The knowledge of chronic lymphocytic leukemia (CLL) has progressively deepened during the last forty years. Research activities and clinical studies have been remarkably fruitful in novel findings elucidating multiple aspects of the pathogenesis of the disease, improving CLL diagnosis, prognosis and treatment. Whereas the diagnostic criteria for CLL have not substantially changed over time, prognostication has experienced an expansion with the identification of new biological and genetic biomarkers. Thanks to next-generation sequencing (NGS), an unprecedented number of gene mutations were identified with potential prognostic and predictive value in the 2010s, although significant work on their validation is still required before they can be used in a routine clinical setting. In terms of treatment, there has been an impressive explosion of new approaches based on targeted therapies for CLL patients during the last decade. In this current chemotherapy-free era, BCR and BCL2 inhibitors have changed the management of CLL patients and clearly improved their prognosis and quality of life. In this review, we provide an overview of these novel advances, as well as point out questions that should be further addressed to continue improving the outcomes of patients.

Chronic lymphocytic leukemia (CLL) is an extremely heterogeneous disease. With the advent of oral targeted agents (Tas) the treatment of CLL has undergone a revolution, which has been accompanied by an improvement in patient’s survival and quality of life. This paradigm shift also affects the value of prognostic and predictive biomarkers and prognostic models, most of them inherited from the chemoimmunotherapy era but with a different behavior with Tas. This review discusses: (i) the role of the most relevant prognostic and predictive biomarkers in the setting of Tas; and (ii) the validity of classic and new scoring systems in the context of Tas. In addition, a critical point of view about predictive biomarkers with special emphasis on 11q deletion, novel resistance mutations, TP53 abnormalities, IGHV mutational status, complex karyotype and NOTCH1 mutations is stated. We also go over prognostic models in early stage CLL such as IPS-E. Finally, we provide an overview of the applicability of the CLL-IPI for patients treated with Tas, as well as the emergence of new models, generated with data from patients treated with Tas.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, but chronological age does not accurately discriminate frailty status at the inter-individual level. Frailty describes a person’s overall resilience. Since CLL is a stressful situation, it is relevant to assess the patient´s degree of frailty, especially before starting antineoplastic treatment. We are in the era of targeted therapies, which have helped to control the disease more effectively and avoid the toxicity of chemo (immuno) therapy. However, these drugs are not free of side effects and other aspects arise that should not be neglected, such as interactions, previous comorbidities, or adherence to treatment, since most of these medications are taken continuously. The challenge we face is to balance the risk of toxicity and efficacy in a personalized way and without forgetting that the most frequent cause of death in CLL is related to the disease. For this purpose, comprehensive geriatric assessment (GA) provides us with the opportunity to evaluate multiple domains that may affect tolerance to treatment and that could be improved with appropriate interventions. In this review, we will analyze the state of the art of GA in CLL through the five Ws.

Interstitial 14q32 deletions involving IGH gene are infrequent events in chronic lymphocytic leukemia (CLL), affecting less than 5% of patients. To date, little is known about their clinical impact and molecular underpinnings, and its mutational landscape is currently unknown. In this work, a total of 871 CLLs were tested for the IGH break‐apart probe, and 54 (6.2%) had a 300 kb deletion of 3′IGH (del‐3′IGH CLLs), which contributed to a shorter time to first treatment (TFT). The mutational analysis by next‐generation sequencing of 317 untreated CLLs (54 del‐3′IGH and 263 as the control group) showed high mutational frequencies of NOTCH1 (30%), ATM (20%), genes involved in the RAS signaling pathway (BRAF, KRAS, NRAS, and MAP2K1) (15%), and TRAF3 (13%) within del‐3′IGH CLLs. Notably, the incidence of TRAF3 mutations was significantly higher in del‐3′IGH CLLs than in the control group (p < .001). Copy number analysis also revealed that TRAF3 loss was highly enriched in CLLs with 14q deletion (p < .001), indicating a complete biallelic inactivation of this gene through deletion and mutation. Interestingly, the presence of mutations in the aforementioned genes negatively refined the prognosis of del‐3′IGH CLLs in terms of overall survival (NOTCH1, ATM, and RAS signaling pathway genes) and TFT (TRAF3). Furthermore, TRAF3 biallelic inactivation constituted an independent risk factor for TFT in the entire CLL cohort. Altogether, our work demonstrates the distinct genetic landscape of del‐3′IGH CLL with multiple molecular pathways affected, characterized by a TRAF3 biallelic inactivation that contributes to a marked poor outcome in this subgroup of patients.

ZMYM3 mutations have been recurrently identified in chronic lymphocytic leukemia (CLL) patients at diagnosis. However, their clinical relevance and functional implications remain poorly defined. Here, we comprehensive characterize the clinical and translational impact of ZMYM3 mutations in CLL. Next-Generation Sequencing (NGS) analyses of 487 CLL cases identified 32 ZMYM3 variants, predominantly manifested as loss-of-function variants. ZMYM3-mutated patients showed a strong enrichment of NOTCH signaling pathway alterations, with 60% harboring NOTCH1 mutations. Clinically, ZMYM3 variants were associated with a higher treatment requirement and a significantly shorter time to first treatment (median: 35 vs 52 months; p=0.010), and stratified clinical outcome in early-stage cases (median: 48 vs 91 months; p=0.016). Multivariable analysis confirmed ZMYM3 mutations as an independent adverse prognostic factor. Using CRISPR/Cas9-edited CLL cells, we demonstrate that ZMYM3 mutations cooperate with NOTCH1 mutations to induce widespread transcriptional dysregulation. Moreover, RNA-sequencing of cellular models and CLL patient samples further revealed that ZMYM3 mutations impact histone acetylation, resulting in reduced chromatin accessibility. Functionally, ZMYM3 mutations promoted apoptosis evasion through caspase downregulation. Importantly, primary ZMYM3-mutated CLL cells exhibited increased sensitivity to BCL-XL inhibition and ibrutinib. Overall, this work establishes the clinical relevance of ZMYM3 mutations and provides novel insights into their contribution to CLL pathophysiology.