Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

Abstract

Key Points• Targeted NGS of relapsed/ refractory CLL reveals a high incidence of concurrent mutations that mostly affect the TP53, ATM, and SF3B1 genes.• Concurrent mutations of the TP53, ATM, and/or SF3B1 genes confer short survival in patients with relapsed/ refractory CLL.Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number and combinations of recurrent gene mutations. The number of genes affected by mutation was ‡2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of ‡2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiplehit profile was associated with a median progression-free survival of 12 months compared with 22.5 months in the remaining patients (P 5 .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome. (Blood. 2015;126(18):2110-2117 IntroductionChronic lymphocytic leukemia (CLL) is characterized by its unique immunophenotype of CD19sIg dim expressing clonal mature B cells and also by a highly variable clinical course. With the emergence of new classes of drugs such as the inhibitor of phosphatidylinositol 3-kinase, idelalisib, 1 and the irreversible inhibitor of Bruton tyrosine kinase, ibrutinib, 2 available treatment options have increased significantly and allow us to begin to develop models of treatment stratification. Over the last 3 years, the CLL genome has been thoroughly characterized by next-generation sequencing (NGS).3 Pioneer reports using this approach unraveled somatic mutations recurrently targeting multiple genes, among which TP53, SF3B1, NOTCH1, MYD88, and ATM were the most frequent. [4][5][6][7][8][9] Large retrospective studies in untreated patients from historical cohorts have recently shown the adverse prognostic impact of the TP53, NOTCH1, and SF3B1 mutations on time to treatment and overall survival (OS). [10][11][12] In addition, mutations in these genes may also be associated with poor progression-free survival (PFS) in frontline patients treated in prospective trials. 13,14 Conversely, the pejorative impact of TP53, SF3B1, and NOTCH1 mutations on the clinical outcome of patients with relapsed/ refractory (R/R) CLL is controversial. [15][16][17] Compared with untreated CLL, relapse, as advanced disease, may be associated with a high level of genomic diversification. 9,18 This process might result in For personal use only. on May 11, 2018. by guest www.bloodjournal.org From accumulation and co-occurrence of these or other genomic events leading to interactions that could be of prognostic relevance. Here, w...

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

“…16 In fact, it has recently been shown that CLL cases co-expressing mutations of TP53, NOTCH1 and BIRC3 have a poorer outcome than cases carrying only TP53 mutations. 17 In line with this, studies have shown that mutations within the aformentioned genes may refine the prognostic value of the Döhner hierarchical classification. 1,18,19 However, it is important to note that none of the recently identified mutations have yet been incorporated into clinical practice.…”

Inhibition of nucleo-cytoplasmic shuttling through XPO1/CRM1: A unique therapeutic approach for treatment of haematological and solid malignancies

“…XPO1 hot mutations (E571) were found in approximately 4% of primary chronic lymphocytic leukemia (CLL) patients [17,18] . Interestingly, high frequency of XPO1 was observed in relapse CLL patient samples compared to untreated [19] . A high rate of XPO1 mutation (E571K) was also seen in primary mediastinal B-cell lymphoma (PMBL) [20] .…”

“…CLL is a lymphoid malignancy and is characterized by immunophenotype of CD19 + CD5 + CD23 + sIg dim expressing clonal mature B cells [43] . Next generation sequencing of untreated and relapsed/refractory CLL showed a high incidence of concurrent mutations that mostly affect the TP53, ATM, SF3B1 and XPO1 genes [19] . Mutations in these genes have a poor prognosis [84][85][86][87][88][89][90][91] .…”

Clinical impact of recurrently mutated genes on lymphoma diagnostics: state-of-the-art and beyond

“…85 Considering the significant differences in mutation frequencies observed between different studies, best exemplified by DLBCL, large-scale efforts are now needed, in particular for rarer entities, to fully understand which genes are the most relevant and will retain independent prognostic impact in relation to other known clinical/molecular markers. This is particularly relevant in light of recent studies [86][87][88] pointing to a prognostic relevance of particular combinations of mutations and/or an increasing R. Rosenquist et al…”