Nilotinib leads to sustained responses in CML patients with residual disease on imatinib

For chronic myeloid leukemia (CML) patients with minimal residual disease on long-term imatinib (Gleevec) therapy, switching to nilotinib (Tasigna) can lead to deep, sustained responses.

The 2-year results from the ENESTcmr (Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Complete Molecular Response) trial show that switching to nilotinib leads to deeper molecular responses in patients who still had evidence of residual disease after long-term therapy with imatinib.

“Significantly more patients achieved confirmed undetectable BCR-ABL in 2 consecutive assessments by 24 months [22.1%] with the switch to nilotinib versus those remaining on imatinib [8.7%],” said lead investigator Nelson Spector, MD, of Federal University of Rio de Janeiro, Rio de Janeiro, Brazil, at the American Society of Clinical Oncology annual meeting in Chicago.

The difference between groups by 24 months has doubled since the 12-month analysis, Dr Spector said. Significantly more patients treated with nilotinib achieved the deepest molecular response or undetectable BCR-ABL compared to imatinib, regardless of the BCR-ABL transcript level at baseline. He noted that no patients achieving and maintaining the deepest molecular response have progressed to advanced stages of CML.

ENESTcmr is an open-label, randomized, prospective, multicenter phase 3 study of 207 patients who received either nilotinib 400 mg twice daily (104 patients) or standard-dose imatinib in 400 mg or 600 mg doses once daily (103 patients). The study was designed to compare the kinetics of molecular response for patients with Philadelphia chromosome-positive CML in chronic phase who had achieved complete cytogenetic response, but were still BCR-ABL positive after at least 2 years of treatment with imatinib. The primary end point was the rate of confirmed best complete molecular response by 12 months of therapy with either tyrosine kinase inhibitor.

“The increase in the rate of confirmed undetectable BCR-ABL in 2 consecutive assessments was 3 times higher with nilotinib [9.6%] than with imatinib [2.9%] from month 12 to 24,” said Dr Spector. Significantly more patients in the nilotinib arm (42.9%) achieved the deepest molecular response than in the imatinib arm (20.8%), and the difference between the arms increased over time from 12 to 24 months. “Improved responses with nilotinib were particularly notable in patients lacking major molecular response (MMR) at study start,” he said.

Most patients remained on study at 24 months. At the time of discontinuation, 10 of 24 patients (41.7%) who discontinued from the nilotinib arm had a deep molecular response compared to none in the imatinib arm.

Most drug-related adverse events occurred in the first 12 months, he said. Half of the events leading to discontinuation in the nilotinib arm were grade 1-2.

Dr Spector said nilotinib should be considered as a leading option for frontline therapy “because it allows many patients to achieve deeper, earlier responses that are associated with improved long-term outcomes.”

He noted that deep molecular responses were also more likely to be sustained in 3 consecutive assessments with nilotinib treatment (15.3% vs 9.7%). Also, in patients highly selected for imatinib tolerance, “switching to nilotinib was associated with more adverse events than remaining on imatinib, although discontinuation rates decreased from 12 to 24 months,” he said.

Dr Spector has received an honorarium from Novartis Pharmaceuticals. Several of his co-authors are consultant/advisers to Novartis Pharmaceuticals, Bristol-Myers Squibb, Pfizer, Teva, Ariad Pharmaceuticals, Roche, and CSL Limited.