Annals of Hematology

, Volume 92, Issue 7, pp 907–915 | Cite as

Effects of imatinib mesylate in patients with polycythemia vera: results of a phase II study

  • Kirsten Merx
  • Alice Fabarius
  • Philipp Erben
  • Martin Griesshammer
  • Andreas Reiter
  • Wolf-Karsten Hofmann
  • Rüdiger Hehlmann
  • Andreas Hochhaus
  • Eva Lengfelder
Original Article


The antiproliferative effects of the tyrosine kinase inhibitor imatinib mesylate were reported in single cases with polycythemia vera (PV). We, therefore, conducted a clinical phase II study to assess the rate and quality of response in patients with PV. Thirty-one patients, with a median age of 64 years (range, 45–84 years), were included. All but one patient were on phlebotomy; 14 (45 %) had previously received cytoreductive therapy. Imatinib was started with 400 mg/day. In 26 % of patients, dose escalation up to 800 mg was performed. After a median treatment duration of 8.3 months (range, 0.1–62.1 months), the overall response rate was 55 %. No complete remission (normalization of all parameters: hematocrit, white blood cell (WBC) count, platelet count, and spleen size determined by ultrasound examination) was reached because the spleen remained enlarged in all patients. Thirteen patients (42 %) achieved partial remission (≥25 % reduction of at least one of the previously mentioned parameters); in 10 of these, the respective reduction was ≥50 %. In four patients (13 %) with minor response, the reduction was <25 %. No change or progressive disease was seen in 14 patients (45 %). The nonresponders had a longer previous disease duration and had received more antecedent cytoreductive therapy (p = 0.009). Compared to baseline characteristics, imatinib induced the reduction of phlebotomies (p = 0.003), of WBC count (p = 0.002), and of platelet count (p = 0.04). Three patients became free from phlebotomies. In six investigated patients, no significant reduction of the JAK2V617F burden was observed despite clinical improvement. The results show that imatinib has moderate cytoreductive effects in PV.


Polycythemia vera Imatinib mesylate Treatment effects 



The following institutions participated in the study: Allgemeines Krankenhaus St. Georg, Hamburg, Germany (N. Schmitz); Onkologische Schwerpunktpraxis, Augsburg, Germany (O. Brudler, B. Heinrich, and M. Bangerter); Onkologische Schwerpunktpraxis, Jena, Germany (S. Hahnfeld); Universitätsklinik Ulm, Ulm, Germany (M. Griesshammer); Medizinische Universitätsklinik Freiburg, Freiburg im Breisgau, Germany (C. Waller); Medizinische Klinik I, Universitätsklinikum Köln, Cologne, Germany (M. Hallek); Onkologische Schwerpunktpraxis, Leer-Emden, Germany (L. Müller); Universitätsmedizin Mannheim, Mannheim, Germany (E. Lengfelder and K Merx); and Onkologische Schwerpunktpraxis, Weiden, Germany (J. Weiß).

Conflict of interest

Eva Lengfelder, Andreas Hochhaus, Andreas Reiter, Wolf-Karsten Hofmann, and Rüdiger Hehlmann are consultants or have advisory roles at Novartis Pharmaceuticals. Eva Lengfelder received research funding for this trial from Novartis Pharmaceuticals.


