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Review of New-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Abstract

Purpose of Review

In this review, we analyzed the available data from clinical trials with new tyrosine kinase inhibitors (TKIs) under development and how to consider chronic myeloid leukemia (CML) patients who had either resistance or intolerance to current TKIs for treatment with such agents.

Recent Findings

Nearly 50% of CML patients treated with TKIs frontline have required a change of therapy by 10 years. Second-line therapy is effective (by achievement of complete cytogenetic response) in only approximately 50% of patients, and available third-generation TKI has been marred by concerns of arterio-occlusive events. These facts highlight the need for additional treatment options.

Summary

New TKIs have shown promising efficacy and tolerance in CML patients with resistance or intolerance to multiple available TKIs. Additional studies will determine their role in the management of CML.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Deininger MW, O'Brien SG, Ford JM, Druker BJ. Practical management of patients with chronic myeloid leukemia receiving imatinib. J Clin Oncol. 2003;21(8):1637–47.

    CAS  Article  Google Scholar 

  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Article  Google Scholar 

  3. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000;50(1):7–33.

    CAS  Article  Google Scholar 

  4. SEER. Cancer Stat Facts: Leukemia — Chronic Myeloid Leukemia (CML) 2020 [Available from: https://seer.cancer.gov/statfacts/html/cmyl.html.

  5. Sasaki K, Strom SS, O'Brien S, Jabbour E, Ravandi F, Konopleva M, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2(5):e186–93.

    Article  Google Scholar 

  6. Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. 1999;341(3):164–72.

    CAS  Article  Google Scholar 

  7. Molica M, Massaro F, Breccia M. Second line small molecule therapy options for treating chronic myeloid leukemia. Expert Opin Pharmacother. 2017;18(1):57–65.

    CAS  Article  Google Scholar 

  8. Cortes JE, Jones D, O'Brien S, Jabbour E, Konopleva M, Ferrajoli A, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28(3):392–7.

    CAS  Article  Google Scholar 

  9. Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30(28):3486–92.

    CAS  Article  Google Scholar 

  10. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96.

    CAS  Article  Google Scholar 

  11. 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(24):2260–70.

    CAS  Article  Google Scholar 

  12. Kantarjian HM, Cortes JE, O'Brien S, Giles F, Garcia-Manero G, Faderl S, et al. Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses. Blood. 2003;101(1):97–100.

    CAS  Article  Google Scholar 

  13. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.

    CAS  Article  Google Scholar 

  14. Cortes J, Rea D, Lipton JH. Treatment-free remission with first- and second-generation tyrosine kinase inhibitors. Am J Hematol. 2019;94(3):346–57.

    PubMed  Google Scholar 

  15. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque 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(20):2333–40.

    CAS  Article  Google Scholar 

  16. 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(24):2251–9.

    CAS  Article  Google Scholar 

  17. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE Trial. J Clin Oncol. 2018;36(3):231–7.

    CAS  Article  Google Scholar 

  18. Schoepfer J, Jahnke W, Berellini G, Buonamici S, Cotesta S, Cowan-Jacob SW, et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1. J Med Chem. 2018;61(18):8120–35.

    CAS  Article  Google Scholar 

  19. •• Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381(24):2315–26 Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein. This phase 1 enrolled chronic-phase chronic myeloid leukemia patients who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors to asciminib. Asciminib was active in heavily pretreated patients with chronic myeloid leukemia who had resistance to or unacceptable side effects from TKIs, including patients with a T315I mutation.

  20. Hochhaus A BC, Rea D, Minami Y, Lomaia E, et al. Asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (Pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). Results from Phase 3 Study ASH annual meeting 2020; Late-Breaking Abstract Session.

  21. Mauro M. J KD, Cortes J, Rea D, Hughes T.P, Minami H et al Combination of asciminib plus nilotinib (NIL) or dasatinib (DAS) in patients with chronic myeloid leukemia (CML): results from phase 1 study EHA Annual Meeting 2019; Abstract ID#: S884.

  22. Mian AA, Rafiei A, Haberbosch I, Zeifman A, Titov I, Stroylov V, et al. PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome-positive (Ph+) leukemias harboring the T315I mutation. Leukemia. 2015;29(5):1104–14.

    CAS  Article  Google Scholar 

  23. •• Turkina AG VO, Lomaia E, Shatokhina E,Shukhov O, Chelysheva EU PF-114: A 4th Generation Tyrosine Kinase-Inhibitor for Chronic Phase Chronic Myeloid Leukaemia Including BCRABL1T315I ASH Annual Meeting 2019; Abstract ID#: 1638. This abstract reported that PF-114 a 4th generation tyrosine kinase inhibitor for chronic phase chronic myeloid leukemia was safe and effective in patients failing ≥2 tyrosine kinase inhibitors including patients with a T315I mutation. The most effective dose was 300 mg/d.

  24. Antelope O, Vellore NA, Pomicter AD, Patel AB, Van Scoyk A, Clair PM, et al. BCR-ABL1 tyrosine kinase inhibitor K0706 exhibits preclinical activity in Philadelphia chromosome-positive leukemia. Exp Hematol. 2019;77:36–40 e2.

