Objective: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. Methods: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. Results: Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (≤10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. Conclusion: These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy.

Keywords:
Dasatinib, Newly diagnosed chronic myeloid leukemia, Molecular response, Halving time, Lymphocytosis
1.
Kantarjian H, O'Brien S, Jabbour E, Shan J, Ravandi F, Kadia T, et al: Impact of treatment end point definitions on perceived differences in long-term outcome with tyrosine kinase inhibitor therapy in chronic myeloid leukemia. J Clin Oncol 2011;29:3173-3178.
2.
Tauchi T, Kizaki M, Okamoto S, Tanaka H, Tanimoto M, Inokuchi K, et al: Seven-year follow-up of patients receiving imatinib for the treatment of newly diagnosed chronic myelogenous leukemia by the TARGET system. Leuk Res 2011;35:585-590.
3.
de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, Bua M, et al: Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 2008;26:3358-3363.
4.
Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boqué C, et al: Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood 2014;123:494-500.
5.
Hughes TP, Saglio G, Kantarjian HM, Guilhot F, Niederwieser D, Rosti G, et al: Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood 2014;123:1353-1360.
6.
Hanfstein B, Shlyakhto V, Lauseker M, Hehlmann R, Saussele S, Dietz C, et al: Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib. Leukemia 2014;28:1988-1992.
7.
Branford S, Yeung DT, Parker WT, Roberts ND, Purins L, Braley JA, et al: Prognosis for patients with CML and >10% BCR-ABL1 after 3 months of imatinib depends on the rate of BCR-ABL1 decline. Blood 2014;124:511-518.
8.
Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al: Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol 2014;32:424-430.
9.
Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, et al: Long-term follow-up of the French Stop Imatinib (STIM1) Study in patients with chronic myeloid leukemia. J Clin Oncol 2017;35:298-305.
10.
Fujisawa S, Nakamae H, Ogura M, Ishizawa K, Taniwaki M, Utsunomiya A, et al: Efficacy and safety of dasatinib versus imatinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP): subset analysis of the DASISION trial with 2-year follow-up. Int J Hematol 2014;99:141-153.
11.
Schiffer CA, Cortes JE, Hochhaus A, Saglio G, le Coutre P, Porkka K, et al: Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia: effects on response and toxicity. Cancer 2016;122:1398-1407.
12.
Iriyama N, Hatta Y, Kobayashi S, Uchino Y, Miura K, Kurita D, et al: The European Treatment and Outcome Study score is associated with clinical outcomes and treatment response following European LeukemiaNet 2013 recommendations in chronic-phase chronic myeloid leukemia. Int J Hematol 2014;100:379-385.
13.
Iriyama N, Fujisawa S, Yoshida C, Wakita H, Chiba S, Okamoto S, et al: Shorter halving time of BCR-ABL1 transcripts is a novel predictor for achievement of molecular responses in newly diagnosed chronic-phase chronic myeloid leukemia treated with dasatinib: results of the D-first study of Kanto CML study group. Am J Hematol 2015;90:282-287.
14.
Yoshida C, Fletcher L, Ohashi K, Wakita H, Kumagai T, Shiseki M, et al: Harmonization of molecular monitoring of chronic myeloid leukemia therapy in Japan. Int J Clin Oncol 2012;17:584-589.
15.
Lee SJ, Jung CW, Kim DY, Lee KH, Sohn SK, Kwak JY, et al: Retrospective multicenter study on the development of peripheral lymphocytosis following second-line dasatinib therapy for chronic myeloid leukemia. Am J Hematol 2011;86:346-350.
16.
Kanda Y: Investigation of the freely available easy-to-use software “EZR” for medical statistics. Bone Marrow Transplant 2013;48:452-458.
17.
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872-884.
18.
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al: Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362:2260-2270.
19.
Hagihara M, Iriyama N, Yoshida C, Wakita H, Chiba S, Okamoto S, et al: Association of pleural effusion with an early molecular response in patients with newly diagnosed chronic-phase chronic myeloid leukemia receiving dasatinib: results of a D-First study. Oncol Rep 2016;36:2976-2982.
20.
Mustjoki S, Ekblom M, Arstila TP, Dybedal I, Epling-Burnette PK, Guilhot F, et al: Clonal expansion of T/NK-cells during tyrosine kinase inhibitor dasatinib therapy. Leukemia 2009;23:1398-1405.
21.
Kim DH, Kamel-Reid S, Chang H, Sutherland R, Jung CW, Kim H-J, et al: Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica 2009;94:135-139.
22.
Kumagai T, Matsuki E, Inokuchi K, Ohashi K, Shinagawa A, Takeuchi J, et al: Relative increase in lymphocytes from as early as 1 month predicts improved response to dasatinib in chronic-phase chronic myelogenous leukemia. Int J Hematol 2014;99:41-52.
23.
Iriyama N, Fujisawa S, Yoshida C, Wakita H, Chiba S, Okamoto S, et al: Early cytotoxic lymphocyte expansion contributes to a deep molecular response to dasatinib in patients with newly diagnosed chronic myeloid leukemia in the chronic phase: results of the D-first study. Am J Hematol 2015;90:819-824.
© 2017 S. Karger AG, Basel
2017
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.