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Chronic lymphocytic leukemia (CLL) has a heterogeneous biological behavior, which is highly influenced by its immunogenetic, epigenetic, and genomic properties. The remarkably variable clinical course of the disease has been associated with genetic features such as chromosomal abnormalities, the presence of either high or low numbers of somatic hypermutations (SHM) in the variable region of the immunoglobulin heavy chain locus (IGHV), and somatic mutations of several specific driver genes. Next-generation sequencing (NGS) technologies have provided a comprehensive characterization of the genomic and epigenomic landscape in CLL, elucidating important underlying mechanisms of the disease's biology. The scope of this review is to summarize the most recent discoveries about novel genetic and epigenetic alterations, discussing their impact on clinical outcomes and response to currently available therapy. [ABSTRACT FROM AUTHOR]

Lenalidomide is a therapeutically effective drug in chronic lymphocytic leukemia (CLL). Twenty-seven CLL patients were treated with lenalidomide in a phase II clinical trial. Ten patients were grouped as responders (R) and 6 as nonresponders (NR). We evaluated T lymphocytes, NK, monocytes and dendritic cells at baseline and after treatment. A gene expression analysis was performed on 16 CLL samples collected before treatment. The levels of immune cells or immune-related cytokines are not different between R and NR patients. However, CLL patients sensitive to lenalidomide clearly show a peculiar gene expression profile in leukemic cells. The most up-regulated gene (fold change =  +23 in R vs. NR) is Wnt inhibitor SHISA homolog 3 (SHISA3). SHISA3highCLL are characterized by a restrained activation of Wnt signaling and sensibility to lenalidomide-induced apoptosis. In conclusion, SHISA3 is a candidate gene for the identification of CLL patients who will benefit of lenalidomide treatment as single agent. [ABSTRACT FROM AUTHOR]

Treatment options for chronic lymphocytic leukemia (CLL) have improved with the introduction of the B-cell receptor inhibitors ibrutinib and idelalisib, and of the BCL2 inhibitor venetoclax. While awaiting the results of head to head comparisons between novel agents and chemoimmunotherapy, predictive biomarkers can assist physicians in treatment tailoring. Though novel agents have modified the landscape of predictors at the time of treatment requirement, the usefulness of historical CLL prognostic biomarkers is still up-to-date when considering anticipation of time to first treatment. This review discusses: (i) disease-related (TP53 defects, immunoglobulin gene mutations), therapy-related (duration of remission), and patient-related (age, comorbidities) biomarkers that can be used in the clinical practice to inform CLL treatment decision either at the time of first line therapy and disease relapse; and (ii) the need of new biomarkers to re-define high-risk CLL because of the questioning by novel agents of historical prognostic factors. [ABSTRACT FROM AUTHOR]

In chronic lymphocytic leukemia, NOTCH1, SF3B1, BIRC3 and TP53 disruptions are recurrent and affect survival. To define their incidence and clinical impact in patients undergoing first-line treatment, we evaluated 163 cases enrolled in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) LLC0405 protocol (fludarabine plus alemtuzumab or fludarabine plus cyclophosphamide), for young patients, or in the ML21445 protocol (chlorambucil plus rituximab), for elderly patients. NOTCH1, SF3B1, BIRC3 and TP53 disruptions were detected in 15.9%, 12.2%, 8.6% and 10.4% of cases. NOTCH1 mutations correlated with a shorter treatment-free interval ( p = 0.058), an unmutated immunoglobulin heavy variable gene ( IGHV) status ( p < 0.0001), CD38 and ZAP-70 expression ( p = 0.0025 and 0.026, respectively) and trisomy 12 ( p = 0.0028), SF3B1 mutations with an unmutated IGHV status ( p = 0.02), and BIRC3 disruptions with an unmutated IGHV configuration ( p = 0.01) and 11q deletion ( p < 0.0001). NOTCH1 and SF3B1 did not appear to impact on overall response, while an inferior response was observed for BIRC3- and TP53-disrupted cases in the LLC0405 and ML21445 protocols, respectively. Progression-free survival, evaluable in the LLC0405 protocol - not affected by NOTCH1, SF3B1 and TP53 - appeared inferior for BIRC3 disruption. NOTCH1 and SF3B1 mutations may be overcome by aggressive regimens, while BIRC3 might impact on outcome also in intensive regimens. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the research study "MGA, a suppressor of MYC, Is Recurrently Inactivated in High Risk Chronic Lymphocytic Leukemia," which appeared in the previous issue.

The author discusses the genetic susceptibility to chronic lymphocytic leukemia (CLL). He says that there are several epidemiological observations related to CLL incidence, which include that it varies across geographic location, predominantly contributed by genetic background rather than environmental factors, and relatives of CLL patients have higher chance of developing CLL. He mentions that genetic predisposition and familial aggregation have role in CLL development.

The author discusses research which investigated Richter syndrome (RS) transformation in chronic lymphocytic leukemia (CLL) patients receiving fludarabine therapy, conducted by M. Solh and colleagues, published within the issue. Topics explored include the clinical characteristics of the RS in CLL patients, the way this transformation allowed identification of proper treatment course targeting CLL progression, and the rate of RS transformation recorded in the study.