Prevalence and dynamics of bcr-abl kinase domain mutations during imatinib treatment differ in patients with newly diagnosed and recurrent bcr-abl positive acute lymphoblastic leukemia

Abstract

Imatinib is highly effective in newly diagnosed, but not in relapsed, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph þ ALL). BCR-ABL tyrosine kinase domain (TKD) mutations are associated with acquired imatinib resistance, but their role in primary resistance is uncertain. Using highly sensitive ligation-PCR and denaturing high-performance liquid chromatography (DHPLC), we identified baseline TKD mutations in 21% and 42% of imatinib-naïve patients with newly diagnosed (n ¼ 26) or recurrent (n ¼ 65) Ph þ ALL, respectively (P ¼ ns). Within 4 weeks of starting the imatinib treatment, absolute levels of mutant bcr-abl transcripts increased significantly in patients with advanced, but not with de novo, Ph þ ALL. The net expansion of pre-existing mutant clones during imatinib treatment resulted in the rapid appearance of initially undetectable TKD mutations, which after 4 weeks were detectable in 70% of patients with advanced disease. There was a high degree of concordance between the type of mutations detected at relapse and during initial imatinib treatment. The profoundly different outgrowth dynamics of leukemic clones with bcr-abl mutations in imatinib-treated patients who differ in their disease history, provides clinical --translational evidence for a contributory role of non-mutational resistance mechanisms, possibly induced by prior chemotherapy. Moreover, the prevalence of pre-existing, clinically relevant TKD may have been underestimated in tyrosine kinase inhibitor-naïve patients with Ph þ ALL.

Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance

“…Indeed, we show that these mutations are rapidly selected for in cells upon inhibitor treatment; increasing up to 50-fold in only 3 days selection with a GI 50 concentration. Mutations conferring resistance to BCR-ABL1 inhibitors have also been shown to be present in both pre-and postinhibitor treated tumors (24,44). Likewise, the p.T790M gatekeeper mutation in EGFR has been detected pretreatment in non-small cell lung cancer, although this mutation is thought to have some oncogenic properties (45)(46)(47).…”

Molecular genetics of B-precursor acute lymphoblastic leukemia

“…The addition of imatinib to intensive chemotherapy in childhood BCR-ABL1-positive ALL results in a 4-year event-free survival rate of 84%, more than double that of historical controls (42). A proportion of patients become resistant to these agents, typically through acquired mutations in the ABL1 kinase domain (43).…”

Detection and management of minimal residual disease in acute lymphoblastic leukemia

“…This may not only explain the lack of treatment efficacy when treating with TKI, but also may also affect the utility of RT-PCR monitoring of relapsed Ph ϩ ALL patients. 56 …”