The CLL14 findings provide new insights into long-term outcomes following venetoclax + obinutuzumab nearly a decade post-treatment.The final results of the CLL14 trial validate the long-term efficacy of 1-year fixed-duration venetoclax plus obinutuzumab in previously untreated patients with chronic lymphocytic leukaemia (CLL) and co-existing conditions.
“After a median follow-up of 9 years (110.1 months), median progression-free survival (PFS) was approximately 6 years and median time to next treatment (TTNT) approached 8 years [in this population],” noted Dr Kirsten Fischer from the University Hospital of Cologne, Germany, at EHA 2026.
Overall survival (OS) was not reached (NR), end-of-treatment minimal residual disease (EoT MRD) status remained a strong prognostic factor for PFS and OS, and the incidence of second primary malignancies (SPMs) was higher in the venetoclax vs chlorambucil group, she added.
PFS was superior in the venetoclax vs chlorambucil group (median 76.6 vs 37.9 months; hazard ratio [HR], 0.50; p<0.001; 9-year PFS rate, 25.6 percent vs 14.4 percent), as was TTNT (median 91.9 vs. 52.5 months; HR, 0.54; p<0.001; 9-year TTNT rate, 39.6 percent vs 23.5 percent). [EHA 2026, abstract S146]
Fifty-four and 111 second-line anti-leukaemia treatments were initiated in the respective venetoclax and chlorambucil groups. “In CLL, second-line therapy is rarely immediate upon progressive disease. Given this, TTNT appears to be a very relevant timepoint and very patient-centered,” Fischer said. “A treatment-free interval of almost 8 years is clinically meaningful.”
In the venetoclax group, median PFS was substantially longer in participants with mutated vs unmutated immunoglobulin heavy chain variable (IGHV; 104.9 vs 64.7 months; HR, 2.74; p<0.001) and those without vs with TP53 mutation/deletion (79.2 vs 49 months; HR, 2.15; p=0.001).
A similar pattern favouring participants with mutated IGHV and without TP53 mutation/deletion was observed in the chlorambucil group (median PFS 62.2 vs 28 months; HR, 3.13; p<0.001 and 39.9 vs 19.8 months; HR, 1.68; p=0.024).
The median OS was NR in the venetoclax group and 112.7 months in the chlorambucil group (HR, 0.80; p=0.161; 9-year OS rate, 59.3 percent vs 51.1 percent). The former had fewer deaths than the latter (n=78 vs 92), with fewer deaths due to progressive disease (n=14 vs 30).
MRD status, SPMs
EOT remission depths were particularly more pronounced in participants with undetectable MRD (time to PFS event from EoT, 76.2 months [MRD <10-6] and 74.8 months [MRD ≥10-6 and <10-5]) than those with detectable MRD (time to PFS event from EoT, 53.3 months [MRD ≥10-5 and <10-4] and 23.5 months [MRD ≥10-4]).
The time to OS event from EoT was NR among participants with MRD <10-4 and 70.5 months among those with MRD ≥10-4 (HR, 3.73). “The shorter OS in patients with detectable MRD highlights the need for dedicated MRD-guided treatment approaches,” Fischer noted.
The venetoclax group had more SPMs than the chlorambucil group (follow-up adjusted incidence rates, 2.6 vs 1.5 per 1,000 patient-months; p=0.047). A majority of SPMs were solid tumours (n=27 vs 18), followed by melanoma (n=9 vs 4).
Therapy-free interval
“Back then, novel targeted therapies required continuous monotherapy. To limit these therapies to a fixed duration, we combined the two most effective compounds—venetoclax and obinutuzumab,” Fischer said. A one-year fixed duration of venetoclax + obinutuzumab is standard of care for previously untreated CLL. [NEJM 2019;380:2225-2236]
A total of 432 participants (median age 72 years) were randomized 1:1 to receive six cycles of venetoclax + obinutuzumab or chlorambucil + obinutuzumab, followed by six cycles of venetoclax or chlorambucil. Sixty percent of participants had unmutated IGHV, and 12 percent had TP53 deletion and/or mutation. The median Cumulative Illness Rating Scale score was 8, and the median creatinine clearance was 66 mL/min. All patients were off treatment for ≥8 years.
According to Fischer, the therapy-free interval post-treatment highlights the benefit of the fixed-duration regimen. “[The current] results provide new insights into long-term outcomes following venetoclax + obinutuzumab nearly a decade post-treatment.”