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Comprehensive analyses of safety and efficacy toward individualizing imatinib dosage in patients with chronic myeloid leukemia

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Abstract

Safety and efficacy outcomes of imatinib treatment were evaluated using extensive clinical data collected from a total of 1003 patients with newly diagnosed chronic myeloid leukemia in chronic phase between 2001 and 2018. By 12 months of imatinib treatment at a fixed dose of 400 mg/day, 45.4% of patients experienced at least one type of dose-limiting toxicities (DLTs). The DLTs that frequently occurred first were thrombocytopenia (40.0%), neutropenia/leukopenia (14.3%) and dermatological reactions (12.1%). Patients with lighter body weight (≤ 64 kg) and older age (> 43 years) experienced a markedly higher occurrence of first DLTs by 12 months than heavier and younger patients (57.9% vs. 30.1%, p < 0.001). On the other hand, 38.9% of patients achieved major molecular response (MMR) at 12 months at the fixed dose. Female patients achieved a greater rate of MMR than male patients (45.6% vs. 35.5%, p = 0.028). In conclusion, patients with light weight and old age are more vulnerable to DLTs, whereas female patients gain more efficacy benefit at the fixed dose. The authors suggest that the initial dose of imatinib should be reduced to 300 mg/day or lower for patients vulnerable to DLTs to diminish the risk of DLTs without compromising the achievement of MMR.

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References

  1. Radich JP, Deininger M, Abboud CN, Altman JK, Berman E, Bhatia R, et al. Chronic myeloid leukemia, version 1.2019, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Cancer Netw. 2018;16(9):1108–35.

    Article  Google Scholar 

  2. An X, Tiwari AK, Sun Y, Ding PR, Ashby CR Jr, Chen ZS. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk Res. 2010;34(10):1255–68.

    Article  CAS  Google Scholar 

  3. Aviles-Vazquez S, Chavez-Gonzalez A, Mayani H. Tyrosine kinase inhibitors (TKI): a new revolution in the treatment of chronic myeloid leukemia (CML). Gac Med Mex. 2013;149(6):646–54.

    PubMed  Google Scholar 

  4. 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.

    Article  Google Scholar 

  5. Ohnishi K, Nakaseko C, Takeuchi J, Fujisawa S, Nagai T, Yamazaki H, et al. Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study. Cancer Sci. 2012;103(6):1071–8.

    Article  CAS  Google Scholar 

  6. Larson RA, Druker BJ, Guilhot F, O’Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study. Blood. 2008;111(8):4022–8.

    Article  CAS  Google Scholar 

  7. Larson RA, Yin OQ, Hochhaus A, Saglio G, Clark RE, Nakamae H, et al. Population pharmacokinetic and exposure-response analysis of nilotinib in patients with newly diagnosed Ph + chronic myeloid leukemia in chronic phase. Eur J Clin Pharmacol. 2012;68(5):723–33.

    Article  CAS  Google Scholar 

  8. Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2007;109(8):3496–9.

    Article  CAS  Google Scholar 

  9. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. 2006;108(1):28–37.

    Article  CAS  Google Scholar 

  10. Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26(10):2172–5.

    Article  CAS  Google Scholar 

  11. Kawaguchi T, Hamada A, Hirayama C, Nakashima R, Nambu T, Yamakawa Y, et al. Relationship between an effective dose of imatinib, body surface area, and trough drug levels in patients with chronic myeloid leukemia. Int J Hematol. 2009;89(5):642–8.

    Article  CAS  Google Scholar 

  12. Thanopoulou E, Judson I. The safety profile of imatinib in CML and GIST: long-term considerations. Arch Toxicol. 2012;86(1):1–12.

    Article  CAS  Google Scholar 

  13. Judson I, Ma P, Peng B, Verweij J, Racine A, di Paola ED, et al. Imatinib pharmacokinetics in patients with gastrointestinal stromal tumour: a retrospective population pharmacokinetic study over time. EORTC Soft Tissue and Bone Sarcoma Group. Cancer Chemother Pharmacol. 2005;55(4):379–86.

