Skip to main content

Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL

Abstract

Although tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), intolerance and resistance to TKIs have been serious problems. Due to a lack of research, the importance of the pharmacokinetics (PK) of TKIs is currently unclear. We examined the PK of the third-generation TKI ponatinib to monitor side effects and efficacy during treatments for one patient with CML-chronic phase (CP-CML) and two who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), one for CML-blastic crisis (BC-CML) and one for Ph + ALL. The patient with CP-CML was intolerant to multiple TKIs (dasatinib, nilotinib, imatinib, and bosutinib) and thus was switched to ponatinib (15 mg/day). The patients who received allo-HSCT for BC-CML and Ph + ALL received ponatinib (15 mg/day) as maintenance therapy. Notably, serial evaluation of the PK of ponatinib showed that the median trough values (ng/ml) were 17.2 (12.2–34.5), 33.1 (21.2–40.3) and 27.7 (13.6–29.9) in patients 1, 2, and 3, respectively. These values were around the target concentration (23 ng/ml). All patients are maintaining complete remission without side effects. In conclusion, serial evaluation of PK of ponatinib may yield meaningful information about its safety and efficacy.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. Fialkow PJ, Jacobson RJ, Papayannopoulou T. Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. Am J Med. 1977;63:125–30.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  3. Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3.

    CAS  Article  Google Scholar 

  4. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367:2075–88.

    CAS  Article  Google Scholar 

  5. 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;348:994–1004.

    CAS  Article  Google Scholar 

  6. 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.

    CAS  Article  Google Scholar 

  7. O'brien SG, Guilhot F, Goldman JM. International randomized study of interferon versus STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia I chronic phase (CML-CP) treated with imatinib (IM). Blood (ASH Annual Meeting Abstracts). 2008;112:186. [abstract].

  8. 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.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  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;99:141–53.

    CAS  Article  Google Scholar 

  11. Nakamae H, Shibayama H, Kurokawa M, Fukuda T, Nakaseko C, Kanda Y, et al. Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: results from the Japanese subgroup of ENESTnd. Int J Hematol. 2011;93:624–32.

    CAS  Article  Google Scholar 

  12. Kawano N, Yoshida S, Kawano S, Takuro K, Yamashita K, Ochiai H, et al. Clinical features and treatment outcomes of 51 patients with chronic myeloid leukemia treated with a tyrosine kinase inhibitor at a single institution from 2002 to 2014. J Clin Exp Hematop. 2016;56:34–42.

    Article  Google Scholar 

  13. Cortes JE, Kim DW, Pinilla-Ibarz J, Lecoutre 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;132:393–404.

    CAS  Article  Google Scholar 

  14. Tojo A, Kyo T, Yamamoto K, Nakamae H, Takahashi N, Kobayashi Y, et al. Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study. Int J Hematol. 2017;106:385–97.

    CAS  Article  Google Scholar 

  15. Hochhaus A, Breccia M, Saglio G, García-Gutiérrez V, Réa D, Janssen J, et al. Expert opinion-management of chronic myeloid leukemia after resistance to second-generation tyrosine kinase inhibitors. Leukemia. 2020;34:1495–502.

    CAS  Article  Google Scholar 

  16. Saini N, Marin D, Ledesma C, Delgado R, Rondon G, Popat UR, et al. Impact of TKI maintenance post-allogeneic transplant in Philadelphia positive acute lymphoblastic leukemia. Blood. 2020;136:1786–9.

    Article  Google Scholar 

  17. Abumiya M, Miura M, Takahashi N. Therapeutic drug monitoring of ponatinib using a simple high-performance liquid chromatography method in Japanese patients. Leuk Res. 2018;64:42–5.

    CAS  Article  Google Scholar 

  18. Kidoguchi K, Ureshino H, Kizuka-Sano H, Yamaguchi K, Katsuya H, Kubota Y, et al. Efficacy and safety of ponatinib for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a case series from a single institute. Int J Hematol. 2021;114:199–204.

    CAS  Article  Google Scholar 

  19. Shimoda k, Takahashi N, Kirito K, Iriyama N, Kawaguchi Y, Kizaki M. JSH practical guidelines for hematological malignancies, 2018: I. Leukemia-4. Chronic myeloid leukemia (CML)/myeloproliferative neoplasms (MPN). Int J Hematol. 2020;112:268–91.

  20. Baccarani M, Castagnetti F, Gugliotta G, Rosti G. A review of the European Leukemia Net recommendations for the management of CML. Ann Hematol. 2015;94(Suppl 2):S141-147.

