Skip to main content
SpringerLink
Log in

Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia

Pediatric Drugs volume 20, pages 593–600 (2018)Cite this article

Abstract

Chronic myeloid leukemia (CML) is a rare hematopoietic stem cell disease that is typically characterized by the abnormal BCR-ABL1 fusion gene on the Philadelphia (Ph) chromosome in neoplastic cells. Dasatinib (Sprycel®) is an orally administered, small molecule tyrosine kinase inhibitor indicated for the treatment of certain hematological malignancies, including Ph-positive CML in the chronic phase (Ph+ CML-CP) in adult and pediatric patients. In open-label phase 1 and phase 2 clinical trials, dasatinib produced early and durable target responses (i.e. molecular, cytogenetic and/or hematologic) in pediatric patients with Ph+ CML-CP that was newly diagnosed or resistant/intolerant to imatinib, with some recipients of the drug also experiencing deep molecular responses. Dasatinib therapy in pediatric patients with Ph+ CML-CP was reported to have a similar safety profile to that observed in adults, except there were no occurrences of pleural effusion, pericardial effusion, pulmonary edema, or pulmonary hypertension adverse events. Although long-term outcomes remain to be determined, dasatinib expands the first- and second-line options available for the treatment of Ph+ CML-CP in pediatric patients.

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

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

References

  1. Hochhaus A, Saussele S, Rosti G, et al. Chronic myeloid leukaemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(Suppl 4):iv41–51.

    Article  CAS  Google Scholar 

  2. Quintás-Cardama A, Cortes J. Molecular biology of bcr-abl1–positive chronic myeloid leukemia. Blood. 2009;113(8):1619–30.

    Article  Google Scholar 

  3. Höglund M, Sandin F, Simonsson B. Epidemiology of chronic myeloid leukaemia: an update. Ann Hematol. 2015;94(2):241–7.

    Article  Google Scholar 

  4. Suttorp M, Millot F. Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. Hematol Am Soc Hematol Educ Program. 2010;2010(1):368–76.

    Article  Google Scholar 

  5. SEER. Cancer stat facts: leukemia - chronic myeloid leukemia (CML). 2018. https://www.seer.cancer.gov/. Accessed 7 Sep 2018.

  6. Millot F, Traore P, Guilhot J, et al. Clinical and biological features at diagnosis in 40 children with chronic myeloid leukemia. Pediatrics. 2005;116(1):140–3.

    Article  Google Scholar 

  7. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN guidelines): chronic myelogenous leukemia (version 1.2018). 2018. https://www.nccn.org/. Accessed 7 Sep 2018.

  8. Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–84.

    Article  CAS  Google Scholar 

  9. Roskoski R Jr. Classification of small molecule protein kinase inhibitors based upon the structures of their drug-enzyme complexes. Pharmacol Res. 2016;103:26–48.

    Article  CAS  Google Scholar 

  10. Bristol-Myers Squibb Company. Sprycel® (dasatinib): US prescribing information. 2006. http://www.packageinserts.bms.com/pi/pi_sprycel.pdf. Accessed 11 Sep 2018.

  11. European Medicines Agency. Dasatinib (Sprycel): EU summary of product characteristics. 2018. http://www.ema.europa.eu/docs/. Accessed 5 Sep 2018.

  12. Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47(27):6658–61.

    Article  CAS  Google Scholar 

  13. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65(11):4500–5.

    Article  Google Scholar 

  14. Tokarski JS, Newitt JA, Chang CY, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006;66(11):5790–7.

    Article  CAS  Google Scholar 

  15. Vajpai N, Strauss A, Fendrich G, et al. Solution conformations and dynamics of ABL kinase inhibitor complexes determined by NMR substantiate the different binding modes of imatinib/nilotinib and dasatinib. J Biol Chem. 2008;283(26):18292–302.

    Article  CAS  Google Scholar 

  16. Reddy EP, Aggarwal AK. The ins and outs of bcr-abl inhibition. Genes Cancer. 2012;3(5–6):447–54.

    Article  CAS  Google Scholar 

  17. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305(5682):399–401.

    Article  CAS  Google Scholar 

  18. Jabbour E, Kantarjian HM, Jones D, et al. Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors. Blood. 2008;112(13):4839–42.

    Article  CAS  Google Scholar 

  19. Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007;92(3):401–4.

    Article  CAS  Google Scholar 

  20. Redaelli S, Piazza R, Rostagno R, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27(3):469–71.

    Article  CAS  Google Scholar 

  21. Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell. 2003;112(6):831–43.

    Article  CAS  Google Scholar 

  22. Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2(2):117–25.

    Article  CAS  Google Scholar 

  23. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–41.

    Article  CAS  Google Scholar 

  24. Garcia-Gomez A, Ocio EM, Crusoe E, et al. Dasatinib as a bone-modifying agent: anabolic and anti-resorptive effects. PLoS One. 2012;7(4):e34914.

    Article  CAS  Google Scholar 

  25. Vandyke K, Dewar AL, Farrugia AN, et al. Therapeutic concentrations of dasatinib inhibit in vitro osteoclastogenesis. Leukemia. 2009;23(5):994–7.

