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Unmutated IGHV as predictive factor for venetoclax/obinutuzumab benefit in frontline CLL

Presented By
Dr Eugen Tausch, University of Ulm, Germany
EHA 2019
Findings from an analysis of genetic aberrations and mutations in patients with chronic lymphocytic leukaemia (CLL) participating in the CLL14 trial were presented by Dr Eugen Tausch (University of Ulm, Germany) [1]. Although both del(17p) and TP53 mutations remain adverse prognostic factors for progression-free survival (PFS) with venetoclax/obinutuzumab treatment, unmutated IGHV was associated with a 3.5-fold improvement in patient response.

Dr Tausch explained: “Genomic aberrations, IGHV mutation status and mutations in genes such as TP53 are established prognostic factors in CLL in the context of chemoimmunotherapy. Their role is less‐well established when using chemotherapy-free treatments.” In summary, the CLL14 trial (n=432) showed that the venetoclax combination reduced the risk of disease progression or death by 65% vs obinutuzumab plus chlorambucil (HR 0.35; 95% CI 0.23-0.53; P<0.001). The overall response rate (ORR) was 85% with venetoclax/obinutuzumab vs 71% in the control arm. The complete response (CR) or CR with incomplete haematologic recovery rates were 50% vs 23%, respectively.

Dr Tausch and colleagues assessed the incidence of genomic aberrations and evaluated their impact on outcomes in the CLL14 trial. The investigators used florescence in situ hybridisation to determine the cytogenetics in 418 patients, the IGHV status with <98% homology cut-off in 408, and used a custom next-generation sequencing panel to evaluate the mutations in 13 genes in 421 of 432 patients in the intention to treat (ITT) population.

The incidence of genomic aberrations was del(17p) in 7% of patients, del(11q) in 18%, +(12q) in 18%, and del(13q) in 53%. Unmutated IGHV was detected in 61% of patients. Regarding gene mutations, the incidence of the following genes was determined: TP53 (10%), NOTCH1 (23%), SF3B1 (16%), ATM (13%), MYD88 (2%), POT1 (5%), BIRC3 (4%), XP1 (6%), NFKB1E (4%), BRAF (4%), EGR2 (4%), RPS15 (5%), and FBXW7 (1%).

Across all genetic variants assessed, the ORR was approximately 80% with venetoclax/obinutuzumab compared with approximately 60% with chlorambucil/obinutuzumab. However, the ORR was reduced in patients with del(17p), del(11q) TP53 mutations, ATM mutations, and BIRC3 mutations treated with the chlorambucil combination. None of these alterations impacted the venetoclax ORR.

Notably, the ORR was approximately 82% in patients with unmutated IGHV with the venetoclax combination, which when taken in multivariate analysis generated a HR of 3.475 (95% CI 1.96-6.15; P<0.001) for the relationship between unmutated IGHV and mutated IGHV. In the venetoclax/obinutuzumab arm, the HR was 1.16 (P=0.73) for patients with unmutated IGHV versus mutated IGHV. The HR was 3.45 (P<0.001) for the same comparison in the chlorambucil arm.

PFS was assessed according to the genetic variables. With median follow‐up of 29 months, 107 PFS events and 37 OS events had occurred in the ITT population. Del(17p) significantly impacted PFS with both venetoclax and chlorambucil; in the venetoclax arm, the HR was 4.42 (P=0.001) for the comparison of no deletion vs deletion and in the chlorambucil arm the HR was 4.64 (P<0.001) for the comparison of no deletion vs deletion. TP53 mutations also affected PFS with both treatments; with venetoclax no TP53 mutation vs TP53 mutation the HR was 3.08 (P=0.01) and with chlorambucil, the HR was 2.74 (P=0.001) for no TP53 mutation vs TP53 mutation.

The PFS of chlorambucil was adversely affected by mutated vs nonmutated BIRC3 (HR 4.0; P=0.001), NOTCH1 (HR 1.74; P=0.03), and ATM (HR 1.77; P=0.06); however, these mutations did not significantly affect PFS with venetoclax. Mutations in the other investigated genes had no effect on either venetoclax or chlorambucil efficacy.

All the genetic subgroups showed more favourable PFS outcomes with venetoclax/ obinutuzumab than with obinutuzumab; these subgroups included patients with del(17p), del(11q), and TP53, NOTCH1, SF3B1, and ATM mutations. High coincidence was found for del(17p) and TP53 mutations. “Both del(17p) and TP53 mutations remain adverse prognostic factors for PFS with venetoclax/obinutuzumab treatment,” Dr Tausch summarised. “Venetoclax was particularly effective in patients with IGHV unmutated; these findings establish IGHV as a predictive rather than prognostic marker.”

    1. Tausch E et al. Abstract S105, 24th Congress of the EHA. June 13-16, Amsterdam, the Netherlands.


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