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TP53 aberrations in CLL
It has also become evident that patients may develop resistance to these targeted therapies. For example, muta- tions in the BTK and PLCG2 genes have been associated with resistance to ibrutinib, while upregulation of anti- apoptotic BCL2 family members has been associated with resistance to venetoclax.101-104 Mechanisms of resist- ance to idelalisib have not yet been fully characterized; because idelalisib inhibits the PI3K p110δ isoform, resist- ance may theoretically involve upregulation of other PI3K isoforms.105 However, in a whole-exome sequencing analysis of 13 patients with CLL who had progressed while on idelalisib plus anti-CD20 treatment in three phase 3 trials, none of the patients had recurrent progres- sion-associated mutations in the PI3K pathway or other related pathways.71
The optimal sequencing of these targeted therapies is currently unknown, but observational studies suggest that patients who discontinue a BCR pathway inhibitor due to toxicity may benefit from an alternative BCR path- way inhibitor. Conversely, those patients who progress under BCR inhibitor therapy fare better with venetoclax than an alternative BCR inhibitor.106,107 Following progres- sion on one or more therapies, allogeneic hematopoietic stem cell transplantation also remains a valid option, especially because these novel therapies may render patients more fit for this procedure.
It is important to note that, until recently, treatment guidelines for patients with TP53 aberrations were based on retrospective analyses and subgroup analyses. Patients with TP53 aberrations are still defined as a high-risk group, despite the development of these newer therapies, but their outcome has greatly improved in recent years. More long-term data and dedicated trials of these new therapies in this population are still needed to understand the long-term prognosis. Nevertheless, these therapies (as monotherapy or in combination) have become the main- stay of treatment in patients with CLL harboring TP53
mutations or del(17p), as well as in relapsed or refractory
CLL and have led to recent updates in treatment guide- lines.34,35,84,85,108,109
Future considerations
As evidence from clinical trials demonstrates, it is important to test accurately for TP53 aberrations (both del[17p] and TP53 mutations) before each line of treat- ment, thus allowing for appropriate treatment decisions to optimize patients’ outcomes. Accurate identification of TP53 mutations demands standardization in sequencing technologies and pathogenicity assessments. Independent evaluation within prospective clinical trials is still required to determine the clinical impact of minor subclonal mutations (<10%). Similarly, given the contin- uing evolution of therapeutic agents in CLL, it is impor- tant to continue to evaluate TP53 aberrations as new ther- apeutic alternatives become available. While allogeneic hematopoietic stem cell transplantation remains the only curative treatment option for patients with CLL harbor- ing TP53 aberrations, the recent approvals of ibrutinib, idelalisib, and venetoclax have provided significantly improved outcomes for this high-risk group of patients.
Acknowledgments
Editorial assistance was provided by Sarah Etheridge, PhD (ApotheCom, London, UK). The editorial assistance was funded by Gilead Sciences Europe, Ltd who had no input into the con- tent of this work. EC is supported by grants from Instituto de Salud Carlos III (PMP15/00007, CIBERONC and ERA-NET TRANSCAN initiative (TRS-2015-00000143) AC15/00028. SP has been supported by the MEYS CZ project CEITEC 2020 (LQ1601) and MH CR grant AZV 15-31834A. SS was sup- ported by the DFG SFB 1074 project B1 and B2. AS was sup- ported by the NIHR Oxford Biomedical Research Centre. The views expressed are those of the authors and do not reflect the views of the United Kingdom’s Department of Health.
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