International Journal of Hematology

, Volume 107, Issue 2, pp 185–193 | Cite as

Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study

  • Naoto Takahashi
  • Tetsuzo Tauchi
  • Kunio Kitamura
  • Koichi Miyamura
  • Yoshio Saburi
  • Yoshihiro Hatta
  • Yasuhiko Miyata
  • Shinichi Kobayashi
  • Kensuke Usuki
  • Itaru Matsumura
  • Yosuke Minami
  • Noriko Usui
  • Tetsuya Fukuda
  • Satoru Takada
  • Maho Ishikawa
  • Katsumichi Fujimaki
  • Hiroshi Gomyo
  • Osamu Sasaki
  • Kohshi Ohishi
  • Takaaki Miyake
  • Kiyotoshi Imai
  • Hitoshi Suzushima
  • Hideki Mitsui
  • Kazuto Togitani
  • Toru Kiguchi
  • Yoshiko Atsuta
  • Shigeki Ohtake
  • Kazunori Ohnishi
  • Yukio Kobayashi
  • Hitoshi Kiyoi
  • Yasushi Miyazaki
  • Tomoki Naoe
  • The Japan Adult Leukemia Study Group
Original Article
  • 800 Downloads

Abstract

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan–Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

Keywords

Imatinib BCR-ABL1 Treatment-free remission Undetectable molecular residual disease Deep molecular response 

Notes

Acknowledgements

The authors would like to thank the investigators and clinical research coordinators of the sites in the JALSG study group and all of the patients who participated in this study. The Ipsogen BCR-ABL1M-BCR IS-PCR kits was provided by Sysmex Co., Ltd., and IS-PCR analysis was performed at the central laboratory of Sysmex Co., Ltd. We thank Ms. Mika Yoshimura and Mr. Yoshiro Ikeuchi at Sysmex Co., Ltd. for their collaboration. We also thank Ms. Saori Takahashi at Akita University for collecting the data and conducting central monitoring of this study. This study was supported by the Practical Research for Innovative Cancer Control program of the Japan Agency for Medical Research and Development (AMED 15ck0106189h0001, 16ck0106189h0002, 17ck0106189h0003).

