Abstract
Simple SummaryChronic lymphocytic leukemia harbors a high degree of genetic variability and interpatient heterogeneity. Some of the genetic alterations have an impact on the disease’s prognosis and evolution, but few data exist about the response to new approved targeted therapies in patients carrying recurrent mutations other than TP53. In this review, we present the knowledge about the impact of these new genetic alterations in the treatment response together with the possibility to use new actionable targets.Chronic lymphocytic leukemia (CLL) is characterized by a high degree of genetic variability and interpatient heterogeneity. In the last decade, novel alterations have been described. Some of them impact on the prognosis and evolution of patients. The approval of BTK inhibitors, PI3K inhibitors and Bcl-2 inhibitors has drastically changed the treatment of patients with CLL. The effect of these new targeted therapies has been widely analyzed in TP53-mutated cases, but few data exist about the response of patients carrying other recurrent mutations. In this review, we describe the biological pathways recurrently altered in CLL that might have an impact on the response to these new therapies together with the possibility to use new actionable targets to optimize treatment responses.
Highlights
In the last decade, genomic and epigenomic studies have unravel novel alterations that play an important role in the prognosis and evolution of chronic lymphocytic leukemia (CLL) [1,2,3,4,5,6], revealing CLL’s genetic and interpatient heterogeneity
Two major strategies have been described for Toll-like receptor (TLR) inhibition: blocking the binding site of TLR ligands to its receptor interfering in the intracellular signaling pathway, which can be achieved by small molecule inhibitors, monoclonal antibodies, oligonucleotides, lipid-A analogs, microRNAs, and nano-inhibitors (Figure 1) [86]; or by inhibiting IRAK proteins from the Myddosome with small molecules
retrovirus-associated DNA sequences (RAS) activates a member of the serine-threonine kinase RAF family (BRAF), that facilitates the phosphorylation of the mitogen-activated ERK kinase (MEK) and MEK activates extracellular signal-regulated kinase (ERK), the most important kinase in the cascade that activates different transcription factors [91]
Summary
Genomic and epigenomic studies have unravel novel alterations that play an important role in the prognosis and evolution of chronic lymphocytic leukemia (CLL) [1,2,3,4,5,6], revealing CLL’s genetic and interpatient heterogeneity. Few data exist about the effect of other recurrent mutations in the response to the new approved targeted therapies (Table 1) In this way, the effect of other mutated genes relevant for the DNA damage response pathway such as ATM, located at 11q region, a region frequently deleted in CLL cases, has not been widely explored, it is accepted that 11q alterations are associated with unfavorable prognosis [24]. Only TP53 and NOTCH1 have a predictive impact, as it has been demonstrated in comparative trials that some treatments have different effect in the presence of these mutations [18,35,36] (Table 1) All this knowledge together with the characterization of the molecular effects of recurrent mutations, foster the development of direct target inhibitors leading to a precision medicine [19,37]. BR: bendamustine + rituximab, Chl: chlorambucil, ChlR: chlorambucil + rituximab, DOR: duration of response, EOCT: end of combination therapy, EOT: end of treatment, FC: fludarabine + cyclophosphamide, FCR: fludarabine + cyclophosphamide + rituximab, GClb: obinutuzumab + chlorambucil, IbrOb: ibrutinib + obinutuzumab, IdeR: idelalisib + rituximab, MRD: minimal residual disease, ObAca: obinutuzumab + acalabrutinib, ObChl: obinutuzumab + chlorambucil, OfChl: ofatumumab + chlorambucil, OfIde: ofatumumab + idelalisib, OS: overall survival, OR: overall response, PFS: progression free survival, R/R: relapsed/refractory patients, RT: Richter transformation, TN: treatment naïve, VAF: variant allele frequency, VenOb: venetoclax + obinutuzumab, VenR: venetoclax + rituximab
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