Survival of Del17p CLL Depends on Genomic Complexity and Somatic Mutation

Abstract

Purpose Chronic lymphocytic leukemia (CLL) with 17p deletion typically progresses quickly and is refractory to most conventional therapies. However, some del(17p) patients do not progress for years, suggesting that del(17p) is not the only driving event in CLL progression. We hypothesize that other concomitant genetic abnormalities underlie the clinical heterogeneity of del(17p) CLL. Experimental Design We profiled the somatic mutations and copy number alterations (CNA) in a large group of del(17p) CLL as well as wild type CLL and analyzed the genetic basis of their clinical heterogeneity. Results We found that increased somatic mutation number associates with poor overall survival independent of 17p deletion (p=0.003). TP53 mutation was present in 81% of del(17p) CLL, mostly clonal (82%), and clonal mutations with del17p exhibit shorter overall survival than subclonal mutations with del17p (p= 0.019). Del(17p) CLL has a unique driver mutation profile, including NOTCH1 (15%), RPS15 (12%), DDX3X (8%) and GPS2 (6%). We found that about half of del(17p) CLL cases have recurrent deletions at 3p, 4p, or 9p and that any of these deletions significantly predicts shorter overall survival. In addition, the number of CNAs, but not somatic mutations, predicts shorter time to treatment among patients untreated at sampling. Indolent del(17p) CLLs were characterized by absent or subclonal TP53 mutation and few CNAs, with no difference in somatic mutation number. Conclusions We conclude that del(17p) has a unique genomic profile and that clonal TP53 mutations, 3p, 4p or 9p deletions, and genomic complexity are associated with shorter overall survival.

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

“…Woyach et al (2014) described characteristic resistance mutations arising during ibrutinib treatment among patients with CLL progression, and a subsequent report detailing outcomes from a large single‐institution cohort of ibrutinib‐treated CLL patients found that the presence of a complex karyotype rather than del(17p) was associated with a 4‐fold increase in the risk for discontinuation due to disease progression during ibrutinib treatment (Maddocks et al , 2015). Findings from subsequent studies also suggest that cytogenetic complexity is a prognostic marker of poorer outcomes in the presence or absence of del(17p) (Thompson et al , 2015; Yu et al , 2017). …”

Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL

“…However, a recent large study of 69 patients with del(17p) and CLL identified 3p, 4p, 8p, and 9p as recurrent events significantly associated with del(17p) but not del(18p). 41 Thus, the possibility remains that del(18p) does not happen by chance in the setting of ibrutinib treatment, and it may cooperate with TP53 in conferring refractoriness to prior therapies and in increasing risk of relapse during ibrutinib treatment. In a way, what we observed here could be similar to the association between del(17p)/TP53 mutations, complex cytogenetics, and enriched 5q/7q loss in the setting of acute myeloid leukemia and myelodysplastic syndrome.…”

Chronic lymphocytic leukaemia genomics and the precision medicine era

“…RPS15 mutations are frequently associated with TP53 mutations. Mutant RPS15 p.G132A experimentally increased TP53 degradation through increased ubiquitination, as compared with wild‐type RPS15 (Ljungstrom et al , ; Yu et al , ).…”

“…Chromosome 2p gain is however associated with advance disease and treatment resistance (Chapiro et al, 2010). A complex karyotype (defined as composed of 3 or more abnormalities) has been associated with an unfavourable prognosis, short time to treatment and poor response to treatment Herling et al, 2016;Yu et al, 2016). Almost 20% of cases with no aberration detected by the standard FISH panels ("normal" FISH) were reported to carry complex karyotypes (Rigolin et al, 2012).…”