The FDA recently expanded the indication for nilotinib to include treatment of first- and second-line pediatric patients 1 year of age or older with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP). This approval is the latest in a series of regulatory milestones that broadens the understanding and clinical use of nilotinib.
Almost all patients with CML have an abnormality known as the Philadelphia chromosome, which produces the protein BCR-ABL. This protein aids the proliferation of malignant white blood cells in affected patients. Worldwide, CML accounts for approximately 3 percent of newly diagnosed childhood leukemia.
The new indications, granted under the FDA's Priority Review designation, are based on two studies evaluating the efficacy and safety of nilotinib in pediatric patients (2 years to fewer than 18 years of age) with Ph+ CML-CP. A total of 69 Ph+ CML-CP pediatric patients, either newly diagnosed or who were resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy, received nilotinib. In newly diagnosed pediatric patients, the major molecular response (MMR; BCR ABL/ABL <=0.1% International Scale) rate was 60.0 percent (95% CI: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR. The cumulative MMR rate among newly diagnosed pediatric patients was 64.0 percent by cycle 12, and the median time to first MMR was 5.6 months (range: 2.7-16.6). In pediatric patients with resistance or intolerance to prior TKI therapy, the MMR rate was 40.9 percent (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR. The cumulative MMR rate among pediatric patients with resistance or intolerance was 47.7 percent by cycle 12, and the median time to first MMR was 2.8 months (range: 0.0-11.3).
Adverse reactions observed in these pediatric studies were generally consistent with those observed in adults, except for laboratory abnormalities of hyperbilirubinemia (grade 3/4: 13%) and transaminase elevation (AST grade 3/4: 1%, ALT grade 3/4: 9%), which were reported at a higher frequency than in adult patients. One resistant or intolerant pediatric CML patient progressed to advanced phase/blast crisis after about 10 months on treatment.
Nilotinib is approved in more than 122 countries for the treatment of chronic phase and accelerated phase Ph+ CML in adult patients resistant or intolerant to at least one prior therapy, including imatinib, and in more than 110 countries for the treatment of adult patients with newly diagnosed Ph+ CML in chronic phase.
In the U.S., nilotinib is now indicated for the treatment of adult and pediatric patients 1 year of age or older with newly diagnosed Ph+ CML-CP. It is also indicated for the treatment of pediatric patients 1 year of age or older with Ph+ CML-CP resistant or intolerant to prior TKI therapy, as well as adult patients with Ph+ CML in chronic phase and accelerated phase, resistant or intolerant to prior therapy that included imatinib.
It is also approved in the EU for the treatment of Ph+ CML in the chronic phase in pediatric patients with resistance or intolerance to prior therapy, including imatinib, and for the treatment of pediatric patients with newly diagnosed Ph+ CML in the chronic phase.