Prognosis of the IGLV3-21R110 Mutation in a Real-Life Chronic Lymphocytic Leukemia Cohort
Authors: Bensalah Merieme , Messaoudi Amal , Fleury Carole , Tueur Giulia , Letestu Rémi , Armand Marine , Brechignac Sabine , Ivanoff Sarah , Vidal Valérie , Rahmé Ramy , Al Nawakil Chadi , Braun Thorsten , Thieblemont Catherine , Florence Cymbalista , Levy Vincent , Baran-Marszak Fanny , Lazarian Grégory 
Published: December 2024

The immunoglobulin heavy-chain variable (IGHV) mutation load is a key marker for prognostication and treatment decision-making in chronic lymphocytic leukemia (CLL). Patients with unmutated IGHV (UM-IGHV) have an inferior prognosis compared to patients with mutated IGHV (M-IGHV). Recent studies have shown that IGLV3-21-expressing B cells can acquire a somatic hypermutation at the splice site between the JL and the CL, changing the glycine at position 110 to arginine (IGLV3-21R110), which triggers autonomous B-cell receptor signaling and confers aggressive disease behavior. Despite its potential impact, screening for the IGLV3-21R110 mutation is not yet included in current treatment algorithms, although it could refine patient prognosis based on IGHV mutation status.

To evaluate the frequency of the IGLV3-21R110 mutation and to assess the real-life prognosis of untreated patients with this mutation, we conducted a retrospective study of 216 CLL patients who were referred to our institute for molecular testing at the time of diagnosis from 2013 to 2024. Patients were selected based on monotypic λ light chain expression. Screening of the IGLV3-21R110 mutation was performed using a restriction fragment length polymorphism technique following PCR amplification of IGLV3-21-IGLJ1/2/3 intron rearrangements.

Among the 216 CLL patients, 47 (21%) harbored the IGLV3-21R110 mutation. The proportion of patients with M-IGHV and U-IGHV was 51% (24/47 patients) and 40% (19/47 patients) respectively, a distribution similar to that of patients without the mutation (i.e. 55% M-IGHV, 43% U-IGHV). When considering all the M-IGHV patients, 20% (24/118) harbored the IGLV3-21R110 mutation. The proportion of patients classified as IGHV with borderline gene mutation (IGHV identity between 97-98%) was higher in the group of patients with IGLV3-21R110 compared to patients without the mutation (4/47, 8.5% versus 1/169, 1%, Fisher's exact test: p&lt;0.001).

Regarding the heavy-chain gene usage, the IGHV3-21 rearrangement with stereotyped subset #2 was found only in patients with the IGLV3-21R110 mutation (17 of 47 patients, 36%). The other most frequent IGHV genes were IGHV3-23 (15%), IGHV3-53 (4%), and IGHV3-11 (6%). This indicates that the majority of patients with the IGLV3-21R110 mutation (63%) fall outside the aggressive IGHV3-21 subset #2 group. Conversely, the most frequent IGHV gene rearrangements found in patients without the IGLV3-21R110 mutation, i.e., IGHV1-69 (18/169, 11%), IGHV3-30 (16/169, 9%), and IGHV4-34 (15/169, 9%), were absent in the group of patients with the IGLV3-21R110 mutation.

Genomic data were available for 105 patients. Consistent with previous observations, the frequency of SF3B1 mutations was significantly higher in the group of patients with the IGLV3-21R110 mutation compared to those without the mutation (59% vs. 13%, Fisher's exact test: p&lt;0.0001). No significant differences were observed for mutations in the NOTCH1, ATM, and TP53 genes.

With a median follow-up of 40 months, 49% (106/216) patients were treated. The time to first treatment (TTFT, defined as the time from diagnosis to first treatment or death) was significantly shorter in patients with the IGLV3-21R110mutation (regardless of IGHV mutation status) compared to patients with M-IGHV (median 37 months vs. 65.8 months; HR:1,77; 95% CI : 1.21-2.59; p=0.01 ), while it was not different from patients with U-IGHV (median 41.7 months; HR: 1.12; 95% CI : 0.76-1.66; p=0.4). When focusing only on M-IGHV patients with or without the mutation, the TTFT for patients with IGLV3-21R110 remained significantly shorter than that for patients without the IGLV3-21R110 mutation (median 38.6 months vs. 65.8 months; HR: 1.91; 95% CI: 1.06-3.43; p=0.0052). Finally, no differences were observed between the different groups for the overall survival. Multivariable analysis is currently ongoing to determine if the mutation is an independent prognostic factor.

To conclude, this study shows that in a real-world setting, IGLV3-21R110 mutation defines a subgroup of CLL patients with poor prognosis, regardless of IGHV mutation status. This group of patients is associated with the SF3B1 mutation and encompasses all cases with IGHV3-21 with stereotyped subset#2. The detection of the IGLV3-21R110 mutation is straightforward and should be integrated into the prognostic evaluation of patients, alongside IGHV mutation status.