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CML cells
The US Food and Drug Administration (FDA) has approved an update to the product label for nilotinib (Tasigna) that includes information about how to discontinue the drug in certain patients.
Nilotinib, which was first approved by the FDA in 2007, is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML).
The updated prescribing information for the drug now outlines which of these patients may be eligible to stop receiving nilotinib.
Patients with chronic phase, Ph+ CML who have been taking nilotinib for 3 years or more (as first-line treatment or after failure with imatinib) and have achieved a sustained deep molecular response may be eligible to stop treatment.
Patients must have maintained a molecular response of at least MR4.0 for 1 year prior to discontinuation and achieved an MR4.5 at their last assessment.
Patients must have typical BCR-ABL transcripts (e13a2/b2a2 or e14a2/b3a2), no history of accelerated phase or blast crisis, and no past attempts at treatment discontinuation that resulted in relapse.
After discontinuation, patients must be monitored for possible loss of major molecular response (MMR). BCR-ABL transcript levels must be assessed and a complete blood count with differential performed monthly for 1 year, then every 6 weeks for the second year, and every 12 weeks thereafter.
BCR-ABL transcript levels should be measured using the MolecularMD MRDxTM BCR-ABL test, an FDA-authorized companion diagnostic validated to measure down to MR4.5.
If patients lose MMR, they must restart nilotinib within 4 weeks and receive the dose level they were receiving prior to discontinuation.
BCR-ABL transcript levels should be monitored every 2 weeks until they are lower than MMR for 4 consecutive measurements. Patients can then return to the original monitoring schedule.
The update of nilotinib’s label to include this information was based on results from 2 single-arm trials—ENESTfreedom and ENESTop.
ENESTfreedom
This phase 2 trial included 215 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 190 patients who had achieved a response of MR4.5 with nilotinib as first-line treatment. The patients had sustained deep molecular response for 1 year prior to treatment discontinuation.
Ninety-six weeks after stopping treatment, 48.9% of patients were still in MMR, also known as treatment-free remission (TFR).
Of the 88 patients who restarted nilotinib due to loss of MMR by the cut-off date, 98.9% were able to regain MMR (n=87). One patient discontinued the study at 7.1 weeks without regaining MMR after reinitiating treatment with nilotinib. Eighty-one patients (92.0%) regained MR4.5 by the cut-off date.
Common adverse events (AEs) in patients who discontinued nilotinib included musculoskeletal symptoms such as body aches, bone pain, and pain in extremities. However, these AEs decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 34.0% to 9.0% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 17.0% during the treatment consolidation phase.
ENESTop
This phase 2 trial included 163 patients with Ph+, chronic phase CML. Researchers evaluated stopping treatment in 126 patients who had previously received imatinib, then switched to nilotinib and sustained a molecular response for 1 year prior to stopping nilotinib.
At 96 weeks, 53.2% of patients were still in TFR.
Fifty-six patients with confirmed loss of MR4.0 or loss of MMR restarted nilotinib by the cut-off date. Of these patients, 92.9% (n=52) regained both MR4.0 and MR4.5.
As in ENESTfreedom, patients who discontinued nilotinib had musculoskeletal symptoms that decreased over time.
The incidence of musculoskeletal pain-related AEs decreased from 47.9% to 15.1% during the first and second 48 weeks of the TFR phase, respectively. In comparison, the incidence of such AEs was 13.7% during the treatment consolidation phase.
Additional data from ENESTop and ENESTfreedom, as well as the recommendations for stopping nilotinib, are included in the updated prescribing information, which is available at https://www.us.tasigna.com/.
