cell lymphoma (ALCL) [abstract]. Blood 2006;108:Abstract 2718.

    • Search Google Scholar
    • Export Citation
  • 59.

    Ansell SM, Horwitz SM, Engert A. Phase I/II study of an anti-CD30 monoclonal antibody (MDX-060) in Hodgkin's lymphoma and anaplastic large-cell lymphoma. J Clin Oncol 2007;25:27642769.

    • Search Google Scholar
    • Export Citation
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