Abstract
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. Novel biomarkers discovered over the past 20 years have revolutionized the way clinicians approach prognostication and treatment especially in the chemotherapy-free era. Herein, we review the best established prognostic and predictive biomarkers in the setting of chemoimmunotherapy (CIT) and novel targeted therapy. We propose that TP53 disruption (defined as either TP53 mutation or chromosome 17p deletion), unmutated immunoglobulin heavy chain variable region gene status (UM IGHV), NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival in the field of novel biomarkers including recurrent gene mutations. We also highlight the predictive role of TP53 disruption, UM IGHV, and NOTCH1 mutation in the setting of CIT and TP53 disruption and CD49d expression in the setting of novel targeted therapy employing B-cell receptor (BCR) and B-cell lymphoma-2 (BCL2) inhibition. Finally, we discuss future directions in the field of biomarker development to identify those with relapsed/refractory disease at risk for progression despite treatment with novel therapies.
Highlights
SF3B1 mutation and/or del11q) and very high (BIRC3 disruption and/or TP53 disruption). These results propose that TP53 disruption, UM immunoglobulin heavy chain variable gene (IGHV) gene mutational status, mutated NOTCH1 and CD49d expression are the most powerful prognosticators in Chronic lymphocytic leukemia (CLL)
TP53 disruption, UM IGHV, NOTCH1 mutation, and CD49d expression are the strongest prognosticators of disease progression and overall survival (OS) in CLL
Our recently published results on CD49d advocate for an updating of the CLL international prognostic index (CLL-IPI) with the inclusion of this variable
Summary
Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable clinical course. They range from host factors (i.e., gender and age) to disease markers (i.e., Rai and Binet staging), antigen expression (i.e., CD38, ZAP70, and CD49d/VLA-4), serology (i.e., lactate dehydrogenase, beta-2-microglobulin [B2M], and thymidine kinase), genetics (i.e., deletion of the short arm of chromosome 17 [del17p] and TP53 gene mutation) and immunogenetics Predictive biomarkers forecast disease response to specific treatments and are clinically useful in tailoring therapy. The purpose of this manuscript is to review well-established and novel biomarkers in CLL discussing their roles as prognostic and/or predictive biomarkers. In the course of this discussion, we aim to review current treatment options and propose a refinement of existing treatment algorithms to more accurately reflect our current knowledge
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