The Evolution of Therapies Targeting Bruton Tyrosine Kinase for the Treatment of Chronic Lymphocytic Leukaemia: Future Perspectives

Abstract

The development of inhibitors of Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL2) has resulted in a paradigm shift in the treatment of chronic lymphocytic leukaemia (CLL) over the last decade. Observations regarding the importance of B-cell receptor signalling for the survival and proliferation of CLL cells led to the development of the first-in-class BTK inhibitor (BTKi), ibrutinib, for the treatment of CLL. Despite being better tolerated than chemoimmunotherapy, ibrutinib does have side effects, some of which are due to the off-target inhibition of kinases other than BTK. As a result, more specific inhibitors of BTK were developed, such as acalabrutinib and zanubrutinib, which have demonstrated equivalent/enhanced efficacy and improved tolerability in large randomized clinical trials. Despite the increased specificity for BTK, side effects and treatment resistance remain therapeutic challenges. As these drugs all bind covalently to BTK, an alternative approach was to develop noncovalent inhibitors of BTK, including pirtobrutinib and nemtabrutinib. The alternative mechanisms of BTK-binding of these agents has the potential to overcome resistance mutations, something that has been borne out in early clinical trial data. A further step in the clinical development of BTK inhibition has been the introduction of BTK degraders, which remove BTK by ubiquitination and proteasomal degradation, in marked contrast to BTK inhibition. This article will review the evolution of BTK inhibition for CLL and offer future perspectives on the sequencing of an increasing number of different agents, and how this may be impacted on by mutations in BTK itself and other kinases.

Taking the Next Step in Double Refractory Disease: Current and Future Treatment Strategies for Chronic Lymphocytic Leukemia

“…8 Following this, more selective next-generation cBTKis such as acalabrutinib and zanubrutinib were developed to OncoTargets and Therapy 2024:17 [181][182][183][184][185][186][187][188][189][190][191][192][193][194][195][196][197][198] improve the efficacy and safety of ibrutinib. 9 Several phase 3 trials confirmed the superior efficacy of these cBTKis as monotherapy or in combination with an anti-CD20 mAb to CITs in the frontline and subsequent treatment settings. [10][11][12][13] Another important treatment target is an anti-apoptotic protein B-cell lymphoma 2 (BCL2), which is overexpressed in CLL cells.…”

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

“…DT2216 (NCT04886622), a potent B-cell CLL/lymphoma 2 (BCL-XL) degrader utilizing von Hippel-Lindau (VHL) E3 ligase recruitment, has entered Phase I clinical study for treating advanced liquid and solid tumors in 2021 78 . To date, more than 19 PROTACs are under evaluation in ongoing clinical trials, targeting POIs such as interleukin-1 receptor-associated kinase 4 (IRAK4) by degrader KT-413 79 , signal transducer and activator of transcription 3 (STAT3) by degrader KT-333 80 , and Bruton's tyrosine kinase (BTK) by degrader NX-5948 81 .…”

Progress of research on PD-1/PD-L1 in leukemia

“…Chemotherapy and anti-CD20 mAbs therapy are the standard of care for patients with CLL ( 133 – 135 ). Currently, it is prominent to improve the complete remission rate and reduce chemotherapy-induced immunosuppression.…”