Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative malignancy characterized by monoclonal B lymphocytosis. BCR signaling plays a critical role in B cell development and survival.

Bruton Tyrosine Kinase inhibitors (BTKi) disrupt the BCR signaling pathway by inactivation of BTK, leading to inhibition of proliferation and survival of CLL cells. There are two classes of BTK inhibitors, covalent and non-covalent. İbrutinif is the first approved covalent BTKi(cBTKi) of its class. The second-generation cBTKi (acalabrutinib and zanubrutinib) were designed to increase selectivity against BTK and reduce off-target toxicity. Continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. Pirtobrutinib, a non-covalent BTKi (ncBTKi), represents a novel class of BTKi developed to improve effectiveness and overcome acquired resistance to cBTKi.

Mutations in BTK, particularly in the c481s region, and mutations in the PLCG2 region are considered the predominant mechanism of BTKi resistance in patients with CLL. Pirtobrutinib, retains kinase inhibition even in the presence of a BTK C481 mutation and demonstrates high specificity for BTK, with minimal off-target effects.

The toxicity profiles of BTKis are closely linked to their kinase-binding patterns, including both on-target inhibition of BTK and variable off-target inhibition of other kinases, such as interleukin-2-inducible T-cell kinase (ITK), tyrosine kinase expressed in hepatocellular carcinoma (TEC), and epidermal growth factor receptor (EGFR) family kinases. AEs such as cardiac arrhythmias, bleeding, diarrhea, arthralgia, hypertension and infection are the primary reasons for ibrutinib discontinuation.

Optimal management of AEs is crucial to achieving good outcomes and maintaining quality of life.