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Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients

Leukemia volume 28, pages 696–698 (2014)Cite this article

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Patients with myelodysplastic syndromes (MDS) often display anemia for which currently available treatment options are limited. In fact, red blood cell (RBC) transfusions remain a crucial therapy although their use is linked to decreased survival. In lower-risk MDS, there is no licensed treatment option available throughout Europe, at present, although erythropoietin receptor stimulating agents (ESA) are active in a well-defined subset of patients with low transfusion burden and low endogenous erythropoietin (EPO) levels.1 Although the mechanism is not clearly defined, EPO-dependent signaling is impaired in the majority of anemic MDS patients. Recent findings suggest that mutations in epigenetic regulators contribute to the pathophysiology of MDS.2, 3 Targeting histone deacetylation (HDAC) with single agent valproic acid (VPA) has been shown to achieve substantial erythroid improvements, especially in IPSS lower-risk patients.4 Panobinostat (LBH589), an oral pan class I/II histone deacetylase inhibitor (HDACi), has shown promising anti-tumor activity in preclinical models and in leukemia patients through inhibiting cellular proliferation and inducing apoptosis.5, 6

After the core phase, patients with stable disease regarding transfusion needs were randomized either to receive further treatment with LBH589 alone or LBH589 plus ESA (‘randomized phase’). This was done in an attempt to investigate whether HDACi mediated by LBH589 might overcome resistance to erythropoiesis-stimulating agents, like recently shown for all-trans retinoic acid.9 Per amendment 2, the study was terminated prematurely due to a lack of an observed response in the 34 patients treated thus far. Results presented are based on the full analysis set population. The study was conducted according to the Declaration of Helsinki, and all patients provided written informed consent.

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References

  1. Hellstrom-Lindberg E, Gulbrandsen N, Lindberg G, Ahlgren T, Dahl IM, Dybedal I et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin+granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol 2003; 120: 1037–1046.

    Article  CAS  Google Scholar 

  2. Bejar R, Stevenson K, Abdel-Wahab O, Galili N, Nilsson B, Garcia-Manero G et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 2011; 364: 2496–2506.

    Article  CAS  Google Scholar 

  3. Shih AH, Abdel-Wahab O, Patel JP, Levine RL . The role of mutations in epigenetic regulators in myeloid malignancies. Nat Rev Cancer 2012; 12: 599–612.

    Article  CAS  Google Scholar 

  4. Kuendgen A, Knipp S, Fox F, Strupp C, Hildebrandt B, Steidl C et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol 2005; 84 (Suppl 1): 61–66.

    Article  CAS  Google Scholar 

  5. Deangelo DJ, Spencer A, Bhalla KN, Prince HM, Fischer T, Kindler T et al. Phase Ia/II, 2-arm, open-label, dose-escalation study of oral panobinostat administered via 2 dosing schedules in patients with advanced hematologic malignancies. Leukemia 2013; 27: 1628–1636.

    Article  CAS  Google Scholar 

  6. Prince HM, Bishton MJ, Johnstone RW . Panobinostat (LBH589): a potent pan-deacetylase inhibitor with promising activity against hematologic and solid tumors. Future Oncol 2009; 5: 601–612.

    Article  CAS  Google Scholar 

  7. Hellstrom-Lindberg E, Negrin R, Stein R, Krantz S, Lindberg G, Vardiman J et al. Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes: proposal for a predictive model. Br J Haematol 1997; 99: 344–351.

    Article  CAS  Google Scholar 

  8. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et alClinical application and proposal for modification of the International Working Group. (IWG) response criteria in myelodysplasia. Blood 2006; 108: 419–425.

    Article  CAS  Google Scholar 

  9. Itzykson R, Ayari S, Vassilief D, Berger E, Slama B, Vey N et al. Is there a role for all-trans retinoic acid in combination with recombinant erythropoetin in myelodysplastic syndromes? A report on 59 cases. Leukemia 2009; 23: 673–678.

    Article  CAS  Google Scholar 

  10. Younes A, Sureda A, Ben-Yehuda D, Zinzani PL, Ong TC, Prince HM et al. Panobinostat in patients with relapsed/refractory Hodgkin's lymphoma after autologous stem-cell transplantation: results of a phase II study. J Clin Oncol 2012; 30: 2197–2203.

    Article  CAS  Google Scholar 

  11. Giver CR, Jaye DL, Waller EK, Kaufman JL, Lonial S . Rapid recovery from panobinostat (LBH589)-induced thrombocytopenia in mice involves a rebound effect of bone marrow megakaryocytes. Leukemia 2011; 25: 362–365.

    Article  CAS  Google Scholar 

  12. Wagner JM, Hackanson B, Lubbert M, Jung M . Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. Clin Epigenetics 2010; 1: 117–136.

    Article  CAS  Google Scholar 

  13. Cashen A, Juckett M, Jumonville A, Litzow M, Flynn PJ, Eckardt J et al. Phase II study of the histone deacetylase inhibitor belinostat (PXD101) for the treatment of myelodysplastic syndrome (MDS). Ann Hematol 2012; 91: 33–38.

    Article  CAS  Google Scholar 

  14. Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007; 110: 2302–2308.

    Article  CAS  Google Scholar 

  15. Voso MT, Santini V, Finelli C, Musto P, Pogliani E, Angelucci E et al. Valproic acid at therapeutic plasma levels may increase 5-azacytidine efficacy in higher risk myelodysplastic syndromes. Clin Cancer Res 2009; 15: 5002–5007.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Universitätsklinikum Dresden, Dresden, Germany

    U Platzbecker, M Wermke & G Ehninger

  2. Universitätsklinikum Leipzig, Leipzig, Germany

    H K Al-Ali

  3. Universitätsklinikum Düsseldorf, Düsseldorf, Germany

    N Gattermann, A Kündgen & U Germing

  4. Universitätsmedizin Göttingen, Göttingen, Germany

    D Haase

  5. Universitätsklinikum Bonn, Bonn, Germany

    V Janzen

  6. Medizinische Hochschule Hannover, Hannover, Germany

    J Krauter

  7. Klinikum rechts der Isar der Technischen Universität München, München, Germany

    K Götze

  8. Universitätsklinikum Ulm, Ulm, Germany

    R Schlenk

  9. Universitätsmedizin Mannheim, Mannheim, Germany

    F Nolte

  10. Charité Berlin, Berlin, Germany

    A Letsch

  11. Universitätsklinikum Frankfurt, Frankfurt, Germany

    O G Ottmann

  12. Universitätsklinikum Freiburg, Freiburg, Germany

    M Lübbert

  13. Novartis Pharma GmbH Nürnberg, Nürnberg, Germany

    H Reinhard, C Weiss, K Lieder & O Leismann

  14. Marienhospital Düsseldorf, Düsseldorf, Germany

    A Giagounidis

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Correspondence to U Platzbecker.

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Competing interests

UP and AG had received speakers honoraria from Novartis Pharma GmbH. All other authors declare no conflict of interest.

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Platzbecker, U., Al-Ali, H., Gattermann, N. et al. Phase 2 study of oral panobinostat (LBH589) with or without erythropoietin in heavily transfusion-dependent IPSS low or int-1 MDS patients. Leukemia 28, 696–698 (2014). https://doi.org/10.1038/leu.2013.325

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