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Chronic Lymphocytic Leukemia

Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia

Leukemia volume 23, pages 1771–1778 (2009)Cite this article

Abstract

Thalidomide represents a promising immunomodulatory drug that targets both leukemia cells and the tumor microenvironment. We treated patients with chronic lymphocytic leukemia (CLL) with a combined thalidomide/fludarabine regimen and monitored cellular and molecular changes induced by thalidomide in vivo before fludarabine treatment. Thalidomide was given daily (100 mg p.o. per day) and fludarabine was administered on days 7–11 (25 mg/m2 i.v. per day) within each 4-week cycle (maximum of 6 cycles). Twenty patients received thalidomide/fludarabine as first-line therapy and 20 patients were previously treated. Unmutated IgVH mutation status was found in 36 cases and 13 had high-risk cytogenetic aberrations (del17p, del11q). The overall response rate was 80 and 25% for untreated and previously treated patients, respectively. Although thalidomide reduced the number of CLL cells, the number of CD3 lymphocytes showed no significant change, but the number of CD4+CD25hiFOXP3+ regulatory T cells (Tregs) was significantly decreased. Gene expression profiling revealed a thalidomide-induced signature containing both targets known to have a function in immunomodulatory drug action as well as novel candidate genes. Combined thalidomide/fludarabine therapy demonstrated efficacy in high-risk patients with CLL. Furthermore, our study provides novel biological insights into thalidomide effect, which might act by enhancing apoptosis of CLL cells and reducing Tregs, thereby enabling T-cell-dependent antitumor effect.

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Acknowledgements

This study was supported by the grants from the Polish Scientific Committee KBN N402 034 31/1138 and N402 10732/3496. KG was supported by a generous scholarship from the Foundation for Polish Science. We are indebted to Annett Habermann, Sabrina Kless, Sabrina Heinrich und Ursula Botzenhardt for excellent technical assistance. We thank Paulina Wlasiuk for excellent technical support.

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Authors and Affiliations

  1. Department of Clinical Immunology, Medical University of Lublin, Lublin, Poland

    K Giannopoulos, A Bojarska-Junak & J Rolinski

  2. Department of Hematooncology, Medical University of Lublin, Lublin, Poland

    K Giannopoulos, A Dmoszynska, M Kowal & E Wąsik-Szczepanek

  3. Department of Internal Medicine III, University of Ulm, Ulm, Germany

    K Giannopoulos, H Döhner, S Stilgenbauer & L Bullinger

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  1. K Giannopoulos
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  2. A Dmoszynska
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  3. M Kowal
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Correspondence to H Döhner.

Additional information

Author's contributions: KG and LB designed research, performed experiments, analyzed data and wrote the paper; AD, MK and EW-S recruited patients and discussed the paper; A B-J performed experiments; AD, JR and SS provided biological material and clinical data, and discussed the paper; AD, SS and HD designed research and discussed the paper.

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Giannopoulos, K., Dmoszynska, A., Kowal, M. et al. Thalidomide exerts distinct molecular antileukemic effects and combined thalidomide/fludarabine therapy is clinically effective in high-risk chronic lymphocytic leukemia. Leukemia 23, 1771–1778 (2009). https://doi.org/10.1038/leu.2009.98

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