Long-term outcome of patients with chronic myeloid leukemia treated with second generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations. Blood [Blood] Journal article

Secondary imatinib resistance in CML is due in 50% of cases to up to 75 different mutations in the BCR-ABL kinase domain, necessitating switch to one of several new tyrosine kinase inhibitors (TKIs) that act differentially on mutated BCR-ABL. We assess here whether scoring mutation based on in vitro IC50 of each TKI-mutation pair can predict long-term clinical outcome. Among 169 patients with CML after imatinib failure, mutations were detected prior to TKI switch in 41 (48%) treated with dasatinib and 45 (52%) treated with nilotinib. IC50 values for each TKI-mutation pair were stratified into high (n=42), intermediate (n=25), low (T315I, n=9), or unknown sensitivity (n=10). Hematologic and cytogenetic response rates were similar for patients with or without mutations. For patients in chronic phase (CP), hematologic and cytogenetic responses correlated with mutation score; tumors with low and intermediate scores having lower response rates than those with highly sensitive mutations, and worse event-free and overall survival. These correlations with overall survival were not seen for advanced phases. Mutation scoring can predict outcome in CML-CP with imatinib failure treated with second generation TKIs and can help in therapy selection. More complex prognostic models will be required for advanced stages of disease.

Blood [Blood]