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.

KEYWORDS:

• BCR inhibitors
• BCL2 inhibitor
• chronic Lymphocytic Leukemia
• clinical outcome
• del(17p)
• ibrutinib
• idelalisib
• venetoclax
• TP53 mutations

Article highlights

• TP53 dysfunction is operationally defined by the presence of del(17p) and/or TP53 mutations.

• TP53 dysfunction is one of the major causes of resistance to chemo-immunotherapy.

• BCR or BCL-2 inhibitors provide an increased likelihood of survival than chemo-immune therapy for patients with TP53 dysfunction.

• Some exploratory analysis of clinical trials as well as real world evidence, suggest that TP53 dysfunction, especially in the biallelic inactivation form, continues to have a negative influence on the clinical outcome of patients treated with the new biological therapies.

• New and more stringent laboratory tests to evaluate the residual P53 protein function in patients with TP53 mutations may plausibly lead to a better risk stratification of patients treated with old and new BCR and BCL-2 inhibitors.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

The work of the authors was funded by unrestricted contribution from GILEAD Sciences Srl. The funding sources had no role in identifying statements, abstracting data, synthesizing results, grading evidence or preparing the manuscript, or in the decision to submit the manuscript for publication (ISR-17-10250). Associazione Italiana Ricerca sul Cancro (AIRC) Grant 5 x mille n.9980, (to F.M., A.N. and M.F.); AIRC and Fondazione CaRiCal co-financed Multi-Unit Regional Grant 2014 n.16695 (to F.M.) Associazione Italiana Ricerca Cancro (AIRC), IG-5506 (to G.F.), IG-14326 (to M.F.), IG-15426 (to F.F.); Compagnia S. Paolo, Turin, Italy (Project 2017.0526 to G.F.) and by the Italian Ministry of Health 5 × 1000 funds 2015 and 2016 and Current Research 2016 (to G.F., G.C. and to F.F.).