Dr Moritz Fürstenau

Final five-year data from the GAIA/CLL13 trial suggest fixed-duration venetoclax-based therapy can deliver durable long-term disease control in chronic lymphocytic leukaemia, while helping clarify how patients respond to subsequent lines of therapy.

The phase III trial published in Blood [link here] found a fixed-duration triplet of venetoclax, obinutuzumab and ibrutinib delivered the strongest disease control, with 81.3% of fit patients remaining progression-free at five years, compared with 69.8% for venetoclax-obinutuzumab, 57.4% for venetoclax-rituximab and 50.7% for standard chemoimmunotherapy.

The findings further cement fixed-duration venetoclax-based therapy as a frontline standard in fit patients with previously untreated chronic lymphocytic leukaemia (CLL), while reinforcing the growing appeal of time-limited treatment strategies that allow prolonged periods off therapy, say investigators.

In the multinational study, Dr Moritz Fürstenau, physician scientist at the University Hospital of Cologne and the German CLL Study Group, and colleagues randomised 926 fit patients with previously untreated CLL and no TP53 abnormalities to chemoimmunotherapy or one of three fixed-duration venetoclax combinations.

Patients in the GV and RV arms generally received 12 cycles of treatment, while patients in the GIV arm could continue ibrutinib maintenance for up to 36 cycles if measurable residual disease remained detectable. Most patients in the triplet arm completed between 13 and 15 cycles.

After a median follow-up of 63.8 months, both venetoclax-obinutuzumab and the triplet GIV regimen significantly outperformed chemoimmunotherapy. GIV reduced the risk of progression or death versus CIT by 66% (HR 0.34; 95% CI 0.24–0.50; p<0.0001) and also improved progression-free survival compared with GV (HR 0.61; 95% CI 0.41–0.91; p=0.005).

The advantage appeared strongest in patients with unmutated IGHV disease, where five-year progression-free survival rates reached:

• 75.9% with GIV
• 59.0% with GV
• 48.3% with RV
• 33.6% with chemoimmunotherapy.

The triplet regimen also produced the lowest need for second-line treatment at five years:

• 7.4% with GIV
• 12.5% with GV
• 22.9% with RV
• 32.9% with chemoimmunotherapy.

The authors said there were “undoubtedly good arguments in favour” of triplet therapy, particularly in higher-risk unmutated IGHV disease where delaying relapse and future treatment burden may carry the greatest clinical value.

By contrast, younger patients with mutated IGHV had similarly favourable outcomes with both targeted therapy and the older fludarabine-cyclophosphamide-rituximab (FCR) chemotherapy regimen, with five-year progression-free survival rates of 88.2% with GIV, 79.8% with GV and 85.7% with FCR.

The study also strengthened the case for obinutuzumab as the preferred antibody partner for venetoclax, with GV outperforming RV for progression-free survival (HR 0.59; 97.5% CI 0.42–0.81; p=0.0002) and time to next treatment.

Despite the stronger disease control with triplet therapy, investigators cautioned that the gains came with greater toxicity and treatment burden.

Early treatment discontinuation occurred in 13.9% of patients in the GIV arm, compared with 6.1% with GV, 7.6% with RV and 18.5% with chemoimmunotherapy. Adverse events led to treatment discontinuation in 11.7%, 3.9%, 4.6% and 14.8% of patients respectively.

Exposure-adjusted cardiac adverse event rates were highest with triplet therapy:

• 15.0 cases per 1000 patient-months with GIV
• 7.0 with GV
• 7.1 with RV.

The investigators also pointed to numerically higher severe infection rates and rare fatal toxicities unique to the GIV arm, including fungal meningoencephalitis and toxic leukoencephalopathy.

“The early discontinuation rate of 13.9% in the triplet arm, while acceptable, remains higher than with venetoclax doublets and reflects that careful patient selection and monitoring is required,” the authors wrote.

Quality-of-life findings reinforced that trade-off. Patients treated with GV or RV reported faster and greater improvements in quality of life than those receiving chemoimmunotherapy, while clinically meaningful improvements in the GIV arm were delayed until around month 15, likely reflecting a higher treatment-related symptom burden, investigators said.

The long-term safety analysis also raised concerns about second cancers. Investigators reported a higher adjusted incidence of second primary malignancies in the triplet arm compared with venetoclax doublets, although Richter’s transformation occurred least frequently with GIV.

They cautioned that “a more complex immunosuppression may come with a higher risk of second cancers” and said the trend warranted close monitoring.

The study also reinforced the prognostic value of measurable residual disease testing, with undetectable MRD at month 15 associated with longer progression-free survival across treatment groups. Detectable MRD at nine months predicted poorer outcomes in most treatment arms, supporting further evaluation of early MRD-guided treatment strategies, they added.

Another clinically important finding was that venetoclax-based retreatment remained effective after relapse, helping address concerns that fixed-duration therapy might exhaust future treatment options.

Two-year treatment-free survival rates after relapse reached:

• 90.5% with venetoclax-based retreatment
• 88.5% with combined BTK inhibitor plus venetoclax therapy
• 77.9% with BTK inhibitor therapy alone.

Importantly, investigators said first-line treatment choice did not appear to compromise the effectiveness of later therapies.

Despite large differences in progression-free survival, overall survival did not significantly differ between treatment arms, with five-year overall survival rates exceeding 90% across all groups.

“This is a common observation in contemporary CLL trials, largely attributable to the availability of effective subsequent therapies, including crossover to targeted agents for patients progressing on CIT,” they wrote. “Interestingly, the first-line treatment that the patients received … did not seem to impact the efficacy of second-line treatments.”

The investigators cautioned that the findings may not fully apply to patients with TP53-aberrant disease, who were excluded from the study, or to older and frailer patients managed outside specialist centres.