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Treatment of myelodysplastic syndromes with excess of blasts by bevacizumab is well tolerated and is associated with a decrease of VEGF plasma level

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Abstract

Myelodysplastic syndromes (MDS) are associated with increased bone marrow vascularity and increased levels of various angiogenic factors including Vascular Endothelial Growth Factor (VEGF) which is implicated in the proliferation and survival of leukemic cells. Before the approval of hypomethylating agents in this indication, the GFM conducted a multicenter phase II trial testing the efficacy and tolerance of bevacizumab, a humanized monoclonal antibody against VEGF, in MDS with excess of marrow blasts and its impact on bone marrow angiogenesis. Twenty-one patients were enrolled (16 males and five females) with a median age of 70 years and 19 were evaluable for haematological response after treatment (5 mg/kg IV every 2 weeks for 12 weeks). WHO diagnosis at baseline was RAEB-1 (38%) and RAEB-2 (62%). Treatment was well tolerated and was associated with significant decrease of VEGF plasma level [median (low quartile–high quartile)] from 65.5 pg/ml [LQ (low-quartile)–HQ (high quartile), 35.3–87.3 to 30.4 pg/ml (LQ–HQ, 22.5–34.0 pg/ml)] (p < 0.01) and reduction of bone marrow angiogenesis from a median of 20 vessels/mm3 (LQ–HQ, 16.5–33 vessels/mm3) to 15.5 vessels/mm3 (LQ–HQ, 10–23.2 vessels/mm3) (p = 0.03). On the other hand, only one patient had a significant haematological response with achievement of RBC transfusion independence. Thus, although bevacizumab had a significant impact on VEGF levels and angiogenesis in our patients, very few responses were seen when this drug was used as single agent. Given its good tolerability profile, however, combination of bevacizumab with other drugs, especially hypomethylating agents, could be considered in MDS.

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Acknowledgements

The authors would like to thank Pr Jean-Francois Michiels and Philippe Lenormand for technical assistance and Nathalie Varoqueaux from Roche for supporting this work.

Funding

The trial was sponsored by Roche Ltd, Paris, France. This work was supported by institutional funds from promotion permanente, CHU de Nice.

Authorship

LL, FD and PF wrote the paper. LL was the principal investigator and takes primary responsibility for the paper. SH and JD performed the laboratory work for this study. BS, JMK, NB, SNA, EW, BR, CB and LM enrolled patients and collected data. IT monitored the clinical trial. MB and LL analyzed bone marrow biopsies. AOH made substantial contributions, critically reviewed and approved the final version of the report. JPC critically reviewed and approved the final version of the report.

Disclosures

Dr. L Legros has been on a board from Roche France Pharmaceuticals.

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Authors and Affiliations

  1. Service d’hématologie clinique, Hôpital de l’Archet, Nice, France

    Laurence Legros, Jean-Michel Karsenti, Lionel Mannone & Irit Touitou

  2. CNRS UMR 6543, Université de Nice Sophia-Antipolis, Institute of Developmental Biology and Cancer Research, Nice, France

    Laurence Legros, Sébastien Huault, Jérome Durivault & Anne-Odile Hueber

  3. Service de Médecine Interne Onco-hématologie et maladies infectieuses, CH d’Avignon, France

    Bohrane Slama

  4. Institut Paoli Calmette, Marseille, France

    Norbert Vey

  5. Hôpital Hautepierre, Strasbourg, France

    Shanti Natarajan-Amé

  6. Hôpital Edouard Herriot, Lyon, France

    Eric Watel

  7. CH Nîmes, Nimes, France

    Bruno Richard

  8. Hôpital Haut-Lévèque, 33604, Pessac, France

    Krimo Bouabdallah

  9. Service d’Anatomie-Pathologique, CHU de Nice, Nice, France

    Maxime Benchetrit & Damien Ambroseti

  10. Hôpital Avicenne (Assistance Publique Hôpitaux de Paris)/Paris 13 University, Bobigny, France

    Pierre Fenaux

  11. Service d’Hématologie, Hôpital Cochin, (Assistance Publique Hôpitaux de Paris), Paris, France

    Francois Dreyfus

  12. Department of Hematology, Archet 1 Hospital, 151, Route de Saint Antoine de Ginestière BP 3079, 06202, Nice Cedex 3, France

    Laurence Legros

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  1. Laurence Legros
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Correspondence to Laurence Legros.

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Legros, L., Slama, B., Karsenti, JM. et al. Treatment of myelodysplastic syndromes with excess of blasts by bevacizumab is well tolerated and is associated with a decrease of VEGF plasma level. Ann Hematol 91, 39–46 (2012). https://doi.org/10.1007/s00277-011-1242-z

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