Epigenetic modifier gene mutations in chronic myeloid leukemia (CML) at diagnosis are associated with risk of relapse upon treatment discontinuation

Non peer reviewe

Impact of age on efficacy and toxicity of nilotinib in patients with chronic myeloid leukemia in chronic phase : ENEST1st subanalysis

Purpose Achievement of deep molecular response with a tyrosine kinase inhibitor in patients with chronic myeloid leukemia (CML) is required to attempt discontinuation of therapy in these patients. The current subanalysis from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study evaluated whether age has an impact on the achievement of deeper molecular responses or safety with frontline nilotinib in patients with CML. Methods ENEST1st is an open-label, multicenter, single-arm, prospective study of nilotinib 300 mg twice daily in patients with newly diagnosed CML in chronic phase. The patients were stratified into the following 4 groups based on age: young (18-39 years), middle age (40-59 years), elderly (60-74 years), and old (>= 75 years). The primary end point was the rate of molecular response 4 ([MR4] BCR-ABL1 Results Of the 1091 patients enrolled, 1089 were considered in the analysis, of whom, 23% (n = 243), 45% (n = 494), 27% (n = 300), and 5% (n = 52) were categorized as young, middle age, elderly, and old, respectively. At 18 months, the rates of MR4 were 33.9% (95% confidence interval [CI], 27.8-40.0%) in the young, 39.6% (95% CI, 35.3-44.0%) in the middle-aged, 40.5% (95% CI, 34.8-46.1%) in the elderly, and 35.4% (95% CI, 21.9-48.9%) in the old patients. Although the incidence of adverse events was slightly different, no new specific safety signals were observed across the 4 age groups. Conclusions This subanalysis of the ENEST1st study showed that age did not have a relevant impact on the deep molecular response rates associated with nilotinib therapy in newly diagnosed patients with CML and eventually on the eligibility of the patients to attempt treatment discontinuation.Peer reviewe

Dasatinib crosses the blood-brain barrier and is an efficient therapy for central nervous system philadelphia chromosome positive leukemia

Although imatinib, a BCR-ABL tyrosine kinase inhibitor, is used to treat acute Philadelphia chromosome-positive (Ph+) leukemia, it does not prevent central nervous system (CNS) relapses resulting from poor drug penetration through the blood-brain barrier. Imatinib and dasatinib (a dual-specific SRC/BCR-ABL kinase inhibitor) were compared in a pre-clinical mouse model of intracranial Ph+ leukemia. Clinical dasatinib treatment in patients with CNS Ph+ leukemia was assessed. In preclinical studies, dasatinib increased survival, whereas imatinib failed to inhibit intracranial tumor growth. Stabilization and regression of CNS disease were achieved with continued dasatinib administration. The drug also demonstrated substantial activity in 11 adult and pediatric patients with CNS Ph+ leukemia. Eleven evaluable patients had clinically significant, long-lasting responses, which were complete in 7 patients. In 3 additional patients, isolated CNS relapse occurred during dasatinib therapy; and in 2 of them, it was caused by expansion of a BCR-ABL-mutated dasatinib-resistant clone, implying selection pressure exerted by the compound in the CNS. Dasatinib has promising therapeutic potential in managing intracranial leukemic disease and substantial clinical activity in patients who experience CNS relapse while on imatinib therapy. This study is registered at ClinicalTrials. gov as CA180006 (#NCT00108719) and CA180015 (#NCT00110097)