Compliance with ethical standards

Conflict of interest

Naoto Takahashi reports grants from Japan Agency for Medical Research and Development, non-financial support from Sysmex Co., Ltd., personal fees from NPO JALSG, during the conduct of the study; grants and personal fees from Novartis Pharma K.K., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants and personal fees from Pfizer Japan Inc., personal fees from Bristol-Myers Squibb K. K., outside the submitted work. Tetsuzo Tauchi reports grants and other from Novartis Pharma K.K., grants and other from Pfizer Japan Inc., other from Bristol-Myers Squibb K. K., other from Otsuka Pharmaceutical Co., Ltd., during the conduct of the study. Koichi Miyamura reports personal fees from Novartis Pharma K.K., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Bristol-Myers Squibb K. K., personal fees from Pfizer Japan Inc., outside the submitted work. Kensuke Usuki reports personal fees from Novartis Pharma K.K., grants from Fujimoto Pharmaceutical, grants from Otsuka Pharmaceutical Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Kyowa Hakko Kirin Co., Ltd., grants from Daiichi Sankyo Co., Ltd., outside the submitted work. Itaru Matsumura reports personal fees from Novartis Pharma K.K., personal fees from Bristol-Myers Squibb K. K., personal fees from Pfizer Japan Inc., personal fees from Otsuka Pharmaceutical Co., Ltd., during the conduct of the study. Yosuke Minami reports grants from Kyowa Hakko Kirin Co., Ltd., grants from Novartis Pharma K.K., grants from Bristol-Myers Squibb K. K., outside the submitted work. Noriko Usui reports personal fees from CIMIC Co., Ltd., personal fees from Takeda Bio Development Center, personal fees from Lilly Japan, personal fees from Pfizer Japan Inc., grants from Pfizer Japan Inc., personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants from Sysmex Co., Ltd., personal fees from Jansen Pharm Co, Ltd., personal fees from Zenyaku Kogyo Co, Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., grants from Kyowa Hakko Kirin Co., Ltd., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Celgene K. K., personal fees from SymBio Pharm Co, Ltd., personal fees from Huya Bioscience International, personal fees from Astellas Pharma Inc., personal fees from Chugai Pharmaceutical Co. Ltd., grants from Bristol-Myers Squibb K. K., personal fees from Bristol-Myers Squibb K. K., grants from Novartis Pharma K.K., grants from Nippon Shinyaku Co. Ltd., grants from Fujimoto Pharmaceutical, grants from Celgene K. K., outside the submitted work. Tetsuya Fukuda reports personal fees from Novartis Pharma K.K., outside the submitted work. Yoshiko Atsuta reports personal fees and other from Otsuka Pharmaceutical Co., Ltd., personal fees and other from Bristol-Myers Squibb K. K., personal fees from Mochida Pharmaceutical Co., Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., outside the submitted work. Yukio Kobayashi reports personal fees from Pfizer Japan Inc., personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Daiichi Sankyo Co., Ltd., personal fees from CIMIC Co., Ltd., outside the submitted work. Hitoshi Kiyoi reports grants from Japan Agency for Medical Research and Development, during the conduct of the study; grants from Chugai Pharmaceutical Co. Ltd., grants and personal fees from Bristol-Myers Squibb K. K., grants from Kyowa Hakko Kirin Co. Ltd., grants from FUJIFILM Corporation, grants from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from Astellas Pharma Inc., grants from Celgene K. K., personal fees from Daiichi Sankyo Co. Ltd., grants and personal fees from Pfizer Japan Inc., grants from Nippon Shinyaku Co. Ltd., grants from Eisai Co. Ltd., grants from Takeda Pharmaceutical Co. Ltd., grants from Ono Pharmaceutical Co. Ltd., grants from Japan Blood Products Organization, outside the submitted work. Yasushi Miyazaki reports personal fees from Sumitomo Dainippon Pharma Co., Ltd., grants and personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from Novartis Pharma K.K., personal fees from Celgene K. K., personal fees from Shinbio, grants from Chugai Pharmaceutical Co. Ltd., grants from Takeda Pharmaceutical Co. Ltd., outside the submitted work. Tomoki Naoe reports grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Fujifilm Corporation, grants from Astellas Pharma Inc., personal fees from Nippon Boehringer Ingelheim Co., Ltd., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., grants from Toyoma Chemical Co., Ltd., outside the submitted work; In addition, TN has a patent Fujifilm Corporation pending. The other authors declare that they have no conflict of interest.

Supplementary material

12185_2017_2334_MOESM1_ESM.docx (25 kb)
Supplementary material 1 (DOCX 24 kb)

