International Journal of Hematology

, Volume 106, Issue 2, pp 229–239 | Cite as

Analysis of adverse events associated with dasatinib and nilotinib treatments in chronic-phase chronic myeloid leukemia patients outside clinical trials

  • Koung Jin Suh
  • Ji Yun Lee
  • Dong-Yeop Shin
  • Youngil Koh
  • Soo-Mee Bang
  • Sung-Soo Yoon
  • Seonyang Park
  • Inho Kim
  • Jeong-Ok Lee
Original Article

Abstract

We analyzed adverse events (AEs) in 201 chronic phase CML patients treated with nilotinib (n = 120) or dasatinib (n = 81) as first- or second-line therapy. The dasatinib group had significantly higher grade 3–4 AEs compared to the nilotinib group (22 vs. 54%, p < 0.001), and had more frequent dose reduction, interruption, and discontinuation (p < 0.001, p = 0.004, and p = 0.006, respectively). Of 59 patients who discontinued treatment, 47 (80%) discontinued treatment due to AEs; 50% of the AEs causing drug discontinuation were of grade 2 severity. Compared to the second-line setting, discontinuation occurred more rapidly in the first-line setting (2.9 vs. 15.6 months, p = 0.015). Pleural effusion occurred in 35% (28/81) of the patients with dasatinib and led to dasatinib discontinuation in 14 patients (grade 2 of 79%). Pulmonary artery hypertension occurred in one patient with dasatinib. Stroke, acute coronary syndrome, and peripheral artery occlusive disease occurred in 5% (6/120) of the patients treated with nilotinib. The dasatinib group had shorter event-free survival than nilotinib group (first-line, p = 0.051; second-line, p = 0.025). In the clinical practice setting, nilotinib or dasatinib use was more frequently interrupted than recommended by guidelines in association with less severe AEs. We believe this phenomenon is attributable to the availability of other TKIs.

Keywords

Nilotinib Dasatinib Toxicity Pleural effusion Discontinuation 

Notes

Compliance with ethical standards

Sources of funding

This study was supported by a grant from the Seoul National University Bundang Hospital Research Fund (Grant No. 11-2011-035).

Role of the funding source

The funding source had no involvement in the study design; the collection, analysis, and interpretation of the data; writing of the report; or the decision to submit the article for publication.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

12185_2017_2225_MOESM1_ESM.docx (52 kb)
Supplementary material 1 (DOCX 51 kb)