    Article  CAS  Google Scholar 

  14. Schmidli H, Peng B, Riviere GJ, Capdeville R, Hensley M, Gathmann I, et al. Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study. Br J Clin Pharmacol. 2005;60(1):35–44.

    Article  CAS  Google Scholar 

  15. Menon-Andersen D, Mondick JT, Jayaraman B, Thompson PA, Blaney SM, Bernstein M, et al. Population pharmacokinetics of imatinib mesylate and its metabolite in children and young adults. Cancer Chemother Pharmacol. 2009;63(2):229–38.

    Article  CAS  Google Scholar 

  16. Takahashi N, Miura M, Scott SA, Kagaya H, Kameoka Y, Tagawa H, et al. Influence of CYP3A5 and drug transporter polymorphisms on imatinib trough concentration and clinical response among patients with chronic phase chronic myeloid leukemia. J Hum Genet. 2010;55(11):731–7.

    Article  CAS  Google Scholar 

  17. Rosti G, Iacobucci I, Bassi S, Castagnetti F, Amabile M, Cilloni D, et al. Impact of age on the outcome of patients with chronic myeloid leukemia in late chronic phase: results of a phase II study of the GIMEMA CML Working Party. Haematologica. 2007;92(1):101–5.

    Article  Google Scholar 

  18. Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38(8):843–53.

    Article  CAS  Google Scholar 

  19. Noh H, Jung SY, Kwak JY, Kim SH, Oh SJ, Zang DY, et al. Determination of a radotinib dosage regimen based on dose-response relationships for the treatment of newly diagnosed patients with chronic myeloid leukemia. Cancer Med. 2018;7(5):1766–73.

    Article  CAS  Google Scholar 

  20. Noh H, Park MS, Kim SH, Oh SJ, Zang DY, Park HL, et al. Optimization of radotinib doses for the treatment of Asian patients with chronic myelogenous leukemia based on dose-response relationship analyses. Leuk Lymphoma. 2016;57(8):1856–64.

    Article  CAS  Google Scholar 

  21. Lin HX, Sjaarda J, Dyck J, Stringer R, Hillis C, Harvey M, et al. Gender and BCR-ABL transcript type are correlated with molecular response to imatinib treatment in patients with chronic myeloid leukemia. Eur J Haematol. 2016;96(4):360–6.

    Article  CAS  Google Scholar 

  22. Branford S, Yeung DT, Ross DM, Prime JA, Field CR, Altamura HK, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121(19):3818–24.

    Article  CAS  Google Scholar 

  23. Radivoyevitch T, Jankovic GM, Tiu RV, Saunthararajah Y, Jackson RC, Hlatky LR, et al. Sex differences in the incidence of chronic myeloid leukemia. Radiat Environ Biophys. 2014;53(1):55–63.

    Article  Google Scholar 

  24. Berger U, Maywald O, Pfirrmann M, Lahaye T, Hochhaus A, Reiter A, et al. Gender aspects in chronic myeloid leukemia: long-term results from randomized studies. Leukemia. 2005;19(6):984–9.

    Article  CAS  Google Scholar 

  25. Demetri GD, Wang Y, Wehrle E, Racine A, Nikolova Z, Blanke CD, et al. Imatinib plasma levels are correlated with clinical benefit in patients with unresectable/metastatic gastrointestinal stromal tumors. J Clin Oncol. 2009;27(19):3141–7.

    Article  CAS  Google Scholar 

  26. Lankheet NA, Knapen LM, Schellens JH, Beijnen JH, Steeghs N, Huitema AD. Plasma concentrations of tyrosine kinase inhibitors imatinib, erlotinib, and sunitinib in routine clinical outpatient cancer care. Ther Drug Monit. 2014;36(3):326–34.

    Article  CAS  Google Scholar 

  27. Shaw HM, Milton GW, Farago G, McCarthy WH. Endocrine influences on survival from malignant melanoma. Cancer. 1978;42(2):669–77.

    Article  CAS  Google Scholar 

  28. Hou J, Zhou Y, Zheng Y, Fan J, Zhou W, Ng IO, et al. Hepatic RIG-I predicts survival and interferon-alpha therapeutic response in hepatocellular carcinoma. Cancer Cell. 2014;25(1):49–63.

