Treatment Refractoriness in Chronic Lymphocytic Leukemia: Old and New Molecular Biomarkers

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Despite its indolent clinical course, therapy refractoriness and disease progression still represent an unmet clinical need. Before the advent of pathway inhibitors, chemoimmunotherapy (CIT) was the commonest option for CLL treatment and is still widely used in areas with limited access to pathway inhibitors. Several biomarkers of refractoriness to CIT have been highlighted, including the unmutated status of immunoglobulin heavy chain variable genes and genetic lesions of TP53, BIRC3 and NOTCH1. In order to overcome resistance to CIT, targeted pathway inhibitors have become the standard of care for the treatment of CLL, with practice-changing results obtained through the inhibitors of Bruton tyrosine kinase (BTK) and BCL2. However, several acquired genetic lesions causing resistance to covalent and noncovalent BTK inhibitors have been reported, including point mutations of both BTK (e.g., C481S and L528W) and PLCG2 (e.g., R665W). Multiple mechanisms are involved in resistance to the BCL2 inhibitor venetoclax, including point mutations that impair drug binding, the upregulation of BCL2-related anti-apoptotic family members, and microenvironmental alterations. Recently, immune checkpoint inhibitors and CAR-T cells have been tested for CLL treatment, obtaining conflicting results. Potential refractoriness biomarkers to immunotherapy were identified, including abnormal levels of circulating IL-10 and IL-6 and the reduced presence of CD27+CD45RO− CD8+ T cells.

Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms

“…The first-in-class covalent BTKi is ibrutinib, a highly potent, first-generation BTKi approved by the Food and Drug Administration (FDA) in 2013 for the treatment of MCL [ 45 ]. Covalent BTKi function by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain [ 13 , 46 ]. This action results in the occupation of the ATP-binding site, preventing the phosphorylation of downstream targets like Akt and PLCγ2 [ 13 ].…”

“…Covalent BTKi function by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain [ 13 , 46 ]. This action results in the occupation of the ATP-binding site, preventing the phosphorylation of downstream targets like Akt and PLCγ2 [ 13 ]. Consequently, BTK signaling is hindered, leading to the inhibition of the BCR pathway observed both in vitro and in vivo [ 47 ].…”

“…In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous BTK signaling activation [ 12 ]. This persistent activation provides a survival and proliferation advantage to the neoplastic clone of B cell neoplasms [ 13 ]. Among B cell malignancies, those in which the most significant results were obtained by BTK targeting are chronic lymphocytic leukemia/small lymphoma (CLL/SLL), mantle cell lymphoma (MCL), lymphoplasmacytic lymphoma (LPL), and diffuse large B cell lymphoma (DLBCL) [ 3 , 14 , 15 , 16 ].…”

“…Importantly, CLL predominantly affects elderly individuals, with a median age at diagnosis of 72 years in high-income countries (HICs) [ 17 , 18 ]. Despite its indolent clinical course and extended overall survival (OS), CLL is not completely curable, and patients refractory to currently available therapies face the risk of disease progression and, eventually, disease-related mortality [ 13 ]. This emphasizes the need to address treatment refractoriness in CLL and to develop novel therapeutic approaches.…”

“…The extensive use of BTKi in multiple B cell malignancies over the years has also led to clinical refractoriness in a fraction of cases, prompting the search for the molecular mechanisms underlying clinical refractoriness [ 13 , 44 ]. On these grounds, the aim of this review is to summarize the mode of action of BTKi and the mechanisms of resistance to BTK targeting in B cell malignancies, with a particular focus on CLL, MCL, LPL, and DLBCL.…”