Tyrosine kinase inhibitor resistance in pediatric chronic myeloid leukemia: a case report
Pediatric chronic myeloid leukemia (CML) is a hematopoietic malignancy, treated by tyrosine kinase inhibitor (TKI). Previously, imatinib resistance in CML was treated with nilotinib as a second line. However, in Indonesia, where the options of TKIs are limited, no case has been reported. We describe TKI-resistance of a pediatric CML case in Dharmais Cancer Hospital, Jakarta. A 17-year-old boy presented with loss of complete hematologic response after 4 years of imatinib treatment. Diagnosis of relapsed CML with blast crisis was confirmed, and nilotinib was given accordingly. He achieved hematological and optimal response after 2 weeks and 3 months of treatment, respectively. However, in the 12-month evaluation, he failed to achieve major molecular response and acquired the second resistance to TKI. Since imatinib resistance marks the poor prognosis, initial optimal response of nilotinib treatment remains inconclusive to predict the final outcome.
Al-Jafar HA, Al-Mulla A, AlDallal S, Buhamad JH, Askar H. Successful nilotinib treatment in a child with chronic myeloid leukemia. Case Rep Oncol. 2015;8(1):122-7. https://doi.org/10.1159/000380905
Medeiros BC, Possick J, Fradley M. Cardiovascular, pulmonary, and metabolic toxicities complicating tyrosine kinase inhibitor therapy in chronic myeloid leukemia: strategies for monitoring, detecting, and managing. Blood Rev. 2018;32(4):289-99. https://doi.org/10.1016/j.blre.2018.01.004
Metibemu DS, Akinloye OA, Akamo AJ, Ojo DA, Okeowo OT, Omotuyi IO, et al. Exploring receptor tyrosine kinases-inhibitors in cancer treatments. Egypt J Med Hum Genet. 2019;20:35. https://doi.org/10.1186/s43042-019-0035-0
Maifrede S, Nieborowska-Skorska M, Sullivan-Reed K, Dasgupta Y, Podszywalow-Bartnicka P, Le BV, et al. Tyrosine kinase inhibitor-induced defects in DNA repair sensitize FLT3(ITD)-positive leukemia cells to PARP1 inhibitors. Blood. 2018;5;132(1):67-77. https://doi.org/10.1182/blood-2018-02-834895
Bauer S, Buchanan S, Ryan I. Tyrosine kinase inhibitors for the treatment of chronic-phase chronic myeloid leukemia: long-term patient care and management. J Adv Pract Oncol. 2016;7(1):42-54. https://doi.org/10.6004/jadpro.2016.7.1.3
Sacha T. Imatinib in chronic myeloid leukemia: an overview. Mediterr J Hematol Infect Dis. 2014;6(1):e2014007. https://doi.org/10.4084/mjhid.2014.007
Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 2009;15(24):7519-27. https://doi.org/10.1158/1078-0432.CCR-09-1068
Zaidi U, Kaleem B, Borhany M, Maqsood S, Fatima N, Sufaida G, et al. Early and sustained deep molecular response achieved with nilotinib in high Sokal risk chronic myeloid leukemia patients. Cancer Manag Res. 2019;11:1493-502. https://doi.org/10.2147/CMAR.S181911
Hijiya N, Schultz KR, Metzler M, Millot F, Suttorp M. Pediatric chronic myeloid leukemia is a unique disease that requires a different approach. Blood. 2018;127(4):392-9. https://doi.org/10.1182/blood-2015-06-648667
Kotiah S. Chronic myelogenous leukemia (CML) staging: phases of chronic myelogenous leukemia [Internet]. Medscape. 2019 [cited 2020 Mar 6]. p. 1. Available from: https://emedicine.medscape.com/article/2006731-overview.
