Efficacy and safety of tyrosine kinase inhibitors for newly diagnosed chronic-phase chronic myeloid leukemia over a 5-year period: results from the Japanese registry obtained by the New TARGET system

Abstract

We report the results of a multicenter observational study using the New TARGET system, in which the effectiveness and safety of tyrosine kinase inhibitors (TKIs) were evaluated in newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients. A total of 506 patients were enrolled between April 2010 and March 2013. Median age was 56 (range 18–92) years; 35% of patients were females. As the first-line therapy, 139 (27.9%), 169 (33.9%) and 144 (28.9%) patients were treated with imatinib, nilotinib, and dasatinib, respectively. Five-year progression-free survival (PFS) and overall survival (OS) were 93.8% and 94.5%, respectively. The OS curve was significantly superior for patients treated with second-generation TKIs than imatinib (P = 0.0068), and an early molecular response (EMR) at 3 months (BCR-ABL1 < 10%) was detected in 328 of 377 patients evaluated for molecular response. The PFS curve was significantly superior for patients with EMR than without (P < 0.0001). Although 12 patients experienced vascular adverse events, no new safety issues were observed in patients with adverse events. The results of this observational study demonstrated that treating newly diagnosed CML-CP patients with TKI results in satisfactory and reliable outcomes.

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References

  1. 1.

    Kizaki M, Okamoto S, Tauchi T, Tanaka H, Tanimoto M, Inokuchi K, et al. Current and future perspectives on the TARGET system: the registration system for Glivec® established by the JSH. Int J Hematol. 2008;88:409–17.

    Article  PubMed  Google Scholar 

  2. 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;35:585–90.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–9.

    Article  CAS  PubMed  Google Scholar 

  5. 5.

    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;362:2260–70.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Nakamae H, Fukuda T, Nakaseko C, Kanda Y, Ohmine K, Ono T, et al. Nilotinib vs. imatinib in Japanese patients with newly diagnosed chronic myeloid leukemia in chronic phase: long-term follow-up of the Japanese subgroup of the randomized ENESTnd trial. Int J Hematol. 2018;107:327–36.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Nakamae H, Fujisawa S, Ogura M, Uchida T, Onishi Y, Taniwaki M, et al. Dasatinib versus imatinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia: a subanalysis of the DASISION 5-year final report. Int J Hematol. 2017;105:792–804.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Valent P, Hadzijusufovic E, Schernthaner GH, Wolf D, Rea D, le Coutre P. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood. 2015;125:901–6.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogné JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol. 2016;2:625–632

    Article  PubMed  Google Scholar 

  12. 12.

    Fujioka I, Takaku T, Iriyama N, Tokuhira M, Kimura Y, Sato E, et al. Features of vascular adverse events in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a retrospective study of the CML Cooperative Study Group database. Ann Hematol. 2018;97:2081–8.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarijan H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Hanfstein B, Müller MC, Hehlmann R, Erben P, Lauseker M, Fabarius A, et al. Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML). Leukemia. 2012;26:2096–102.

    Article  CAS  Google Scholar 

  15. 15.

    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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Jain P, Kantarjian H, Nazha A, O’Brien S, Jabbour E, Romo CG, et al. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood. 2013;121:4867–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    NCCN. Chronic myeloid leukemia. NCCN clinical practice guidelines in oncology; Version 1:16. 2019

  18. 18.

    Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen JJWM, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv41–51.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128:17–23.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk Lymphoma. 2016;57:1300–10.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by research funding from Novartis Pharmaceuticals and Bristol-Myers Squibb to JSH. The authors would like to thank all study participants and their families, and the study investigators at participating study sites. We also thank the New TARGET data center (EPS. Co.) for managing and monitoring the study. The following investigators and institutes participated in this study [Descending order of registered patient number (ITT)]: M. Kizaki, S. Mori, T. Nemoto, M. Sagawa, T. Tabayashi, M. Tokuhira, T. Tomikawa, R. Watanabe [Saitama Medical University Saitama Medical Center]; Y. Hatta, Y. Inoue, N. Iriyama, S. Kobayashi, Y. Kobayashi, D. Kurita [Nihon University Itabashi Hospital]; D. Karigane, H. Kasahara, Y. Koda, Y. Miyakawa, K. Murakami, S. Okamoto, S. Watanuki [Keio University Hospital]; T. Ono, Y. Nagata, A. Takeshita [Hamamatsu University Hospital]; N. Takahashi, Y. Kameoka, T. Yoshioka, S. Takahashi [Akita University Hospital]; N. Usui [The Jikei University Hospital]; K. Dan, K. Inokuchi, K. Nakamura [Nippon Medical School Hospital]; D. Abe, C. Nakaseko, C. Ohwada, E. Sakaida, N. Shimizu, M. Takeuchi [Chiba University Hospital]; S. Arai, Y. Kogure, A. Koya, Y. Masamoto, A. Masuda, K. Nakazaki, K. Toyama [Tokyo University Hospital]; Y. Hiroshima, N. Ichikawa, T. Kirihara, H. Kobayashi, I. Shimizu, M. Sumi, T. Ueki [Nagano Red Cross Hospital]; S. Hagiwara, R. Hirai, T. Miwa, F. Nakamura, M. Nakamura, M. Takeshita, A. Tanimura [Center Hospital of National Center for Global Health and Medicine]; F. Hayakawa, Y. Ishikawa, H. Kiyoi, M. Murata, A. Tomita [Nagoya University Hospital]; T. Kurokawa, C. Sugimori [Toyama Red Cross Hospital]; A. Arai, O. Miura, M. Yamamoto [Tokyo Medical And Dental University, Medical Hospital]; K. Imai, N. Kobayashi, K. Minauchi, M. Obara, S. Ota [Sapporo Hokuyu Hospital]; T. Ikezoe, M. Mori, M. Sakai, A. Taniguchi, K. Togitani [Kochi Medical School Hospital]; H. Hayakawa, T. Kajiguchi, S. Kamoshita [Tosei General Hospital]; E. Otsuka, A. Nishida, M. Saburi, Y. Saburi [Oita Prefectural Hospital]; H. Iida, C. Kato, Y. Kojima, H. Ohashi, Y. Miyata, K. Sugimoto, H. Yamamoto, T. Yokozawa [National Hospital Organization Nagoya Medical Center]; T. Kamae, J. Kuyama, H. Mitsui, Y. Morikawa, Y. Uchida [Otemae Hospital]; T. Ashida, C. Hirase, K. Kawanishi, I. Matsumura, J. Miyatake, Y. Morita, T. Sano, T. Shimada, H. Tanaka, Y. Taniguchi, Y. Tatsumi, K. Yamaguchi [Kindai University Hospital]; F. Ishida, K. Momose, H. Nakazawa, S. Nishina, H. Sakai, N. Sekiguchi, [Shinshu University Hospital]; Y. Ito, K. Ohyashiki, T. Tauchi [Tokyo Medical University Hospital]; T. Hata, Y. Imaizumi, D. Imanishi, H. Itonaga, J. Makiyama, Y. Sawayama, J. Taguchi, M. Taguchi, H. Taniguchi [Nagasaki University Hospital]; G. Eguchi, M. Matsuda, N. Yamairi [PL General Hospital]; N. Fukushima, K. Ozeki, A. Kohno [Konan Kosei Hospital]; T. Sakura, S. Takada [Gunma Saiseikai Maebashi Hospital]; T. Kobayashi, H. Sakamaki [Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital]; N. Asou, T. Kawaguchi [Kumamoto University Hospital]; T. Kiguchi, T. Masunari, N. Sezaki [Chugoku Central Hospital]; M. Iino [Yamanashi Prefectural Central Hospital]; K. Morinaga [Fukui Prefectural Hospital]; K. Ikeda, K. Ogawa, H. Noji [Fukushima Medical University Hospital]; H. Iwasaki, K. Takenaka, T. Miyamoto [Kyushu University Hospital]; H. Handa, H. Murakami, N. Tsukamoto [Gunma University Hospital]; T. Eto, H. Henzan [Hamanomachi Hospital]; Y. Kamitsuji, N. Uoshima [Matsushita Memorial Hospital]; M. Hagihara, H. Takahashi [Yokohama City University Hospital]; N. Emi, M. Okamoto [Fujita Health University Hospital]; K. Kawakami, M. Waki [Kagawa Prefectural Central Hospital]; N. Fukuhara, H. Harigae [Tohoku University Hospital]; T. Murayama, I. Mizuno [Hyogo Cancer Center]; H. Okumura [Toyama Prefectural Central Hospital]; Y. Tsutsumi [Hakodate Municipal Hospital]; K. Usuki [NTT Medical Center Tokyo]; T. Fujisaki [Matsuyama Red Cross Hospital]; Y. Maeda [Okayama University Hospital]; Y. Suehiro [National Hospital Organization Kyushu Cancer Center]; H. Suzushima [Kumamoto Shinto General Hospital]; K. Yamamoto [Yokohama City Minato Red Cross Hospital]; Y. Kanakura [Osaka University Hospital]; K. Nagasaki [Kurume University Hospital]; H. Muto [Tokyo Metropolitan Otsuka Hospital]; S. Fujisawa [Yokohama City University Medical Center]; M. Adachi [Sapporo Hokushin Hospital]; A. Mugitani [Fuchu Hospital]; S. Yamasaki [National Hospital Organization Kyushu Medical Center]; Y. Adachi [JCHO Kobe Central Hospital]; T. Kamimura [Harasanshin Hospital]; Y. Takamatsu [Fukuoka University Hospital]; T. Ryu [JCHO Tokyo Yamate Medical Center]; S. Chiba [Tsukuba University Hospital]; K. Ohishi [Mie University Hospital]; K. Suzuki [Japanese Red Cross Medical Center]; D. Ogawa [Nagasaki Prefecture Shimabara Hospital]; H. Mihara [Aichi Medical University Hospital]; Y. Kobayashi [Japanese Red Cross Kyoto Daini Hospital]; H. Fujita [Saiseikai Yokohamashi Nanbu Hospital]; K. Kubo [Aomori Prefectural Central Hospital]; A. Yokota [Chiba Aoba Municipal Hospital]; K. Miyamura [Japanese Red Cross Nagoya Daiichi Hospital]; C. Yoshida [National Hospital Organization Mito Medical Center]; S. Nakachi [Ryukyu University Hospital]; T. Myojyo [Edogawa Hospital]; A. Kitabayashi [Akita Kousei Medical Center]; J. Suzumiya [Shimane University Hospital]; M. Hino [Osaka City University Hospital]; A. Wakita [Nagoya City East Medical Center]; T. Shibata [Murakami Karindoh Hospital]; T. Takahashi [Tenshi Hospital]; H. Takamatsu [Keiju Medical Center]; K. Fujimaki [Fujisawa City Hospital]; K. Tajika [Yokohama Minami Kyousai Hospital]; M. Mita [Shirakawa Kosei General Hospital]; Y. Terui [The Cancer Institute Hospital of JFCR]; M. Ito [Kyoto City Hospital]; T. Yamane [Osaka City General Hospital]; K. Yamamoto [Aichi Cancer Center Hospital]; T. Yamauchi [Fukui University Hospital]; Y. Kohara [Showa Inan General Hospital]; C. Takebayashi [JR Tokyo General Hospital]; A. Inagaki [Nagoya City West Medical Center]; M. Tsuji [Japanese Red Cross Otsu Hospital]; H. Shinzaki [Sunagawa City Medical Center]; Y. Moriuchi [Sasebo City General Hospital]; M. Ishikawa [Saitama Medical University International Medical Center; K. Miyazaki [Kitasato University Hospital]; E. Shima [Hokusetsu General Hospital]; N. Kinugawa [Shonan Kamakura General Hospital].