  1. 1.
    Gruppo Italiano Studio Polycythemia vera (1995) The natural history of 1213 patients followed for 20 years. Ann Intern Med 123:656–664CrossRefGoogle Scholar
  2. 2.
    Lengfelder E, Merx K, Hehlmann R (2006) Diagnosis and therapy of polycythemia vera. Semin Thromb Hemost 32:267–275PubMedCrossRefGoogle Scholar
  3. 3.
    James C, Ugo V, Couédic J, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434:1144–1148PubMedCrossRefGoogle Scholar
  4. 4.
    Cross N (2011) Genetic and epigenetic complexity in myeloproliferative disorders. Hematology Am Soc Hematol Educ Program 2011:208–214Google Scholar
  5. 5.
    Siitonen T, Savolainen ER, Koistinen P (1994) Expression of the c-kit proto-oncogene in myeloproliferative disorders and myelodysplastic syndromes. Leukemia 8:631–637PubMedGoogle Scholar
  6. 6.
    Ratajczak MZ, Luger SM, DeRiel K, Abrahm J, Calabretta B, Gewirtz AM (1992) Role of the KIT protooncogene in normal and malignant human hematopoiesis. Proc Natl Acad Sci U S A 89:1710–1714PubMedCrossRefGoogle Scholar
  7. 7.
    Fontalba A, Real PJ, Fernandez-Luna JL, Agirre X, Prosper F, Richard C (2006) Identification of c-Kit gene mutations in patients with polycythemia vera. Leuk Res 30:1325–1326PubMedCrossRefGoogle Scholar
  8. 8.
    Barbui T, Barosi G, Birgegard G, Rumi E, Boveri E, Ruggeri M et al (2011) Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 29:761–770PubMedCrossRefGoogle Scholar
  9. 9.
    Landolfi R, Marchioli R, Kutti J, Gisslinger H, Tognoni G, Patrono C, Barbui T (2004) Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350:114–124PubMedCrossRefGoogle Scholar
  10. 10.
    Löfvenberg E, Nordenson I, Wahlin A (1990) Cytogenetic abnormalities and leukemic transformation in hydroxyurea-treated patients with Philadelphia chromosome negative chronic myeloproliferative disorders. Cancer Genet Cytogenet 67:49–57Google Scholar
  11. 11.
    Barosi G, Birgegard G, Finazzi G, Griesshammer M, Harrison C, Hasselbalch H, Kiladijan JJ, Lengfelder E, Mesa R, Mc Mullin MF, Passamonti F, Reilly JT, Vannucchi AM, Barbui T (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 148:961–963PubMedCrossRefGoogle Scholar
  12. 12.
    Lengfelder E, Berger U, Hehlmann R (2003) Interferon alpha in the treatment of polycythemia vera. Ann Hematol 79:103–109CrossRefGoogle Scholar
  13. 13.
    Silver RT (2006) Long-term effects of the treatment of polycythemia vera with recombinant interferon-alpha. Cancer 107:451–458PubMedCrossRefGoogle Scholar
  14. 14.
    Kiladjian JJ, Cassinat B, Chevret S, Turlure P, Cambier N, Roussel M, Bellucci S, Grandchamp B, Chomienne C, Fenaux P (2008) Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 112:3065–3072PubMedCrossRefGoogle Scholar
  15. 15.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, Lydon NB, Kantarjian H, Capdeville R, Ohno-Jones S, Sawyers CL (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344:1031–1037PubMedCrossRefGoogle Scholar
  16. 16.
    Pardanani A, Tefferi A (2004) Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood 104:1931–1939PubMedCrossRefGoogle Scholar
  17. 17.
    Oehler L, Jaeger E, Eser A, Sillaber C, Gisslinger H, Geissler K (2003) Imatinib mesylate inhibits autonomous erythropoiesis in patients with polycythemia vera in vitro. Blood 102:2240–2242PubMedCrossRefGoogle Scholar
  18. 18.
    Gaikwad A, Verstovsek S, Yoon D, Chang KT, Manshouri T, Nussenzveig R, Cortes J, Vainchenker W, Prchal JT (2007) Imatinib effect on growth and signal transduction in polycythemia vera. Exp Hematol 35:931–938PubMedCrossRefGoogle Scholar
  19. 19.
