Search

Simple Summary: Recent advances in treating elderly patients with chronic lymphocytic leukemia (CLL) have emphasized the importance of geriatric assessment (GA) to evaluate patient fitness and predict treatment outcomes. Targeted therapies (BTK inhibitors and venetoclax) have demonstrated significant clinical benefits and are now a reality in CLL treatment. They have a different toxicity profile that may affect frailty. Therefore, incorporating GA before treatment initiation, considering physical and cognitive function, emotional health, comorbidity, polypharmacy, nutrition, and social support, is essential. 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. [ABSTRACT FROM AUTHOR]

In total, 3 HG3 WT,3HG3 TP53 MUT, 3 HG3-del(11q), 5 HG3del(11q) TP53 MUT, and 5 HG3-del(11q) ATM MUT TP53 MUT clones were generated. Interestingly,HG3-del(11q) ATM MUT TP53 MUT cellsfailedtoengraftandcompetewith HG3-del(11q) and HG3-del(11q) TP53 MUT cells, almost disappearingfrombothspleenandbonemarrow2weeks aftercellinjection(Figure4B). Datawerefittedinanexponential growthequation,andtimepointvaluesarepresentedasthemean±SEM.(C)RepresentativeimmunoblotanalysesofHG3 WT,HG3TP53 MUT, HG3-del(11q),HG3-del(11q)TP53 MUT,andHG3-del(11q)ATM MUT TP53 MUT wholecelllysates.ATM,PARP1,andCaspase-3proteinexpression and/orcleavagewereanalyzed. -actinwasusedasloadingcontrol.(D)CellcyclephasedistributionofHG3-editedcelllinesuponexposureto irradiationattheindicatedtimepoints. In addition, HG3 TP53 MUT, and HG3-del(11q) TP53 MUT cells showed a G2/M cell cycle arrest in accordance with TP53-defective cell-cycle phenotype, 37 which was also overcame 48 hours post-IR. [Extracted from the article]

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next‐generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR‐CLLs) and we demonstrate that IGHR‐CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non‐Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR‐CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR‐CLLs patients showed a shorter TFT than CLL patients carrying 13q−, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR‐CLLs, but also refined the prognosis of low‐risk cytogenetic patients (13q−/normal FISH). Hence, our study demonstrates that IGHR‐CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk‐stratification CLL model. What's new? The prognostic significance of the immunoglobulin heavy chain (IGH) translocation in chronic lymphocytic leukemia (CLL) is controversial and its mutational profile remains unknown. Here, the authors assessed for the first time the genetic landscape of CLL patients with IGH rearrangements by targeted next‐generation sequencing, characterising recurrently‐mutated genes with prognostic implications and demonstrating that these entities exhibit an intermediate mutational profile between CLL and non‐Hodgkin lymphoma. Moreover, the findings showed that the incorporation of next‐generation sequencing and the IGH‐probe in the CLL‐fluorescence in situ hybridisation panel used in clinical routine could be useful, especially for elucidating prognosis in normal FISH cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic lymphocytic leukemia (CLL) is characterized by a highly variable clinical course. Thus, predicting the outcome of patients with this disease is a topic of special interest. The rapidly changing treatment landscape of CLL has questioned the value of classical biomarkers and prognostic models. Herein we examine the current state-of-the-art of prognostic and predictive biomarkers in the setting of new oral targeted agents with special focus on the most controversial findings over the last years. We also discuss the available information on the role of "old" and "new" prognostic models in the era of oral small molecules. 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. [ABSTRACT FROM AUTHOR]