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Polycythemia vera and hydroxyurea resistance/intolerance: a monocentric retrospective analysis

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Abstract

Hydroxyurea (HU) resistance or intolerance occurs in 15 to 24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy, intolerance has no prognostic value. We assessed the occurrence of HU resistance or intolerance comparing the original (ELNo) versus the modified European Leukemia Net (ELNm) criteria as applied in recent large clinical trials including PV patients. We retrospectively analyzed 106 patients with PV treated with HU at the University Hospitals of Leuven between 1990 and 2016 for occurrence of HU resistance/intolerance when using both ELNo as ELNm. After a mean duration of treatment of 5.1 years, when applying the ELNo 20.7% of patients had shown resistance or intolerance to HU in comparison to 39.6% when using the ELNm. When using the ELNo 4.7% of patients were resistant to HU versus 23.6% when applying the ELNm. In total, 16.0% of patients were HU intolerant. This rate was identical when using both ELNo and ELNm. 20.7% of PV patients were considered as HU-resistant or intolerant when using the original ELN criteria. However, when applying the modified ELN criteria 39.6% of PV patients were resistant or intolerant to HU. In our hands, no patient received a minimum dose of 2 g HU a day, as such the ELNm seem better adapted for daily clinical use. However, the prognostic value of HU-resistance in PV, when defined by the ELNm, still needs to be confirmed.

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References

  1. Vannucchi AM (2010) Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia. Intern Emerg Med 5(3):177–184

    Article  PubMed  Google Scholar 

  2. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM et al (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127(20):2391–2405

    Article  CAS  PubMed  Google Scholar 

  3. Moulard O, Mehta J, Fryzek J, Olivares R, Igbal U, Mesa R (2014) Epidemiology of myelofibrosis, essential thrombocythemia, and polycythemia vera in the European Union. Eur J Haematol 92(4):289–297

    Article  PubMed  Google Scholar 

  4. Tefferi A (2010) Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1. Leukemia 24(6):1128–1138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Tefferi A, Rumi E (2013) Finazzi Gea. Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study. Leukemia 27(9):1874–1881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Marchioli R, Finazzi G, Landolfi R, Kutti J, Gisslinger H, Patrono C, Marilus R, Villegas A, Tognoni G, Barbui T (2005) Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23(10):2224–2232

    Article  PubMed  Google Scholar 

  7. Cerquozzi S, Tefferi A (2015) Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J 5:e366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Geyer H, Scherber R, Kosiorek H, Dueck AC, Kiladjian JJ, Xiao Z, Slot S, Zweegman S, Sackmann F, Fuentes AK, Hernández-Maraver D, Döhner K, Harrison CN, Radia D, Muxi P, Besses C, Cervantes F, Johansson PL, Andreasson B, Rambaldi A, Barbui T, Bonatz K, Reiter A, Boyer F, Etienne G, Ianotto JC, Ranta D, Roy L, Cahn JY, Maldonado N, Barosi G, Ferrari ML, Gale RP, Birgegard G, Xu Z, Zhang Y, Sun X, Xu J, Zhang P, te Boekhorst PA, Commandeur S, Schouten H, Pahl HL, Griesshammer M, Stegelmann F, Lehmann T, Senyak Z, Vannucchi AM, Passamonti F, Samuelsson J, Mesa RA (2016) Symptomatic profiles of patients with polycythemia Vera: implications of inadequately controlled disease. J Clin Oncol 34(2):151–159

    Article  CAS  PubMed  Google Scholar 

  9. Anderson LA, James G, Duncombe AS, Mesa R, Scherber R, Dueck AC, de Vocht F, Clarke M, McMullin MF (2015) Myeloproliferative neoplasm patient symptom burden and quality of life: evidence of significant impairment compared to controls. Am J Hematol 90(10):864–870

    Article  PubMed  Google Scholar 

  10. Mesa R, Miller CB, Thyne M, Mangan J, Goldberger S, Fazal S, Ma X, Wilson W, Paranagama DC, Dubinski DG, Boyle J, Mascarenhas JO (2016) Myeloproliferative neoplasms (MPNs) have a significant impact on patients’ overall health and productivity: the MPN landmark survey. BMC Cancer 16:167

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, de Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T, CYTO-PV Collaborative Group (2013) Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 368(1):22–33

    Article  CAS  PubMed  Google Scholar 

  12. Rumi E, Cazzola M (2017) Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood 129(6):680–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McMullin MF, Wilkins BS, Harrison CN (2016) Management of polycythaemia vera: a critical review of current data. Br J Haematol 172(3):337–349

    Article  PubMed  Google Scholar 

  14. Barbui T, Tefferi A, Vannucchi AM, Passamonti F, Silver RT, Hoffman R, Verstovsek S, Mesa R, Kiladjian JJ, Hehlmann R, Reiter A, Cervantes F, Harrison C, Mc Mullin MF, Hasselbalch HC, Koschmieder S, Marchetti M, Bacigalupo A, Finazzi G, Kroeger N, Griesshammer M, Birgegard G, Barosi G (2018) Philadelphia chromosome-negative classical myeloproliferative neoplasms: revised management recommendations from European LeukemiaNet. Leukemia 32(5):1057–1069

    Article  PubMed  PubMed Central  Google Scholar 

  15. Griesshammer M, Gisslinger H, Mesa R (2015) Current and future treatment options for polycythemia vera. Ann Hematol 94(6):901–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Reiter A, Harrison C (2016) How we identify and manage patients with inadequately controlled polycythemia Vera. Curr Hematol Malig Rep 11(5):356–367

