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A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia

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Abstract

Cytoreductive therapy is used in high-risk essential thrombocythemia (ET) to reduce risk of thrombohemorrhagic complications. Anagrelide is an orally active, quinazolone-derived platelet-lowering agent approved for first-line treatment of high-risk ET in Japan. Long-term safety and efficacy data were collected from 53 Japanese high-risk ET patients (Study 308); 41 patients who completed Study 308 entered this phase 3b, open-label extension (Study 309; NCT01467661). Reductions in mean platelet counts occurred throughout the study, from 1021.6 × 109/L (at Study 308 baseline) to 675.4 × 109/L at final assessment. At month 48 (since Study 308 enrollment), mean platelet count was 444.5 × 109/L in the 10 patients who completed 4 years of therapy. Overall, platelet counts decreased from 1088.3 × 109/L at Study 308 baseline (n = 33) to 473.5 × 109/L at final assessment (n = 31). Long-term platelet count reductions were maintained without marked changes in mean anagrelide dose. Anagrelide was generally well tolerated, with anemia (54.7%) and headache (49.1%) as the most frequent adverse events. These findings indicate that anagrelide effectively reduces platelet counts in high-risk Japanese ET patients, with titration resulting in a well-tolerated, effective and sustainable dose. In conclusion, these results support anagrelide administration to high-risk Japanese ET patients using individualized dosing strategies defined in instructions previously approved in Europe and the USA.

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References

  1. Falchi L, Bose P, Newberry KJ, Verstovsek S. Approach to patients with essential thrombocythaemia and very high platelet counts: what is the evidence for treatment? Br J Haematol. 2017;176:352–64.

    Article  PubMed  Google Scholar 

  2. Rumi E, Cazzola M. How I treat essential thrombocythemia. Blood. 2016;128:2403–14.

    Article  CAS  PubMed  Google Scholar 

  3. Vainchenker W, Constantinescu SN, Plo I. Recent advances in understanding myelofibrosis and essential thrombocythemia. F1000 Res. 2016;5.

    Article  CAS  Google Scholar 

  4. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al. WHO classification of tumours of haemopoietic and lymphoid tissues. 4th ed. Lyon: LARC Press; 2008.

    Google Scholar 

  5. Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29:761–70.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Dan K, Yamada T, Kimura Y, Usui N, Okamoto S, Sugihara T, et al. Clinical features of polycythemia vera and essential thrombocythemia in Japan: retrospective analysis of a nationwide survey by the Japanese Elderly Leukemia and Lymphoma Study Group. Int J Hematol. 2006;83:443–9.

    Article  PubMed  Google Scholar 

  7. Kiladjian JJ, Chevret S, Dosquet C, Chomienne C, Rain JD. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol. 2011;2929:3907–13.

    Article  Google Scholar 

  8. Kanakura Y, Miyakawa Y, Wilde P, Smith J, Achenbach H, Okamoto S. Phase III single-arm study investigating the efficacy, safety, and tolerability of anagrelide as a second-line treatment in high-risk Japanese patients with essential thrombocythemia. Int J Hematol. 2014;100:353–60.

    Article  CAS  PubMed  Google Scholar 

  9. Gisslinger H, Gotic M, Holowiecki J, Penka M, Thiele J, Kvasnicka HM, et al. Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET Study, a randomized controlled trial. Blood. 2013;121:1720–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Harrison CN, Campbell PJ, Buck G, Wheatley K, East CL, Bareford D, et al. Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia. N Engl J Med. 2005;353:33–45.

    Article  CAS  PubMed  Google Scholar 

  11. Besses C, Kiladjian JJ, Griesshammer M, Gugliotta L, Harrison C, Coll R, et al. Cytoreductive treatment patterns for essential thrombocythemia in Europe. Analysis of 3643 patients in the EXELS study. Leuk Res. 2013;37:162–8.

    Article  PubMed  Google Scholar 

  12. Gugliotta L, Besses C, Griesshammer M, Harrison C, Kiladjian JJ, Coll R, et al. Combination therapy of hydroxycarbamide with anagrelide in patients with essential thrombocythemia in the evaluation of Xagrid(R) efficacy and long-term safety study. Haematologica. 2014;99:679–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. European Medicines Agency. Xagrid summary of product characteristics. 2016. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000480/human_med_001153.jsp&mid=WC0b01ac058001d124. Accessed 6 Oct 2017.

  14. Shimomura T, Wakabayashi I. Regional differences in prevalence of anemia found by periodic health checkups at workplaces in Japan. Sangyo Eiseigaku Zasshi. 2010;52:21–7.

    Article  PubMed  Google Scholar 

  15. Passamonti F, Rumi E, Arcaini L, Boveri E, Elena C, Pietra D, et al. Prognostic factors for thrombosis, myelofibrosis, and leukemia in essential thrombocythemia: a study of 605 patients. Haematologica. 2008;93:1645–51.

    Article  PubMed  Google Scholar 

  16. Tefferi A, Gangat N, Wolanskyj AP, Schwager S, Pardanani A, Lasho TL, et al. 20 + yr without leukemic or fibrotic transformation in essential thrombocythemia or polycythemia vera: predictors at diagnosis. Eur J Haematol. 2008;80:386–90.