    Silver RT, Bourla MH, Vandris K, Fruchtman S, Spivak JL, Feldman EJ, Salvado AJ (2012) Treatment of polycythemia vera with imatinib mesylate. Leuk Res 36:156–162PubMedCrossRefGoogle Scholar
  20. 20.
    Nussenzveig RH, Cortes J, Sever M, Quintás-Cardama A, Ault P, Manshouri T, Bueso-Ramos C, Prchal JT, Kantarjian H, Verstovsek S (2009) Imatinib mesylate therapy for polycythemia vera: final result of a phase II study initiated in 2001. Int J Hematol 90:58–63PubMedCrossRefGoogle Scholar
  21. 21.
    Pierre R, Imbert M, Thiele J, Vardiman JW, Brunning RD, Flandrin G (2001) Polycthaemia vera. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) World Health Organization classification of tumors. Pathology and genetics. Tumors of haematopoietic and lymphoid tissues. IARC, Lyon, pp 32–34Google Scholar
  22. 22.
    Schoch C, Schnittger S, Bursch S, Gerstner D, Hochhaus A, Berger U, Hehlmann R, Hiddemann W, Haferlach T (2002) Comparison of chromosome banding analysis, interphase- and hypermetaphase-FISH, qualitative and quantitative PCR for diagnosis and for follow-up in chronic myeloid leukemia: a study on 350 cases. Leukemia 16:53–59PubMedCrossRefGoogle Scholar
  23. 23.
    Shaffer L, Slovak M, Campbell L (2009) ISCN 2009: an international system for human cytogenetic nomenclature. Karger, BaselGoogle Scholar
  24. 24.
    Jones A, Kreil S, Zoi K, Waghorn K, Curtis C, Zhang L et al (2005) Widespread occurrence of the JAK2V617F mutation in chronic myeloproliferative disorders. Blood 106:2162–2168PubMedCrossRefGoogle Scholar
  25. 25.
    Krämer A, Reiter A, Kruth J, Erben P, Hochhaus A, Müller M et al (2007) JAK2-V617F mutation in a patient with Philadelphia-chromosome-positive chronic myeloid leukaemia. Lancet Oncol 8:658–660PubMedCrossRefGoogle Scholar
  26. 26.
    Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, Waltzman R, Stalbovskaya V et al (2012) JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366:787–798PubMedCrossRefGoogle Scholar
  27. 27.
    Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF et al (2012) A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366:799–807PubMedCrossRefGoogle Scholar
  28. 28.
    Jones CM, Dickinson TM, Salvado A (2008) Phase II open label trial of imatinib in polycythemia rubra vera. Int J Hematol 88:489–494PubMedCrossRefGoogle Scholar
  29. 29.
    Kuriakose E, Vandris K, Wang YL, Chow W, Jones AV, Christos P, Cross NC, Silver RT (2012) Decrease in JAK2 V617F allele burden is not a prerequisite to clinical response in patients with polycythemia vera. Haematologica 97:538–542PubMedCrossRefGoogle Scholar
  30. 30.
    Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Müller MC, Pletsch N et al (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642PubMedCrossRefGoogle Scholar
  31. 31.
    Najean Y, Rain JD, for the French Polycythemia Study Group (1997) Treatment of polycythemia vera: the use of hydroxyurea and pipobroman in 292 patients under the age of 65 years. Blood 90:3370–3377PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kirsten Merx
    • 1
  • Alice Fabarius
    • 1
  • Philipp Erben
    • 1
  • Martin Griesshammer
    • 2
  • Andreas Reiter
    • 1
  • Wolf-Karsten Hofmann
    • 1
  • Rüdiger Hehlmann
    • 1
  • Andreas Hochhaus
    • 3
  • Eva Lengfelder
    • 1
  1. 1.III. Medizinische Klinik, Hämatologie und OnkologieUniversitätsmedizin MannheimMannheimGermany
  2. 2.Johannes Wesling KlinikumMindenGermany
  3. 3.Abteilung Hämatologie und internistische Onkologie, Klinik für Innere Medizin IIUniversitätsklinikum JenaJenaGermany

Personalised recommendations