Abstract

Most CML patients are sensitive to imatinib mesylate (IM), however, a small fraction develop resistance, mostly through the emergence onset of BCR-ABL mutation. Dasatinib and nilotinib, novel tyrosine kinase inhibitors (NTKIs), are active against most of IM resistant BCR-ABL kinase domain mutants except T315I. Although T315I mutation has been highly resistant to IM and both NTKIs, precise clinical characteristics and outcome have not been known yet. A total of 81 patients with various phases of CML who were intolerant or were resistant to IM (M:F-52:29, median age: 43 years, range; 12–74 years) were enrolled in this study between May 2005 and Sep 2006. Eighty one patients had received dasatinib and/or nilotinib in phase II or extended access program. At the time of IM failure and every 3 months during NTKIs treatment, mutations were screened by both ASO-PCR and direct sequencing. Clinical characteristics and outcome probabilities were statistically analyzed. T315I was detected in 20 of 31 patients (65%) harboring kinase domain mutations; 9 patients had mutation before NTKIs treatment and 11 patients were developing mutation after NTKIs treatment. Median age was 33 years (range, 19–74 years). Transcripts were Major BCR for all patients and 8 patients had received prior interferon therapy. 6 patients had additional chromosomal abnormalities (ACA) at diagnosis. At the time of T315I emergence, 8 patients were CP, 6 patients were AP, and 6 in BC (4 in myeloid and 2 in lymphoid). Median accumulate dose per day was 398.8 mg/day (range, 205.3–600.0 mg/day). 13 patients were received dasatinib, 5 received nilotinib and 2 received both dasatinib and nilotinib. The best response to NTKIs was complete cytogenetic response (CCyR) in 6 and complete hematologic response (CHR) in 8. Median overall survival (OS) from NTKIs start was 7.0 months for advanced phase and 12.3 months for chronic phase. The 3 year survival rate was 21.5%, with median value was 8.4 months in all patients. With NTKIs therapies [median follow-up, 9.7 months (range, 0.7–27.3 months)], 8 patients are alive (40%); 6 patients are alive with active disease and 2 patients are alive with ongoing response. 10 patients died of disease progression and 2 patients died of pneumonia. Low grade disease phase at discovery of T315I mutation (log-rank P=0.0237) demonstrated significantly favorable outcome but after NTKIs treatment, there was no difference in OS between disease phases (log-rank P=0.271). And there was no difference in OS between T315I mutation and other mutations (P=0.147). However the ACA at diagnosis (P=0.029) and achievement of best CCyR during NTKIs treatment (P=0.085) was different in OS. And there was significant difference in survival between patients with and without ACA and achievement of best CCyR during NTKIs treatment (log-rank P=0.0235), suggesting they have prognostic influences on survival as T315I mutation. In summary, our findings confirm that ACA at diagnosis and achievement of best CCyR during NTKIs treatment are statistically significant prognostic information with respect to survival probability at patients with T315I mutation. However T315I mutation was highly resistant to NTKIs as well as IM, and are associated with poor outcome. As diverse outcomes in patients with T315I mutation have been demonstrated, different strategies such as MK-0457 and/or novel T315I mutation inhibitor should be applied.

Author notes

Disclosure: No relevant conflicts of interest to declare.