Glavni cilj ovog preglednog rada je predstaviti novu klasu lijekova u kroničnoj limfocitnoj leukemiji (KLL), najčešćoj leukemiji odrasle dobi, inhibitore staničnog signaliziranja B receptora (BCR). KLL se klasično liječila imunokemoterapijom, no pojedini bolesnici (poodmakla životna dob, nepovoljni biološki faktori) imali su lošu prognozu. S boljim razumijevanjem patogeneze unutarstaničnih putova pojavila se mogućnost selektivne inhibicije i ciljane terapije u KLL. Prvi lijek u svojoj klasi ibrutinib, inhibitor bruton kinaze, pokazao se superiornim u fazama III kliničkih pokusa te je eliminirao negativne prognostičke faktore u liječenju KLL, pogotovo del (17p), s adekvatnim profi lom toksičnosti što su prepoznale regulatorne agencije. Drugi BCR inhibitori idelalisib i venetoklaks su iznimno aktivni u relapsnom okruženju, no idelalisib se pokazao neprihvatljivo toksičnim u prvoj liniji liječenja što nam može poslužiti kao lekcija u dizajnu kliničkih pokusa s ovim lijekovima. Usprkos učinkovitosti, potreban je dodatni napredak u ovom području koji se nalazi u kombinacijama s imunoterapijom ili imunokemoterapijom, te mogućoj međusobnoj kombinaciji kako bismo dodatno poboljšali ishode. No, najveća zapreka BCR inhibitorima da uđu u široku praksu je njihova cijena i utjecaj na zdravstveni sustav što nažalost ograničuje našu mogućnost da liječimo bolesnike s KLL u eri bez kemoterapije.The main aim of this review is to present a novel class of agents, the inhibitors of B cell receptor (BCR) signaling pathway, used in the treatment of chronic lymphocytic leukemia (CLL) as the most common leukemia in the Western world. Traditionally, CLL was treated with immunochemotherapy, but certain subpupulations (elderly, biological prognostic factors) had poor outcome. With advances in our understanding the pathogenesis of intracellular pathways, the possibility of selective inhibition and targeted therapy in CLL has arisen. The fi rst agent in the class of BCR inhibitors, ibrutinib, a Bruton kinase inhibitor, has been shown superior in phase III clinical trials eliminating negative prognostic factors such as del(17p), with adequate toxicity profi le, which was recognized by the respective regulatory agencies. Other BCR inhibitors idelalisib and venetoclax are extremely active in relapsed setting, but unfortunately, idelalisib combinations in fi rst line clinical trials resulted in unacceptable toxicity, which is a cautionary tale on designing trials. Despite their effi cacy, we are only at the beginning to improve them by combination with monoclonal antibodies, immunochemotherapy, or between each other to improve outcomes of CLL treatment even further. However, the main obstacle to chemo-free era in CLL is their price resulting in limited access to these agents and inequity in the modern treatment of CLL
