Emerging Therapies in CLL in the Era of Precision Medicine

Simple Summary Despite being a slow-proliferating disease, chronic lymphocytic leukemia (CLL) is an incurable and frequently reoccurring adult leukemia. Although large-scale genome-wide next-generation sequencing studies have provided insights into CLL's transcriptome and mutational landscape, the molecular mechanisms underlying disease progression remain incompletely understood. Over time, the treatment landscape in CLL has shifted from chemoimmunotherapies (CIT) to targeted therapies, but resistance mechanisms have emerged, leading to progression such as Richter's transformation (RT). As a result, there remains an unmet clinical need to identify new therapeutic strategies. In our review article, we aim to evaluate the past and current state of CLL treatment in both frontline and relapsed/refractory settings and also explore mitochondrial reprogramming, metabolic alterations, and RNA splicing as potential novel therapeutic targets. Over the past decade, the treatment landscape of CLL has vastly changed from the conventional FC (fludarabine and cyclophosphamide) and FCR (FC with rituximab) chemotherapies to targeted therapies, including inhibitors of Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) as well as inhibitors of BCL2. These treatment options dramatically improved clinical outcomes; however, not all patients respond well to these therapies, especially high-risk patients. Clinical trials of immune checkpoint inhibitors (PD-1, CTLA4) and chimeric antigen receptor T (CAR T) or NK (CAR NK) cell treatment have shown some efficacy; still, long-term outcomes and safety issues have yet to be determined. CLL remains an incurable disease. Thus, there are unmet needs to discover new molecular pathways with targeted or combination therapies to cure the disease. Large-scale genome-wide whole-exome and whole-genome sequencing studies have discovered genetic alterations associated with disease progression, refined the prognostic markers in CLL, identified mutations underlying drug resistance, and pointed out critical targets to treat the disease. More recently, transcriptome and proteome landscape characterization further stratified the disease and revealed novel therapeutic targets in CLL. In this review, we briefly summarize the past and present available single or combination therapies, focusing on potential emerging therapies to address the unmet clinical needs in CLL.