PROGNOSTIC VALUE OF ADDITIONAL CHROMOSOMAL ABERRATIONS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA ON TYROSINEKINASE INHIBITORS THERAPY
About the author:
Dmytrenko I. V., Minchenko Zh. M., Fedorenko V. G., Dyagil I. S.
Type of article:
Prognostic significance of additional chromosomal abnormalities (ACAs) for tyrosinekinase inhibitors therapy (TKI) response in chronic myeloid leukemia (CML) patients is discussed. In many ways, this uncertainty is dueto the low frequency as well as the high variability of ACAs in patients with chronic phase CML. In this study, rate of this phenomenon and its impact on the resistance to TKI therapy in CML patients was evaluated. Overall, 502 (91.8%) patients had only the classic translocation t(9;22)(q34;q11) without ACAs at diagnosis. 45 (8.2%) patients presented with additional cytogenetic findings at diagnosis: 29 (5.3%) patients had variant translocations t(9;V;22), which were formed by three chromosomes, and in 16 patients (2.9%) had ACAs. One patient had both and was included in the group of patients with ACAs. The analysis of the tumor clone reduction dynamics by the Kaplan-Meier method did not reveal statistically significant differences in the cumulative complete cytogenetic and major molecular response rates (p = 0.712 and p = 0.111 respectively) between the patients with classical translocation t(9;22), patients with variant translocations and patients with ACAs. Analysis of long-term outcomes demonstrated inferior event-free (EFS), progression-free (PFS) and overall survival (OS) in CML patients with ACA at diagnosis. At 3 years, for patients with a classic translocation, patients with ACAs, and patients with a variant translocation t(9;V;22), the probability of EFS was 84,9% (95% СI, 81,2% – 88,6%), 93,8% (95% CI, 81,8% – 100,0%) and 43,9% (95% CI, 17,4% – 70,4%), respectively. The probability of PFS was 92,0% (95% СІ, 89,3% – 94,7%), 93,3% (95% СІ, 80,8% – 100,0%) and 60,6% (95% СІ, 35,9% – 85,3%), respectively. The probability of OS was 93,8% (95% CІ, 91,3% – 96,4%), 93,8% (95% CІ, 82,1% – 100,0%) and 76,2% (95% CІ, 65,2% – 87,2%), respectively. No statistical difference was observed between the patients with classic translocation t(9;22) and those with variant translocations in terms of EFS, PFS and OS. Chromosomal abnormalities that appeared in CML patients at diagnosis and are not classic CML-specific translocation t(9;22)(q34;q11) may impair the prognosis of disease outcome. The presence of variant transactions in diagnosis does not impact the TKI therapy effectiveness. Additional chromosomal abnormalities in Ph+ cells lead to loss of the achieved cytogenetic and/or molecular response, disease progression, and the overall survival reduction in CML patients, treated with TKI.
chromosomal aberrations, chronic myeloid leukemia, prognostic factors, resistance, tyrosine kinase inhibitors.
- de Klein A, van Kessel AG, Grosveld G, Bartram CR, Hagemeijer A, Bootsma D, et al. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature. 1982;300(5894):765-7.
- Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36(1):93-9.
- Wang W, Cortes JE, Tang G, Khoury JD, Wang S, Bueso-Ramos CE, et al. Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy. Blood. 2016;127:2742-50.
- Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood. 2013;122(6):872-84.
- Cortes JE, Talpaz M, O’Brien S, Faderl S, Garcia-Manero G, Ferrajoli A, et al. Staging of chronic myeloid leukemia in the imatinib era: an evaluation of the World Health Organization proposal. Cancer. 2006;106(6):1306-15.
- Shaffer LG, McGowan-Jordan J, Schmid M. ISCN 2013: An International System for Human Cytogenetic Nomenclature (2013). Basel: Karger; 2013. 140 p.
- Hasting R, Howell R, Bricarelli FD, Kristoffersson U, Cavani S. General Guidelines and Quality Assurance for Cytogenetics. E.C.A. News Letter. 2012;29:7-27.
- Atramentova LA. Dizayn i statistika biologicheskogo issledovania. Kharkov: NTMT; 2015. 269 s. [in Russian].
- Sharashova YeYe, Kholmatova KK, Gorbatova MA, Grzhibovskiy AM. Primeneniye analiza vyzhivayemosti v zdravookhranenii s ispol’zovaniyem paketa statisticheskikh programm SPSS. Nauka i zdravookhraneniye. 2017;5:5-28. [in Russian].
- Milojkovic1 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.
Publication of the article:
«Bulletin of problems biology and medicine» Issue 1 Part 2 (149), 2019 year, 229-234 pages, index UDK 575.116.4:616.155.392-002.2-037-085