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

Rate of response and progression- free survival (PFS) were superior with venetoclax (Venclexta) versus chlorambucil in patients with chronic lymphocytic leukemia (CLL) who also received obinutuzumab (Gazyva), and this trend was observed across all genetic subgroups.

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

Eugen Tausch, MD, of Ulm University, Germany, explained: “Genomic aberrations,IGHV-mutation status, and mutations in genes such asTP53are established prognostic factors in CLL in the context of chemoimmunotherapy. Their role is [not as] well established when using chemotherapy- free treatments.”

CLL14 Trial

Overall results from the open-label phase III CLL14 trial were presented at the 2019 American Society of Clinical Oncology Annual Meeting and published simultaneously in theNew England Journal of Medicine.2 The data from the trial also served as the basis of the May 2019 FDA approval of venetoclax for the frontline treatment of patients with CLL or small lymphocytic lymphoma.³

The CLL14 study enrolled 432 patients with previously untreated CLL and relevant comorbidities, including those with a chronic inflammatory response syndrome score greater than 6 or kidney disease represented by creatinine clearance of less than 70 mL/min. The patients were randomized into 2 equal groups to receive 6 cycles of obinutuzumab plus 12 cycles of either venetoclax or chlorambucil. The median patient age was 72 years (range, 41-89 years), the median chronic inflammatory response syndrome score was 8, and the median creatinine clearance was 66.4 mL/min.²

The venetoclax combination treatment 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 objective response rate (ORR) was 85% with venetoclax/ obinutuzumab versus 71% in the control arm. The complete response or complete response with incomplete hematologic recovery rates were 50% versus 23%, respectively.

Analysis of Genetic Markers and Outcomes

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 approximate ORRs for the venetoclax and chlorambucil arms were 80% and 60%, respectively.¹

The investigators used fluorescence in situ hybridization to determine the cytogenetics in 418 patients and theIGHVstatus with <98% homology cutoff in 408 patients, and they used a custom next-generation sequencing panel to evaluate the mutations in 13 genes in 421 of 432 patients in the intention-to-treat population.

The ORR was lowered in patients with deletion of 17p (del[17p]), deletion of 11q (del[11q]), orTP53,ATM, orBIRC3mutations who were treated with the chlorambucil combination. None of these alterations affected the venetoclax ORR.

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

&ldquo;Venetoclax was particularly effective in patients withIGHV-unmutated disease; these findings establishIGHVas a predictive rather than prognostic marker,&rdquo; Tausch commented.

The incidence of genomic aberrations were del(17p) in 7% of patients, del(11q) in 18%, trisomy 12q in 18%, and deletion of 13q in 53%. UnmutatedIGHVwas detected in 61% of patients. The incidence of the following gene mutations 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%), andFBXW7(1%).

PFS was assessed according to the genetic variables. With median follow-up of 29 months, 107 PFS events and 37 overall survival events had occurred in the intention-to-treat population.

&ldquo;Both del(17p) andTP53mutations remain adverse prognostic factors for PFS with venetoclax/obinutuzumab treatment,&rdquo; Tausch said.

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 del(17p) versus del(17p), and in the chlorambucil arm the HR was 4.64 (P<.001) for the same comparison.

TP53mutations also affected PFS with both treatments: for patients without and withTP53who were treated with venetoclax, the HR was 3.08 (P= .01); for patients with the same characteristics treated with chlorambucil, the HR was 2.74 (P= .001).

The PFS of chlorambucil was adversely affected by mutated versus nonmutatedBIRC3(HR, 4.0;P= .001),NOTCH1(HR, 1.74;P= .03), andATM(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 the efficacy of either venetoclax or chlorambucil.

All of the genetic subgroups showed more favorable PFS outcomes with venetoclax than with obinutuzumab; these subgroups included patients with del(17p), del(11q), andTP53,NOTCH1,SF3B1, andATMmutations. High coincidence was found for del(17p) andTP53mutations.

&ldquo;These data demonstrate that PFS and response are superior in patients receiving venetoclax/ obinutuzumab and support unmutatedIGHVas a predictive factor for increased benefit from venetoclax,&rdquo; Tausch concluded.

References

1. Tausch E, Bahlo J, Robrecht S, et al. Genetic markers and outcome in the CLL14 trial of the GCLLSG comparing front line obinutuzumab plus chlorambucil or venetoclax in patients with comorbidity. Hematol Oncol. 2019;37(suppl 2; abstr 047). doi: 10.1002/hon.53_2629.
2. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225- 2236. doi: 10.1056/NEJMoa1815281.
3. FDA approves venetoclax for CLL and SLL. FDA website. bit.ly/2wgFCRI. Published May 15, 2019. Accessed August 21, 2019.