TP53 dysfunction in chronic lymphocytic leukemia: clinical relevance in the era of B-cell receptors and BCL-2 inhibitors

Abstract

Introduction. Patients with TP53 dysfunction, assessed by del(17p) or TP53 mutations, respond poorly to chemo-immunotherapy and fare better with the new therapies (BCR and BCL-2 inhibitors); however, it is unclear whether their response is similar to that of patients without anomalies or whether there is currently an adequate determination of TP53 dysfunction. Area covered.A literature search was undertaken on clinical trials and real-world experience data on patients with TP53 dysfunction treated with different protocols. Moreover, data on the TP53 biological function and on the tests currently employed for its assessment were reviewed. Expert opinion.Although TP53 dysfunction has less negative influence on the new biological therapies, patients with these alterations, particularly those with biallelic inactivation of TP53, have a worst outcome with these therapies than those without alterations. At present, a determination of TP53, particularly with next generation sequencing (NGS) methodologies, may be sufficient for the identifications of the patients unsuitable for chemo-immunotherapy, although integration with del(17p) would be advisable. For the future, more extensive determinations of the TP53 status, including functional assays, may become part of the current armamentarium for a better patient stratification and treatment with newer protocols.

The Role of Tumor-Associated Macrophages in Hematologic Malignancies

“…Biological variables, such as cytogenetic aberrations and immunoglobulin heavy chain variable region genes (IGHV) mutational status, represent the most important factors to consider before treatment choice [ 63 ]. The highest risk group is represented by CLL harboring TP53 mutations and/or del(17p), in which targeted therapy is strongly recommended as first-line regimen [ 64 , 65 ].…”

Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

“…Furthermore, there is evidence that CLL patients with TP53 dysfunction [measured as del(17p) and/or TP53 mutations] progress more rapidly to stages requiring treatment. Together, these considerations indicate that TP53 alterations facilitate clonal expansion and disease progression irrespective of the impact they may have on therapy (78). The presence of a P53 dysfunction has a definite negative impact on the effect of chemo-immunotherapy, whereas such impact appears to be less pronounced in patients treated with BCR inhibitors (e.g.…”

Effectiveness of ibrutinib as first‐line therapy for chronic lymphocytic leukemia patients and indirect comparison with rituximab‐bendamustine: Results of study on 486 cases outside clinical trials

“…2,3 Polymerization is exponentially dependent on deoxy Hb S concentration. 4 Thus, relatively small changes in deoxyHb S concentration will significantly impact polymerization, red blood cell sickling, and ultimately the clinical course of the disease.…”