Earlier in 2018, nilotinib (Tasigna) was approved for the treatment of pediatric patients aged ≥ 1 year with newly diagnosed Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (CML-CP) or Philadelphia chromosome–positive CML-CP resistant or intolerant to prior tyrosine kinase inhibitor therapy.^1,2

Supporting Efficacy Data

Approval was based on findings in 69 pediatric patients with Philadelphia chromosome–positive CML-CP from 2 single-arm multicenter trials: CAMN107A2120 in pediatric patients with Philadelphia chromosome–positive CML-CP resistant or intolerant to imatinib or dasatinib (Sprycel; n = 11) and CAMN107A2203 in pediatric patients with Philadelphia chromosome–positive CML-CP resistant or intolerant to imatinib or dasatinib (n = 33) and newly diagnosed Philadelphia chromosome–positive CML-CP (n = 25).² In both trials, patients received nilotinib at 230 mg/m² twice daily, rounded to the nearest 50-mg dose (maximum single dose of 400 mg) in 28-day treatment cycles. The median time on treatment with nilotinib was 13.8 months (range = 0.7–30.9 months).

In 44 patients with resistant or intolerant Philadelphia chromosome–positive CML-CP, major molecular response (BCR-ABL/ABL ≤ 0.1% international scale) was achieved in 18 patients (40.9%) at 12 cycles. In 25 patients with newly diagnosed Philadelphia chromosome–positive CML-CP, the major molecular response was achieved in 15 patients (60.0%) at 12 cycles. In patients with resistant/intolerant CML, the cumulative major molecular response rate was 47.7% (21/44) by cycle 12. BCR-ABL/ABL ≤ 0.0032% international scale (MR4.5) was achieved by the cutoff date in 4.5% of patients with resistant/intolerant CML and in 28.0% of those with newly diagnosed CML.

How It Works

Nilotinib is a BCR-ABL kinase inhibitor that binds to and stabilizes the inactive conformation of the kinase domain of the ABL protein. In vitro, nilotinib inhibited BCR-ABL–mediated proliferation of murine leukemic cell lines and human cell lines derived from patients with Philadelphia chromosome–positive CML. Under the conditions of the assays, nilotinib was able to overcome imatinib resistance resulting from BCR-ABL kinase mutations in 32 of 33 mutations tested.

How It Is Used 

The recommended dose of nilotinib for pediatric patients is 230 mg/m² orally twice daily rounded to the nearest 50-mg dose (to a maximum single dose of 400 mg). Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity.

Product labeling contains detailed instructions on discontinuation of treatment after sustained molecular response (MR4.5) and reinitiation of treatment in patients who lose molecular response after discontinuation of nilotinib therapy.

Product labeling provides instructions on dose modifications in pediatric patients for QT interval prolongation, neutropenia and thrombocytopenia, elevated serum lipase or amylase level, elevated bilirubin level, elevated hepatic transaminase levels, and other nonhematologic toxicities and with concomitant use of strong CYP3A4 inhibitors if use of such strong inhibitors cannot be avoided. Concomitant use of strong CYP3A4 inhibitors and strong CYP3A4 inducers should be avoided.

Safety Profile

Overall, the most commonly reported nonhematologic adverse events (≥ 20% of patients) in adult and pediatric patients receiving nilotinib in clinical trials were nausea, rash, headache, fatigue, pruritus, vomiting, diarrhea, cough, constipation, arthralgia, nasopharyngitis, pyrexia, and night sweats. Hematologic adverse events included thrombocytopenia, neutropenia, and anemia.

In the two studies in pediatric patients, the most common nonhematologic adverse events (> 20% of patients) were headache, rash, hyperbilirubinemia, alanine transaminase (ALT) level increase, pyrexia, nausea, upper respiratory tract infection, aspartate transaminase (AST) level increase, and vomiting. The most common grade 3 or 4 non-hematologic adverse events (> 5% of patients) were ALT increase and hyperbilirubinemia. Among lab abnormalities, hyperbilirubinemia (13% grade 3 or 4), AST elevation (1% grade 3 or 4), and ALT elevation (9% grade 3 or 4) were reported at a higher frequency than in adult patients. The most common hematologic adverse events of any grade were decreased total white blood cell count (54%), decreased platelet count (44%), decreased absolute neutrophil count (41%), decreased absolute lymphocyte count (32%), and decreased hemoglobin (30%). Increases in the corrected QT interval by Fredericia (QTcF) > 30 msec from baseline were observed in 17 patients (25%). No patient had an absolute QTcF of > 500 msec or a QTcF increase of > 60 msec from baseline. Adverse events led to discontinuation of nilotinib in 9 patients (13%), with causes including hyperbilirubinemia (6%) and rash (4%).

Nilotinib has a boxed warning for QT prolongation and sudden death. Patients should be monitored for hypokalemia and hypomagnesemia prior to starting treatment and periodically thereafter. Electrocardiography to monitor QTc should be performed at baseline, 7 days after starting treatment, and periodically thereafter, as well as after any dose adjustments. Sudden death has been reported in patients receiving nilotinib. The drug should not be given to patients with hypokalemia, hypomagnesemia, or long QT syndrome. Concomitant use with drugs known to prolong QT interval and strong CYP3A4 inhibitors should be avoided. Food should be avoided for 2 hours before and 1 hour after taking a dose.

Nilotinib also carries warnings/precautions for myelosuppression; cardiac and arterial vascular occlusive events; pancreatitis and elevated serum lipase; hepatotoxicity; electrolyte abnormalities (hypophosphatemia, hypokalemia, hyperkalemia, hypocalcemia, and hyponatremia); tumor-lysis syndrome; hemorrhage; fluid retention; effects on growth and development in pediatric patients; embryofetal toxicity; and treatment discontinuation. With regard to treatment discontinuation, patients must have typical BCR-ABL transcripts. A U.S. Food and Drug Administration (FDA)-authorized test with a detection limit below MR4.5 must be used to determine eligibility for treatment discontinuation. Patients must be frequently monitored by the FDA-authorized test to detect possible loss of remission.

Patients must be monitored regularly for complete blood cell counts, serum lipase, hepatic function, and electrolytes. Electrolyte abnormalities should be corrected prior to starting treatment. Nilotinib is contraindicated in patients with hypokalemia, hypomagnesemia, or long QT syndrome. Women should be advised not to breastfeed while receiving nilotinib. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves nilotinib for pediatric patients with newly diagnosed or resistant/intolerant Ph+ CML in chronic phase. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm602264.htm. Accessed September 27, 2018.

2. Tasigna (nilotinib) capsules prescribing information, Novartis, March 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/-label/2018/022068s027lbl.pdf. Accessed September 27, 2018.