Hochhaus A, Druker BJ, Larson RA, O'Brien SG, Gathmann I, Guilhot F. IRIS 6-year follow-up: sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2007;110(11):25. https://doi.org/10.1182/blood.V220.127.116.11
Millot F, Guilhot J, Baruchel A, Petit A, Bertrand Y, Mazingue F, 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. https://doi.org/10.1182/blood-2014-05-578567
DeAngelo DJ, Attar EC. Use of dasatinib and nilotinib in imatinib-resistant chronic myeloid leukemia: translating preclinical findings to clinical practice. Leuk Lymphoma. 2010;51(3):363-75. https://doi.org/10.3109/10428190903518295
Shin J, Koh Y, Yoon SH, Cho JY, Kim DY, Lee KH, et al. A phase 4 study of nilotinib in Korean patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTKorea. Cancer Med. 2018;7(5):1814-23. https://doi.org/10.1002/cam4.1450
Neelakantan P, Apperley JF. Therapy in Practice: nilotinib for treatment of chronic myeloid leukemia in light of the current evidence and guidelines. Clin Pract. 2013;10(3):283-91. https://doi.org/10.2217/cpr.13.24
Hughes TP, Munhoz E, Aurelio Salvino M, Ong TC, Elhaddad A, Shortt J, et al. Nilotinib dose-optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd. Br J Haematol. 2017;179(2):219-28. https://doi.org/10.1111/bjh.14829
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408-17. https://doi.org/10.1056/NEJMoa062867
FDA. FDA approves nilotinib for pediatric patients with newly diagnosed or resistant/intolerant Ph+ CML in chronic phase [Internet]. 2018 [cited 2020 Jan 5]. p. 1. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nilotinib-pediatric-patients-newly-diagnosed-or-resistantintolerant-ph-cml-chronic.
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(6):872-84. https://doi.org/10.1182/blood-2013-05-501569
Jain P, Kantarjian H, Alattar ML, Jabbour E, Sasaki K, Nogueras Gonzalez G, et al. Analysis of long term responses and their impact on outcomes in patients with chronic phase CML treated with four different TKI modalities - analysis of 5 prospective clinical trials. Lancet Haematol. 2015;2(3):e118-28.
Jain P, Kantarjian H, Nazha A, O'Brien S, Jabbour E, Romo CG, et al. Early responses predict better outcomes in patients with newly diagnosed chronic myeloid leukemia: results with four tyrosine kinase inhibitor modalities. Blood. 2013;121(24):4867-74. https://doi.org/10.1182/blood-2013-03-490128
Chansung K, Sirijerachai C, Lekhakula A, Viboonjuntra P, Niparuck P, Pauvilai T, et al. Nilotinib as second-line therapy in patients with chronic myeloid leukemia in chronic phase: Thailand experience. Blood. 2016;128(22):5448. https://doi.org/10.1182/blood.V128.22.5448.5448
Hochhaus A, Rosti G, Cross NC, Steegmann JL, le Coutre P, Ossenkoppele G, et al. Frontline nilotinib inpatients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia. 2016;30(1):57-64. https://doi.org/10.1038/leu.2015.270
Cannella L, Breccia M, Stefanizzi C, Napoleone L, Santopietro M, Alimena G. Dasatinib overcomes imatinib and nilotinib failure in Philadelphia chromosome positive chronic myeloid leukemia with different mechanisms of resistance. Leuk Lymphoma. 2009;50(5):848-50. https://doi.org/10.1080/10428190902829425
Copyright (c) 2020 Mururul Aisyi, Ayu Hutami Syarif, Nur Asih, Agus Kosasih
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Authors who publish with Medical Journal of Indonesia agree to the following terms:
- Authors retain copyright and grant Medical Journal of Indonesia right of first publication with the work simultaneously licensed under a Creative Commons Attribution-NonCommercial License that allows others to remix, adapt, build upon the work non-commercially with an acknowledgment of the work’s authorship and initial publication in Medical Journal of Indonesia.
- Authors are permitted to copy and redistribute the journal's published version of the work non-commercially (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in Medical Journal of Indonesia.