What is the role of Tasigna (Nilotinib) in the treatment of Chronic Myeloid Leukemia (CML)?

From the Guidelines

Tasigna (nilotinib) is a recommended treatment option for chronic myeloid leukemia (CML), particularly for patients who are resistant or intolerant to prior therapy, including imatinib, as stated in the European LeukemiaNet 2020 recommendations 1.

Key Points to Consider

• The European LeukemiaNet 2020 recommendations suggest that first-line treatment for CML should be a tyrosine kinase inhibitor (TKI), with generic imatinib being the cost-effective initial treatment in chronic phase CML 1.
• Nilotinib, the active ingredient in Tasigna, has shown superior efficacy compared to imatinib in achieving faster and deeper molecular responses in CML patients 1.
• Common side effects of Tasigna include rash, headache, fatigue, nausea, and elevated liver enzymes, while more serious concerns include QT interval prolongation and potential cardiovascular events 1.
• Regular monitoring of blood counts, liver function, and BCR-ABL transcript levels is essential to track treatment response, and patients should avoid grapefruit products and certain medications that may interact with Tasigna 1.
• Treatment with Tasigna is typically long-term, with some patients potentially eligible for treatment-free remission after sustained deep molecular response 1.

Dosage and Administration

• The standard dosage of Tasigna is 300 mg twice daily for newly diagnosed patients and 400 mg twice daily for resistant/intolerant patients, taken on an empty stomach (at least 2 hours before and 1 hour after food) 1.
• Patients should be closely monitored for side effects, and dose adjustments may be necessary to minimize toxicity while maintaining efficacy 1.

Comparison with Other TKIs

• The European LeukemiaNet 2020 recommendations suggest that dasatinib, nilotinib, and bosutinib are available as first-line treatment options for CML, with generic imatinib being the cost-effective initial treatment in chronic phase CML 1.
• A comparison of the incidence of myelosuppression among different TKIs, including nilotinib, dasatinib, and bosutinib, is provided in Table 7 of the European LeukemiaNet 2016 recommendations 1.

Patient Monitoring and Follow-up

• Regular monitoring of blood counts, liver function, and BCR-ABL transcript levels is essential to track treatment response and minimize toxicity 1.
• Patients should be closely monitored for side effects, and dose adjustments may be necessary to minimize toxicity while maintaining efficacy 1.

From the FDA Drug Label

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

Tasigna (nilotinib) is used for the treatment of:

• Ph+ CML-CP (Chronic Phase): Nilotinib is used for the treatment of newly diagnosed Ph+ CML-CP.
• Resistant or intolerant Ph+ CML-CP and CML-AP (Accelerated Phase): Nilotinib is used for the treatment of resistant or intolerant Ph+ CML-CP and CML-AP. Nilotinib is effective in overcoming imatinib resistance resulting from BCR-ABL kinase mutations in patients with Ph+ CML 2.

From the Research

Efficacy of Tasigna for CML

• Tasigna (nilotinib) is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (CML-CP) who are newly diagnosed or intolerant of or resistant to imatinib 3, 4.
• In a phase II study, 59% of patients with CML-CP achieved major cytogenetic response, and 45% achieved complete cytogenetic response while on study 3.
• The estimated rate of overall survival (OS) and progression-free survival (PFS) at 48 months was 78% and 57%, respectively 3.
• Deeper levels of molecular responses at 3 and 6 months were highly positively correlated with long-term outcomes, including PFS and OS at 48 months 3.

Safety and Tolerability

• Nilotinib is safe and effective for long-term use in responding patients with CML-CP who are intolerant of or resistant to imatinib 3.
• Common serious drug-related adverse reactions in CML-CP patients included thrombocytopenia and neutropenia 5.
• In CML-AP patients, common serious drug-related adverse reactions included thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia 5.
• Nilotinib prolongs the QT interval and sudden deaths have been reported 5.

Comparison with Imatinib

• Nilotinib has been shown to be superior to imatinib as first-line therapy for chronic myeloid leukemia 4.
• The ENESTnd study demonstrated that nilotinib is more potent than imatinib and has significant efficacy in patients with CML in chronic phase, accelerated phase, and blastic phase, following imatinib failure 4.

Dose Optimization

• Dose optimization of tyrosine kinase inhibitors, including nilotinib, is a new therapeutic challenge in the treatment of CML 6.
• Dose reduction may be considered to reduce adverse events and improve quality of life, but may also affect the achievement and maintenance of cytogenetic and molecular responses 6.