    Article  CAS  Google Scholar 

  29. Khoury HJ, Cortes JE, Kantarjian H, Baccarani M, Shah NP, Bradley-Garelik MB, et al. Safety and efficacy of dasatinib (DAS) vs. imatinib (IM) by baseline comorbidity in patients with chronic myeloid leukemia in chronic phase (CML-CP): analysis of the DASISION Trial. Blood. 2010;116(21):1401.

    Article  Google Scholar 

  30. Molica M, Canichella M, Colafigli G, Latagliata R, Diverio D, Alimena G, et al. Body mass index does not impact on molecular response rate of chronic myeloid leukaemia patients treated frontline with second generation tyrosine kinase inhibitors. Br J Haematol. 2018;182(3):427–9.

    Article  Google Scholar 

  31. Marcucci G, Perrotti D, Caligiuri MA. Understanding the molecular basis of imatinib mesylate therapy in chronic myelogenous leukemia and the related mechanisms of resistance. Commentary re: A. N. Mohamed et al., The effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin. Cancer Res. 2003;9:1333–37. Clin Cancer Res. 2003;9(4):1248–52.

  32. Sacha T. Imatinib in chronic myeloid leukemia: an overview. Mediterr J Hematol Infect Dis. 2014;6(1):e2014007.

    Article  Google Scholar 

  33. Jain RK, Lee JJ, Hong D, Markman M, Gong J, Naing A, et al. Phase I oncology studies: evidence that in the era of targeted therapies patients on lower doses do not fare worse. Clin Cancer Res. 2010;16(4):1289–97.

    Article  CAS  Google Scholar 

  34. Takahashi N, Wakita H, Miura M, Scott SA, Nishii K, Masuko M, et al. Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia. Clin Pharmacol Ther. 2010;88(6):809–13.

    Article  CAS  Google Scholar 

  35. Antoun S, Baracos VE, Birdsell L, Escudier B, Sawyer MB. Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma. Ann Oncol. 2010;21(8):1594–8.

    Article  CAS  Google Scholar 

  36. Fukudo M, Ito T, Mizuno T, Shinsako K, Hatano E, Uemoto S, et al. Exposure-toxicity relationship of sorafenib in Japanese patients with renal cell carcinoma and hepatocellular carcinoma. Clin Pharmacokinet. 2014;53(2):185–96.

    Article  CAS  Google Scholar 

  37. Huillard O, Mir O, Peyromaure M, Tlemsani C, Giroux J, Boudou-Rouquette P, et al. Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients. Br J Cancer. 2013;108(5):1034–41.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by the National Research Foundation of Korea (No. 2018R1D1A1B07044329), the Foundation of Pharmacy Education and Research, Seoul National University; and the Research Institutes of Pharmaceutical Sciences, Seoul National University.

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Author notes

  1. Dong-Wook Kim and Jangik I. Lee contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, College of Pharmacy, Seoul National University, 1 Gwanak-Ro, Gwanak-Gu, Seoul, 08826, Republic of Korea

    Hyejin Shin, Su Young Jung & Jangik I. Lee

  2. Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea

    Hyejin Shin, Su Young Jung & Jangik I. Lee

  3. Leukemia Research Institute, The Catholic University of Korea, Seoul, South Korea

    Soo Young Choi, Kyung-Mi Kee, Soo-Hyun Kim, Seon-Young Yang & Dong-Wook Kim

  4. Department of Hematology, Catholic Hematology Hospital, Leukemia Research Institute, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 06591, Republic of Korea

    Dong-Wook Kim

  5. Department of Pharmacy, College of Pharmacy, Yonsei University, Incheon, South Korea

    Hayeon Noh

  6. Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Republic of Korea

    Dae Young Zang

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  1. Hyejin Shin
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Shin, H., Choi, S.Y., Kee, KM. et al. Comprehensive analyses of safety and efficacy toward individualizing imatinib dosage in patients with chronic myeloid leukemia. Int J Hematol 111, 417–426 (2020). https://doi.org/10.1007/s12185-019-02805-9

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  • DOI: https://doi.org/10.1007/s12185-019-02805-9

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