The Role of Alemtuzumab in the Management of T-Cell Malignancies

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T-cell malignancies are rare, making up 10% to 15% of all lymphoid neoplasms in adults. They include many different types of disorders such as T-cell prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, adult T-cell leukemia/lymphoma, cutaneous T-cell lymphoma, and peripheral T-cell lymphoma, which are themselves divided into multiple subcategories. Most T-cell malignancies arise as a result of chromosomal abnormalities, including T-cell receptor rearrangement anomalies. Viral infections are implicated in the development of adult T-cell leukemia/lymphoma and some cases of peripheral T-cell lymphoma have been linked to Epstein-Barr virus or human immunodeficiency virus infection. With the possible exception of T-cell large granular lymphocytic leukemia, which often has an indolent course, T-cell malignancies have not responded well to conventional chemotherapeutic treatment. The introduction of monoclonal antibodies for the treatment of cancer has changed the outlook for patients with T-cell malignancies. Recent studies with single-agent alemtuzumab, an anti-CD52 monoclonal antibody, have shown improved response rates and survival in patients with T-cell prolymphocytic leukemia and cutaneous T-cell lymphoma. Preliminary data also suggest that alemtuzumab may have activity in patients with heavily pretreated peripheral T-cell lymphoma who are refractory to conventional chemotherapy. Preclinical studies with mice bearing human adult T-cell leukemia/lymphoma cells suggest that alemtuzumab may have a potential therapeutic role in this setting. Treatment of T-cell hematologic malignancies with alemtuzumab appears promising. Earlier treatment and combination with chemotherapeutic agents may improve treatment outcome for patients with these malignancies and allow for consolidation with stem cell transplant strategies in selected patients.

Section snippets

Presentation

T-PLL is a rare form of lymphocytic leukemia with a broad morphologic spectrum that can vary from a nongranular, basophilic cytoplasm with a prominent central nucleolus to cells with a markedly irregular nucleus and a less prominent nucleolus. Patients with T-PLL usually present with splenomegaly, hepatomegaly, lymphadenopathy, skin lesions, serous effusions, and rapidly rising peripheral blood lymphocyte counts. The bone marrow, lymph nodes, and skin may be diffusely infiltrated, but unlike

Conclusion

Except for ALK+ anaplastic large-cell lymphoma, T-cell hematologic malignancies have a poor prognosis with conventional therapy. Few patients achieve complete remission of their disease, relapse is inevitable, and associated with resistance to treatment. The almost ubiquitous presence of the CD52 antigen on the surface of these tumor cells suggests that immunotherapy with the anti-CD52 monoclonal antibody alemtuzumab may be valuable in the treatment of these diseases. Recent results obtained in

References (103)

  • T. Lamy et al.

    Current conceptsLarge granular lymphocyte leukemia

    Blood Rev

    (1999)
  • W.Y. Tsang et al.

    In situ localization of Epstein-Barr virus encoded RNA in non-nasal/nasopharyngeal CD56-positive and CD56-negative T-cell lymphomas

    Hum Pathol

    (1994)
  • C. Man et al.

    Deletion 6q as a recurrent chromosomal aberration in T-cell large granular lymphocyte leukemia

    Cancer Genet Cytogenet

    (2002)
  • V. Bigouret et al.

    Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors

    Blood

    (2003)
  • L.L. Siu et al.

    Comparative genomic hybridization analysis of natural killer cell lymphoma/leukemia. Recognition of consistent patterns of genetic alterations

    Am J Pathol

    (1999)
  • T.P. Loughran et al.

    Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate

    Blood

    (1994)
  • M.D. Rosenblum et al.

    Efficacy of alemtuzumab treatment for refractory T-cell large granular lymphocytic leukemia

    Blood

    (2004)
  • M.W. Bekkenk et al.

    CD56+ hematological neoplasms presenting in the skinA retrospective analysis of 23 new cases and 130 cases from the literature

    Ann Oncol

    (2004)
  • T. Portis et al.

    The contribution of NF-kappa B activity to spontaneous proliferation and resistance to apoptosis in human T-cell leukemia virus type 1 Tax-induced tumors

    Blood

    (2001)
  • J.J. Scarisbrick et al.

    Allelotyping in mycosis fungoides and Sezary syndromeCommon regions of allelic loss identified on 9p, 10q, and 17p

    J Invest Dermatol

    (2001)
  • J.J. Herrmann et al.

    Treatment of mycosis fungoides with photochemotherapy (PUVA)Long-term follow-up

    J Am Acad Dermatol

    (1995)
  • K.S. McGinnis et al.

    Low-dose oral bexarotene in combination with low-dose interferon alfa in the treatment of cutaneous T-cell lymphomaClinical synergism and possible immunologic mechanisms

    J Am Acad Dermatol

    (2004)
  • T.M. Kuzel et al.

    Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma

    Blood

    (1996)
  • M.N. Saleh et al.

