ERIC recommendations for TP53 mutation analysis in CLL - 2024 update

[Jm954]

Following on from the interesting discussion on testing for 17p del and TP53 disruption/mutations I thought it might be worth posting this paper which sets out how this testing and analysis is done. It's published by ERIC, the European Research Initiative on CLL, and is the 2024 update of the last recommendations for TP53 analysis in CLL from 2018.

TP53 and 17p del testing is still important in the days of targeted therapies, although less crucial. Unfortunately, decisions regarding the cut off points or thresholds for reporting are not clear cut and based on the current knowledge of the relevance of low-burden TP53-mutated clones, a specific variant allele frequency (VAF) cut-off for reporting TP53 mutations is no longer recommended, but instead, the need for thorough method validation by the reporting laboratory is emphasized.

A TP53 aberration is defined as either the deletion of the TP53 gene locus on 17p13 [del(17p)] or the presence of a mutation, i.e., somatic change in the sequence of the TP53gene (TP53mut). The frequency of TP53 aberrations in patients with chronic lymphocytic leukemia (CLL) is higher in those with unmutated immunoglobulin heavy variable (IGHV) genes. Generally, the frequency is low at diagnosis (5-10% of patients, depending on the method used), it is slightly higher in cohorts of patients entering frontline treatment (10–20%; Fig. 1), and further increases in later disease stages, predominantly in chemoimmunotherapy (CIT)-treated patients and Richter transformation (up to 50%) In patients with CLL, del(17p) is mostly accompanied by TP53 mutations, and sole del(17p) is infrequent, while sole TP53 mutations are more commonly found.

The prognostic value of TP53 aberrations is evident early in the course of CLL. Several prognostic scores developed to predict time-to-first-treatment (TTFT) include TP53aberrations as a variable. The CLL international prognostic index (CLL-IPI) incorporate TP53 aberrations as an independent predictor of shorter TTFT. A recent ERIC study and a single centre study from MD Anderson revealed that TP53 aberrations predict TTFT only in patients with unmutated IGHV genes.

TP53 aberrations also have paramount prognostic value in treated patients with CLL since, generally, they confer a worse prognosis with all available treatments, including agents targeting B cell receptor (BcR) signaling and BCL2, at least in the relapsed/refractory setting.

Predictive value of TP53 alterations

The predictive value of TP53 aberrations is clear when CIT regimens are included among the treatment options: in fact, targeted agents as either monotherapy or in combination outperformed CIT regimens in the frontline and R/R settings and represent the preferred option for these patients. Use of CIT allows the TP53 clone to grow and become dominant.

The clinical relevance of low-burden TP53 mutations is still debated. The vast majority of evidence was obtained in the era of CIT, and no clinical trial was designed to assess their impact.

It is recommended assessing del(17p) first and then TP53 testing only in cases without del(17p). However, following this two-step procedure can be difficult and may cause treatment delays, therefore, it is preferred to analyse both TP53 gene mutations and locus deletions simultaneously, if possible.

For TP53 variant detection, the preferred methodology is NGS, but Sanger sequencing can still be used if NGS is not available

The full technical methodology is in the paper, together with more detail regarding the significance of the burden of TP53 mutations.

nature.com/articles/s41375-...

Jackie

[mrsjsmith]

Thank you Jackie,

Something I will try to get my brain around. When I was diagnosed with these mutations in 2018 I hadn’t heard of them, so I decided not to worry about something I didn’t understand, so far so good 🤞

Colette

[CLLerinOz Administrator]

Thanks for this update, Jackie.

It's good to see that TP53 testing has become more readily available. Originally, it was only possible for many of us in Australia to access it through a trial or through philanthropic funding but it is now much more widely accessible here as the test was added to the Medical Benefits Schedule (MBS) in November 2023.

This means that Australians can now access funded testing to determine "Characterisation of a variant or variants in a panel of at least 25 genes using DNA and RNA [or DNA only], requested by a specialist or consultant physician, to determine the diagnosis, prognosis and/or management of a patient presenting with a clinically suspected haematological malignancy of lymphoid origin."

The schedule allows for testing "Applicable once per diagnostic episode, at diagnosis, disease progression or relapse."

The MBS lists a separate item number and fees for testing methodology using 1) DNA and RNA www9.health.gov.au/mbs/full... , and another for 2) DNA only www9.health.gov.au/mbs/full..., to reflect laboratories' different testing capabilities.

More information is available here:

mbsonline.gov.au/internet/m...

Here are a couple of extracts from that document:

"For patients with clinical or laboratory evidence of a suspected haematological malignancy, a NGS gene panel test during the initial work-up or at suspected disease progression/relapse will assist diagnosis and/or management. Patients will then have access to treatment that is clinically appropriate and reflects modern clinical practice – which will lead to better health outcomes."

"Testing should include, but not be restricted to, genes described in the current World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms or other appropriate international guidelines."

CLLerinOz

[AussieNeil Partner Administrator]

Patient Power have a 3.5 minute transcripted video by Dr Kerry Rogers, CLL Specialist at The James, Ohio State University, where she explains the importance of TP53 status for those who are also FISH 17p del patientpower.info/chronic-l...

Neil

[Adlucy]

Thank you for posting this Jackie. I need to get my brain around it. When diagnosed I spent a lot of time researching exactly TP53 and other mutations meant. I was three years from diagnosis to starting treatment.