Genetic Analysis Provides Insight Into Venetoclax/Obinutuzumab Benefit in Frontline CLL

In a careful evaluation of chemotherapy‐free regimens, the combination of obinutuzumab (Gazyva) plus venetoclax (Venclexta) compared to obinutuzumab plus chlorambucil, objective and complete response rates, as well as progression-free survival (PFS) were superior with the venetoclax combination in the overall study population and across all genetic subgroups evaluated in patients with chronic lymphocytic lymphoma (CLL).

Findings from this analysis of genetic aberrations and mutations in patients with CLL participating in the CLL14 trial were presented at the 15th International Conference on Malignant Lymphoma (ICML 2019).¹

Eugen Tausch, MD, University of Ulm in Ulm, Germany 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.”

Overall results from the CLL14 trial were presented at the 2019 ASCO Annual Meeting² and were the basis of the May 2019 FDA approval of venetoclax plus obinutuzumab for the frontline treatment of patients with CLL or small lymphocytic lymphoma.

The venetoclax combination reduced the risk of disease progression or death by 65% versus obinutuzumab plus chlorambucil (HR, 0.35; 95% CI, 0.23-0.53; P <.001). The overall response rate (ORR) was 85% with venetoclax/obinutuzumab versus 71% in the control arm. The complete response (CR) or CR with incomplete hematologic recovery rates were 50% versus 23%, respectively.

Tausch and colleagues assessed the incidence of genomic aberrations and evaluated their impact on outcomes in the CLL14 trial. Across all genetic variants assessed, the ORR was approximately 80% with venetoclax/obinutuzumab compared to approximately 60% with chlorambucil/obinutuzumab.

The ORR was lowered 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.

The ORR was approximately 82% in patients with unmutated IGHV with the venetoclax combination. In multivariate analysis, the HR was 3.475 (95% CI, 1.96-6.15; P <.001) for the relationship between unmutated IGHV and mutated IGHV. In the venetoclax arm, the HR was 1.16 (P = .73) for patients with unmutated IGHV versus mutated IGHV. The HR was 3.45 (P <.001) for the same comparison in the chlorambucil arm.

“Venetoclax was particularly effective in patients with IGHV unmutated; these findings establish IGHV as a predictive rather than prognostic marker,” Tausch commented.

The CLL14 study enrolled 432 patients with previously untreated CLL and relevant comorbidities, including Chronic Inflammatory Response Syndrome (CIRS) score >6 or kidney disease represented by creatinine clearance < 70 ml/min. The patients were randomized equally to receive 6 cycles of obinutuzumab plus either 12 cycles of venetoclax or 12 cycles of chlorambucil. The median patient age was 72 years old, the median CIRS score was 8, and the median creatinine clearance was 66.4 mL/min.

The investigators used florescence in situ hybridization (FISH) to determine the cytogenetics in 418 patients, the IGHV status with <98% homology cutoff 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%).

Progression-free survival was assessed according to the genetic variables. With median follow&#8208;up of 29 months, 107 PFS events and 37 OS events had occurred in the ITT population.

“Both del(17p) and TP53 mutations remain adverse prognostic factors for PFS with venetoclax/obinutuzumab treatment,” Tausch commented.

Del(17p) significantly impacted PFS with both venetoclax and chlorambucil; in the venetoclax arm, the HR was 4.42 (P = .001) for the comparison of no deletion versus deletion and in the chlorambucil arm the HR was 4.64 (P <.001) for the comparison of no deletion versus deletion.

TP53 mutations also affected PFS with both treatments; with venetoclax no TP53 mutation versus TP53 mutation the HR was 3.08 (P = .01) and with chlorambucil, the HR was 2.74 (P = .001) for no TP53 mutation versus TP53 mutation.

The PFS of chlorambucil was adversely affected by mutated versus nonmutated BIRC3 (HR 4.0, P = .001), NOTCH1 (HR 1.74; P = .03), and ATM (HR 1.77; P = .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 of the genetic subgroups showed more favorable PFS outcomes with venetoclax 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.

“These data demonstrate that PFS and response are superior in patients receiving venetoclax/obinutuzumab and support unmutated IGHV as a predictive factor for increased benefit from venetoclax,” summarized Tausch.

References

1. Tausch E. Genetic markers and outcome in the CLL14 trial of the GCLLSG comparing front line obinutuzumab plus chlorambucil or venetoclax in patients with comorbidity. Presented at: 2019 International Conference on Malignant Lymphoma; June 18-22, 2019; Lugano, Switzerland. Abstract 047.
2. Fischer K, Al-Sawaf O, Bahlo J, et al. Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD—) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities. J Clin Oncol. 2019;37(suppl; abstr 7502).

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