Innovation in the prognostication of chronic lymphocytic leukemia: how far beyond TP53 gene analysis can we go?

Abstract

T he prognostication of patients with chronic lymphocytic leukemia (CLL) currently relies on both clinical and biological parameters ( Figure 1). The prime example concerns the TP53 gene, whereby inactivation of TP53, resulting from either a mutation or chromosome 17p deletion, is associated with a short time to progression, an early need for treatment, and an overall dismal outcome.1,2 The presence of TP53 aberrations is also a strong predictor of treatment response, as patients carrying such lesions respond poorly to standard chemoimmunotherapy (CIT) (i.e. fludarabine, cyclophosphamide, and rituximab).3 Although TP53 abnormalities are infrequent at diagnosis (5%-10%), they are found in 40%-50% of advanced or therapy-refractory cases, hence underscoring the need to re-assess TP53 gene status as the disease progresses and clones evolve. 2,4,5 TP53 inactivation in CLL was identified more than 20 years ago in the context of advanced disease, chemo-refractoriness and poor clinical outcome. However, almost a decade passed before the analysis of TP53 defects by fluorescence in situ hybridization (FISH) was introduced into routine clinical practice, spurred on by the establishment of the Döhner hierarchical classification of cytogenetic abnormalities. 1 In this model, patient stratification was based on the presence of recurrent chromosomal aberrations (17p deletion, including the TP53 locus, 11q deletion, including the ATM locus, trisomy 12 and 13q deletion), with patients carrying del(17p) having the shortest survival.1 More recently, studies have shown that approximately 80% of patients harboring del(17p) also carry a mutation on the second allele of the TP53 gene. 4,6,7 Conversely, only approximately 60% of patients with TP53 mutations carry del(17p); nevertheless, studies have revealed that both biallelic and monoallelic defects (sole mutation or sole deletion) convey an equally poor prognosis. The poor prognosis conveyed by TP53 aberrations is mainly due to refractoriness to CIT treatment. 4-8The advent of agents acting independently of the p53 pathway looks promising for the treatment of CLL patients carrying TP53 aberrations. Recently, two inhibitors of B-cell receptor (BCR) signaling, namely ibrutinib [inhibitor of Bruton's tyrosine kinase (BTK)], and idelalisib [inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ)] have been approved by both the Food and Drug administration (FDA) and the European Medicines Agency (EMA) for the first-line treatment of cases harboring del(17p)/TP53 mutations or the treatment of CLL cases refractory to CIT or unfit for CIT. 9,10 Additional small molecules targeting other pathophysiological processes are set to be approved, e.g. the BH3 mimetic ABT199 (Venetoclax), with preliminary results indicating efficacy in del(17p)/TP53 mutated CLL cases. 11These new therapeutic options have also accelerated the need to analyze del(17p)/TP53 mutations prior to therapy, and the European Research Initiative on CLL (ERIC) (www.ericll.org) has been at the forefront of this field by: i) for...

Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

“…Our study further serves to highlight the fact that even findings within smaller subsets help to dissect the pathophysiology of CLL, and may eventually have clinical usability akin to the known prognostication value of TP53 gene mutations, despite being present in only 5-10% of cases at diagnosis or the association between subset #8 (0.6% of all CLL) and Richter's transformation. 15,46 Overall, since the distinct genomic profiles evidenced amongst stereotyped CLL subsets are potentially linked to varying mechanisms of clinical aggressiveness based on a reliance on specific intracellular signaling pathways, our findings may have important implications for patient monitoring and therapeutic management in the era of targeted pathway inhibition.…”

The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia

“…In newly diagnosed CLL patients, TP53 disruption is relatively infrequent (5%‐10%), while the frequency increases during the progression of disease, and may reach up to 50% at refractoriness . Previous studies have found that the majority (70%) of patients carrying del(17p) also harbored TP53 mutations in the remaining allele and 40% of patients carried isolated TP53 mutations . Those studies have established the fact that del(17p) and TP53 mutations conveys a poor outcome …”

“…carrying del(17p) also harbored TP53 mutations in the remaining allele 7 and 40% of patients carried isolated TP53 mutations. 8 Those studies have established the fact that del(17p) and TP53 mutations conveys a poor outcome. 2,[9][10][11] We observed that not all CLL patients with TP53 disruption have similarly dismal outcomes in our study.…”

Management of high risk chronic lymphocytic leukaemia (CLL) patients in Australia

“…Loss of p53 function in CLL can occur due to del(17p) or TP53 variants . While TP53 variants often coincide with del(17p) (80–90%), sole TP53 variants can also occur in the absence of del(17p) . Aberrations in TP53 are detected by gene sequencing.…”

“…7 While TP53 variants often coincide with del(17p) (80-90%), sole TP53 variants can also occur in the absence of del(17p). 8,9 Aberrations in TP53 are detected by gene sequencing. Testing by fluorescence in situ hybridisation (FISH) may miss more than 30% of all TP53 abberations.…”