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Correspondence to Naoto Takahashi.

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M. Kizaki reports personal fees from Bristol-Myers Squibb, Celgene, Nippon Shinyaku, Takeda Pharmaceutical, and Ono Pharmaceutical, and grants from Kyowa Hakko Kirin, Chugai Pharmaceutical, and Pfizer, outside the submitted work; N. Takahashi reports grants and personal fees from Novartis Pharmaceuticals, Pfizer, and Otsuka Pharmaceutical, personal fees from Bristol-Myers Squibb, and grants from Kyowa Hakko Kirin, Astellas Pharma, Chugai Pharmaceutical, Asahi Kasei Pharma, Ono Pharmaceutical, and Eisai Pharmaceuticals, outside the submitted work; S. Okamoto reports grants and personal fees from Otsuka Pharmaceutical, Novartis Pharmaceuticals, Bristol-Meyer Squib, Astellas Pharma, Kyowa Hakko Kirin, and Chugai Pharmaceutical, and personal fees from Pfizer, outside the submitted work; T. Ono reports grants from Celgene, Kyowa Hakko Kirin, Chugai Pharmaceutical, and Merck Sharp & Dohme, and personal fees from Novartis Pharmaceuticals, Bristol-Myers Squibb, Pfizer, and Otsuka Pharmaceutical, outside the submitted work; N. Usui reports personal fees from AbbVie Inc., Astellas Pharma, Bristol-Myers Squibb, Celgene, Chugai Pharmaceutical, CIMIC, Huya Bioscience International, Kyowa Hakko Kirin, Nippon Shinyaku Pharmaceutical, Daiichi Sankyo, Otsuka Pharmaceutical, Pfizer, SymBio Pharmaceuticals, Sysmex, Takeda Pharmaceutical, Takara Bio Inc., Sumitomo Dainippon Pharma, Zenyaku Kogyo, Alexion Pharmaceuticals, Taisho Toyama Pharmaceutical, Mochida Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, and Meiji Seika Pharma, outside the submitted work; K. Inokuchi reports grants and personal fees from Bristol-Myers Squibb, personal fees from Novartis Pharmaceuticals, Celgene, and Pfizer, outside the submitted work; C. Nakaseko reports grants and personal fees from Pfizer, grants from Kyowa Hakko Kirin, Daiichi Sankyo, Astellas Pharma, Ono Pharmaceutical, Takeda Pharmaceutical, and Chugai Pharmaceutical, personal fees from Novartis Pharmaceuticals, and Celgene, outside the submitted work; M. Kurokawa reports grants from Novartis Pharmaceuticals, Bristol-Meyer Squib, Astellas Pharma, Kyowa Hakko Kirin, Pfizer, Takeda Pharmaceutical, Ono Pharmaceutical, and Nippon Shinyaku Pharmaceutical, and personal fees from Celgene, and Shionogi, outside the submitted work; T. Kawaguchi reports grants and personal fees from MSD, and personal fees from Pfizer, Alexion Pharma, and Novartis Pharmaceuticals, outside the submitted work; R. Suzuki reports personal fees from Bristol-Meyer Squib, Novartis Pharmaceuticals, Kyowa-Hakko Kirin, Chugai Pharmaceutical, Shionogi, Takeda Pharmaceutical, Meiji Seika Pharma, MSD, Otsuka Pharmaceutical, Sawai, Celgene, Sumitomo Dainippon Pharma, Eisai Pharmaceuticals, Alexion Pharma, Sanofi, Gilead Sciences, Abbvie Inc., Mundi Pharma, Jazz Pharma, Ono Pharmaceutical, and Janssen Pharmaceuticals, outside the submitted work; K. Yamamoto reports grants and personal fees from Astra-Zeneca, Celgene, Chugai Pharmaceutical, Eisai Pharmaceuticals, MSD, Novartis Pharmaceuticals, Ono Pharmaceutical, Takeda Pharmaceutical, and Zenyaku, and grants from AbbVie Inc., ARIAD, Bayer, Gilead Sciences, Solasia Pharma, and SymBio, and personal fees from Bristol-Myers Squibb, Kyowa Hakko Kirin, Meiji Seika Pharma, Mochida, Mundipharma, Otsuka Pharmaceutical, Pfizer, Sumitomo Dainippon Pharma, and Boehringer Ingelheim, outside the submitted work; I. Matsumura reports grants and personal fees from Bristol-Myers Squibb, Novartis Pharmaceuticals, during the conduct of the study, grants and personal fees from Nippon Shinyaku Pharmaceutical, Celgene, Pfizer, Otsuka Pharmaceutical, Kyowa Hakko Kirin, Ono Pharmaceutical, Sumitomo Dainippon Pharma, Shionogi, and Teijin Pharma, personal fees from Janssen Pharmaceutical, Boehringer Ingelheim, Sanofi, grants from Chugai Pharmaceutical, Eisai Pharmaceuticals, MSD, Asahi Kasei Pharma, Astellas Pharma, Takeda Pharmaceutical, Japan Blood Products Organization, Nihon Pharmaceutical, and Daiichi Sankyo, outside the submitted work; the other authors have nothing to disclose.

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Masahiro Kizaki, Naoto Takahashi, Tatsuya Kawaguchi, Ritsuro Suzuki, Kazuhito Yamamoto, Kazunori Ohnishi, Itaru Matsumura, Tomoki Naoe: Committee of the New Target System in Japanese Society of Hematology.

A list of investigators and institutes participated in this study are given in Acknowledgements.

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Kizaki, M., Takahashi, N., Iriyama, N. et al. Efficacy and safety of tyrosine kinase inhibitors for newly diagnosed chronic-phase chronic myeloid leukemia over a 5-year period: results from the Japanese registry obtained by the New TARGET system. Int J Hematol 109, 426–439 (2019). https://doi.org/10.1007/s12185-019-02613-1

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Keywords

  • BCR-ABL1
  • Tyrosine kinase inhibitor (TKI)
  • Chronic myeloid leukemia (CML)
  • Early molecular response (EMR)
  • Overall survival (OS)