Immunological changes with kinase inhibitor therapy for chronic lymphocytic leukemia

Abstract

Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib. While opportunistic infections and viral reactivations occur with both ibrutinib and idelalisib, these complications are less common and less severe with ibrutinib, especially when used as monotherapy without additional immunosuppressive agents. This review discusses the impact of ibrutinib and idelalisib on the immune system, including infectious and auto-immune complications as well as their specific effects on the B-cell, T-cell, and myeloid compartment.

Distinct immune composition in lymph node and peripheral blood of CLL patients is reshaped during venetoclax treatment

“…20,21 Although experience so far indicates that most novel targeted therapeutic strategies do not have such unfavorable effects on T cells, targeted agents may also influence the immune system of CLL patients. 22 The Bruton tyrosine kinase (BTK) inhibitor ibrutinib alters T, NK, and myeloid cell function, which may result, in part, from off-target inhibition of other kinases, such as interleukin-2 (IL-2)-inducible T-cell kinase. [23][24][25][26] However, some of these T-cell alterations have also been observed in patients treated with the more selective BTK inhibitor acalabrutinib, which does not inhibit inducible T-cell kinase, implying that on-target effects via the eradication of CLL cells also eventually affect the nonmalignant immune system.…”

Deciphering the complex circulating immune cell microenvironment in chronic lymphocytic leukemia using patient similarity networks

“…Although these drugs target predominantly CLL cells [5,6,7,38], there is growing evidence of their effects on the microenvironment. Ibrutinib and idelalisib have been shown to have an immunomodulatory effect on T cells [5,13,39,40,41,42], NK cells [43], monocytes [13], and production of Th2 cytokines [44], depending on the time of treatment [13]. Also venetoclax has been shown to modulate number and activation of T and B cells, restore NK cell function and reduce overproduction of in ammatory cytokines [45].…”

Deciphering The Complex Circulating Immune Cell Microenvironment in Chronic Lymphocytic Leukemia Using Patient Similarity Networks

“…Although these drugs target predominantly CLL cells [5,6,7,38], there is growing evidence of their effects on the microenvironment. Ibrutinib and idelalisib have been shown to have an immunomodulatory effect on T cells [5,13,39,40,41,42], NK cells [43], monocytes [13], and production of Th2 cytokines [44], depending on the time of treatment [13]. Also venetoclax has been shown to modulate number and activation of T and B cells, restore NK cell function and reduce overproduction of inflammatory cytokines [45].…”