In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

BackgroundTyrosine kinase inhibitors (TKIs) have dramatically changed the prognosis of patients with chronic myeloid leukemia (CML). They have a distinct toxicity profile that includes glycometabolic alterations: i.e. diabetes mellitus (DM), impaired fasting glucose (IFG), and the metabolic syndrome (MS). The aim of this study was to evaluate the prevalence of these alterations in a cohort of CML-chronic phase patients treated with imatinib, dasatinib or nilotinib.MethodsThe study involved 168 consecutive CML-chronic phase patients with no history of DM/IFG or MS. Anthropometric and metabolic parameters were assessed, and DM/IFG and MS were diagnosed based on the criteria of the American Diabetes Association and the National Cholesterol Education Program-Adult Treatment Panel III, respectively.ResultsThe nilotinib group had significantly higher levels of fasting plasma glucose, insulin, C-peptide, insulin resistance, and total and LDL cholesterol than the imatinib and dasatinib groups. DM/IFG were identified in 25% of the imatinib- and dasatinib-treated patients, and 33% of those in the nilotinib cohort (p = 0.39 vs imatinib and p = 0.69 vs dasatinib). A diagnosis of MS was made in 42.4% of the imatinib-treated patients, 37.5% of the dasatinib-treated patients, and 36.1% of the nilotinib-treated patients (p = 0.46 vs imatinib and p = 0.34 vs dasatinib).ConclusionsTreatment with nilotinib does not seem to induce DM/IFG or the MS to a significantly higher extent than imatinib or dasatinib, though it causes a worse glycometabolic profile. These findings suggest the need for a close monitoring of glucose and lipid metabolism and a multidisciplinary approach in patients treated with nilotinib.