What is the role of Tyrosine Kinase Inhibitor (TKI)?

From the Guidelines

Tyrosine Kinase Inhibitors (TKIs) play a crucial role in the treatment of chronic myeloid leukemia (CML) by blocking specific enzymes involved in cell growth and division, with the most recent and highest quality study recommending their use as first-line therapy for CML patients 1. The primary function of TKIs is to interrupt signaling pathways that drive cancer cell proliferation, with common TKIs including imatinib, erlotinib, sunitinib, and dasatinib. Each TKI targets specific tyrosine kinases, such as imatinib targeting BCR-ABL in CML. Some key points to consider when using TKIs include:

• Dosing varies by medication and indication, with imatinib typically given at 400-600mg daily for CML
• Side effects commonly include skin rash, diarrhea, fatigue, and liver function abnormalities
• Regular monitoring of blood counts, liver function, and cardiac function is essential during treatment
• TKIs have revolutionized cancer treatment by offering targeted therapy with fewer side effects than traditional chemotherapy, though resistance can develop over time through mutations in the target kinases
• Treatment duration depends on the specific cancer type and response, with some patients requiring indefinite therapy while others may discontinue after achieving sustained remission The most recent study from 2020 recommends the use of TKIs as first-line therapy for CML patients, with a focus on maximizing the possibility of stopping TKI therapy and achieving "treatment-free remission" (TFR) 1. Some of the key recommendations for the management of CML with TKIs include:
• The choice of TKI should be based on treatment goals, age, and comorbidities, as well as the adverse event profile of the available drugs
• Imatinib, dasatinib, and nilotinib are the most commonly used TKIs for the treatment of CML
• The management of adverse events is crucial to minimize their impact on the patient's quality of life and to ensure optimal treatment outcomes
• Regular monitoring of the patient's response to treatment and adjustment of the treatment plan as needed is essential to achieve the best possible outcomes.

From the FDA Drug Label

Imatinib mesylate is a protein-tyrosine kinase inhibitor that inhibits the BCR-ABL tyrosine kinase, the constitutive abnormal tyrosine kinase created by the Philadelphia chromosome abnormality in CML Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer

The role of Tyrosine Kinase Inhibitor (TKI) is to:

• Inhibit specific tyrosine kinases involved in tumor growth and progression
• Induce apoptosis in cancer cells
• Inhibit cell proliferation and tumor angiogenesis Key TKIs mentioned include:
• Imatinib: inhibits BCR-ABL tyrosine kinase, PDGF, and SCF-mediated cellular events
• Sunitinib: inhibits multiple RTKs, including PDGFR, VEGFR, KIT, and FLT3 2 3

From the Research

Role of Tyrosine Kinase Inhibitor (TKI)

• Tyrosine Kinase Inhibitors (TKIs) have transformed chronic myelogenous leukemia in chronic phase (CML-CP) into a non-fatal chronic disease, allowing for a possible treatment goal of "treatment-free remission (TFR)" 4.
• TKIs target the BCR::ABL1 oncogene, which is characterized by the presence of the Philadelphia chromosome, and have improved CML-related mortality from 10% to 20% per year to 1% to 2% per year 5.
• The selection of a TKI for the first-line treatment of CML-CP involves considering factors such as patient medical background, desired treatment goal (survival or TFR), and cost 4.
• There are several types of TKIs available, including imatinib, nilotinib, dasatinib, and bosutinib, each with its own pros and cons, and the optimal use of these agents is crucial for achieving the desired treatment goal while minimizing adverse events 4, 5, 6.

Types of TKIs and Their Effects

• First-generation TKIs, such as imatinib, and second-generation TKIs, such as bosutinib, dasatinib, and nilotinib, have been approved for the treatment of CML 5.
• Second-generation TKIs have been shown to have faster and deeper treatment responses than imatinib, but may also have additional adverse effects, such as pleural effusion, arterio-occlusive events, and gastrointestinal disturbance 5, 7.
• Nilotinib, a second-generation TKI, has been shown to be highly active against a wide range of imatinib-resistant BCR-ABL mutants and has been approved for the treatment of newly diagnosed or imatinib-resistant or -intolerant CML 7.

Comparative Effectiveness of TKIs

• A systematic review and meta-analysis of eight randomized trials found that newer generation TKIs (NG-TKIs) were more effective than imatinib in achieving major molecular response (MMR) and preventing progression to an accelerated phase/blast crisis 8.
• The study found that NG-TKIs showed a significantly greater likelihood of MMR and lower likelihood of progression to an accelerated phase/blast crisis compared to imatinib, but did not find a significant difference in complete cytogenetic response (CCyR), progression-free survival, and overall survival between NG-TKIs and imatinib 8.