Molecular Genetics of High-risk Chronic Lymphocytic Leukemia

Davide Rossi; Gianluca Gaidano


Expert Rev Hematol. 2012;5(6):593-602. 

In This Article

Five-year View

The observation that NOTCH1, SF3B1 and BIRC3 mutations are enriched in fludarabine-refractory CLL, and the trend towards a mutual exclusion of these lesions with TP53 abnormalities, point to NOTCH1, SF3B1 and BIRC3 mutations as attractive biomarkers for the identification of chemorefractory but TP53 wild-type CLL. However, the translation of NOTCH1, SF3B1 and BIRC3 mutations into clinically useful biomarkers for the early identification of chemorefractory CLL patients requires a formal demonstration that these lesions associate with poor response and/or short PFS after treatment in prospectively collected CLL cohorts.

NOTCH1, SF3B1 and BIRC3 mutations are structural alterations of the CLL genome affecting functionally relevant domains of the NOTCH1, SF3B1 and BIRC3 proteins that, conceivably, might exert a direct causative role at some stage of the leukemogenesis process. However, with the exception of scattered evidence on the activation of NOTCH1 signaling in CLL, the biology of NOTCH1, SF3B1 and BIRC3 mutations in CLL remains to be elucidated and requires dedicated studies.

Given the availability of inhibitory drugs in clinical and preclinical development; NOTCH1, SF3B1 and NF-κB represent promising targets for molecular therapy in poor-risk refractory CLL. In fact, this is a disease setting enriched in NOTCH1, SF3B1 and BIRC3 mutations and in which conventional immunochemotherapy is largely ineffective.

CLL biomarkers, including those tailored at identifying refractory patients, have been developed in patients treated with chemo-/immunochemo-therapy. Based on early results from clinical trials, B-cell receptor signaling kinases inhibitors, namely ibrutinib (PCI - 32765; Bruton's tyrosine kinase inhibitor) and GS1101 (phosphatidylinositol 3-kinase delta inhibitor), appear to have substantial and prolonged clinical activity in CLL patients, including refractory cases and cases harboring 17p13 deletion, and will conceivably change the treatment scenario in CLL.[77] In this new landscape, several approaches to the management of CLL will conceivably be revised,[78] including the way in which we define and identify high-risk CLL.