Age and Genetics Drive Real-World CLL Treatment Choices

New real-world evidence reveals, for likely the first time, how clinicians in France choose between 5 approved first-line therapies for chronic lymphocytic leukemia (CLL), and the answer comes down to 2 contrasting patient profiles: younger patients steered toward time-limited combination regimens, and older patients guided toward continuous oral Bruton tyrosine kinase (BTK) inhibitor therapy for its outpatient convenience.

Publishing their findings in a recent issue of Cancer,¹ investigators explained how the treatment landscape for CLL has transformed dramatically over the past decade. In France, 5 chemo-free first-line options are currently reimbursed: the first-generation BTK inhibitor ibrutinib, the second-generation agents acalabrutinib (with or without obinutuzumab) and zanubrutinib, and 2 fixed-duration combination regimens: obinutuzumab plus venetoclax (O-Ven) and venetoclax plus ibrutinib (Ven-I).^2-9 All have demonstrated superiority over legacy chemoimmunotherapy, yet there have been no direct comparisons against another in a treatment-naive population.

With no head-to-head trial data to guide decisions in certain patient subgroups, clinicians have been left to consider genetic risk profiles, comorbidities, patient preferences, and logistical practicalities. The present study is the first to systematically examine what actually drives these choices in routine clinical practice.

Between February and September 2024, investigators from 25 centers affiliated with the French Innovative Leukemia Organization enrolled 282 treatment-naive patients with diagnosed CLL who required first-line therapy. For each patient discussed at a mandatory multidisciplinary consultation meeting, the treating physician completed a standardized questionnaire capturing that patient’s characteristics, genetic data, selected treatment, and the criteria that motivated the choice. Multiple correspondence analysis and hierarchical clustering were then applied to identify decision-making patterns.

The median (IQR) patient age at treatment decision was 72 years (63.8-79.0), most were male patients (61.6%), 71.8% of patients had a tumoral form of CLL, 55.1% of patients had a cytopenia, 44.3% had mutated immunoglobulin heavy chain variable region (IGHV) status, 18.0% had an 11q deletion, 12.1% had a TP53 mutation, 7.9% had a complex karyotype, and 6.9% had a 17p deletion.

Investigators’ Key Findings

More than half of patients (51.1%) received the fixed-duration O-Ven combination, BTK inhibitors were prescribed to 26.2%, and Ven-I was prescribed to 16.0%. No patient received first-line chemotherapy

Among the patients prescribed BTK inhibitors, zanubrutinib accounted for 52.7% of prescriptions and acalabrutinib for 36%, while ibrutinib was used in only 10.8%—a pattern the authors attribute to prescribers extrapolating the superior tolerability of second-generation agents seen in the relapsed setting (ELEVATE-RR [NCT02477696] and ALPINE [NCT03734016] trials) into the frontline.

Mutated IGHV status was strongly associated with O-Ven use (OR, 3.87; P < .0001), while TP53 mutation was the dominant predictor of zanubrutinib prescription (OR, 14.58; P < .0001). Also, patients with 17p deletion were nearly 5 times more likely to receive zanubrutinib than those without it. The authors highlighted that these results are a powerful indicator that genetics shaped treatment selection.

Older patients were significantly more likely to receive BTK inhibitors, while the Ven-I combination was used more often in younger patients with bulky disease, a finding linked partly to concerns about cardiovascular toxicity of ibrutinib-containing regimens in frailer patients.

Overall, the most frequently reported decision criteria were prognostic/genetic factors (59.8%) and preference for fixed-duration therapy (49.8%). Comorbidities, particularly cardiovascular, influenced decisions in 29.5% of cases.

Two Distinct Patient Clusters

Clustering analysis crystallized these patterns into 2 clearly differentiated groups:

• Cluster 1 (n = 175) comprised younger patients (median age, 69 years), predominantly with mutated IGHV, few high-risk genetic features, and no renal dysfunction. Most received fixed-duration therapy, at 77.1% for O-Ven and 22.9% for Ven-I, with fixed treatment duration cited as the key criterion in 76% of cases.
• Cluster 2 (n = 79) was older (median age, 78 years), carried substantially higher rates of TP53 mutation (30.3% vs 0.6%) and 17p deletion (14.9% vs 0.6%), and was treated almost exclusively with BTK inhibitors (zanubrutinib, 49.4%; acalabrutinib, 34.2%); outpatient management feasibility was a decisive factor in over half of these cases.

Why These Results Matter

The authors note that treatment guidelines currently offer limited differentiation between available agents for patients with unmutated IGHV, leaving clinicians to balance clinical evidence with patient-level realities. This study makes those real-world trade-offs visible for the first time. Notably, decision-making was consistent across academic and nonacademic centers—suggesting these patterns reflect broad national practice rather than institutional variation.

The findings carry practical implications for guideline development and patient counseling, the authors concluded. The appeal of outpatient, continuous BTK inhibitor therapy for elderly patients is clear, but the authors caution that this convenience must be weighed against accumulating evidence of treatment-emergent resistance mutations and adverse effects with long-term exposure.

“These real‐life data underscore the importance of balancing clinical efficacy with patient-specific factors, such as age, comorbidities, and treatment logistics,” they said, “when selecting the optimal therapeutic approach for CLL.”

References

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3. Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/nejmoa1509388
4. Woyach JA, Ghia P, Byrd JC, et al. B-cell receptor pathway mutations are infrequent in patients with chronic lymphocytic leukemia on continuous ibrutinib therapy. Clin Cancer Res. 2023; 29(16): 3065-3073. doi:10.1158/1078-0432.ccr-22-3887
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