Real-World Study Shows Comparable Survival Outcomes With First-Line Ibrutinib in High-Risk and Non-High-Risk CLL/SLL

Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL; CLL/SLL) who harbor high-risk cytogenetic abnormalities demonstrated similar overall survival (OS) outcomes to those without these features when treated with first-line (1L) ibrutinib (Imbruvica; Janssen Biotech), according to a retrospective analysis of real-world data. The study findings were published in Blood Advances.¹

Microscopic cellular structure of chronic lymphocytic leukemia | Image Credit: ©AI Photo Stock - stock.adobe.com

In CLL/SLL, genetic markers play a key role in guiding treatment decisions and predicting disease outcomes. High-risk abnormalities such as deletion 17p [del(17p)], deletion 11q [del(11q)], and unmutated immunoglobulin heavy chain variable region (IGHV) are associated with more aggressive disease and poorer responses to therapy. For example, del(17p) involves the loss of the TP53 tumor suppressor gene and is strongly linked to shorter remission durations and rapid progression. In contrast, mutated IGHV is considered a favorable marker, associated with slower disease progression and longer time to next treatment.²

Targeted therapies like ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, have significantly changed the treatment landscape for CLL/SLL and demonstrated meaningful efficacy in clinical trials. However, real-world data reflecting broader patient populations and longer-term outcomes are essential to confirm whether this holds true in routine clinical practice. This study aimed to assess whether 1L ibrutinib could overcome the traditionally poor prognosis associated with high-risk features in a real-world setting.^1,2

The large-scale study utilized a deidentified, nationwide electronic health record-derived database to evaluate real-world OS (rwOS) among 1242 patients with CLL/SLL treated with 1L ibrutinib (median age 70 years). Of these, 969 patients were categorized as having high-risk disease based on the presence of at least one of the following: del(17p), del(11q), or unmutated IGHV. The remaining 273 patients did not meet these criteria and were classified as non-high risk.¹

In the high-risk group, 32.9% had del(17p), 36.7% had del(11q), and 58.7% had unmutated IGHV. Using inverse probability of treatment weighting to adjust for baseline differences between groups, the study found no statistically significant difference in rwOS between the high-risk and non-high-risk cohorts. The hazard ratio (HR) for rwOS was 1.09 (95% CI, 0.79 to 1.51), indicating comparable survival outcomes.¹

A sensitivity analysis excluding del(11q) from the high-risk definition yielded similar findings, with an HR of 1.19 (95% CI, 0.86 to 1.64), and the median rwOS was not reached in either cohort. Among patients with Medicare coverage, a subgroup representing an older population, the results remained consistent, with an HR of 0.98 (95% CI, 0.63 to 1.53).¹

The findings suggest that 1L ibrutinib may help level the playing field for patients with high-risk cytogenetics, offering similar survival benefits regardless of risk status. Although these results do not negate the prognostic value of cytogenetics, they reinforce the clinical utility of BTK inhibitors in overcoming traditional high-risk markers in CLL/SLL.

As real-world evidence continues to grow in importance, this study provides reassurance for clinicians that ibrutinib remains an effective frontline option even for patients historically considered high risk. Further research, particularly prospective studies, will be critical to confirm these outcomes and refine treatment strategies based on individual risk profiles.

REFERENCES

1. Allen J, Ran T, Ding Z, et al. Real-world survival outcomes in first-line ibrutinib-treated patients with high-risk CLL/SLL. Blood Adv. May 12, 2025. Doi:10.1182/bloodadvances.2024015417

2. Targeted therapies transform cll care: inside the era of BTK and BCL-2 inhibitors. Pharmacy Times. April 29, 2025. Accessed May 15, 2025. https://www.pharmacytimes.com/view/targeted-therapies-transform-cll-care-inside-the-era-of-btk-and-bcl-2-inhibitors