CLL14 Final Analysis Shows Long-Term PFS Gain With Venetoclax/Obinutuzumab in Previously Untreated CLL

Fixed-duration venetoclax (Venclexta) plus obinutuzumab (Gazyva) maintained a progression-free survival (PFS) benefit vs chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) and coexisting comorbidities, according to final analysis data from the phase 3 CLL14 trial (NCT02242942) presented at the 2026 EHA Congress.¹

Findings showed that at a median observation time of 110.1 months, venetoclax/obinutuzumab (n = 216) reduced the risk of progression or death by 50% compared with chlorambucil/obinutuzumab (n = 216; HR, 0.50; 95% CI, 0.39-0.63; P < .001). The median PFS was 76.6 months with venetoclax/obinutuzumab vs 37.9 months with chlorambucil/obinutuzumab. The 9-year PFS rates were 25.6% vs 14.4%, respectively.

Earlier data from CLL14 supported the May 2019 FDA approval of venetoclax plus obinutuzumab for the treatment of patients with CLL or small lymphocytic lymphoma.²

How was the CLL14 trial designed?

CLL14 was a randomized, phase 3 study conducted across 196 sites in 21 countries that enrolled patients with previously untreated CLL with coexisting conditions defined by a Cumulative Illness Rating Scale (CIRS) score greater than 6 and/or creatinine clearance less than 70 mL/min.¹

A total of 432 patients were randomly assigned 1:1 to receive venetoclax/obinutuzumab for 6 cycles each, followed by venetoclax monotherapy for 6 cycles, or chlorambucil plus obinutuzumab for 6 cycles each, followed by chlorambucil alone for 6 cycles.

The primary end point was investigator-assessed PFS; key secondary end points included time to next treatment (TTNT), overall survival (OS), minimal residual disease (MRD) negativity, and safety.

Baseline characteristics were well-balanced between the two arms. In the venetoclax/obinutuzumab arm, median age was 72 years, median CIRS score was 9, and IGHV-unmutated disease was present in 61% of patients. TP53 deletion or mutation was present in 12% of patients in each arm.

What were the additional efficacy and subgroup findings?

Findings also showed that the median TTNT was 91.9 months with venetoclax/obinutuzumab vs 52.5 months with chlorambucil-obinutuzumab (HR, 0.54; 95% CI, 0.43-0.70; P < .0001), with 39.6% of patients in the venetoclax/obinutuzumab arm remaining free of next-line therapy at 9 years vs 23.5% in the control arm. Fewer patients in the venetoclax/obinutuzumab arm ultimately required subsequent anti-leukemic therapy (54 vs 111).

Furthermore, patients with mutated IGHV achieved a median PFS of 104.9 months with venetoclax/obinutuzumab vs 64.7 months in those with unmutated IGHV treated with venetoclax/obinutuzumab (HR, 2.74; 95% CI, 1.85-4.06; P < .001). Among patients with TP53 deletion or mutation, median PFS with venetoclax/obinutuzumab was 49.0 months (4.1 years) vs 79.2 months in those without this alteration (HR, 2.15; 95% CI, 1.36-3.40; P = .001).

Median OS was not reached with venetoclax/obinutuzumab vs 112.7 months with chlorambucil/obinutuzumab (HR, 0.80; 95% CI, 0.59-1.09; P = .161); the difference did not reach statistical significance. Nine-year OS rates were 59.3% and 51.1%, respectively.

Notably, deaths attributable to disease progression or relapse-related treatment were nearly halved in the venetoclax-obinutuzumab arm (14 vs 30 deaths), suggesting that disease-related mortality was reduced despite the absence of a formal OS benefit at this analysis.

What did the long-term safety analysis show?

A higher incidence of second primary malignancies (SPMs) was observed in the venetoclax-obinutuzumab arm vs the chlorambucil-obinutuzumab arm at the final analysis. The follow-up–adjusted SPM incidence rate was 2.6 per 1,000 patient-months with venetoclax-obinutuzumab vs 1.5 with chlorambucil-obinutuzumab (P = .047). Solid tumors accounted for the majority of SPMs (27 vs 18), with melanoma comprising 9 vs 4 cases and hematologic malignancies 4 vs 3 cases across the two arms.

References

1. Fischer K, Al-Sawaf O, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: final analysis of the randomized phase 3 CLL14 study. Presented at: 2026 EHA Congress; June 11-14, 2026; Stockholm, Sweden. Abstract S146.
2. AbbVie announces US FDA approval of Venclexta (venetoclax) as a chemotherapy-free combination regimen for previously untreated chronic lymphocytic leukemia patients. News release. AbbVie. May 15, 2019. Accessed June 12, 2026. https://news.abbvie.com/2019-05-15-AbbVie-Announces-US-FDA-Approval-of-VENCLEXTA-R-venetoclax-as-a-Chemotherapy-Free-Combination-Regimen-for-Previously-Untreated-Chronic-Lymphocytic-Leukemia-Patients