Newer Agents Should Be Used in First Line for Older Patients With CLL

With a gap in clinical trial data on patients with chronic lymphocytic leukemia (CLL) who are aged 80 and older, researchers have published new findings from a retrospective study suggesting that newer targeted therapies yield a significant survival advantage for older patients.¹

Older regimens for CLL were frequently used in older patients and were associated with significantly shorter overall survival, the authors found. | image credit: Saiful52 - stock.adobe.com

Approximately 1 in 3 patients with CLL will be aged 80 years or older by the time they receive first-line CLL treatment, though they remain underrepresented from pivotal trials of promising emerging treatments. For example, pivotal trials for ibrutinib (Imbrivuca; Pharmacyclics) and venetoclax (Venclexta; AbbVie and Genentech) were mostly comprised of patients aged under 80.^2-3

With these new data, published in a letter to the editor in American Journal of Hematology, researchers argue that these newer targeted therapies, including Bruton tyrosine kinase inhibitors (BTKis) and venetoclax, should be standard first-line treatment for patients aged 80 years or older.

“Our study is one of few studies that compares survival and TTNT across CLL frontline therapies over 30 years in the U.S. and Europe,” described the researchers. “Consistent with prior studies, we found that novel agents are associated with an improved survival in adults ≥80 years old.”

Researchers of the new analysis compiled 3 decades’ worth of data on patients included in the Mayo Clinic CLL Database, as well as a nationwide Danish study. Across the 653 patients, overall survival was just over 3 (3.1) years, representing results of patients receiving newer targeted agents as well as older treatments like alkylating agents or purine analogs.

However, when looking at outcomes for patients receiving treatment with a BTKi or venetoclax, survival was notably longer, with median OS not reached among this subgroup of patients. For these 82 patients, half received ibrutinib, 16 received the newer BTKi acalabrutinib (Calquence; AstraZeneca), and 18 received venetoclax, all with or without anti-CD20 antibody such as obinutuzumab.

The 2-year OS for venetoclax-treated patients was 100%, with a 5-year OS of 75%. While the follow-up for this group was shorter, no patients had died at the time of analysis. BTKi-treated patients had a 2-year OS of 83% and a 5-year OS of 48%. Though there was a trend suggesting longer OS for acalabrutinib versus ibrutinib, the study was underpowered to detect statistically significant differences.

“These results propose that novel agents should be considered for frontline therapy in patients ≥80 years old,” explained the researchers. “There was a suggestion that venetoclax-based treatment may have a longer OS compared with BTKi. However, this finding should be interpreted with caution due to our small subgroups and potential selection bias, such as frailty or presence of 17p deletion.”

Older regimens were frequently used, noted in nearly 3 in 4 patients. These traditional treatment regimens were associated with significantly shorter OS (HR, 2.8; P < .001) and shorter time to next treatment (HR, 2.9; P = .002).

Alkylators accounted for 354 cases and had the lowest median OS (2.5 years). OS was slightly better for the 90 patients receiving anti-CD20 monotherapy (3.9 years) and for the 55 patients receiving purine analogs (3.5 years).The researchers noted the absence of data on dose adjustments or treatment interruptions included in their study.

References

1. Tsang M, Hampel PJ, Rabe KG, et al. Comparison of frontline therapies in older adults age ≥80 years with chronic lymphocytic leukemia (CLL): A Mayo Clinic and Danish nation-wide study. Am J Hem. Published online June 18, 2025. doi:10.1002/ajh.27747

2. 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

3. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380:2225-2236. doi: 10.1056/NEJMoa1815281