Contributions
Abstract: PB1817
Type: Publication Only
Background
While chronic myeloid leukemia (CML) can successfully be treated with tyrosine kinase inhibitors (TKIs), mutations in the BCR-ABL1 kinase domain are the most prevalent cause of TKI resistance. More than 100 BCR-ABL1 kinase domain point mutations with various frequencies of incidence, domain positions and implications on TKI response in CML are associated with TKI resistance. Here we present our data concerning prognostic significance of BCR-ABL1 kinase domain mutations dynamics in Russian CML patients according the follow-up study having been performed during the last 10 years.
Aims
To determine the frequency dynamics of BCR-ABL1 mutations in CML patients and its prognostic significance.
Methods
In this study we have included 1077 TKI resistant CML patients from 112 hospitals of 77 Russian cities having been observed during the period from 2006 to 2016. BCR-ABL1 kinase domain point mutations in mRNA samples from peripheral blood cells were analyzed by means of PCR followed by Sanger sequencing. Statistical analysis was performed using SPSS 22.0 (IBM, USA) and Excel 2013 (Microsoft, USA). Critical p-value was set to 0.05.
Results
1077 TKI resistant CML patients were analyzed, among them were 41,5% men (n=447) and 58,5% women (n=630), median age – 50 (from 15 to 74). BCR-ABL1 mutations were found in 30,8% (332/1077) CML pts. We have detected a total of 415 mutations in 332 patients, giving rise for 58 different mutation variants. Mutation associated resistance rate was higher in women to compare with men (72,3% against 63,2%, p=0,001). It turned out that F317L and H396R mutations were statistically more frequent in women, meanwhile T315I mutation prevailed in men group (Pearson's χ2<0,05). It was of a sudden that BCR-ABL1 mutation distribution significantly varied according the particular CML pts city location throughout the different regions of Russia. Although for the period from 2006 to 2016 there were no detectable changes in mutation frequency spectrum (Pearson’s χ2 is 0,062), the total amount of mutations associated with TKI CML resistance has decreased from 36,6% in 2006-2008 to 24,95% in 2013-2016, but still remained significant. For particular mutations the following dynamics was detected: frequency of imatinib-resistant mutations decreased gradually from 2006 to 2016, while the rate of F317L and F359V mutations underlining resistance to second generation TKI increased in 2013-2016. T315I mutation rate expanded to the maximal level in 2014 and abruptly decreased afterwards. This tendency change may be the consequence of the second generation TKIs and other therapeutic strategies involvement into clinical practice.
Conclusion
As far as different BCR-ABL1 kinase domain mutations are associated with various types of mutation associated resistance to TKI treatment, the detection of trends in mutation distribution in CML patients receiving TKI treatment is very important for long time treatment strategy decision making and early prognosis of resistance. We believe here that regional difference of mutation profiles should also be considered. Therefore, to enable correct triggering of particular types of TKI for CML treatment it is necessary to obtain data of when, which and where a particular type of BCR-ABL1 mutation is prone to appear in a distinguished cohort of CML pts.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Resistance, Mutation, Chronic myeloid leukemia, BCR-ABL
Abstract: PB1817
Type: Publication Only
Background
While chronic myeloid leukemia (CML) can successfully be treated with tyrosine kinase inhibitors (TKIs), mutations in the BCR-ABL1 kinase domain are the most prevalent cause of TKI resistance. More than 100 BCR-ABL1 kinase domain point mutations with various frequencies of incidence, domain positions and implications on TKI response in CML are associated with TKI resistance. Here we present our data concerning prognostic significance of BCR-ABL1 kinase domain mutations dynamics in Russian CML patients according the follow-up study having been performed during the last 10 years.
Aims
To determine the frequency dynamics of BCR-ABL1 mutations in CML patients and its prognostic significance.
Methods
In this study we have included 1077 TKI resistant CML patients from 112 hospitals of 77 Russian cities having been observed during the period from 2006 to 2016. BCR-ABL1 kinase domain point mutations in mRNA samples from peripheral blood cells were analyzed by means of PCR followed by Sanger sequencing. Statistical analysis was performed using SPSS 22.0 (IBM, USA) and Excel 2013 (Microsoft, USA). Critical p-value was set to 0.05.
Results
1077 TKI resistant CML patients were analyzed, among them were 41,5% men (n=447) and 58,5% women (n=630), median age – 50 (from 15 to 74). BCR-ABL1 mutations were found in 30,8% (332/1077) CML pts. We have detected a total of 415 mutations in 332 patients, giving rise for 58 different mutation variants. Mutation associated resistance rate was higher in women to compare with men (72,3% against 63,2%, p=0,001). It turned out that F317L and H396R mutations were statistically more frequent in women, meanwhile T315I mutation prevailed in men group (Pearson's χ2<0,05). It was of a sudden that BCR-ABL1 mutation distribution significantly varied according the particular CML pts city location throughout the different regions of Russia. Although for the period from 2006 to 2016 there were no detectable changes in mutation frequency spectrum (Pearson’s χ2 is 0,062), the total amount of mutations associated with TKI CML resistance has decreased from 36,6% in 2006-2008 to 24,95% in 2013-2016, but still remained significant. For particular mutations the following dynamics was detected: frequency of imatinib-resistant mutations decreased gradually from 2006 to 2016, while the rate of F317L and F359V mutations underlining resistance to second generation TKI increased in 2013-2016. T315I mutation rate expanded to the maximal level in 2014 and abruptly decreased afterwards. This tendency change may be the consequence of the second generation TKIs and other therapeutic strategies involvement into clinical practice.
Conclusion
As far as different BCR-ABL1 kinase domain mutations are associated with various types of mutation associated resistance to TKI treatment, the detection of trends in mutation distribution in CML patients receiving TKI treatment is very important for long time treatment strategy decision making and early prognosis of resistance. We believe here that regional difference of mutation profiles should also be considered. Therefore, to enable correct triggering of particular types of TKI for CML treatment it is necessary to obtain data of when, which and where a particular type of BCR-ABL1 mutation is prone to appear in a distinguished cohort of CML pts.
Session topic: 8. Chronic myeloid leukemia - Clinical
Keyword(s): Resistance, Mutation, Chronic myeloid leukemia, BCR-ABL