    Article  PubMed  Google Scholar 

  17. Kiladjian JJ, Chevret S, Dosquet C, Chomienne C, Rain JD (2011) Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol 29(29):3907–3913

    Article  PubMed  Google Scholar 

  18. Finazzi G, Caruso V, Marchioli R, Capnist G, Chisesi T, Finelli C, Gugliotta L, Landolfi R, Kutti J, Gisslinger H, Marilus R, Patrono C, Pogliani EM, Randi ML, Villegas A, Tognoni G, Barbui T, ECLAP Investigators (2005) Acute leukemia in polycythemia vera: an analysis of 1638 patients enrolled in a prospective observational study. Blood 105(7):2664–2670

    Article  CAS  PubMed  Google Scholar 

  19. Antonioli E, Guglielmelli P, Pieri L, Finazzi M, Rumi E, Martinelli V, Vianelli N, Luigia Randi M, Bertozzi I, de Stefano V, Za T, Rossi E, Ruggeri M, Elli E, Cacciola R, Cacciola E, Pogliani E, Rodeghiero F, Baccarani M, Passamonti F, Finazzi G, Rambaldi A, Bosi A, Cazzola M, Barbui T, Vannucchi AM, On behalf of the AGIMM Investigators (2012) Hydroxyurea-related toxicity in 3,411 patients with Ph’-negative MPN. Am J Hematol 87(5):552–554

    Article  PubMed  Google Scholar 

  20. Alvarez-Larran A, Pereira A, Cervantes F, Arellano-Rodrigo E, Hernandez-Boluda JC, Ferrer-Marin F, Angona A, Gomez M, Muina B, Guillen H, Teruel A, Bellosillo B, Burgaleta C, Vicente V, Besses C (2012) Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 119(6):1363–1369

    Article  CAS  PubMed  Google Scholar 

  21. Alvarez-Larran A, Kerguelen A, Hernandez-Boluda JC, Perez-Encinas M, Ferrer-Marin F, Barez A et al (2016) Frequency and prognostic value of resistance/intolerance to hydroxycarbamide in 890 patients with polycythaemia vera. Br J Haematol 172(5):786–793

    Article  CAS  PubMed  Google Scholar 

  22. Parasuraman S, DiBonaventura M, Reith K, Naim A, Concialdi K, Sarlis NJ (2015) Patterns of hydroxyurea use and clinical outcomes among patients with polycythemia vera in real-world clinical practice: a chart review. Exp Hematol Oncol 5:3

    Article  CAS  PubMed  Google Scholar 

  23. Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch H et al (2010) A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. Br J Haematol 148:961–963

    Article  PubMed  Google Scholar 

  24. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Mesa R, He S, Jones MM, Garrett W, Li J, Pirron U, Habr D, Verstovsek S (2015) Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med 372(5):426–435

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Passamonti F, Griesshammer M, Palandri F, Egyed M, Benevolo G, Devos T, Callum J, Vannucchi AM, Sivgin S, Bensasson C, Khan M, Mounedji N, Saydam G (2017) Ruxolitinib for the treatment of inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): a randomised, open-label, phase 3b study. Lancet Oncol 18(1):88–99

    Article  CAS  PubMed  Google Scholar 

  26. Vannucchi AM, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F et al (2015) Ruxolitinib versus Standard Therapy for the Treatment of Polycythemia Vera. https://doi.org/10.1056/NEJMoa1409002

  27. Silver RT (2006) Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 107(3):451–458

    Article  CAS  PubMed  Google Scholar 

  28. Mesa R, Verstovsek S, Kiladjian JJ, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Zhen H, Jones MM, Parasuraman S, Li J, Côté I, Habr D, Vannucchi AM (2016) Changes in quality of life and disease-related symptoms in patients with polycythemia vera receiving ruxolitinib or standard therapy. Eur J Haematol 97(2):192–200

    Article  CAS  PubMed  Google Scholar 

  29. Verstovsek S, Vannucchi AM, Griesshammer M, Masszi T, Durrant S, Passamonti F, Harrison CN, Pane F, Zachee P, Kirito K, Besses C, Hino M, Moiraghi B, Miller CB, Cazzola M, Rosti V, Blau I, Mesa R, Jones MM, Zhen H, Li J, Francillard N, Habr D, Kiladjian JJ (2016) Ruxolitinib versus best available therapy in patients with polycythemia vera: 80-week follow-up from the RESPONSE trial. Haematologica 101(7):821–829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Internal Medicine, University Hospitals of Leuven, Leuven, Belgium

    T. Demuynck

  2. Department of Hematology, University Hospitals of Leuven, Herestraat 49, 3000, Leuven, Belgium

    G. Verhoef, M. Delforge, P. Vandenberghe & Timothy Devos

  3. Department of Human Genetics, KU Leuven, Leuven, Belgium

    P. Vandenberghe

  4. Laboratory of Experimental Transplantation, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium

    Timothy Devos

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  1. T. Demuynck
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Correspondence to Timothy Devos.

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Thomas Demuynck, Gregor Verhoef, Michel Delforge, and Peter Vandenberghe have no conflict of interest to declare. Timothy Devos did participate in an advisory board for Novartis and Gilead.

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Demuynck, T., Verhoef, G., Delforge, M. et al. Polycythemia vera and hydroxyurea resistance/intolerance: a monocentric retrospective analysis. Ann Hematol 98, 1421–1426 (2019). https://doi.org/10.1007/s00277-019-03654-6

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  • DOI: https://doi.org/10.1007/s00277-019-03654-6

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