    Antitumor activity of DAB389IL-2 fusion toxin in mycosis fungoides

    J Am Acad Dermatol

    (1998)
  • D.J. Lenihan et al.

    Cardiac toxicity of alemtuzumab in patients with mycosis fungoides/Sezary syndrome

    Blood

    (2004)
  • J. Lundin et al.

    CorrespondenceNo cardiac toxicity associated with alemtuzumab therapy for mycosis fungoides/Sézary syndrome

    Blood

    (2005)
  • A. Zettl et al.

    Genomic profiling of peripheral T-cell lymphoma, unspecified, and anaplastic large T-cell lymphoma delineates novel recurrent chromosomal alterations

    Am J Pathol

    (2004)
  • A. Mori et al.

    High tumor necrosis factor-alpha levels in the patients with Epstein-Barr virus-associated peripheral T-cell proliferative disease/lymphoma

    Leuk Res

    (2003)
  • J.P. Dutcher

    The role of Epstein-Barr virus and elevated levels of tumor necrosis factor in determining prognosis in Asian peripheral T-cell lymphomas

    Leuk Res

    (2003)
  • E. Weidmann et al.

    Combination chemoimmunotherapy using alemtuzumab, fludarabine, cyclophosphamide, and doxorubicin is an effective first-line regimen in peripheral T-cell lymphomas

    Blood

    (2004)
  • A.W. Goldrath et al.

    Selecting and maintaining a diverse T-cell repertoire

    Nature

    (1999)
  • U. Bommhardt et al.

    Molecular and cellular mechanisms of T cell development

    Cell Mol Life Sci

    (2004)
  • T. Sugimoto et al.

    T-cell receptor gammadelta T-cell leukemia with the morphology of T-cell prolymphocytic leukemia and a postthymic immunophenotype

    Ann Hematol

    (2001)
  • S. Stilgenbauer et al.

    Biallelic mutations in the ATM gene in T-prolymphocytic leukemia

    Nat Med

    (1997)
  • M.A. Yuille et al.

    The ataxia telangiectasia gene in familial and sporadic cancer

    Recent Results Cancer Res

    (1998)
  • L. Virgilio et al.

    Identification of the TCL1 gene involved in T-cell malignancies

    Proc Natl Acad Sci U S A

    (1994)
  • J. Soulier et al.

    A complex pattern of recurrent chromosomal losses and gains in T-cell prolymphocytic leukemia

    Genes Chromosomes Cancer

    (2001)
  • K. Kojima et al.

    14q11 abnormality and trisomy 8q are not common in Japanese T-cell prolymphocytic leukemia

    Int J Hematol

    (1998)
  • J. Mercieca et al.

    The role of pentostatin in the treatment of T-cell malignanciesanalysis of response rate in 145 patients according to disease subtype

    J Clin Oncol

    (1994)
  • J. Delgado et al.

    Are activation markers (CD25, CD38 and CD103) predictive of sensitivity to purine analogues in patients with T-cell prolymphocytic leukemia and other lymphoproliferative disorders?

    Leuk Lymphoma

    (2002)
  • R. Pawson et al.

    Treatment of T-cell prolymphocytic leukemia with human CD52 antibody

    J Clin Oncol

    (1997)
  • M.J. Keating et al.

    Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed

    J Clin Oncol

    (2002)
  • C. Dearden et al.

    Very high response rates in previously untreated T-cell Prolymphocytic leukaemia patients receiving alemtuzumab (Campath-1H) therapy

    Blood

    (2003)
  • G. Hopfinger et al.

    T-PLL-1 Protocol of the German CLL Study Group (GCLLSG) - A prospective phase II trial of fludarabine phosphate, mitoxantrone and cyclophosphamide (FMC) followed by alemtuzumab consolidation as first line treatment in T-PLL

    Blood

    (2003)
  • B. Krishnan et al.

    Clinical outcome of stem cell transplantation (SCT) in patients with T cell prolymphocytic leukaemia (T-PLL) previously treated with alemtuzumabA multicentre experience

    (2005)
  • A. Absi et al.

    Prolymphocytic leukemia

    Curr Treat Options Oncol

    (2005)
  • N.H. Dang et al.

    T-large granular lymphocyte lymphoproliferative disorderExpression of CD26 as a marker of clinically aggressive disease and characterization of marrow inhibition

    Br J Haematol

    (2003)
  • K.F. Wong et al.

    Chromosomal abnormalities in T-cell large granular lymphocyte leukaemiaReport of two cases and review of the literature

    Br J Haematol

    (2002)
  • M. Skacel et al.

    Recurrent genomic imbalances in T-cell large granular lymphocytes (T-LGL) leukemia detected by array-based comparative genomic hybridization (CGH)

    Blood

    (2003)
  • Y. Saunthararajah et al.

    Coincident myelodysplastic syndrome and T-cell large granular lymphocytic diseaseClinical and pathophysiological features

    Br J Haematol

    (2001)

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