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

Abstract

Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

Figure 1.

Frequency, localization and dynamics of EGR2 mutations. (a) Frequency of EGR2 mutations in investigated cohorts. (b) Localization of mutations identified in EGR2. (c) Co-existing mutations in 38 EGR2-mutated CLL patients. (d) Clonal dynamics of six EGR2-mutated CLL patients. The first 5 patients received FCR therapy between the first (blue bars) and second (green bars) time point sample, while the last patient remained untreated at the second time point (7 years between the samples).

Figure 2.

Clinical impact of EGR2 mutations in 1178 CLL patients from the screening cohort. (a) Time-to-first-treatment and (b) overall survival in the screening cohort according to EGR2 mutation status. (c) Time-to-first-treatment and (d) overall survival in the screening cohort according to the established hierarchy for genomic aberrations and EGR2 mutation status. Patients with TP53abn and concomitant EGR2 mutation are grouped into the TP53abn group (TTFT, n = 7; OS, n = 8).

Figure 3.

Clinical impact of EGR2 mutations in 366 patients from the UK LRF CLL4 trial and 486 patients from the CRC cohort. (a) Overall survival in the UK CLL4 validation cohort according to EGR2 mutation status. (b) Overall survival in the UK CLL4 validation cohort according to the established hierarchy for genomic aberrations and EGR2 mutation status. Patients with TP53abn and concomitant EGR2 mutation are grouped into the TP53abn group (n = 1). (c) Time-to-first-treatment and (d) overall survival in the CRC validation cohort according to EGR2 mutation status.