IGLV3-21 ^R110 Is a Prognostic Marker for Early Stage CLL Patients Under Ibrutinib Treatment or Watch & Wait: Results from the Double-Blind, Randomized, Placebo-Controlled GCLLSG CLL12 Trial

INTRODUCTION: IGLV3-21 ^R110 is a point mutation that can confer the ability for autonomous signaling to B cell receptors (BCR) using light chains encoded by the allele IGLV3-21 ∗ 01 or IGLV3-21 ∗ 04. Chronic lymphocytic leukemia (CLL) patients with IGLV3-21 ^R110 have a shorter time to first treatment and shorter overall survival, independent of their IGHV mutational status. However, outcomes of CLL patients using IGLV3-21 ^R110 have not been evaluated in clinical trials of BTK inhibitors.

METHODS: The CLL12 trial was a prospective, double-blind, randomized phase 3 trial that compared ibrutinib (ibr, n=182) vs. placebo (pcb, n=181) in previously untreated Binet A CLL patients with intermediate to very high risk, while low risk patients were assigned to watch & wait (w&w, n=152). The primary endpoint of the study was event-free survival (EFS) (event defined as death, symptomatic progression or initiation of CLL treatment), while overall survival (OS) was a secondary endpoint. The IGLV3-21 locus was sequenced via amplicon-based targeted next generation sequencing (tNGS) in 514 of 515 samples collected at enrolment. IGLV rearrangements and point mutations were detected with ScanIndel as well as IgCaller and the results of the genetic analyses were correlated with outcome.

RESULTS: IGHV was unmutated (U-IGHV) in 148 (28.3%) patients (w&w n=8, pcb n=70, ibr n=70) and 10 patients belonged to stereotyped B cell receptor (BCR) subset 2 (w&w n=2, pcb n=1, ibr n=7). IGLV3-21 rearrangement was found in 34 of 514 patients (6.6%) and was more frequent in the intermediate/high risk groups (pcb n=16, ibr n=13) than in the low risk group (w&w n=5). Twenty of 34 patients with IGLV3-21 rearrangement had an IGLV3-21 ^R110 mutation (w&w n=3/5, pcb n=10/16, ibr n=7/13). For 5 patients with IGLV3-21 (3 pcb, 2 ibr) the mutational status for IGLV3-21 ^R110 could not be determined by tNGS.

In the total cohort, IGLV3-21 ^R110 often co-occurred with mutations in SF3B1 (odds ratio 8.54, p < 0.001), but not with mutations in TP53 or any of the other frequently mutated genes in CLL. Conversely, SF3B1 mutations were not enriched in subset 2 patients (p = 0.165). Also, there was no association of IGLV3-21 ^R110 or IGLV3-21 usage in general with IGHV mutational status.

At a median follow-up of 69.3 months, there were 166 events for EFS and 32 for OS. CLL with IGLV3-21 had a shorter EFS in the pcb (HR 1.93, CI95% 1.05-3.55, p=0.033) and ibr (HR 3.71, CI95% 1.62-8.46, p=0.002) arm (Figure 1A). The estimated 5-year EFS rate was 51.0% without and 21.4% with IGLV3-21 rearrangementin the pcb group vs. 80.7% and 44.8% in the ibr group, respectively. Similarly, IGLV3-21 ^R110 associated with shorter EFS with ibr (HR 3.30, CI95% 1.17-9.31, p=0.024) while no impact was observed in the pcb group (HR 1.51, CI95% 0.66-3.46, p=0.332, Figure 1B). Patients with IGLV3-21 ^R110 mutation and ibr treatment had an estimated 5-year EFS rate similar to that of patients in the pcb group without IGLV3-21 ^R110 (50.0% vs. 49.8%). In low risk patients with w&w, both IGLV3-21 rearrangement and IGLV3-21 ^R110 were adverse markers for EFS (HR 4.99, CI95% 1.52-16.41, p=0.008 and HR 17.0, CI95% 4.99-58.13, p<0.001, respectively).

For the full trial, we observed a prognostic impact of IGLV3-21 in the M-IGHV (HR 3.87, CI95% 2.14-6.99, p<0.001) but not in the U-IGHV (HR 1.61, CI95% 0.74-3.54, p=0.233) group.

Multivariable analysis for the treatment arms including the IGLV3-21 ^R110 status and other variables associated significantly with EFS in univariate analyses (treatment arm, serum β2-microglobulin, IGHV status, del(17p), del(11q), +(12), mutations in XPO1, NOTCH1, SF3B1 and NFKBIE) revealed presence of IGLV3-21 ^R110 (HR 2.76, CI95% 1.32-5.80, p = 0.007) as an independent prognostic factor.

OS was excellent in all genetic subgroups and in all arms of the trial. The estimated 5-year OS rate was between 92.9% and 95.8% for any of the 4 subgroups defined jointly by IGHV status and presence of IGLV3-21 ^R110.

CONCLUSIONS: IGLV3-21 ^R110 was identified as an independent prognostic factor for shorter EFS in early stage CLL with intermediate/high risk score and was associated with reduced ibrutinib efficacy in the CLL12 trial.