Nilotinib: First-line Treatment Option for Chronic-phase CML?

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In the first head-to-head comparison of targeted oral tyrosine kinase inhibitors as initial treatment for early-stage chronic myeloid leukemia (CML), molecular and cytogenetic remissions were more common with nilotinib compared with imatinib, the previous standard for treating early-stage CML, said Giuseppe Saglio, MD.

The finding could elevate nilotinib to first-line treatment in early CML. Currently, nilotinib is approved for the treatment of patients with Philadelphia chromosome–positive (Ph+) CML in the chronic and accelerated phases who are resistant to prior therapy.

"The superior efficacy and favorable tolerability profile of nilotinib compared with imatinib suggests that nilotinib may become the standard of care in newly diagnosed CML," said Saglio, University of Turin, Italy, and lead investigator of the comparison.

In the open-label study, 846 patients with newly diagnosed Ph+ CML in chronic phase were randomized to either 400 mg of imatinib once daily or 300 mg or 400 mg of nilotinib twice daily. Follow-up lasted about 5 years.

At 12 months, the rates of major molecular response (the primary end point of the study) were 44% with 300 mg nilotinib, 43% with 400 mg of nilotinib, and 22% with 400 mg of imatinib.

The median time to a major molecular response was faster by about 2.5 months in the nilotinib groups compared with the imatinib group.

Saglio noted that molecular monitoring is the most sensitive measure of CML disease burden. "Major molecular response is associated with an extremely low rate of disease progression," he said. Of the patients who experienced progression of disease in this study, none achieved a major molecular response, he said.

Complete cytogenetic responses at 12 months were also significantly better in the nilotinib recipients: 80% with nilotinib 300 mg; 78% with nilotinib 400 mg; and 65% with imatinib 400 mg.

Rates of progression to accelerated phase or blast crisis were 3.9% in the imatinib group compared with less than 0.7% and 0.4% in the patients treated with 300 mg and 400 mg of nilotinib, respectively.

According to Bayard L. Powell, MD, chief, Section of Hematology and Oncology at Wake Forest University, Winston-Salem, North Carolina, the difference between nilotinib and imatinib in rates of progression to accelerated phase or blast crisis is the most meaningful finding of the study, "because people who go into accelerated phase or blast phase don't really have the opportunity for second-line therapy."

Nilotinib was superior to imatinib on efficacy end points across all risk groups of patients based on their Sokal score (a risk index based on six criteria).

Seven percent to 11% of patients in each group discontinued their study drug because of adverse events or abnormalities in laboratory values, with no significant differences between groups. Four percent of patients in the imatinib group discontinued because of treatment failure, 4% discontinued because of disease progression, and 2% because of suboptimal response. Edema and weight gain occurred more often with imatinib therapy. Grade 3 or 4 toxicities were rare in any group.

In commenting on the study, Rick Van Etten, MD, PhD, director of the Tufts Medical Center Cancer Center, Boston, agreed that the finding "could be used to argue for nilotinib as firstline therapy."

More potent agents lead to impressive complete cytogenetic responses
Additional studies of nilotinib and dasatinib, another oral tyrosine kinase inhibitor that is several times as potent as imatinib, show favorable efficacy on major molecular response in patients with newly diagnosed CML. Both sets of data were reported by Jorges E. Cortes, MD, professor and deputy chair, Department of Leukemia, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston.

The two studies he presented were identical in the nature of their design. In the open-label, single-agent trials, the efficacy of either nilotinib, 400 mg twice daily, or dasatinib, 100 mg/day (given as either 50 mg twice daily or 100 mg once daily), was investigated as first-line therapy in chronic-phase CML.

In the nilotinib study, 32 (63%) of 51 patients who were followed for at least 3 months achieved a complete molecular response and 98% achieved a complete cytogenetic response.

In the dasatinib study, major molecular response was achieved in 70% and a complete cytogenetic response was achieved in 98% of the 50 patients who were followed for at least 3 months.

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Last modified: July 22, 2021