Do tyrosine-kinase inhibitors (TKIs), such as tasinga (likely referring to a brand name, with the generic name not specified), cause immunosuppression in patients?

Do Tyrosine Kinase Inhibitors Cause Immunosuppression?

Tyrosine kinase inhibitors (TKIs) do not cause clinically significant immunosuppression in the traditional sense, though they have complex immunomodulatory effects that vary by specific agent and can actually enhance certain immune functions while potentially affecting others. The evidence consistently shows that TKIs used as monotherapy do not require antimicrobial prophylaxis, distinguishing them from truly immunosuppressive therapies 1.

Evidence from Hematologic Malignancy Guidelines

The most authoritative guidance comes from the 2022 European Conference on Infections in Leukemia (ECIL) guidelines, which systematically evaluated TKIs used in acute myeloid leukemia 1:

• FLT3 inhibitors (gilteritinib, midostaurin) show "no documented mechanism of immunosuppression" 1
• No systemic antimicrobial prophylaxis is recommended when these agents are given as monotherapy 1
• Standard infection management protocols apply only when TKIs are combined with cytotoxic chemotherapy, not due to the TKI itself 1

Immunomodulatory Effects vs. Immunosuppression

The critical distinction is that TKIs are immunomodulatory rather than immunosuppressive 2, 3:

• TKIs can enhance anti-tumor and anti-viral immunity by increasing natural killer (NK) cells, NK-LGL cells, and T-LGL populations, particularly with dasatinib in CMV-infected patients 2
• Gene expression studies demonstrate upregulation of antiviral genes (CD28, IFN-gamma) and downregulation of proviral genes (ARG-1, CEACAM1) during imatinib treatment 3
• Clinical observations show remarkably low rates of COVID-19 infection in chronic myeloid leukemia patients receiving TKIs, suggesting preserved or enhanced immune function 3

Specific TKI Considerations

In Vitro vs. Clinical Effects

While in vitro studies show TKIs can inhibit T-cell proliferation and activation (with dasatinib having more profound effects due to broader kinase inhibition), these laboratory findings do not translate to clinically significant immunosuppression 1:

• Imatinib shows low incidence (2%) of opportunistic infections in large series 1
• Second-generation TKIs (nilotinib, dasatinib, bosutinib) in first-line therapy show no significantly increased infection rates compared to imatinib 1

Context-Dependent Risk

The infection risk depends heavily on the clinical context 1:

• TKIs combined with cytotoxic chemotherapy require standard antimicrobial prophylaxis due to chemotherapy-induced neutropenia, not the TKI 1
• Advanced disease phase and prior intensive chemotherapy increase infection risk independent of TKI use 1
• Dasatinib at higher doses in BCR-ABL1 positive acute leukemia shows ~50% infection incidence, but this occurs in heavily pretreated patients receiving combination therapy 1

Hepatitis B Reactivation Risk

TKIs are classified as moderately immunosuppressive regarding HBV reactivation risk 1:

• Tyrosine kinase inhibitors (imatinib, nilotinib) have been associated with HBV reactivation in patients with chronic myeloid leukemia and other malignancies 1
• This risk is substantially lower than with B-cell depleting agents (rituximab) or high-dose corticosteroids 1
• HBV screening and monitoring is recommended, but the approach is less intensive than for highly immunosuppressive agents 1

Vaccination Considerations

Patients on TKIs can mount effective vaccine responses, contrasting sharply with truly immunosuppressive therapies 1:

• Small studies show no significant difference in protective antibody responses to influenza vaccination in patients on sorafenib or sunitinib compared to healthy controls 1
• Ibrutinib-treated CLL patients achieved seroprotective titers in up to 74% after influenza vaccination 1
• mTOR inhibitors (everolimus, temsirolimus) may actually enhance immune responses 1

This stands in stark contrast to B-cell depleting therapies (rituximab), where vaccination within 6 months is discouraged due to profound immunosuppression 1.

Clinical Management Implications

No special antimicrobial prophylaxis is needed for TKI monotherapy 1:

• Use standard infection management protocols as for the underlying malignancy
• Reserve prophylaxis for combination regimens that include cytotoxic chemotherapy
• Monitor for differentiation syndrome (which can mimic infection) with IDH inhibitors 1

Drug Interactions

Monitor for CYP3A4 interactions that can affect both TKI levels and antifungal prophylaxis 1:

• Strong CYP3A4 inhibitors (itraconazole, posaconazole, voriconazole) require close monitoring for QT prolongation with midostaurin 1
• Avoid combination with strong CYP3A4 inducers 1

COVID-19 Context

During the COVID-19 pandemic, TKIs were not associated with increased mortality risk 1:

• Real-world data from CCC19 and TERAVOLT registries showed non-cytotoxic targeted therapies had no association with COVID-19-related mortality (HR 1.04) 1
• PI3K/AKT/mTOR and MAPK pathway inhibitors may theoretically affect immune function, but preliminary data did not establish increased COVID-19 mortality 1

Critical Caveats

Avoid confusing TKI effects with underlying disease or combination therapy effects 1:

• Infections in TKI-treated patients often reflect the underlying malignancy, disease phase, or concurrent chemotherapy rather than TKI-induced immunosuppression
• Febrile neutropenia and serious infections in advanced phase patients receiving TKIs typically result from disease burden and prior intensive therapy 1
• The term "immunosuppression" is misleading for TKIs—they are better characterized as having selective immunomodulatory effects that can be beneficial 2, 3