References

  1. 1.
    Garcia-Manero G, Faderl S, O’Brien S, Cortes J, Talpaz M, Kantarjian HM. Chronic myelogenous leukemia: a review and update of therapeutic strategies. Cancer. 2003;98(3):437–57.CrossRefPubMedGoogle Scholar
  2. 2.
    Jemal A, Tiwari RC, Murray T, Ghafoor A, Samuels A, Ward E, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54(1):8–29.CrossRefPubMedGoogle Scholar
  3. 3.
    Redaelli A, Bell C, Casagrande J, Stephens J, Botteman M, Laskin B, et al. Clinical and epidemiologic burden of chronic myelogenous leukemia. Expert Rev Anticancer Ther. 2004;4(1):85–96.CrossRefPubMedGoogle Scholar
  4. 4.
    Cortes JE, Talpaz M, Kantarjian H. Chronic myelogenous leukemia: a review. Am J Med. 1996;100(5):555–70.CrossRefPubMedGoogle Scholar
  5. 5.
    Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131(3):207–19.CrossRefPubMedGoogle Scholar
  6. 6.
    O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994–1004.CrossRefPubMedGoogle Scholar
  7. 7.
    Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.CrossRefPubMedGoogle Scholar
  8. 8.
    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(10):917–27.CrossRefPubMedGoogle Scholar
  9. 9.
    Kizaki M, Okamoto S, Tauchi T, et al. Current and future perspectives on the TARGET system: the registration system for Glivec established by the JSH. Int J Hematol. 2008;88(4):409–17.CrossRefPubMedGoogle Scholar
  10. 10.
    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(5):585–90.CrossRefPubMedGoogle Scholar
  11. 11.
    JSH. Clinical practice guidelines in hematology malignancy. In: Usui N, Kizaki M, Shimoda K, Takahashi N, editors. CML/MPN. Tokyo: Kanehara Shuppan, Co. Ltd.; 2013.Google Scholar
  12. 12.
    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(6):872–84.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319–25.CrossRefPubMedGoogle Scholar
  14. 14.
    Corbin AS, Agarwal A, Loriaux M, Cortes J, Deininger MW, Druker BJ. Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity. J Clin Investig. 2011;121(1):396–409.CrossRefPubMedGoogle Scholar
  15. 15.
    Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119(6):1501–10.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Barrett AJ, Ito S. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century. Blood. 2015;125(21):3230–5.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Gratwohl A, Brand R, Apperley J, Crawley C, Ruutu T, Corradini P, et al. Allogeneic hematopoietic stem cell transplantation for chronic myeloid leukemia in Europe 2006: transplant activity, long-term data and current results. An analysis by the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2006;91(4):513–21.PubMedGoogle Scholar
  18. 18.
    Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre stop imatinib (STIM) trial. Lancet Oncol. 2010;11(11):1029–35.CrossRefPubMedGoogle Scholar
  19. 19.
    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(3):298–305.CrossRefPubMedGoogle Scholar
  20. 20.
    Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–22.CrossRefPubMedGoogle Scholar
  21. 21.
    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(5):424–30.CrossRefPubMedGoogle Scholar
  22. 22.
    Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2(12):e528–35.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee SE, Choi SY, Song HY, Kim SH, Choi MY, Park JS, et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016;101(6):717–23.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Rea D, Nicolini FE, Tulliez M, Guilhot F, Guilhot J, Guerci-Bresler A, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846–54.CrossRefPubMedGoogle Scholar
  25. 25.
    Rea D, Cayuela JM. Treatment-free remission in patients with chronic myeloid leukemia. Int J Hematol. 2017;. doi: 10.1007/s12185-017-2295-0.PubMedGoogle Scholar
  26. 26.
    Matsuki E, Ono Y, Sakurai M, Kunimoto H, Ishizawa J, Shimizu T, et al. Discontinuation of imatinib in patients with CML and sustained complete molecular response (CMR) for over 2 years in the Japanese population—an interim analysis of KEIO STIM study. Blood. 2011;118(21):1608.Google Scholar
  27. 27.
    Takahashi N, Kyo T, Maeda Y, Sugihara T, Usuki K, Kawaguchi T, et al. Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia. Haematologica. 2012;97(6):903–6.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mita A, Miyamura K, Hino M, Watakabe K, Takahashi K, Yoshimoto M, et al. Evaluating sensitivity of Ipsogen BCR-ABL1 Mbcr IS-MMR DX Kit for scoring molecular response. J Blood Disord Transfus. 2015;6(5):314.Google Scholar
  29. 29.
    Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48(3):452–8.CrossRefPubMedGoogle Scholar
  30. 30.
    NCCN. NCCN clinical practice guidelines in oncology. Chronic myeloid leukemia; Version 2. 2017;MS18−19.Google Scholar
  31. 31.
    Mahon F, Richter J, Guilhot J, Hjorth-Hansen H, Almeida A, Janssen JWM, et al. Cessation of tyrosine kinase inhibitors treatment in chronic myeloid leukemia patients with deep molecular response: results of the Euro-Ski trial. Blood. 2016;128(22):787.Google Scholar