    Article  PubMed  Google Scholar 

  17. Solberg LA Jr, Tefferi A, Oles KJ, Tarach JS, Petitt RM, Forstrom LA, et al. The effects of anagrelide on human megakaryocytopoiesis. Br J Haematol. 1997;99:174–80.

    Article  CAS  PubMed  Google Scholar 

  18. Mazur EM, Rosmarin AG, Sohl PA, Newton JL, Narendran A. Analysis of the mechanism of anagrelide-induced thrombocytopenia in humans. Blood. 1992;79:1931–7.

    CAS  PubMed  Google Scholar 

  19. Espasandin YR, Glembotsky AC, Grodzielski M, Lev PR, Goette NP, Molinas FC, et al. Anagrelide platelet-lowering effect is due to inhibition of both megakaryocyte maturation and proplatelet formation: insight into potential mechanisms. J Thromb Haemost. 2015;13:631–42.

    Article  CAS  PubMed  Google Scholar 

  20. Hong Y, Wang G, Del Arroyo AG, Hernandez J, Skene C, Erusalimsky JD. Comparison between anagrelide and hydroxycarbamide in their activities against haematopoietic progenitor cell growth and differentiation: selectivity of anagrelide for the megakaryocytic lineage. Leukemia. 2006;20:1117–22.

    Article  CAS  PubMed  Google Scholar 

  21. Tomer A. Effects of anagrelide on in vivo megakaryocyte proliferation and maturation in essential thrombocythemia. Blood. 2002;99:1602–9.

    Article  CAS  PubMed  Google Scholar 

  22. Birgegård G, Besses C, Griesshammer M, Gugliotta L, Harrison CN, Hamdani M, et al. Treatment of essential thrombocythemia in Europe: a prospective long-term observational study of 3649 high-risk patients in the Evaluation of Anagrelide Efficacy and Long-term Safety study. Haematologica. 2018;103:51–60.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Frewin R, Dowson A. Headache in essential thrombocythaemia. Int J Clin Pract. 2012;66:976–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank the patients and acknowledge the contribution of all investigators who participated in this study. The study was sponsored by Shire Pharmaceutical Development Ltd, Basingstoke, UK. Under the direction of the authors, Peter Birch and Rachel Brown of ACUMED, an Ashfield business, part of UDG Healthcare plc, provided writing and editorial assistance funded by Shire. All authors reviewed the manuscript drafts and approved the submission for publication.

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Authors and Affiliations

  1. Graduate School of Medicine, Osaka University, Osaka University Hospital, C9, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yuzuru Kanakura

  2. Tokai University School of Medicine, Isehara, Japan

    Yukari Shirasugi

  3. Department of Hematology, Nippon Medical School, Tokyo, Japan

    Hiroki Yamaguchi

  4. Juntendo University Shizuoka Hospital, Shizuoka, Japan

    Michiaki Koike

  5. Niigata Cancer Center Hospital, Niigata, Japan

    Takaaki Chou

  6. Keio University Hospital, Tokyo, Japan

    Shinichiro Okamoto

  7. Research & Development, Shire GmbH, Zug, Switzerland

    Heinrich Achenbach

  8. Global Biometrics, Shire Pharmaceuticals, Lexington, MA, USA

    Jingyang Wu

  9. Chiba University Hospital, Chiba, Japan

    Chiaki Nakaseko

  10. International University of Health and Welfare School of Medicine, Narita, Japan

    Chiaki Nakaseko

Authors
  1. Yuzuru Kanakura
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  2. Yukari Shirasugi
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  3. Hiroki Yamaguchi
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  4. Michiaki Koike
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  5. Takaaki Chou
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  6. Shinichiro Okamoto
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  7. Heinrich Achenbach
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  8. Jingyang Wu
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  9. Chiaki Nakaseko
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Corresponding author

Correspondence to Yuzuru Kanakura.

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Conflict of interest

Yuzuru Kanakura: grants from Kyowa Hakko Kirin, Shionogi, Chugai Pharmaceutical, Pfizer, Eisai, Astellas, Nippon Shinyaku, Alexionpharma, Bristol-Myers Squibb, Toyama Chemical, and Fujimotoseiyaku. Yukari Shirasugi: honoraria from Novartis. Hiroki Yamaguchi: none. Michiaki Koike: none. Takaaki Chou: honoraria from Celgene, Novartis, Takeda, Bristol-Myers Squibb. Shinichiro Okamoto: none. Henri Achenbach: employed by Shire, stock or other interests in Shire. Jingyang Wu: employed by Shire, stock or other interests in Shire. Chiaki Nakaseko: none.

Additional information

Study carried out at: Department of Hematology and Oncology, Osaka University Graduate School of Medicine, C9, 2-2, Yamada-oka, Suita, Osaka 565-0871, Japan.

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Kanakura, Y., Shirasugi, Y., Yamaguchi, H. et al. A phase 3b, multicenter, open-label extension study of the long-term safety of anagrelide in Japanese adults with essential thrombocythemia. Int J Hematol 108, 491–498 (2018). https://doi.org/10.1007/s12185-018-2510-7

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  • DOI: https://doi.org/10.1007/s12185-018-2510-7

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