FDA Expands Indication for Nilotinib

The FDA expanded the indication for nilotinib (Tasigna; Novartis) for the treatment of children with newly diagnosed Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in the chronic phase (CP) who are at least a year old, as well as those who are resistant to or cannot tolerate imatinib (Gleevec; Novartis). The approval, granted near the end of March, adds to the short list of treatment options for this small patient population—CML represents just 3% of childhood leukemias.

A tyrosine kinase inhibitor (TKI) that targets BCR–ABL, nilotinib was already approved for these indications in adults. In November 2017, another BCR–ABL TKI, dasatinib (Sprycel; Bristol-Myers Squibb) was greenlighted for pediatric patients with newly diagnosed or previously treated Ph+ CML-CP, although without the age restriction. Studies have shown both drugs to be more potent than imatinib.

The new nilotinib approvals were based on two studies evaluating its efficacy and safety in young children with Ph+ CML-CP. A total of 69 patients who were either newly diagnosed or resistant or intolerant to prior TKI therapy, including imatinib, received the drug.

In newly diagnosed patients, the major molecular response (MMR) rate was 60% at 12 cycles, with 15 children achieving MMR—meaning that the amount of BCR–ABL in the blood is less than 0.1%. The cumulative MMR rate among newly diagnosed pediatric patients was 64% by cycle 12, and the median time to first MMR was 5.6 months. Among patients with resistance or intolerance to prior TKI therapy, the MMR rate was 40.9% at 12 cycles, with 18 patients achieving MMR. The cumulative MMR rate among these patients was 47.7% by cycle 12, and the median time to first MMR was 2.8 months.

Which drug to try first remains an open question, says Raul Ribeiro, MD, of St. Jude Children's Research Hospital in Memphis, TN, who notes that there is no strong evidence that dasatinib is superior to nilotinib. “Superiority would include more efficacy, less toxicity, and lower cost,” he says. “These sorts of analyses have not been performed in pediatric CML yet.”

However, says Stephen Hunger, MD, of Children's Hospital of Philadelphia, PA, “given the small number of children diagnosed with CML each year—about 100 in the U.S.—this will probably never happen.” Even in adults, he adds, “there is no consensus regarding which of these three drugs [dasatinib, nilotinib, or imatinib] is optimal first-line treatment.”

Side effects and other medical conditions could factor into the initial treatment decision, as could dosing. “Nilotinib is generally given twice daily and dasatinib is generally given once daily. The once-daily dosing of dasatinib might help with compliance in some patients, particularly teenagers,” Hunger says. “It is good to have multiple options to select from,” even though imatinib will likely remain the first choice, at least for now, due to cost and other considerations.

Regardless of the medication chosen, quick, sustained responses are critical for patients with CML. “After being in molecular remission for several years, these patients are candidates to stop the medication,” says Ribeiro, but he adds a note of caution. “The hypothesis is that a drug that induces a fast and deep molecular response is associated with the higher frequency of sustained remission after the drug is discontinued when compared with, for example, imatinib. This possibility remains conjectural.” –Suzanne Rose