From Biomarkers to Models in the Changing Landscape of Chronic Lymphocytic Leukemia: Evolve or Become Extinct

Abstract

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.

Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL)

“…This clinical heterogeneity has important consequences for clinical follow-up, therapeutic strategies, and patient survival. Because of this, several prognostic and predictive biomarkers have been identified over the years [ 2 ]; the most relevant being deletions and/or mutations in TP53 , located at 17p13, and the mutational status of the variable region of the immunoglobulin heavy chain (IGHV) gene [ 1 ]. FISH analysis of the four-probe set included in Dohner’s hierarchical model [targeting deletions on 13q14, 11q22 ( ATM ), 17p13 ( TP53 ), and trisomy of chromosome 12] is currently considered the gold standard for cytogenetic assessment in CLL [ 3 ].…”

TRAF3 alterations are frequent in del‐3′IGH chronic lymphocytic leukemia patients and define a specific subgroup with adverse clinical features

“…Taking into account that this study was retrospective and more than 90% of patients received chemotherapeutic regimens, several limitations were found to answer further questions. It would be of great interest to assess the response to novel drugs according to TRAF3 status in CLL, as well as to evaluate its potential value as a prognostic and predictive biomarker in the era of novel agents 41,59 . In addition, performing a sequential genetic analysis during disease evolution could help to understand when the del‐3′IGH usually appears and if this cytogenetic alteration plays a role as an early or late alteration in CLL.…”

“…prognostic and predictive biomarker in the era of novel agents. 41,59 In addition, performing a sequential genetic analysis during disease evolution could help to understand when the del-3 0 IGH usually appears and if this cytogenetic alteration plays a role as an early or late alteration in CLL. Moreover, 14q deletion including del-3 0 IGH may encompass other genes (apart from those analyzed in this study) that could also influence CLL pathogenesis and prognosis, and further investigations on the molecular landscape of this entity would be relevant.…”

The Mysterious Actor—γδ T Lymphocytes in Chronic Lymphocytic Leukaemia (CLL)

“…Nevertheless, this disease is highly heterogeneous, with some patients having a more aggressive course, particularly those with unmutated immunoglobulin heavy chain genes (IGHV), and del(17p), del(11q) and TP53 gene mutations [ 9 , 10 ]. Immunophenotypic markers, such as CD38 and ZAP-70, are widely accepted as indicators of a poor prognosis [ 11 , 12 ]. CD38 expression correlates with IGHV mutational status, but may also have independent prognostic significance.…”