References

  1. 1.
    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;122:872–84.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim D-W, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brümmendorf TH, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123:2317–24.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    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;27:107–12.CrossRefPubMedGoogle Scholar
  6. 6.
    Gora-Tybor J, Medras E, Calbecka M, Kolkowska-Leśniak A, Ponikowska-Szyba E, Robak T, et al. Real-life comparison of severe vascular events and other non-hematological complications in patients with chronic myeloid leukemia undergoing second-line nilotinib or dasatinib treatment. Leuk Lymphoma. 2015;56:2309–14.CrossRefPubMedGoogle Scholar
  7. 7.
    Busque L, Gratton M-O, Harnois M, et al. Real life analysis of CML management demonstrates that second-line therapy is frequently used but is prematurely discontinued for intolerance: report of the groupe Quebecois De Recherche En LMC-NMP. Haematologica. 2015;100:231.Google Scholar
  8. 8.
    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.CrossRefPubMedGoogle Scholar
  9. 9.
    Charlson M, Szatrowski TP, Peterson J, Gold J. Validation of a combined comorbidity index. J Clin Epidemiol. 1994;47:1245–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Hochhaus A, O’Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L, et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia. 2009;23:1054–61.CrossRefPubMedGoogle Scholar
  12. 12.
    DeAngelo DJ. Managing chronic myeloid leukemia patients intolerant to tyrosine kinase inhibitor therapy. Blood Cancer J. 2012;2:e95.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Baccarani M, Pileri S, Steegmann J-L, Muller M, Soverini S, Dreyling M, et al. Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23:vii72–7.CrossRefPubMedGoogle Scholar
  14. 14.
    Rosti G, Castagnetti F, Gugliotta G, Palandri F, Martinelli G, Baccarani M. Dasatinib and nilotinib in imatinib-resistant Philadelphia-positive chronic myelogenous leukemia: a “head-to-head comparison”. Leuk Lymphoma. 2010;51:583–91.CrossRefPubMedGoogle Scholar
  15. 15.
    Sasaki K, Lahoti A, Jabbour E, Jain P, Pierce S, Borthakur G, et al. Clinical safety and efficacy of nilotinib or dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia and pre-existing liver and/or renal dysfunction. Clin Lymphoma Myeloma Leuk. 2016;16:152–62.CrossRefPubMedGoogle Scholar
  16. 16.
    Gambacorti-Passerini C, Aroldi A, Cordani N, Piazza R. Chronic myeloid leukemia: second-line drugs of choice. Am J Hematol. 2016;91:67–75.CrossRefPubMedGoogle Scholar
  17. 17.
    Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk Lymphoma. 2016;57:1300–10.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang J, Shen Z-X, Saglio G, Jin J, Huang H, Hu Y, et al. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood. 2015;125:2771–8.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Moslehi JJ, Deininger M. Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia. J Clin Oncol. 2015;33:4210–8.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Porkka K, Khoury HJ, Pquette RL, Matloub Y, Sinha R, Cortes JE. Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion. Cancer. 2010;116:377–86.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Quintas-Cardama A, Kantarjian H, O’Brien S, Borthakur G, Bruzzi J, Munden R, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–14.CrossRefPubMedGoogle Scholar
  22. 22.
    Montani D, Bergot E, Günther S, Savale L, Bergeron A, Bourdin A, et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation. 2012;125:2128–37.CrossRefPubMedGoogle Scholar
  23. 23.
    Shah NP, Wallis N, Farber HW, Mauro MJ, Wolf RA, Mattei D, et al. Clinical features of pulmonary arterial hypertension in patients receiving dasatinib. Am J Hematol. 2015;90:1060–4.CrossRefPubMedGoogle Scholar
  24. 24.
    Dumitrescu D, Seck C, ten Freyhaus H, Gerhardt F, Erdmann E, Rosenkranz S. Fully reversible pulmonary arterial hypertension associated with dasatinib treatment for chronic myeloid leukaemia. Eur Respir J. 2011;38:218–20.CrossRefPubMedGoogle Scholar
  25. 25.
    Mattei D, Feola M, Orzan F, Mordini N, Rapezzi D, Gallamini A. Reversible dasatinib-induced pulmonary arterial hypertension and right ventricle failure in a previously allografted CML patient. Bone Marrow Transpl. 2009;43:967–8.CrossRefGoogle Scholar
  26. 26.
    Rasheed W, Flaim B, Seymour JF. Reversible severe pulmonary hypertension secondary to dasatinib in a patient with chronic myeloid leukemia. Leuk Res. 2009;33:861–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Marin D, Bazeos A, Mahon F-X, Eliasson L, Milojkovic D, Bua M, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Guerin A, Bollu V, Guo A, Griffin JD, Yu AP, Wu EQ. Comparison of adherence between nilotinib and dasatinib as second-line therapies in chronic myeloid leukemia. Blood. 2010;116:3437–3437.Google Scholar
  29. 29.
    Chen L, Wu EQ. Adherence and persistence among chronic myeloid leukemia patients during second-line tyrosine kinase inhibitor treatment. J Manag Care Spec Pharm. 2015;21:1088.CrossRefPubMedGoogle Scholar
  30. 30.
    Whalen J, Stillman I, Ambavane A, Felber E, Makenbaeva D, Bolinder B. Cost-effectiveness analysis of second-line tyrosine kinase inhibitor treatment for chronic myelogenous leukemia. J Med Econ. 2016;19:445–61.CrossRefPubMedGoogle Scholar
  31. 31.
    Rochau U, Kluibenschaedl M, Stenehjem D, Kuan-Ling K, Radich J, Oderda G, et al. Effectiveness and cost-effectiveness of sequential treatment of patients with chronic myeloid leukemia in the united states: a decision analysis. Leuk Res Treat. 2015;2015:982395.Google Scholar
  32. 32.
    Efficace F, Baccarani M, Breccia M, Saussele S, Abel G, Caocci G, et al. International development of an EORTC questionnaire for assessing health-related quality of life in chronic myeloid leukemia patients: the EORTC QLQ-CML24. Qual Life Res. 2013;23:825–36.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  1. 1.Department of Internal MedicineSeoul National University Bundang HospitalSeongnam-SiKorea
  2. 2.Department of Internal Medicine, Seoul National University HospitalSeoul National University College of MedicineSeoulKorea
  3. 3.Department of Internal MedicineInje University Haeundae Paik HospitalBusanKorea
  4. 4.Cancer Research InstituteSeoul National University College of MedicineSeoulKorea

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