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Acalabrutinib Safe in Patients with Previously Untreated Chronic Lymphocytic Leukemia

December 30, 2021

Preliminary results from a phase I/II study of the second-generation Bruton's tyrosine kinase (BTK) inhibitor acalabrutinib in patients with previously untreated chronic lymphocytic leukemia (CLL) showed that the drug was well tolerated and had a favorable safety profile in the majority of patients. John C. Byrd, MD, from The Ohio State University Comprehensive Cancer Center, and authors presented the study's findings at the ASCO Annual Meeting.

"BTK is a critical therapeutic target in CLL," Dr. Byrd and co-authors explained. "Acalabrutinib is an irreversible, selective BTK inhibitor that has demonstrated clinical efficacy in relapsed CLL." Based on those results, the investigators evaluated the safety of acalabrutinib in the front-line setting. Of note, the U.S. Food and Drug Administration approved ibrutinib, a first-generation BTK inhibitor, for the first-line treatment of CLL in March 2016.

The study enrolled patients with previously untreated CLL who met the following inclusion criteria:

  • International Workshop on Chronic Lymphocytic Leukemia 2008 criteria for treatment, irrespective of any cytopenias
  • Eastern Cooperative Oncology Group performance status of 0-2
  • Contraindications for chemoimmunotherapy

Patients were excluded if they had significant cardiovascular disease.

Patients received oral acalabrutinib 100 mg twice daily (n=37) or 200 mg once daily (n=37). The median patient age was 64 years (range = 48-85 years), most had an unmutated IGHV gene (57%; n=38/67), and 47 percent had bulky lymph nodes (≥5 cm).

The median time on the study for all 74 patients was 11 months (range = 1-15 months). The analysis included data up to December 7, 2015, when, 72 patients were evaluable.

"In patients with previously untreated CLL, [we observed] a favorable safety profile and high response rate [97%] with acalabrutinib therapy," the authors wrote.

Most adverse events (AEs) were grade ≤2, including the following grade 1/2 AEs:

  • headache (42%)
  • diarrhea (35%)
  • arthralgia (22%)
  • contusion (18%)
  • nausea (18%)
  • weight gain (18%)

Grade 3/4 AEs that occurred in ≥2 patients included syncope (n=2) and hypertension (n=2). One grade 5 pneumonia was reported, and one grade 3 upper gastrointestinal bleed occurred.

Treatment-related lymphocytosis occurred in 53 percent of patients (n=39/74) and resolved in 97 percent of those patients (n=38/39). Lymphocytosis peaked at a median of one week and was resolved by a median of seven weeks (range = 3-15 weeks).

After a median time to response of two months (range = 2-8 months), the best overall response rate (the study's secondary endpoint) was 96 percent:

  • 86% achieved a partial response (PR)
  • 10% achieved a PR with lymphocytosis (PRL)
  • 4% had stable disease

Of those who achieved a response of PRL or better, with 12 months of follow-up, no death or disease progression was reported.

The median progression-free survival had not been reached at the time of data cut-off. Dr. Byrd and co-authors also noted that no CLL progression or Richter's transformations have occurred. This clinical activity was observed in both acalabrutinib dosing cohorts, they added.

Based on the early results from this study, a global phase III trial comparing acalabrutinib plus obinutuzumab versus chlorambucil in patients with previously untreated CLL is ongoing.


Byrd JC, Jones JA, Furman RR, et al. Acalabrutinib, a second-generation bruton tyrosine kinase (Btk) inhibitor, in previously untreated chronic lymphocytic leukemia (CLL). Abstract #7521. Presented at the 2016 American Society of Clinical Oncology Annual Meeting, June 6, 2016; Chicago, IL


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