Are Tyrosine Kinase Inhibitors (TKI) immunosuppressive?

From the Guidelines

Yes, tyrosine kinase inhibitors (TKIs) have immunosuppressive properties, as they can inhibit T-cell proliferation and activation, leading to an increased risk of infections, particularly with dasatinib, which has been found to have a more profound immunosuppressive effect compared to other TKIs 1.

Immunossuppressive Effects of TKIs

The immunosuppressive effects of TKIs occur because tyrosine kinases are essential components of signaling pathways involved in immune cell activation and cytokine production. For example, TKIs inhibit T cell receptor signaling, reduce cytokine production, and impair lymphocyte proliferation.

• TKIs like imatinib, dasatinib, and nilotinib have been shown to have inhibitory effects on T-cell proliferation and activation in vitro studies 1.
• The degree of immunosuppression varies among different TKIs, with some being more potent immunosuppressants than others, and dasatinib has been found to have a more profound immunosuppressive effect compared to other TKIs 1.
• Patients taking TKIs may have an increased risk of infections, though this risk is generally lower than with conventional immunosuppressive drugs like corticosteroids or calcineurin inhibitors.

Clinical Implications

The immunosuppressive property of TKIs has led to investigation of these medications as potential treatments for autoimmune diseases and prevention of transplant rejection.

• However, the increased risk of infections associated with TKIs, particularly with dasatinib, should be carefully considered in clinical practice, and patients should be closely monitored for signs of infection 1.
• The incidence of infections with TKIs is generally lower than with conventional immunosuppressive drugs, but the risk is still present, and clinicians should be aware of this potential complication when prescribing TKIs.

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 Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome positive chronic myeloid leukemia.

The FDA drug label does not answer the question.

From the Research

Tyrosine Kinase Inhibitors (TKI) and Immunosuppression

• The provided studies do not directly address the question of whether Tyrosine Kinase Inhibitors (TKI) are immunosuppressive 2, 3, 4, 5, 6.
• These studies focus on the efficacy and safety of TKIs in the treatment of chronic myeloid leukemia (CML) and other cancers, as well as their mechanisms of action and resistance 2, 3, 4, 5, 6.
• There is no mention of immunosuppressive effects of TKIs in the provided studies, suggesting that this topic may not be directly addressed in the available research.

Mechanism of Action of TKIs

• TKIs work by targeting and inhibiting specific tyrosine kinase proteins that are involved in cancer cell growth and metastasis 5, 6.
• Imatinib, a specific TKI, stabilizes the inactive form of Bcr-Abl, an oncoprotein involved in malignant transformation in CML 6.
• TKIs can also target other tyrosine kinase proteins, such as Kit, which is involved in gastrointestinal stromal tumor (GIST) 6.

Efficacy and Safety of TKIs

• TKIs have been shown to be effective in the treatment of CML and other cancers, with improved survival outcomes and molecular response rates 3, 4.
• However, the long-term effects of TKIs and their ability to completely eradicate CML are still unknown, and clinical resistance to TKIs has emerged 6.