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Treatment-free remission and immunity in chronic myeloid leukemia

  • Progress in Hematology
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Abstract

Chronic myeloid leukemia (CML) is caused by the reciprocal translocation t(9;22)(q34;q11), resulting in the BCR-ABL1 fusion gene. BCR-ABL1 tyrosine kinase inhibitors (TKIs) improve overall survival in patients with chronic phase CML (CML-CP). Approximately half of the patients who achieve a durable deep molecular response can achieve sustained treatment-free remission (TFR) after TKI discontinuation; thus TFR is now a therapeutic goal for most patients with CML-CP. Sensitive BCL-ABL1 transcript detection methods reveal that evidence of residual CML cells remains in patients who achieve sustained TFR, indicating that the host immune system protects against CML relapse. The human immune system is composed of innate and adaptive arms. Natural killer cells are major components of the innate immune system, while T cells are major components of the adaptive immune system. Myeloid-derived suppressor cells and regulatory T cells, both suppressors of the immune response, have important roles in the regulation of CML. Here, we review the current understanding of the immune response in CML, especially in TFR.

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References

  1. 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 

  2. Ureshino H, Kamachi K, Kimura S. Surrogate markers for treatment-free remission in patients with chronic myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2020;20:785–90.

    Article  PubMed  Google Scholar 

  3. 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;122:515–22.

    Article  CAS  PubMed  Google Scholar 

  4. Mahon F-X, Réa 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;11:1029–35.

    Article  CAS  PubMed  Google Scholar 

  5. 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:e528–35.

    Article  PubMed  Google Scholar 

  6. Takahashi N, Nishiwaki K, Nakaseko C, Aotsuka N, Sano K, Ohwada C, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018;103:1835–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kimura S, Imagawa J, Murai K, Hino M, Kitawaki T, Okada M, et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI trial): a single-arm, multicentre, phase 2 trial. Lancet Haematol. 2020;7:e218–25.

    Article  PubMed  Google Scholar 

  8. Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gómez Casares MT, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31:1525–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19:747–57.

    Article  CAS  PubMed  Google Scholar 

  10. Vivier E, Raulet DH, Moretta A, Caligiuri MA, Zitvogel L, Lanier LL, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Sourdive DJD, Murali-Krishna K, Altman JD, Zajac AJ, Whitmire JK, Pannetier C, et al. Conserved T cell receptor repertoire in primary and memory CD8 T cell responses to an acute viral infection. J Exp Med. 1998;188:71–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zehn D, King C, Bevan MJ, Palmer E. TCR signaling requirements for activating T cells and for generating memory. Cell Mol Life Sci. 2012;69:1565–75.

    Article  CAS  PubMed  Google Scholar 

  13. Kumagai T, Nakaseko C, Nishiwaki K, Yoshida C, Ohashi K, Takezako N, et al. Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation. Cancer Sci. 2018;109:182–92.

    Article  CAS  PubMed  Google Scholar 

  14. Matsushita M, Ozawa K, Suzuki T, Nakamura M, Nakano N, Kanchi S, et al. CXorf48 is a potential therapeutic target for achieving treatment-free remission in CML patients. Blood Cancer J. 2017;7:e601–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ureshino H, Shindo T, Tanaka H, Saji H, Kimura S. HLA polymorphisms are associated with treatment-free remission following discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia. Mol Cancer Ther. 2021;20:142–9.

    Article  CAS  PubMed  Google Scholar 

  16. Jo T, Noguchi K, Hayashi S, Irie S, Hayase R, Shioya H, et al. Long-lasting memory of cellular immunity in a chronic myeloid leukemia patient maintains molecular response 5 after cessation of dasatinib. Oncol Lett. 2018;15:2935–8.

    PubMed  Google Scholar 

  17. Schütz C, Inselmann S, Sausslele S, Dietz CT, Müller MC, Eigendorff E, et al. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017;31:829–36.

    Article  PubMed  Google Scholar 

  18. Nishikawa H, Sakaguchi S. Regulatory T cells in tumor immunity. Int J Cancer. 2010;127:759–67.

    CAS  PubMed  Google Scholar 

  19. Hughes A, Clarson J, Tang C, Vidovic L, White DL, Hughes TP, et al. CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors. Blood. 2017;129:1166–76.

