Treatment with obinutuzumab plus venetoclax (VenG) was associated with improved outcomes compared with obinutuzumab plus chlorambucil (CGlb) among patients with chronic lymphocytic leukemia (CLL) and established unfavorable genetic factors, according to a study published in Blood.1
“Genetic parameters are established prognostic factors in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy, but are less well studied with novel compounds,” the authors wrote.
Unmutated IGHV, mutated TP53, and deletion of chromosome 17p (del[17p]) that contains the TP53 locus, are associated with progression and shorter survival among patients with CLL treated with chemoimmunotherapy. Other genetic markers have been identified that are also prognostic for outcomes.
This analysis used data from the multicenter, phase 3 CLL14 trial, which randomly assigned 432 patients with CLL to receive first-line VenG or CGlb. The analysis used fluorescence in situ hybridization (FISH), DNA sequencing, and next-generation sequencing to evaluate genetic prognostic factors.
Among patients with available results (94% to 97% of the cohort), del(17p) was present in 7% of patients, del(11q) in 18%, trisomy 12 (+12) in 18%, and del(13q) in 35%. TP53 mutations were present in 10% of cases and IGHV was unmutated in 60%. Genetic findings were balanced between the treatment groups.
Across all subgroups, VenG resulted in a higher overall response rate (ORR) of 85% compared with 50% with CGlb. The CR rate was also higher with VenG at 71% compared with 23% with CGlb.
The ORR and CR rates remained similar with VenG regardless of the presences of del(17p), del(11q), mutated TP53, and other mutated genes such as ATM or BIRG3. This was not the case with GClb, in which del(17p), del(11q), unmutated IGHV, and mutations in TP53, ATM, or BIRC3 were associated with lower ORR and CR rates.
Progression-free survival (PFS), however, was significantly shorter among patients with del(17p) or mutated TP53 with either VenG or GClb, after a median follow-up of 28 months. With VenG, the 2-year PFS was 65% among patients with del(17p) compared with 91% without the deletion (hazard ratio [HR], 4.42; 95% CI, 1.88-10.39). Poorer PFS was more pronounced with GClb, with a 2-year rate of 23% with del(17p) compared with 68% without the deletion (HR, 4.64; 95% CI, 2.36-10.39). The PFS was also shorter with mutated TP53 with VenG (HR, 3.08; 95% CI, 1.31-7.25) or GClb (HR, 2.74; 95% CI, 1.50-5.00).
In a multivariate analysis, only del(17p) was significantly associated with poorer PFS among patients treated with VenG. In contrast, del(17p), del(11q), unmutated IGHV, and mutations in TP53, BIRC3, and SF3B1 were associated with poorer PFS with CGlb.
The authors concluded that, “Although del(17p) and mutated TP53 were associated with adverse outcome in both treatment groups, VenG improved PFS of these patients significantly, and affected patients should preferably be treated with a novel compound.”
Tausch E, Schneider C, Robrecht S, et al. Prognostic and predictive impact of genetic markers in patients with CLL treated with obinutuzumab and venetoclax. Blood. 2020;135(26):2402-2412.