    Article  Google Scholar 

  25. •• Cortes J KD-W, Nicolini EF, Saikia T, Charbonnier A, Apperley J et al. Phase 1 trial of K0706, a novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI): in patients with chronic myelogenous leukemia (CML) and Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) failing ≥ 3 prior TKI therapies: Initial Safety and Efficacy ASH Annual Meeting 2019; Abstract ID#: 4158. This abstract demonstarted that vodobatinib (K0706) has an acceptable safety profile with activity in heavily pre-treated patients with chronic myeloid leukemia who had failed at least ≥3 prior lines of tyrosine kinase inhibitors.

  26. Liu X, Wang G, Yan X, Qiu H, Min P, Wu M, et al. Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors. Cell Biosci. 2019;9:88.

    Article  Google Scholar 

  27. •• An Updated Safety and Efficacy Results of Phase 1 Study of HQP1351, a Novel 3rd Generation of BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI Resistant Chronic Myeloid Leukemia ASH Annual Meeting 2019; Abstract ID#: 493 [Internet]. This abstract showed that Olverembatinib (HQP1351) was well tolerated and exhibited significant and durable antitumor activity in patients with chronic myeloid leukemia who had tyrosine kinase inhibitor-resistant, including those with aT315I mutation.

  28. Steegmann JL, Baccarani M, Breccia M, Casado LF, Garcia-Gutierrez V, Hochhaus A, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30(8):1648–71.

    CAS  Article  Google Scholar 

  29. Cortes JE, Khoury HJ, Kantarjian HM, Lipton JH, Kim DW, Schafhausen P, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91(12):1206–14.

    CAS  Article  Google Scholar 

  30. Shah NP, Rousselot P, Schiffer C, Rea D, Cortes JE, Milone J, et al. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034. Am J Hematol. 2016;91(9):869–74.

    CAS  Article  Google Scholar 

  31. Giles FJ, le Coutre PD, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, et al. Nilotinib in imatinib-resistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study. Leukemia. 2013;27(1):107–12.

    CAS  Article  Google Scholar 

  32. • Loscocco F, Visani G, Galimberti S, Curti A, Isidori A. BCR-ABL independent mechanisms of resistance in chronic myeloid leukemia. Front Oncol. 2019;9:939. This article reported that resistance to tyrosine kinase inhibitors might occur through kinase-independent mechanisms, mainly due to leukemia stem cells.

  33. • Shah M, Bhatia R. Preservation of quiescent chronic myelogenous leukemia stem cells by the bone marrow microenvironment. Adv Exp Med Biol. 2018;1100:97–110. Tyrosine kinase inhibitors are unable to eradicate leukemia stem cells, leading to re-emergence of the disease while on therapy.

  34. Branford S, Wang P, Yeung DT, Thomson D, Purins A, Wadham C, et al. Integrative genomic analysis reveals cancer-associated mutations at diagnosis of CML in patients with high-risk disease. Blood. 2018;132(9):948–61.

    CAS  Article  Google Scholar 

  35. Dasatinib and Venetoclax in Treating Patients With Philadelphia Chromosome Positive or BCR-ABL1 Positive Early Chronic Phase Chronic Myelogenous Leukemia 2020 [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT02689440.

  36. Ruxolitinib in Treating Participants With Chronic Myeloid Leukemia With Minimal Residual Disease While on Therapy With Tyrosine Kinase Inhibitors 2020 [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT01751425.

  37. Pegylated Interferon Alfa-2b and Nilotinib for Augmentation of Complete Molecular Response in Chronic Myeloid Leukaemia (PInNACLe) 2014 [Internet]. Available from: https://clinicaltrials.gov/ct2/show/NCT02001818.

  38. Bose P, Park H, Al-Khafaji J, Grant S. Strategies to circumvent the T315I gatekeeper mutation in the Bcr-Abl tyrosine kinase. Leuk Res Rep. 2013;2(1):18–20.

    PubMed  PubMed Central  Google Scholar 

  39. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre PD, Paquette R, Chuah C, et al. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393–404.

    CAS  Article  Google Scholar 

  40. Naqvi K, Cortes JE, Luthra R, O'Brien S, Wierda W, Borthakur G, et al. Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations. Int J Hematol. 2018;107(6):689–95.

    CAS  Article  Google Scholar 

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Correspondence to Jorge Cortes.

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Conflict of Interest

Mahran Shoukier and Michal Kubiak have no conflict of interest. Jorge Cortes reports grants from BMS, grants and personal fees from Novartis, grants and personal fees from Pfizer, grants and personal fees from Takeda, grants from Sun Pharma, outside the submitted work.

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Shoukier, M., Kubiak, M. & Cortes, J. Review of New-Generation Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia. Curr Oncol Rep 23, 91 (2021). https://doi.org/10.1007/s11912-021-01087-x

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  • DOI: https://doi.org/10.1007/s11912-021-01087-x

Keywords

  • Chronic myeloid leukemia
  • Tyrosine kinase Inhibitors
  • New generations
  • Side effects