Nilotinib shows improved response in newly diagnosed CML

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Nilotinib Bests Imatinib for Newly Diagnosed Chronic-Phase CML
Elsevier Global Medical News. 2009 Dec 10, S London

NEW ORLEANS (EGMN) - Nilotinib is superior to imatinib for inducing deep remissions in patients with newly diagnosed chronic myeloid leukemia in the chronic phase, according to results of the first head-to-head trial of these two oral agents in this setting.

Compared with imatinib (Gleevec), which is the current standard of care for chronic myeloid leukemia (CML), nilotinib (Tasigna) is a more potent and more selective inhibitor of the BCR-ABL protein that drives the disease, lead author Dr. Giuseppe Saglio said at the annual meeting of the American Society of Hematology.

The major molecular response rate was twice as high in the nilotinib arm of the 846-patient study, he reported. In addition, significantly fewer patients progressed to accelerated phase or blast crisis. "Despite the excellent results that can be achieved with imatinib, progression still occurs in a small proportion of patients and is associated with a poor outcome in terms of overall survival," Dr. Saglio noted.

The randomized, open-label, phase III trial - called ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials of Newly Diagnosed Patients) - enrolled adults from 35 countries who had received a diagnosis of Philadelphia chromosome-positive (Ph+) CML in chronic phase in the past 6 months. The only prior therapies permitted were hydroxyurea, anagrelide, and up to 2 weeks of imatinib.

The patients were stratified by Sokal risk score and assigned to nilotinib 300 mg twice daily (282 patients), nilotinib 400 mg twice daily (281 patients), or imatinib 400 mg once daily (283 patients).

Overall, the trial population had a median age of 47 years. Importantly, 28% of patients had high-risk Sokal scores, noted Dr. Saglio, who is a hematologist at the University of Turin (Italy).

With a median follow-up of 14 months, the median dose intensity was nearly the same as the planned dose in all three treatment groups. "This means the treatments were well tolerated," he commented. In all, 16% of imatinib patients had dose escalation to 400 mg twice daily, as allowed by the protocol.

The rates of study discontinuation because of adverse events or laboratory abnormalities were 7% with lower-dose nilotinib, 11% with higher-dose nilotinib, and 8% with imatinib.

In intention-to-treat analyses, the 12-month rates of major molecular response (a reduction of the ratio of BCR-ABL:ABL to 0.1% or less on the international scale) were twice as high with nilotinib at the lower dose and the higher dose (44% and 43%, respectively) as with imatinib (22%) (P less than .0001 for both comparisons).

Moreover, patients treated with nilotinib were more likely to have deeper major molecular responses, both in terms of a reduction of the BCR-ABL:ABL ratio to 0.01% or less (24% and 21% vs. 10%) and in terms of a reduction of this ratio to 0.0032% or less - the most sensitive measure of leukemic burden available (13% and 12% vs. 4%).

The 12-month rates of complete cytogenetic response were also better with nilotinib at both the lower dose (80%) and higher dose (78%), compared with imatinib (65%) (P less than .0001 and P = .0005, respectively).

Fully 3.9% of patients assigned to imatinib progressed to accelerated phase or blast crisis, but only 0.7% assigned to lower-dose nilotinib and 0.4% assigned to higher-dose nilotinib did (P = .0095 and P = .0037, respectively). None of the patients who achieved a major molecular response had such progression, whereas three achieving complete cytogenetic response did, Dr. Saglio noted, confirming that "the quality of the response is the best predictor of the risk of undergoing subsequent progression of disease."

Rates of drug-related adverse events of grade 3/4 were generally low in all groups, although grade 3/4 neutropenia occurred in 10%-12% of nilotinib patients and in 20% of imatinib patients. The imatinib group was more likely to experience nausea, muscle spasms, diarrhea, vomiting, and fluid retention of any grade, whereas the nilotinib groups were more likely to experience rash, headache, pruritus, and alopecia of any grade.

Cardiac QTcF prolongation by greater than 30 msec occurred in 26% of nilotinib patients, compared with 18% of their imatinib counterparts, but prolongation by more than 60 msec was rare. None of the patients had a decrease in left ventricular ejection fraction.

"Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML patients," Dr. Saglio concluded.

He disclosed that he is a consultant and a member of the speakers bureau for Novartis and Bristol-Myers Squibb Co.

Imatinib is the standard first-line treatment for Ph+ CML. Nilotinib and dasatinib (Sprycel) are Food and Drug Administration-approved for treatment of patients who become resistant to or intolerant of imatinib therapy. Both drugs are in clinical trials designed to lead to applications for approval as first-line therapies.

Commenting on the nilotinib trial in an interview, Dr. Richard A. Van Etten, director of the Tufts Medical Center Cancer Center in Boston, noted that although responses to imatinib catch up with those to newer tyrosine kinase inhibitors like nilotinib by 18-24 months, patients are at risk for progression in the interim. Aside from cardiotoxicity, the adverse effect profile of nilotinib is better, he noted.

But comparative costs will be an issue, given that imatinib will become generic in 2014, according to Dr. Van Etten. Indeed, he said, some companies claim that they will be able to manufacture the drug for only $5 per treatment day.

"If [nilotinib] gets approved based on [ENESTnd] data," he predicted, "you will find a lot of people using it because the argument will be, why have this vulnerable period and put patients at risk of disease progression when you can give a drug that has a better toxicity profile - costs be damned."

A reasonable alternative strategy, he added, would be to use imatinib with intensive monitoring to catch the rare progressions very early and intervene with salvage therapy.