Opinion: What defines high-risk CLL in the post-chemoimmunotherapy era?

Abstract

The definition of high-risk chronic lymphocytic leukemia (CLL) was relatively simple in the chemoimmunotherapy era, as it was defined by only one genomic marker, TP53 alteration, along with poor responses to purine-analogue based treatment (1). While other biomarkers such as unmutated IGHV, del(11q), high ZAP70 expression and high CD38 expression were associated with inferior prognosis, TP53 deficiency by mutation and/or del (17p) remained the only biomarker that clearly guided treatment decisions (2).The emergence of targeted compounds has rendered chemoimmunotherapy virtually obsolete for CLL treatment, with it remaining an option only for patients with a mutated IGHV, normal TP53 and a non-complex karyotype (3). Instead, non-chemotherapeutic targeted treatment has now become the standard of care. Approved treatment options in firstand second-line include continuous treatment with a covalent BTK inhibitor (e.g. ibrutinib, acalabrutinib) plus/minus anti-CD20 monoclonal antibody (4-9), fixed duration therapy with the BCL2 inhibitor venetoclax plus anti-CD20 monoclonal antibody (10, 11), fixed duration therapy with venetoclax plus ibrutinib (12, 13), and for TP53 altered cases, continuous monotherapy with venetoclax (14). Moreover, clinical trials are currently evaluating triple drug regimens that combine BTK and BCL2 inhibitors with anti-CD20 treatment (15-18). Looking forward, non-covalent BTK inhibitors (e.g. pirtobrutinib and nemtabrutinib) (19, 20), BTK degraders (e.g. NX-2127) (21), and second-generation BCL2 inhibitors (e.g. Lisaftoclax) ( 22) are promising alternatives in clinical development, along with immunotherapeutic approaches such as CAR T-cells and bispecific antibodies.The paradigm shift from chemoimmunotherapy to targeted therapy and the everincreasing number of treatment options has meant that defining high-risk CLL is less straight-forward. This is mainly because BTK and BCL2 inhibitors have been demonstrated to markedly improve progression-free and overall survival (PFS and OS) in TP53-deficient and IGHV unmutated CLL patients (4,5,7,9, 10,14,(23)(24)(25). Limited data from clinical trials evaluating ibrutinib first-line and acalabrutinib have even raised the possibility that BTKinhibition may overcome the adverse effects of TP53 deficiency (5,6,9,26). Although resultsFrontiers in Oncology frontiersin.org 01

Complex karyotype in chronic lymphocytic leukemia

“…While previously mentioned established prognostic factors have been proven to be clinically valuable, they are not without limitations. New and more accurate prognostic factors may be needed to capture the heterogeneity of CLL, provide more accurate predictions, and guide personalized treatment decisions (12)(13). Advances in genomics and other technologies have made it possible to identify new prognostic factors, such as complex karyotype (CK), tumor microenvironment, epigenetic changes, and others (12)(13)(14)(15).…”