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Preferential sensitivity of hematopoietic (HPs) and mesenchymal (MPs) progenitors to fludarabine suggests impaired bone marrow niche and HP mobilization

Leukemia volume 22, pages 2131–2134 (2008)Cite this article

A Corrigendum to this article was published on 12 November 2008

B-chronic lymphocytic leukemia remains an incurable disease. Intensification regimens and hematopoietic stem cell (HSC) autografts are currently being tested to improve aggressive B-chronic lymphocytic leukemia control. Several trials have documented the difficulty of mobilizing HSC by granulocyte colony-stimulating factor after treatment with fludarabine (FDR), which is considered the most effective first-line treatment. This negative effect on HSC egress appears to persist for several months after the last treatment cycle and could be correlated with circulating platelet levels.1, 2 As previously reported, in vivo FDR-induced cytopenia suggests toxicity against hematopoietic progenitors (HPs). We postulated that FDR might impair two major cell components of the bone marrow niche, mesenchymal and hematopoietic cells.

In conclusion, whereas clinical data argue for an hematopoietic and immune cell specificity of FDR, the scope of its action is larger than expected and involves endothelial, epithelial and nurse-like cells,8 as well as MC as demonstrated here. Possible impairment of hematopoietic and stromal components might contribute to a certain extent to the myelosuppression observed in vivo, but also to the antileukemic effect of FDR in B-chronic lymphocytic leukemia, by modifying the environment of the B-cell clone. Furthermore, our surviving MC presented biological impairments that were transmissible to their progeny, thus accounting for the lasting effect observed in vivo. Moreover, FDR is able to modify or select HP so as to favor their retention in bone marrow, which could partly explain the reported impairment of in vivo HSC mobilization by granulocyte colony-stimulating factor alone. Besides, the residual toxicity observed on their mesenchymal progeny could explain the in vivo persistence of this effect. Understanding the mechanisms involved in FDR toxicity would make it possible to propose therapeutic strategies with less side effects.

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Acknowledgements

We thank Anne-Sophie Michallet (Hopital Lyon Sud) for helpful discussions and Dominique Chadeyron for manuscript preparation. This work was supported by grants from the Ligue contre le Cancer (Puy-de-Dôme), Association Laurette Fugain and Shering France.

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Authors and Affiliations

  1. Hematology (Biology), CHU Hôtel-Dieu, Clermont-Ferrand, France

    M G Berger, J Berger & C Richard

  2. UPRES EA 3846, Faculté Médecine, Université de Clermont 1, Clermont-Ferrand, France

    M G Berger, J Berger & O Tournilhac

  3. Department of Hematology and Cell Therapy, CHU Hôtel-Dieu, Clermont-Ferrand, France

    S Jeanpierre & V M Satta

  4. Université de Lyon, Lyon, France

    S Jeanpierre & V M Satta

  5. ISPB, Université de Lyon 1, Lyon, France

    S Jeanpierre & V M Satta

  6. INSERM, U590, Lyon, France

    S Jeanpierre & V M Satta

  7. IFR62, Lyon, France

    F E Nicolini & M Michallet

  8. Department of Hematology, E Herriot Hospital, Lyon, France

    O Tournilhac

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  1. M G Berger
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Correspondence to V M Satta.

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Berger, M., Berger, J., Richard, C. et al. Preferential sensitivity of hematopoietic (HPs) and mesenchymal (MPs) progenitors to fludarabine suggests impaired bone marrow niche and HP mobilization. Leukemia 22, 2131–2134 (2008). https://doi.org/10.1038/leu.2008.167

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