    Article  Google Scholar 

  21. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European Leukemia Net 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    CAS  Article  Google Scholar 

  22. Kawano N, Okuda S, Yoshida S, Kugimiya H, Ito M, Horikawa N, et al. Successful treatment of lymphoid blastic crisis in chronic myelogenous leukemia with the additional bcr/abl transcript using imatinib-combined chemotherapy and high-dose chemotherapy with allogeneic bone marrow stem cell transplantation. Int J Hematol. 2011;94:561–6.

    CAS  Article  Google Scholar 

  23. Nagafuji K, Miyamoto T, Eto T, Ogawa R, Okumura H, Takase K, et al. Prospective evaluation of minimal residual disease monitoring to predict prognosis of adult patients with Ph-negative acute lymphoblastic leukemia. Eur J Haematol. 2019;103:164–71.

    CAS  Article  Google Scholar 

  24. Sugita J, Kagaya Y, Miyamoto T, Shibasaki Y, Nagafuji K, Ota S, et al. Myeloablative and reduced-intensity conditioning in HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide. Bone Marrow Transplant. 2019;54:432–41.

    CAS  Article  Google Scholar 

  25. O’Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009;16:401–12.

    CAS  Article  Google Scholar 

  26. Valentin GG, Michael WD, Maria RB, Vamsi KK, Luke A, Charles C, et al. The OPTIC study: a multicenter, randomized, phase 2 Trial to evaluate three starting doses of ponatinib with response-based dose reduction in patients with chronic phase chronic myeloid leukemia resistant to prior tyrosine kinase therapy, clinical lymphoma, myeloma. Leukemia. 2018;18:S228–S229. https://doi.org/10.1016/j.clml.2018.07.104.

  27. Cortes J. Interim analysis (IA) of OPTIC: a dose-ranging study of three ponatinib (PON) starting doses. In: American Society of Clinical Oncology Virtual Meeting (ASCO20; May 29–May 31, 2020), 2020 Abstract #7502. 2020.

  28. Sora F, Chiusolo P, Laurenti L, Soverini S, Sica S. Ponatinib before and after allogeneic stem cell transplantation for Ph+ acute lymphoblastic leukemia or lymphoid blast crisis of chronic myelogenous leukemia: a single-center experience. J Bone Res. 2016;4:2. https://doi.org/10.4172/2572-4916.1000169.

    Article  Google Scholar 

  29. Miura M, Takahashi N. Management using the plasma concentration of tyrosine kinase inhibitors for the treatment of chronic myelogenous leukemia: an update. Rinsho Ketsueki. 2019;60:1140–7.

    PubMed  Google Scholar 

  30. Taniguchi Y, Takahashi N, Miura M, Hirase C, Sueda S, Espinoza JL, et al. The impact of hemodialysis and liver cirrhosis on the plasma concentrations of tyrosine kinase inhibitors in a patient with chronic myeloid leukemia. Intern Med. 2020;59:2745–9.

    Article  Google Scholar 

Download references

Acknowledgements

We are grateful to the staff for good care and nursing at our institution.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Noriaki Kawano.

Ethics declarations

Conflict of interest

The authors (Noriaki Kawano, Masatomo Miura, Taro Tochigi, Takashi Nakaike, Kiyoshi Yamashita, Koichi Mashiba, Ikuo Kikuchi) have no conflicts of interest to declare. Shinya Kimura reports that he has received speaker’s fees from Novartis Pharmaceuticals, Grants and speaker’s fees from Bristol Myers Squibb, Pfizer and Otsuka Pharmaceutical, Grants from Kyowa Hakko Kirin, Astellas Pharma, Chu-gai Pharmaceutical, Asahi Kasei Pharma, Nippon Shinyaku, Ono Pharmaceutical, Eisai Pharmaceuticals, Taiho, Pharmaceutical, Ohara pharmaceutical and Takeda outside of the submitted work. Naoto Takahashi reports that he has received Grants and speaker’s fees from Novartis Pharmaceuticals, speaker’s fees from Bristol Myers Squibb, Grants and speaker’s fees from Pfizer, Grants and speaker’s fees from Otsuka Pharmaceutical, Grants from Kyowa Hakko Kirin, Grants from Astellas Pharma, Grants from Chugai Pharmaceutical, Grants from Asahi Kasei Pharma, Grants from Ono Pharmaceutical, and Grants from Eisai Pharmaceuticals, outside of the submitted work. The remaining authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kawano, N., Kimura, S., Miura, M. et al. Serial evaluation of the pharmacokinetics of ponatinib in patients with CML and Ph + ALL. Int J Hematol 114, 509–516 (2021). https://doi.org/10.1007/s12185-021-03186-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-021-03186-8

Keywords

  • The pharmacokinetics
  • Target concentration
  • Ponatinib
  • CML
  • Ph + ALL