1. Fuerst, Markl L.

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ORLANDO, Florida-Dose optimization of the second-generation tyrosine kinase inhibitor nilotinib leads to high rates of major molecular response (MMR) at two years in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP), according to data presented here at the ASH Annual Meeting (Abstract 344).

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In the pivotal "Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients" (ENESTnd) study, frontline nilotinib in 300 mg and 400 mg twice-daily doses resulted in higher rates of deep molecular response and lower rates of disease progression than use of imatinib in patients with CML-CP.


Some patients in the lower-dose nilotinib arm with suboptimal response or treatment failure entered an extension study in which they received the higher dose of the drug, following dose escalation. "Several patients achieved improved responses, and minimal changes in the safety profile were seen," said the study's lead author, Timothy P. Hughes, MD, of the South Australian Health and Medical Research Institute and Clinical Professor of Medicine at the University of Adelaide.


Study Details

The ENEST-Extending Molecular Responses (ENESTxtnd) study was conducted to further investigate the efficacy and safety of frontline nilotinib and evaluate novel dose optimization strategies. The 24-month, Phase III study included 421 de novo patients, median age of 48, with CML-CP within six months of diagnosis.


The initial dose of nilotinib for all patients was 300 mg twice daily, with dose escalation to 400 mg twice daily permitted for patients with suboptimal response or when treatment remained ineffective.


Hughes reported that dose reduction to nilotinib at 450 mg once daily was performed as required by the protocol, and re-escalation was permitted following improvement from adverse events. Successful re-escalation was defined as four or more weeks of nilotinib at 300 mg twice daily with no dose adjustments for any adverse events.


The primary endpoint was the rate of major molecular response by 12 months. A total of 78 percent of the patients completed 24 months of treatment. "The vast majority of patients were on the desired dose, and 20 percent dose-escalated and remained on the higher dose," Hughes said.


Two-thirds of the patients successfully attempted re-escalation, and 71 percent of them achieved MMR. The median time to first MMR was six months for all patients.


Of the 88 patients with dose escalation due to a lack of efficacy, three of 10 patients who escalated doses at three months achieved MMR. "It is difficult to get these patients into molecular response," Hughes noted. Among the 22 patients who dose-escalated at six months, 55 percent achieved MMR.


Among the 144 patients with dose reductions, 85 percent had an MMR with re-escalation, which compares favorably with the results in the ENESTnd trial, he said. The dose intensity was increased slowly, which led to fewer discontinuations than in the earlier trial.


The cumulative rates of MMR were higher in the ENESTxtnd trial (71% at 12 months, 81% at 24 months) than in the earlier ENESTnd trial (55% at 12 months, 71% at 24 months).


Only seven patients had disease progression, and three of them did not have a complete cytogenetic response. The majority of patients progressed after 12 months, he said.


The estimated progression-free survival and overall survival rates were both 97 percent at 24 months.


Side Effects

The most frequently reported non-hematologic adverse events were headache (18.5% of patients), rash (18.3%), and nausea (14.5%). The cardiovascular event rate was 4.5 percent, which was equivalent to the rate in the earlier trial, Hughes noted. This included ischemic heart disease (14 patients), ischemic cerebrovascular event (one patient), peripheral artery disease (five patients), and another cardiovascular event (one patient).


Hematologic toxicity-primarily neutropenia and thrombocytopenia-was as expected. "The safety profile was similar to that in other reports of frontline nilotinib," Hughes said.


Summing Up

Summing up, he said that 21 percent of patients dose-escalated due to lack of efficacy, and about two-thirds of them then achieved an MMR by 24 months. One-third of patients had dose reductions, and about two-thirds of them successfully re-escalated to a dose of nilotinib of 300 mg twice daily, with the vast majority achieving MMR by 24 months.


"Results from this study demonstrated the feasibility of nilotinib dose-optimization with high response rates among patients with dose adjustments and a high rate of successful dose re-escalation among patients with dose reductions."


Dose optimization may have contributed to the high rates of MMR by one and two years, he added. "Overall, results from ENESTxtnd were consistent with those from prior studies and support frontline nilotinib for patients with newly diagnosed CML."


'Extremely Powerful Drug, but with an Achilles Heel'

In an interview, the moderator of a news conference that featured the study, Guiseppe Saglio, MD, Professor of Hematology at the University of Turin and San Luigi University Hospital in Italy, said: "It is important to understand the optimization of the best dose of nilotinib. Nilotinib is an extremely powerful drug. But it has an Achilles heel of a higher incidence of cardiovascular events. With time, this accumulates. Dose dependency has been established in several studies. To have the best efficacy and less toxicity, we need to provide nilotinib therapy to achieve fast molecular responses."