BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance

Abstract

Background:BCR-ABL1 mutation analysis is recommended for chronic myeloid leukaemia patients. However, mutations may become undetectable after changing therapy, and it is unknown whether they have been eradicated.Methods:We examined longitudinal data of patients with imatinib-resistant mutations, which became undetectable by Sanger sequencing to determine whether mutations could reappear, and the related circumstances.Results:Identical imatinib- and nilotinib-resistant mutations reappeared following further therapy changes in five patients, and was associated with subsequent nilotinib resistance in four.Conclusion:The data suggest that some BCR-ABL1 mutations may persist at undetectable levels for many years after changing therapy, and can be reselected and confer resistance to subsequent inhibitors.

The impact of multiple low-level BCR-ABL1 mutations on response to ponatinib

“…Of the remaining 37 mutations, 6 had previously been detected by Sanger sequencing in samples from the same patients collected during prior therapy (T315I, n 5 2; E255V, n 5 2; Y253H and E275K, n 5 1 each); the other 31 mutations had not been previously detected (T315I, n 5 7; E255K, n 5 10; E255V, n 5 4; Y253H, n 5 3; Q252H, n 5 2; and L298V, F317L, M351T, F359V, and F359I, n 5 1 each). This indicates the enrichment or expansion of preexisting mutant clones present below the detection sensitivity of MS 23 were observed in 7 patients. Since we demonstrated previously that CP-CML patients with .1 mutation detectable by MS after imatinib resistance were significantly more likely to acquire new mutations during second-line therapy with nilotinib or dasatinib than patients with #1 mutation, 5 we investigated whether this was also the case for patients treated with ponatinib.…”

Compound mutations in BCR-ABL1 are not major drivers of primary or secondary resistance to ponatinib in CP-CML patients

“…Previous studies have demonstrated that some mutants can be rapidly deselected in the absence of kinase inhibition. [21][22][23] Therefore, some mutations may have become undetectable by SS at the time of the postbaseline analysis. Of the 129 patients evaluated, 8 harbored mutations that were not detected at baseline by NGS (Table 3).…”

Utilization of Next-Generation Deep Sequencing to Analyze BCR-ABL1 Kinase Domain Mutation for Imatinib-Resistant Chronic Myeloid Leukemia Patients in Vietnam

“…The mutation can persist at low level for many years before leading to subsequent therapy resistance. [6,7]. Therefore, NGS is suitable for sensitive detection of BCR-ABL1 relevant to TKI choice in imatinib-resistant patients and this is strongly supported by Soverini et al [29].…”

“…Despite the high response rate, treatment resistance to TKIs within CML patients have been observed elsewhere, which count for 20%-40% [5]. Primary (intrinsic) resistance is defined as lack of initial response and secondary (acquired) resistance is defined as loss of achieved response during TKI treatment [6,7]. According to the National Comprehensive Cancer Network (NCCN) guidelines version 4, 2016, resistance is defined as the patients who gained no achieved response, or failed to achieve partial cytogenetic response (PCyR) at 3 months, or failed to achieve complete cytogenetic response at 12 months and 18 months.…”