Mutations in chronic lymphocytic leukemia and how they affect therapy choice: focus on NOTCH1, SF3B1, and TP53

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by a relatively small number of recurrent genetic defects. These can be evaluated by clinically available methods such as fluorescent in situ hybridization and targeted sequencing approaches to provide data that can be very helpful in prognostication and planning of treatment. Acquired defects in the p53 pathway, activating mutations of NOTCH1, and dysfunctional mutations of SF3B1 and BIRC3 identify patients with higher risk of progressive disease, poorer responses to conventional chemoimmunotherapy, and shorter survival. Risk stratification using these data can identify patients with aggressive CLL who require careful monitoring and are unlikely to have durable responses to chemoimmunotherapy at disease progression. Patients with defective DNA damage repair mechanisms because of p53 dysfunction should be considered for non-chemotherapy-based regimens including tyrosine kinase inhibitors, BCL2 inhibitors, monoclonal antibodies, and immunological therapies including allogeneic transplantation and chimeric antigen receptor-targeted T cells. Conversely, patients with no high-risk mutations can usually be monitored for a prolonged time and are likely to have durable responses to chemoimmunotherapy at disease progression. New technologies for genetic analysis such as targeted next-generation sequencing have the potential to make these analyses cheaper, faster, and more widely available. Comprehensive genetic analysis of patients both at diagnosis and before treatment for progressive disease could become an integral component of care for CLL. Learning Objectives• To understand the role of recurrent genetic lesions in the biology of CLL • To use this knowledge for prognostication and selection of therapy

TP53 Mutation and Its Prognostic Significance in Waldenstrom's Macroglobulinemia

“…Our study thus led us to propose that it might be primetime for a systematic evaluation of TP53 alteration through mutation and/or deletion as part of the prognostic pretreatment package of WM at diagnosis, in order to identify patients with TP53 Alt that might benefit more from BTK inhibitors (13). Interestingly, we observed the absence of mutations of ATM in our cohort suggesting different genomic features between CLL and WM (5,6). Similarly, we found no relationship (Continued.)…”

“…We thus investigated the effect of either of three compounds that showed activity in TP53 Mut condition, independently of the mechanism of loss of function of p53. Preliminary data showed the great interest for BTK inhibitors in relapsed WM and in CLL with TP53 alteration (6,13,26,35). We have evaluated the in vitro responses of WM to ibrutinib according to their TP53 status and showed that ibrutinib may induce apoptosis and loss of viability in WM, independently of p53 alteration.…”

“…No association was observed between TP53 Mut and MYD88 mutations, and CD79A/CD79B or CXCR4 mutations (n ¼ 125). We then sought to study the incidence of ATM mutations associated with chemoresistance and or alteration in DNA damage response in CLL (5,6). No mutation of ATM was found in our cohort of WM.…”

“…The deletion of the short arm of chromosome 17 (Del17p) that contains the TP53 gene is often monoallelic, and mutations may occur on the remaining allele of TP53 (5)(6)(7). The prevalence of TP53 alterations, either mutation or deletion, differs considerably between tumor types and stages of lymphoid disorders; nevertheless, p53 inactivation is often associated with cancer progression and drug resistance (1,6,8,9).…”

“…The deletion of the short arm of chromosome 17 (Del17p) that contains the TP53 gene is often monoallelic, and mutations may occur on the remaining allele of TP53 (5)(6)(7). The prevalence of TP53 alterations, either mutation or deletion, differs considerably between tumor types and stages of lymphoid disorders; nevertheless, p53 inactivation is often associated with cancer progression and drug resistance (1,6,8,9). The mutations of TP53, especially when located in the DNA-binding domain, are associated with a greater risk of more aggressive disease, poorer responses to conventional chemoimmunotherapy, and short survival in numerous lymphoid disorders, including chronic lymphocytic leukemia (CLL) and marginal zone lymphoma (6,(10)(11)(12).…”