CLL14 Frontline Combo Results Bolstered by Real-World Outcomes

The combination of venetoclax (Venclexta; AbbVie/Genentech) and obinutuzumab (Gazyva; Genentech) provides durable survival and safety for patients with previously untreated chronic lymphocytic leukemia (CLL), both in a randomized trial and in real-world clinical practice, according to posters presented at the European Hematology Association (EHA) 2026 Congress. Investigators delivered final results of the CLL14 study as well as updates from an international evidence database and a cohort of hospitals in Italy.

CLL14 Final Readout: Median Progression-Free Survival Tops 6 Years

A presentation of the final results of the randomized phase 3 CLL14 trial (NCT02242942) confirms the long-term efficacy of the 1-year venetoclax-obinutuzumab combination in patients with previously untreated CLL and coexisting conditions,¹ closing the loop that began with publication of initial results in 2019.² The final results deliver updates on the 432 patients randomly assigned to receive either venetoclax-obinutuzumab (VO; n = 216) or chlorambucil-obinutuzumab (CO; n = 216) after a median follow-up time of 110.1 months.¹ Lead author Kirsten Fischer, MD, of the University Hospital of Cologne in Germany, noted in her oral presentation of the data at EHA 2026 that these participants, with their coexisting condition burden and older median age, “reflect the patients we are seeing daily in clinical care.”

Median progression-free survival (PFS) was 76.6 months in the VO arm vs 37.9 months in the CO arm, for an HR of 0.50 in the former (95% CI, 0.39-0.63; P < .001). In addition to the smaller number of patients experiencing disease progression in the VO arm (87 vs 144), the VO arm reported a significantly longer time to next treatment, at a median of 91.9 vs 52.5 months (HR, 0.54, 95% CI, 0.43-0.70; P < .001). Researchers noted the effects of 17p deletion and unmutated IGHV status on predicting worse PFS in the VO arm.

At 6 years after completing treatment, 22 patients in the VO arm and 6 in the CO arm had achieved undetectable minimal residual disease (MRD). “Remission depth translated into highly prolonged [PFS],” Fischer said, but whether MRD can be used to guide therapy in this setting is not yet fully understood.

There were fewer deaths in the VO arm (78 vs 92), and the median overall survival was not reached in the VO group but was 112.7 months in the CO group (HR, 0.80; 95% CI, 0.59-1.09; P = .161). Investigators observed a higher rate of second primary malignancies excluding nonmelanoma skin cancers in the VO group (19.3% vs 11.2%) but no other safety signals.

With these findings confirming that VO “achieves enduring long-term efficacy” in the first-line CLL setting, Fisher said, the investigator team is “incredibly keen on finding a way to keep collecting prospective data on this patient population.” To further this aim, she and colleagues have launched the CLL2000 study of patients alive after completion of the CLL13, CLL14, and CLL17 trials. Information will be collected at annual routine clinic visits, with blood sampling optional, to ascertain their survival status, quality of life, and other key outcomes without imposing a heavy monitoring burden.

CLL Real-World Evidence Database Confirms Survival Edge

Adding real-world credibility to back up these clinical trial results, another poster at EHA presented an analysis of data from the international CLL Collaborative Study of Real-World Evidence (CORE).³ For this analysis, researchers selected patients with either CLL or small lymphocytic lymphoma who received VO in the first line starting when they were younger than 55 years old. The 85 patients included showed a median VO treatment duration of 11.0 months, with 29.4% of patients still on the regimen at the end of follow-up. The overall response rate in the 70 patients with available data was 94.3%, and the PFS rate at 24 months was 98.3%.

Interestingly, unmutated IGHV status did not seem to depress the odds of survival as it had in the CLL14 trial data: In the CORE database, the 41 patients with unmutated IGHV and available response data had a 95.1% overall response rate and a 100% PFS rate at 24 months. However, the CLL14 results encompassed a longer follow-up time and larger cohort.

The poster authors concluded that these real-world data support the effectiveness of VO in first-line CLL treatment, although they noted that “longer follow-up in this cohort is needed to confirm response durability, as well as in a larger sample of patients with other high-risk features.”

Italian Clinical Practice Results Affirm Safety and Feasibility

A third poster reported on longitudinal data from clinical practice across hospitals in Italy as well as the CLL13 and CLL14 trials, revealing that outcomes with VO were consistent across settings.⁴ PFS was comparable across the trial and practice cohorts divided by fitness, at 88.7% and 87.7% in unfit patients and 92.8% and 96.3% in fit patients. Venetoclax dose-intensity reductions to below 70% were more common in the clinical trial cohort than the clinical practice patients across treatment timepoints, and rates of grade 3 or greater infections were generally low (4%-7%) and did not show a clear advantage for either setting.

The authors wrote that “in spite of the more systematic reporting in clinical trials and the short [follow-up] time of the [clinical practice] data, the analysis supports VO use as frontline treatment in routine clinical practice.”

References

1. Fischer K, Al-Sawaf O, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: final results of the randomized CLL14 study. Presented at: EHA 2026; June 11-14, 2026; Stockholm, Sweden. Presentation S146.

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. Chang A, Leslie L, Martinez-Calle M, et al. Treatment outcomes with first-line venetoclax+obinutuzumab therapy in younger adults with chronic lymphocytic leukemia/small lymphocytic lymphoma: a real-world, international study. Poster presented at: EHA 2026; June 11-14, 2026; Stockholm, Sweden. Poster PS1717.

4. Zappaterra A, Robrecht S, Giza A, et al. Feasibility and safety of venetoclax–obinutuzumab in fit and unfit chronic lymphocytic leukemia patients: comparison of CLL13 and CLL14 pooled analysis with an Italian clinical practice cohort. Poster presented at: EHA 2026; June 11-14, 2026; Stockholm, Sweden. Poster PF607.