    Article  CAS  PubMed  Google Scholar 

  20. Irani YD, Hughes A, Clarson J, Kok CH, Shanmuganathan N, White DL, et al. Successful treatment-free remission in chronic myeloid leukaemia and its association with reduced immune suppressors and increased natural killer cells. Br J Haematol. 2020;191:433–41.

    Article  CAS  PubMed  Google Scholar 

  21. Savani BN, Rezvani K, Mielke S, Montero A, Kurlander R, Carter CS, et al. Factors associated with early molecular remission after T cell-depleted allogeneic stem cell transplantation for chronic myelogenous leukemia. Blood. 2006;107:1688–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Rea D, Henry G, Khaznadar Z, Etienne G, Guilhot F, Nicolini F, et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica. 2017;102:1368–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ilander M, Olsson-Strömberg U, Schlums H, Guilhot J, Brück O, Lähteenmäki H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31:1108–16.

    Article  CAS  PubMed  Google Scholar 

  24. Yeung DT, Tang C, Vidovic L, White DL, Branford S, Hughes TP, et al. KIR2DL5B genotype predicts outcomes in CML patients treated with response directed sequential imatinib/nilotinib strategy. Blood. 2015;126:2720–3.

    Article  CAS  PubMed  Google Scholar 

  25. Ureshino H, Shindo T, Kojima H, Kusunoki Y, Miyazaki Y, Tanaka H, et al. Allelic polymorphisms of KIRs and HLAs predict favorable responses to tyrosine kinase inhibitors in CML. Cancer Immunol Res. 2018;6:745–54.

    Article  CAS  PubMed  Google Scholar 

  26. Caocci G, Martino B, Greco M, Abruzzese E, Trawinska MM, Lai S, et al. Killer immunoglobulin-like receptors can predict TKI treatment-free remission in chronic myeloid leukemia patients. Exp Hematol. 2015;43:1015–8.

    Article  CAS  PubMed  Google Scholar 

  27. Kantarjian HM, Hughes TP, Larson RA, Kim D-W, Issaragrisil S, le Coutre P, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35:440–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood. 2006;107:4532–9.

    Article  CAS  PubMed  Google Scholar 

  29. Simonsson B, Gedde-Dahl T, Markevärn B, Remes K, Stentoft J, Almqvist A, et al. Combination of pegylated IFN-α2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia. Blood. 2011;118:3228–35.

    Article  CAS  PubMed  Google Scholar 

  30. Ross DM, Pagani IS, Irani YD, Clarson J, Leclercq T, Dang P, et al. Lenalidomide maintenance treatment after imatinib discontinuation: results of a phase 1 clinical trial in chronic myeloid leukaemia. Br J Haematol. 2019;186:e56-60.

    PubMed  Google Scholar 

  31. Kreutzman A, Juvonen V, Kairisto V, Ekblom M, Stenke L, Seggewiss R, et al. Mono/oligoclonal T and NK cells are common in chronic myeloid leukemia patients at diagnosis and expand during dasatinib therapy. Blood. 2010;116:772–82.

    Article  CAS  PubMed  Google Scholar 

  32. Kreutzman A, Yadav B, Brummendorf TH, Gjertsen BT, Lee Hee M, Janssen J, et al. Immunological monitoring of newly diagnosed CML patients treated with bosutinib or imatinib first-line. OncoImmunol. 2019;8:1–13.

    Article  Google Scholar 

  33. Fei F, Yu Y, Schmitt A, Rojewski MT, Chen B, Greiner J, et al. Effects of nilotinib on regulatory T cells: the dose matters. Mol Cancer. 2010;9:1–10.

    Article  Google Scholar 

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Funding

This work was supported by research grants from JSPS KAKENHI (19K17860, HU) and Okinaka Memorial Institute for Medical Research (HU).

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  1. Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Hiroshi Ureshino

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  1. Hiroshi Ureshino
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Correspondence to Hiroshi Ureshino.

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Ureshino, H. Treatment-free remission and immunity in chronic myeloid leukemia. Int J Hematol 113, 642–647 (2021). https://doi.org/10.1007/s12185-021-03117-7

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  • DOI: https://doi.org/10.1007/s12185-021-03117-7

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