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Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide

Leukemia volume 30, pages 2405–2409 (2016)Cite this article

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Lenalidomide (LEN) treatment leads to red blood cell transfusion independence in approximately two-thirds of anemic myelodysplastic syndrome (MDS) patients with del(5q).1 Some patients also experience cytogenetic remissions, whereas in others the del(5q) abnormality persists.1 Furthermore, responses also occur in ~25% of MDS patients without del(5q).2 This suggests that, in addition to del(5q), other molecular lesions may also be associated with sensitivity to LEN. To date, apart from del(5q), no reliable predictive factors for LEN responsiveness have been reported, but clinically patients with early MDS, normal/low-risk cytogenetics, or anemia with preserved platelet and neutrophil counts appear to be better LEN candidates than those with more advanced disease, complex cytogenetics and cytopenias.3 On a molecular level, although initial attempts to prospectively identify responders based on gene expression patterns suggested response-specific signatures,4 they have not been translated into an actionable test, and have not been validated in non-del(5q) cases.5 Recently, the mechanism of action of LEN has been attributed to induction of ubiquitination and enhanced degradation of casein kinase 1A1 (CK1α) by the E3 ubiquitin ligase cereblon.6

To identify new biomarkers of sensitivity to LEN, using next-generation sequencing, we determined whether recurrent mutations can help predict response or resistance to LEN in patients with myeloid malignancies.

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Acknowledgements

This work was supported in part by National Institutes of Health grants R01HL118281 and Celgene Award RV-TR-MYELOID-PI-004593 to J.P. Maciejewski and by the Edward P. Evans Foundation to JPM and MAS. This work was supported in part by a grant from the Instituto de Salud Carlos III, Ministerio de Economia y Competividad, Spain (PI 11/02010 and PI/14/00013); by the Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER) (RD12/0036/0044); Sociedad Española Hematología y Hemoterapia; 2014 SGR225 (GRE) Generalitat de Catalunya, by José Carreras Leukämie-Stiftung, Ref. AR 14/34; economical support from Fundació Internacional Josep Carreras and from Celgene Spain. The research leading to this invention has received funding from ‘la Caixa’ Foundation.

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Authors and Affiliations

  1. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    E Negoro, C Polprasert, N Hosono, H Makishima, B Przychodzen, C Hirsch, M J Clemente, A Nazha, M A Sekeres & J P Maciejewski

  2. Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA

    T Radivoyevitch

  3. Josep Carreras Leukaemia Research Institute, Barcelona, Spain

    V Adema & F Sole

  4. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    H Makishima

  5. Hematology Unit, AOU Careggi, University of Florence, Firenze, Italy

    V Santini

  6. Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, USA, FL

    K L McGraw & A F List

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  1. E Negoro
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  2. T Radivoyevitch
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  3. C Polprasert
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  7. B Przychodzen
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  8. C Hirsch
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  9. M J Clemente
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  11. V Santini
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  13. A F List
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  14. F Sole
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  15. M A Sekeres
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  16. J P Maciejewski
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Corresponding author

Correspondence to J P Maciejewski.

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Competing interests

MAS serves on an advisory board for Celgene, Corp. JPM has received speaking honoraria from Celgene.

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Supplementary Information accompanies this paper on the Leukemia website

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Negoro, E., Radivoyevitch, T., Polprasert, C. et al. Molecular predictors of response in patients with myeloid neoplasms treated with lenalidomide. Leukemia 30, 2405–2409 (2016). https://doi.org/10.1038/leu.2016.228

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