    Article  CAS  Google Scholar 

  26. Brownlow N, Mol C, Hayford C, et al. Dasatinib is a potent inhibitor of tumour-associated macrophages, osteoclasts and the FMS receptor. Leukemia. 2009;23(3):590–4.

    Article  CAS  Google Scholar 

  27. Vandyke K, Dewar AL, Diamond P, et al. The tyrosine kinase inhibitor dasatinib dysregulates bone remodeling through inhibition of osteoclasts in vivo. J Bone Miner Res. 2010;25(8):1759–70.

    Article  CAS  Google Scholar 

  28. Schiffer CA, Cortes JE, Hochhaus A, et al. Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia: effects on response and toxicity. Cancer. 2016;122(9):1398–407.

    Article  CAS  Google Scholar 

  29. Kim DH, Kamel-Reid S, Chang H, et al. Natural killer or natural killer/T cell lineage large granular lymphocytosis associated with dasatinib therapy for Philadelphia chromosome positive leukemia. Haematologica. 2009;94(1):135–9.

    Article  CAS  Google Scholar 

  30. European Medicines Agency. Assessment report: Sprycel. 2018. http://www.ema.europa.eu/ema/. Accessed 5 Sep 2018.

  31. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362(24):2260–70.

    Article  CAS  Google Scholar 

  32. Keating GM. Dasatinib: a review in chronic myeloid leukaemia and Ph+ acute lymphoblastic leukaemia. Drugs. 2017;77(1):85–96.

    Article  CAS  Google Scholar 

  33. Zwaan CM, Rizzari C, Mechinaud F, et al. Dasatinib in children and adolescents with relapsed or refractory leukemia: results of the CA180-018 phase I dose-escalation study of the Innovative Therapies for Children with Cancer Consortium. J Clin Oncol. 2013;31(19):2460–8.

    Article  CAS  Google Scholar 

  34. Porkka K, Koskenvesa P, Lundan T, et al. Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system Philadelphia chromosome-positive leukemia. Blood. 2008;112(4):1005–12.

    Article  CAS  Google Scholar 

  35. Migden MR, Rischin D, Schmults CD, et al. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma. N Engl J Med. 2018;379(4):341–51.

    Article  CAS  Google Scholar 

  36. Christopher LJ, Cui D, Wu C, et al. Metabolism and disposition of dasatinib after oral administration to humans. Drug Metab Dispos. 2008;36(7):1357–64.

    Article  CAS  Google Scholar 

  37. Gore L, Kearns PR, de Martino ML, et al. Dasatinib in pediatric patients with chronic myeloid leukemia in chronic phase: results from a phase II trial. J Clin Oncol. 2018;36(13):1330–8.

    Article  Google Scholar 

  38. Cortes JE, Saglio G, Kantarjian HM, 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(20):2333–40.

    Article  CAS  Google Scholar 

  39. Shah NP, Rousselot P, Schiffer C, 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.

    Article  CAS  Google Scholar 

  40. Buchdunger E, Zimmermann J, Mett H, et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res. 1996;56(1):100–4.

    CAS  PubMed  Google Scholar 

  41. Millot F, Guilhot J, Baruchel A, et al. Impact of early molecular response in children with chronic myeloid leukemia treated in the French Glivec phase 4 study. Blood. 2014;124(15):2408–10.

    Article  CAS  Google Scholar 

  42. Hijiya N, Schultz KR, Metzler M, et al. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2016;127(4):392–9.

    Article  CAS  Google Scholar 

  43. Copland M, Hamilton A, Elrick LJ, 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(11):4532–9.

    Article  CAS  Google Scholar 

  44. Graham SM, Jørgensen HG, Allan E, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002;99(1):319–25.

    Article  CAS  Google Scholar 

  45. Jørgensen HG, Allan EK, Jordanides NE, et al. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34 + CML cells. Blood. 2007;109(9):4016–9.

    Article  Google Scholar 

  46. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108(6):1809–20.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

During the peer review process, the manufacturer of dasatinib was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.

Author information

Authors and Affiliations

  1. Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand

    Emma H. McCafferty, Sohita Dhillon & Emma D. Deeks

Authors
  1. Emma H. McCafferty
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sohita Dhillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Emma D. Deeks
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emma H. McCafferty.

Ethics declarations

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

Emma McCafferty, Sohita Dhillon and Emma Deeks are salaried employees of Adis/Springer, are responsible for the article content and declare no relevant conflicts of interest.

Additional information

The manuscript was reviewed by: F. Millot, Department of Pediatric Hematology-Oncology, CIC 1402 INSERM, CHU la Milétrie, Poitiers, France; F. Mechinaud, The Royal Children’s Hospital, Melbourne, Australia.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McCafferty, E.H., Dhillon, S. & Deeks, E.D. Dasatinib: A Review in Pediatric Chronic Myeloid Leukemia. Pediatr Drugs 20, 593–600 (2018). https://doi.org/10.1007/s40272-018-0319-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-018-0319-8

search

Navigation