  32. 32.
    Ilander M, Olsson-Stromberg U, Schlums H, Guilhot J, Bruck O, Lahteenmaki H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31(5):1108–16.CrossRefPubMedGoogle Scholar
  33. 33.
    Saussele S, Richter J, Hochhaus A, Mahon FX. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30(8):1638–47.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Michor F, Hughes TP, Iwasa Y, Branford S, Shah NP, Sawyers CL, et al. Dynamics of chronic myeloid leukaemia. Nature. 2005;435(7046):1267–70.CrossRefPubMedGoogle Scholar
  35. 35.
    Roeder I, Horn M, Glauche I, Hochhaus A, Mueller MC, Loeffler M. Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications. Nat Med. 2006;12(10):1181–4.CrossRefPubMedGoogle Scholar
  36. 36.
    Deininger M. Hematology: curing CML with imatinib—a dream come true? Nat Rev Clin Oncol. 2011;8(3):127–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29(5):999–1003.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mori S, Vagge E, le Coutre P, Abruzzese E, Martino B, Pungolino E, et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015;90(10):910–4.CrossRefPubMedGoogle Scholar
  39. 39.
    Hughes TP, Boquimpani CM, Takahashi N, Benyamini N, Clementino NC, Shuvaev V, et al. Treatment-free remission in patients with chronic myeloid leukemia in chronic phase according to reasons for switching from imatinib to nilotinib: subgroup analysis from ENESTop. Blood. 2016;128(22):792.Google Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Naoto Takahashi
    • 1
  • Tetsuzo Tauchi
    • 2
  • Kunio Kitamura
    • 3
  • Koichi Miyamura
    • 4
  • Yoshio Saburi
    • 5
  • Yoshihiro Hatta
    • 6
  • Yasuhiko Miyata
    • 7
  • Shinichi Kobayashi
    • 8
  • Kensuke Usuki
    • 9
  • Itaru Matsumura
    • 10
  • Yosuke Minami
    • 11
  • Noriko Usui
    • 12
  • Tetsuya Fukuda
    • 13
  • Satoru Takada
    • 14
  • Maho Ishikawa
    • 15
  • Katsumichi Fujimaki
    • 16
  • Hiroshi Gomyo
    • 17
  • Osamu Sasaki
    • 18
  • Kohshi Ohishi
    • 19
  • Takaaki Miyake
    • 20
  • Kiyotoshi Imai
    • 21
  • Hitoshi Suzushima
    • 22
  • Hideki Mitsui
    • 23
  • Kazuto Togitani
    • 24
  • Toru Kiguchi
    • 25
  • Yoshiko Atsuta
    • 26
  • Shigeki Ohtake
    • 27
  • Kazunori Ohnishi
    • 28
  • Yukio Kobayashi
    • 29
  • Hitoshi Kiyoi
    • 30
  • Yasushi Miyazaki
    • 31
  • Tomoki Naoe
    • 7
  • The Japan Adult Leukemia Study Group
  1. 1.Department of Hematology, Nephrology and RheumatologyAkita University Graduate School of MedicineAkitaJapan
  2. 2.Department of HematologyTokyo Medical University, Tokyo Medical UniversityTokyoJapan
  3. 3.Division of HematologyIchinomiya Municipal HospitalIchinomiyaJapan
  4. 4.Department of HematologyJapanese Red Cross Nagoya First HospitalNagoyaJapan
  5. 5.Department of HematologyOita Prefectural HospitalOitaJapan
  6. 6.Division of Hematology and RheumatologyNihon University School of MedicineTokyoJapan
  7. 7.National Hospital OrganizationNagoya Medical CenterNagoyaJapan
  8. 8.Division of HematologyNational Defense Medical CollegeTokorozawaJapan
  9. 9.Department of HematologyNTT Medical Center TokyoTokyoJapan
  10. 10.Department of Hematology and Rheumatology, Faculty of MedicineKindai UniversityOsaka-SayamaJapan
  11. 11.Department of HematologyNational Cancer Center Hospital EastKashiwaJapan
  12. 12.Department of Clinical Oncology/HematologyThe Jikei University School of MedicineTokyoJapan
  13. 13.Department of HematologyTokyo Medical and Dental UniversityTokyoJapan
  14. 14.Leukemia Research CenterSaiseikai Maebashi HospitalMaebashiJapan
  15. 15.Department of HematologySaitama Medical University International Medical CenterSaitamaJapan
  16. 16.Department of HematologyFujisawa City HospitalFujisawaJapan
  17. 17.Department of HematologyHyogo Cancer CenterAkashiJapan
  18. 18.Department of HematologyMiyagi Cancer CenterNatoriJapan
  19. 19.Department of Transfusion Medicine and Cell TherapyMie University HospitalTsuJapan
  20. 20.Department of Oncology/HematologyShimane University HospitalIzumoJapan
  21. 21.Department of HematologySapporo Hokuyu HospitalSapporoJapan
  22. 22.Department of HematologyKumamoto Shinto General HospitalKumamotoJapan
  23. 23.Department of HematologyOtemae HospitalOsakaJapan
  24. 24.Department of Hematology and Respiratory MedicineKochi Medical SchoolKochiJapan
  25. 25.Department of HematologyChugoku Central HospitalFukuyamaJapan
  26. 26.Japanese Data Center for Hematopoietic Cell TransplantationNagoyaJapan
  27. 27.Kanazawa UniversityKanazawaJapan
  28. 28.Japanese Red Cross Aichi Blood CenterSetoJapan
  29. 29.Hematology DivisionInternational University of Health and Welfare, Mita HospitalTokyoJapan
  30. 30.Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan
  31. 31.Department of HematologyNagasaki UniversityNagasakiJapan

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