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Reversal of T-cell tolerance in myelodysplastic syndrome through lenalidomide immune modulation

Leukemia volume 26, pages 1425–1429 (2012)Cite this article

Myelodysplastic syndromes (MDS) represent a spectrum of senescence-dependent, hematopoietic stem cell disorders1 with dysplastic cytological features, ineffective hematopoiesis, and a propensity for transformation into acute myeloid leukemia.2 Response biomarkers to inform delegation of FDA-approved therapies such as the thalidomide analog lenalidomide (Revlimid, Celgene Inc., Warren, NJ, USA) are needed to improve outcomes. High rates of erythroid response to lenalidomide occur in del(5q)-MDS patients because of suppression of haplodeficient phosphatases encoded within the proximal commonly deleted region.3 A previous report showing that bone marrow lymphoid aggregates appear in association with hematological response implicates immune modulation in this process.4 Thalidomide, lenalidomide and other structural analogs of this drug class induce potent immune modulation independent of del(5q), with documented activation of T-cells and NK-cells both in vitro and in vivo in multiple myeloma and chronic lymphocytic leukemia.5, 6, 7

In an effort to understand how lenalidomide's immunomodulatory activity may be linked to hematological response in MDS, we evaluated T-cell activity before and after lenalidomide treatment in vitro, and examined in vivo immune correlation related to hematological response based on International Working Group 2000 criteria. For this analysis, 100 patients with pathologically defined MDS were consented at Moffitt Cancer Center to evaluate immune responses. A total of 13 of these were low-risk, treated with lenalidomide, and had samples collected before and after treatment. Blood samples from an additional five patients with only lenalidomide pretreatment samples available were used for in vitro experiments, but did not contribute to hematological response analysis. Clinical characteristics and lenalidomide responses are shown in Supplementary Table 1. There was no difference between responders (R) and nonresponders (NR) with regard to international prognostic score, World Health Organization classification or age (P=0.224).

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Acknowledgements

Support for this study was provided by NIH grant CA129952-02. We thank the Flow Cytometry Core Facility for their assistance with this project, the Malignant Hematology Program for assistance with patient sample collection and Celgene Corporation for supplying lenalidomide for in vitro studies.

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Authors and Affiliations

  1. Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA

    J M McDaniel

  2. Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    J M McDaniel, J X Zou & P K Epling-Burnette

  3. Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    W Fulp & D-T Chen

  4. Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    A F List

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Correspondence to P K Epling-Burnette.

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Competing interests

Dr List is a consultant, honoraria, member of the scientific advisory board, principal investigator for, and receives clinical research support from Celgene Corporation. J McDaniel, Dr Zou, Dr Fulp, Dr Chen and Dr Epling-Burnette declare no conflict of interest.

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McDaniel, J., Zou, J., Fulp, W. et al. Reversal of T-cell tolerance in myelodysplastic syndrome through lenalidomide immune modulation. Leukemia 26, 1425–1429 (2012). https://doi.org/10.1038/leu.2011.359

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