Haematologica, Vol 94, Issue 10, 1407-1414 doi:10.3324/haematol.2009.009191
Copyright © 2009 by Ferrata Storti Foundation
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Lymphoproliferative Disorders

Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia

Sanjay R. Mohan1, Michael J. Clemente1, Manuel Afable1, Heather N. Cazzolli1, Nelli Bejanyan1, Marcin W. Wlodarski1,2, Alan E. Lichtin1, Jaroslaw P. Maciejewski1

1 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
2 Division of Pediatric Hematology and Oncology, University of Freiburg, Berlin, Germany

Correspondence: Jaroslaw P. Maciejewski, Taussig Cancer Center/R40, 9500 Euclid Avenue, Cleveland, OH 44195, USA. E-mail:maciejj{at}cc.ccf.org

Background: T-cell large granular lymphocytic leukemia is a clonal proliferation of cytotoxic T-lymphocytes which often results in severe cytopenia. Current treatment options favor chronic immunosuppression. Alemtuzumab, a humanized monoclonal antibody against glycophosphatidylinositol-anchored CD52, is approved for patients refractory to therapy in other lymphoid malignancies.

Design and Methods: We retrospectively examined treatment outcomes in 59 patients with CD8+ T-cell large granular lymphocytic leukemia, 41 of whom required therapy. Eight patients with severe refractory cytopenia despite multiple treatment regimens had been treated with subcutaneous alemtuzumab as salvage therapy. Flow cytometry was used to monitor expression of glycophosphatidylinositol-anchored CD52, CD55, and CD59 as well as to characterize T-cell clonal expansions by T-cell receptor variable β-chain (Vβ) repertoire.

Results: Analysis of the effects of alemtuzumab revealed remissions with restoration of platelets in one of one patient, red blood cell transfusion independence in three of five patients and improvement of neutropenia in one of three, resulting in an overall response rate of 50% (4/8 patients). Clonal large granular lymphocytes exhibited decreased CD52 expression post-therapy in patients refractory to treatment. Samples of large granular lymphocytes collected prior to therapy also unexpectedly had a significant proportion of CD52-negative cells while a healthy control population had no such CD52 deficiency (p=0.026).

Conclusions: While alemtuzumab may be highly effective in large granular lymphocytic leukemia, prospective serial monitoring for the presence of CD52-deficient clonal cytotoxic T-lymphocytes should be a component of clinical trials investigating the efficacy of this drug. CD52 deficiency may explain lack of response to alemtuzumab, and such therapy may confer a survival advantage to glycophosphatidylinositol-negative clonal cytotoxic T-lymphocytes.

Key words: large granular lymphocytic, alemtuzumab, therapy.


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Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches
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R. Zambello and G. Semenzato
Large granular lymphocyte disorders: new etiopathogenetic clues as a rationale for innovative therapeutic approaches
Haematologica, October 1, 2009; 94(10): 1341 - 1345.
[Full Text] [PDF]