Zanubrutinib Tops Rivals in Real-World CLL Survival Study

Zanubrutinib was associated with meaningfully longer treatment duration, lower discontinuation rates, and better overall survival (OS) compared with acalabrutinib and ibrutinib among Medicare beneficiaries aged 65 and older with treatment-naive chronic lymphocytic leukemia (CLL), according to a large retrospective observational study published in Oncology and Therapy.¹ The analysis is believed to be the largest real-world comparison of first-line covalent Bruton tyrosine kinase (BTK) inhibitors.

What Did the Medicare Claims Data Reveal?

The study drew on the 100% deidentified Medicare Fee-For-Service (FFS) database, identifying 10,523 patients who initiated first-line zanubrutinib (n = 3006; 28.6%), acalabrutinib (n = 4309; 40.9%), or ibrutinib (n = 3208; 30.5%) monotherapy between January 1, 2020, and September 30, 2025. The median (IQR) age across all cohorts was 77 years (72-82). The primary outcome of interest was patient outcome with each of the BTK inhibitors in those 65 years and older.

Median real-world time to treatment discontinuation (rwTTD) was not reached for zanubrutinib compared with 24 months for acalabrutinib and 14 months for ibrutinib. The probabilities of remaining on treatment at 24 months were 63.2%, 48.9%, and 35.1%, respectively. This was measured at 12 and 24 months after the index date. In adjusted analyses accounting for age, sex, race/ethnicity, Charlson Comorbidity Index (CCI) score, and year of index, zanubrutinib was associated with a 43% lower risk of discontinuation vs ibrutinib (adjusted HR [AHR], 0.57; 95% CI, 0.51-0.64) and a 14% lower risk vs acalabrutinib (AHR, 0.86; 95% CI, 0.78-0.94).

Real-world time to next treatment (rwTTNT) was also not reached for zanubrutinib, whereas the patients who received acalabrutinib had a median of 40 months and patients who received ibrutinib had a median of 20 months. Adjusted analyses showed a 37% lower risk of advancing to next treatment or death for zanubrutinib vs ibrutinib (AHR, 0.63; 95% CI, 0.55-0.71) and a 13% lower risk vs acalabrutinib (AHR, 0.87; 95% CI, 0.78-0.96). At 24 months, 86.1% of zanubrutinib-treated patients remained on first-line therapy vs 71.2% for acalabrutinib and 55.9% for ibrutinib.

How Did Survival Outcomes Compare Across Agents?

Median real-world overall survival (rwOS) was not reached in any treatment group, but survival probabilities diverged meaningfully at 12 and 24 months. Zanubrutinib-treated patients had a 24-month survival probability of 85.9% vs 79.7% for those receiving acalabrutinib and 75.4% for ibrutinib. After adjustment, zanubrutinib was associated with a 36% lower risk of death compared with ibrutinib (AHR, 0.64; 95% CI, 0.54-0.77; P < .0001) and a 24% lower risk compared with acalabrutinib (AHR, 0.76; 95% CI, 0.66-0.88; P = .0002), both considered statistically significant.

Subgroup analyses by age—65 to 74 years, 75 to 84 years, and 85 and older—showed broadly consistent patterns for rwTTD and rwTTNT. The survival advantage of zanubrutinib over acalabrutinib on rwOS was statistically significant among patients aged 65 to 74 years (AHR, 0.55; 95% CI, 0.38-0.81; P = .002) and 75 to 84 years (AHR ,0.73; 95% CI, 0.59-0.91; P = .005), but did not reach significance in patients 85 years and older (AHR, 0.91; 95% CI, 0.73-1.12; P = .35). The authors noted that limited follow-up time in older subgroups may have reduced statistical power.

Why Might Tolerability Drive Durability?

The study did not capture reasons for treatment discontinuation, but the authors pointed to a broader body of evidence suggesting that adverse event profiles distinguish the 3 agents in clinically meaningful ways. For example, ibrutinib’s off-target kinase inhibition has long been associated with elevated rates of atrial fibrillation, hypertension, and bleeding—toxicities that contribute to high real-world discontinuation rates. Notably, baseline atrial fibrillation prevalence was lower in the ibrutinib cohort (11.6%) than in those treated with zanubrutinib (17.1%) or acalabrutinib (17.2%), suggesting that physicians may already be steering cardiac-risk patients away from ibrutinib in routine practice.

Second-generation covalent BTK inhibitor agents were designed to reduce these off-target effects through greater BTK selectivity, and real-world data have increasingly borne that out.² Previous research also shows zanubrutinib to be a well-tolerated option in relapsed/refractory CLL, with low rates of treatment-limiting toxicities, particularly among patients with preexisting cardiovascular comorbidities.³

What Are the Implications for Managed Care and Prescribing Decisions?

CLL predominantly affects older adults—the median age at diagnosis is approximately 70 years—and Medicare is the dominant payer for this population. Treatment durability and its downstream effects on health care resource utilization are central to the value equation. The results align with and extend prior real-world work showing that patients who received zanubrutinib had the lowest overall discontinuation rate among covalent BTK inhibitor users, including in patients aged 65 and older.⁴

Limitations acknowledged by the authors include the absence of key clinical and molecular variables—such as IGHV mutation status, del(17p), and TP53 status—that cannot be captured in claims data but can influence treatment selection and outcomes. Reasons for treatment discontinuation were also unavailable. The zanubrutinib cohort had shorter median follow-up (15.8 months) than acalabrutinib (20.7 months) or ibrutinib (34.9 months). The study population was also limited to Medicare FFS beneficiaries aged 65 and older and may not generalize to younger patients or those enrolled in Medicare Advantage plans.

“These data reinforce that zanubrutinib may represent a comparatively superior treatment option for older adults with CLL,” the authors concluded, “and highlights the need for additional studies evaluating FDA-approved BTK inhibitors to further clarify differences in real-world effectiveness and safety.”

References

1. Ermann DA, Stephens DM, Wang X, et al. Real-world outcomes among Medicare beneficiaries treated with Bruton tyrosine kinase inhibitors for treatment-naïve CLL. Oncol Ther. Published online June 22, 2026. doi:10.1007/s40487-026-00452-9
2. Haumschild R, Jacobs R. Examining safety and efficacy of BTK inhibitors in CLL and SLL treatment. AJMC^®. February 1, 2024. Accessed June 24, 2026. https://www.ajmc.com/view/examining-safety-and-efficacy-of-btk-inhibitors-in-cll-and-sll-treatment
3. Shaw ML. Zanubrutinib demonstrates favorable tolerability in R/R CLL/SLL. AJMC. April 3, 2026. Accessed June 24, 2026. https://www.ajmc.com/view/zanubrutinib-demonstrates-favorable-tolerability-in-r-r-cll-sll
4. Ailawadhi S, Challagulla S, Chuang PY, Furnback W, Yang K. Real-world treatment utilization patterns, discontinuation and healthcare resource utilization of first-line BTK inhibitors among elderly patients ≥65 years in CLL. Expert Rev Hematol. 2026;19(5):539-546. doi:10.1080/17474086.2026.2628534