Recurrent mutations refine prognosis in chronic lymphocytic leukemia

Abstract

Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia

“…CHD2 15 , MED12 16 , NFKBIE 17 , POT1 18 , RPS15 19 , SETD2 20 , XPO1 21 ). Though integration of molecular information has been proposed to improve classical risk stratification models [22][23][24][25] , a substantial proportion of patients with a dismal clinical course will not be captured by these algorithms, hence indicating a need to identify additional molecular markers of disease aggressiveness.…”

Novel prognostic molecular factors: a quantum leap in the field of chronic lymphocytic leukemia

“…Some correlations between SF3B1 mutations and other lesions have been described in CLL. It was noticed that SF3B1 mutations occur more frequently in association with 11q22-q23 deletion, ATM mutations and unmutated IGHV status while negative correlation was observed with trisomy 12 and isolated del13q [68,70]. The assessment of SF3B1 mutation status may contribute to the identification of poor-risk CLL patients and in combination with conventional lesions of CLL may refine the disease prognosis [62,68].…”

“…The incidence of SF3B1 mutations appears to increase over time and they are correlated with a more advanced clinical stage. Therefore, the SF3B1 mutations should be taken into account as an important marker of the disease progression or even one of its mechanisms [70].…”

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

“…[78][79] In a recent multicenter study conducted within ERIC, sequencing of TP53, NOTCH1, SF3B1, BIRC3 and MYD88 was performed in a large patient series (totaling 3,490 patients), revealing that TP53 and SF3B1 mutations, but not NOTCH1 mutations, remained as independent prognostic markers of shorter time to first treatment in multivariate analysis, even amongst patients expressing unmutated IGHV genes. 50 A few published clinical trials have also pointed to a prognostic and even predictive role of SF3B1 and NOTCH1 mutations in CLL, 28 where, in particular, the latter confers resistance to the anti-CD20 monoclonal antibodies rituximab 29 and ofatumumab, 80 however, this needs further exploration and validation. Currently, as a new ERIC project, a dedicated NGS-based gene panel (including 11 genes) has been designed with the purpose to test different targeted enrichment techniques and evaluate intercenter variability and reproducibility.…”

“…exclusive to) a particular entity and can also be found in other lymphomas, though generally at lower frequencies (Table 1). For instance, the MYD88 L265P mutation is detected in a significant fraction of DLBCL of the activated B-cell-like subtype (ABC DLBCL), 5 as well as in primary cutaneous, 45 the central nervous system 46 and testicular large B-cell lymphomas, 47 but also in a minority of patients with CLL 4,[48][49][50] and SMZL. 16,51 As another example, STAT3 mutations have been reported, albeit rarely, in immune, mainly hypoplastic, bone marrow failure characterizing a subset of patients with severe aplastic anemia or myelodysplastic syndrome.…”