Acalabrutinib Yields Frontline PFS Benefit Over Chlorambucil/Rituximab in CLL

According to results from a phase 3 study conducted in Asia, acalabrutinib (Calquence) significantly reduced the risk of progression or death compared with chlorambucil and rituximab (Rituxan) in medically unfit patients with treatment-naive chronic lymphocytic leukemia (CLL).¹

The data, published in Annals of Hematology, indicate that the trial met its primary end point of progression-free survival (PFS) with a hazard ratio of 0.08 (P <.0001), amounting to a 92% reduction in the risk of progression or death with acalabrutinib vs chlorambucil and rituximab in both the overall study population and a China-specific cohort. Overall response rates were 76.6% with acalabrutinib vs 71.8% with chlorambucil plus rituximab. Median duration of response was not reached in the acalabrutinib arm compared with 11.6 months in the chlorambucil plus rituximab arm.

Safety findings favored acalabrutinib on cardiovascular measures typically associated with Bruton tyrosine kinase (BTK) inhibitor therapy. No cases of atrial fibrillation or hypertension were observed in patients treated with acalabrutinib. The authors characterized acalabrutinib as well tolerated overall, with a safety profile consistent with prior studies of the agent in CLL.

Study Design

The randomized, multicenter, open-label phase 3 study was designed to evaluate the efficacy and safety of acalabrutinib vs chlorambucil plus rituximab in previously untreated CLL.² As of the January 3, 2024, data cutoff, 155 patients had been enrolled across the overall cohort, including 77 patients randomized to acalabrutinib and 78 to chlorambucil plus rituximab. Within the China-specific subgroup, 53 patients received acalabrutinib and 50 received chlorambucil plus rituximab.

The primary end point was PFS; secondary end points included overall response rate and duration of response, along with measures of safety.

Clinical Context and Limitations

Acalabrutinib is a selective, covalent BTK inhibitor already approved in multiple countries for CLL. In China, acalabrutinib is approved for treatment of patients with CLL who have received at least 1 prior therapy.¹ For those who have not received prior therapy, chlorambucil plus rituximab has served as a standard chemoimmunotherapy option for older or less fit patients who may not tolerate more intensive regimens. The current study was thus designed to evaluate whether acalabrutinib could offer an alternative to chemoimmunotherapy in an Asian population of patients considered medically unfit for more intensive frontline treatment.

The authors acknowledged several limitations of the current study, including the use of chlorambucil plus rituximab as the comparator as it is no longer considered a preferred regimen in many contemporary treatment guidelines, as well as a relatively short follow-up that precluded meaningful overall survival analyses. They also noted that additional real-world studies in China and other Asian countries will be important to determine whether broader access to acalabrutinib translates into similar clinical benefit in routine practice.

Nevertheless, the results of this study add to a growing body of evidence supporting BTK inhibition as a frontline option for this patient population, particularly in regions where acalabrutinib has not yet been broadly approved for treatment-naive disease. The authors noted that the efficacy and safety findings were consistent with those observed in the global phase 3 ELEVATE-TN trial (NCT02475681), which evaluated acalabrutinib with or without obinutuzumab (Gazyva) vs chlorambucil plus obinutuzumab in a predominantly North American and European population. Similar to ELEVATE-TN, acalabrutinib produced durable responses and a significant improvement in PFS over chemoimmunotherapy,³ supporting the reproducibility of its benefit across geographically distinct patient populations.

“These results, in a population of patients from across Asia, are consistent with results from other global studies showing that acalabrutinib is an effective and well-tolerated treatment for patients with [treatment-naive] CLL,” study authors Li et al concluded.

REFERENCES

1. Li J, Yi S, Nguyen T, et al. Acalabrutinib vs chlorambucil plus rituximab in untreated chronic lymphocytic leukemia: A randomized phase 3 Asian study. Ann Hematology. 2026;105(8). doi:10.1007/s00277-026-07006-z

2. Study of Acalabrutinib Versus Chlorambucil Plus Rituximab in Adult Subjects With Previously Untreated Chronic Lymphocytic Leukemia. ClinicalTrials.gov. Updated June 16, 2026. Accessed July 31, 2026. https://clinicaltrials.gov/study/NCT04075292

3. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood. 2025;146(11):1276-1285. doi:10.1182/blood.2024024476