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Summary The Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose-optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re-escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR-ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re-escalation). The safety profile of nilotinib was consistent with prior studies. The most common non-haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

Imatinib is widely used to treat chronic myeloid leukemia and gastrointestinal stromal tumors. The agent, administered orally, has approximately 98% oral bioavailability, achieves maximum plasma concentration approximately 2-4 hours after ingestion, and has a plasma half-life of approximately 18 hours. As maintaining an adequate plasma imatinib concentration is essential to achieving a favorable therapeutic response, it is important to determine whether gastrointestinal surgery, pathologic conditions, or anatomic changes negatively affect imatinib absorption, and thereby result in subtherapeutic plasma imatinib concentrations. We describe a 36-year-old, morbidly obese woman with chronic myeloid leukemia who received treatment with alpha-interferon and cytarabine over 5 years. Her chemotherapy was then switched to imatinib 400 mg/day because she failed to achieve a molecular response with the other two agents. A complete molecular response was achieved with imatinib. Four years later, she underwent a sleeve gastrectomy while receiving imatinib. Imatinib plasma pharmacokinetic values were assessed before and on four occasions during the year after the sleeve gastrectomy. The patient's trough plasma concentration before surgery (1558 ng/ml) was consistent with those found in the literature (>/= 1000 ng/ml), whereas her trough concentrations after surgery were 46-60% lower (629-836 ng/ml) than the preoperative value. Despite this, the patient remained in complete molecular remission for 1 year after surgery. Monitoring plasma imatinib concentrations is recommended in morbidly obese patients with chronic myeloid leukemia or gastrointestinal stromal tumors who undergo gastric procedures. Additional pharmacokinetic studies, however, are needed in these patients.

The development of Bcr-Abl tyrosine kinase inhibitors has dramatically changed the prognosis of patients with newly diagnosed chronic myeloid leukemia (CML). Standard-dose imatinib (400 mg/day in chronic phase, 600 mg/day in advanced CML) now dominates the management of this disease, producing considerably higher hematologic, cytogenetic, and molecular response rates than seen with previous drug therapies. However, although many patients respond well to standard-dose imatinib initially, some patients do not achieve adequate levels of response or discontinue therapy because of resistance. One approach to improving treatment response with first-line imatinib may be to increase the imatinib dose (800 mg/day), although recent trial data indicate that overall increases in response rates may be modest. Newer Bcr-Abl tyrosine kinase inhibitors can induce responses in patients with all phases of imatinib-resistant CML, even those with imatinib-resistant mutations in the BCR-ABL gene. Furthermore, in initial studies, first-line dasatinib or nilotinib treatment has produced response rates that compare favorably with historical controls treated with imatinib, although confirmation is required from head-to-head clinical trials. Future clinical approaches may include drug combinations, which may allow quiescent leukemia stem cells to be eradicated. Further improvements in drug treatment for first-line CML are expected during the next few years.