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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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.
KeywordsAnagrelide Essential thrombocythemia Japan
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.
Compliance with ethical standards
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.
- 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
- 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.CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle 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.
- 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.CrossRefPubMedGoogle 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.CrossRefPubMedPubMedCentralGoogle Scholar