February 2014, Vol 3, No 1

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Ph+ CML: Deep Molecular Response Achieved and Sustained More Often With Nilotinib


Three large randomized phase 3 trials demonstrated superiority of nilotinib over imatinib in achieving molecular response (MR) and complete cytogenetic response (CyR) across various populations of patients with Philadelphia chromosome–positive chronic myeloid leukemia (Ph+ CML), including those who had a suboptimal response to frontline imatinib.

LASOR: Frontline Imatinib Failures

In patients who do not achieve a complete CyR with frontline imatinib, higher rates of MR are achieved by switching to nilotinib compared with
escalating the dose of imatinib to 600 mg daily, reported Jorge E. Cortes, MD, chair, CML and AML sections, MD Anderson Cancer Center, Houston, TX.

“Patients with suboptimal CyR to imatinib represent a significant unmet need in the treatment of CML chronic phase,” said Cortes. “This important study is the only randomized evaluation of imatinib dose escalation versus switching to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population.”

The study included 191 adults with suboptimal CyR to frontline treatment with imatinib 400 mg once daily who were randomized to nilotinib 400 mg twice daily or imatinib 600 mg once daily. The primary end point, complete CyR at 6 months, was observed in 49.0% and 42.1% of patients in the nilotinib and imatinib arms, respectively, but this difference failed to achieve significance (P=.3844). The high rate of crossover from imatinib to nilotinib confounded the results, said Cortes. Fifteen patients in the imatinib arm crossed over, compared with 6 in the nilotinib arm.

“None of the nilotinib patients who crossed over to imatinib versus 6 of the 15 imatinib patients who crossed over to nilotinib achieved complete CyR at the primary analysis time point 6 months after randomization,” he noted.

The clinical benefit of nilotinib is therefore best evaluated when considering crossover patients as nonresponders, he said. In this type of analysis, 47 of 86 patients (54.7%) in the nilotinib arm and 34 of 88 (38.6%) in the imatinib arm achieved complete CyR at 6 months.

ENESTnd: Newly Diagnosed Patients

Updated 5-year data from the open-label, randomized multicenter ENESTnd trial support nilotinib as first-line therapy in adults with newly diagnosed Ph+ CML in chronic phase, said Giuseppe Saglio, MD, director of the department of molecular medicine and targeted therapy, University of Turin, Italy. Some 846 patients were randomized to nilotinib 300 mg twice daily, nilotinib 400 mg twice daily, or imatinib 400 mg once daily.

The rates of early and deeper sustained MR, including MR4.5, were higher with nilotinib at either dosage compared with imatinib. At 1 year, the rate of MR4.5 was 6% to 19% greater with nilotinib compared with imatinib, and by 5 years, this difference reached 21% to 23%, said Saglio.
Further, fewer patients on nilotinib progressed to accelerated phase/blast crisis (AP/BC). The estimated rates of patients whose disease did not progress to AP/BC at 5 years were 99.3% and 98.7% in the nilotinib arms (300 mg and 400 mg twice daily, respectively) versus 95.2% in the imatinib arm.

Fifteen patients treated with imatinib had CML-related deaths, compared with 10 patients in the nilotinib arms. Estimated overall survival at 5 years was 93.6% and 96.0% in the nilotinib 300-mg and 400-mg twice-daily arms, respectively, compared with 91.6% in the imatinib arm.

ENESTcmr: Patients With Residual Disease

Three-year data from ENESTcmr, an open-label, randomized phase 3 study, demonstrate that Ph+ CML patients with detectable BCR-ABL following long-term treatment with imatinib achieved deeper molecular responses after switching to nilotinib, reported Brian Leber, MD, associate professor of pathology and molecular medicine, McMaster University, Hamilton, Canada.

In ENESTcmr, 207 patients were randomized to nilotinib 400 mg twice daily or imatinib 400 mg or 600 mg once daily. Seven of 32 responders in the imatinib arm achieved MR4.5 after switching to nilotinib. Among patients without documented MR4.5 at baseline, the cumulative incidence of MR4.5 was higher in patients randomized to nilotinib versus imatinib (46.9% vs 33.3%; P=.0453). MR4.5 was achieved faster, with a median time to response of 24.0 months in the nilotinib arm, and was not reached in the imatinib arm (P=.0011). By 36 months, no patients in either arm had progressed to AP/BC.

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