Acalabrutinib Induces Durable Remission in Patients With Treatment Naïve Chronic Lymphocytic Leukemia

Treatment with the next-generation covalent Bruton tyrosine kinase (BTK) inhibitor acalabrutinib was safe and led to durable, long-term remission in a small group of patients with previously untreated chronic lymphocytic leukemia (CLL), according to a study published in Blood.

“These findings suggest that acalabrutinib represents an acceptable treatment option for patients with treatment-naïve CLL and should be further evaluated in head-to-head trials with other standard-of-care therapies in this population,” said lead author John Byrd, MD, of The Ohio State University Comprehensive Cancer Center.

Prior to the arrival of BTK inhibitors, the CLL treatment landscape had been mostly dominated by standard-of-care chemoimmunotherapy, Dr. Byrd added. In addition to ibrutinib, another BTK inhibitor, acalabrutinib, is approved for use in treatment-naïve and relapsed/refractory CLL/small lymphocytic lymphoma (SLL).

In this study, Dr. Byrd and researchers looked at the long-term safety and efficacy of acalabrutinib in 99 patients with treatment-naïve CLL/SLL who participated in the phase I/II ACE-CL-001 trial.

To be eligible for enrollment, patients were required to have either declined, or had comorbidities that prevented the initiation of, chemoimmunotherapy. The investigators evaluated patients at the screening phase, weekly (first month), biweekly (second month), monthly for four months, and every three months thereafter. Each evaluation included an assessment of medical history, physical examinations, and toxicities. The median age of the study participants was 64 years. Nearly half of patients (47%) had high-risk disease. The medium treatment duration in the 37 patients who initially received acalabrutinib 200 mg was 13.7 months.

“Acalabrutinib represents an acceptable treatment option for patients with treatment-naïve CLL and should be further evaluated in head-to-head trials.”

—John Byrd, MD

Approximately 62% of patients were immunoglobulin heavy chain variable region (IGHV)-unmutated, and 18% of patients tested positive for TP53 aberrations.

After a median follow-up of 53 months, 85 patients remained on treatment. A total of 14 patients had discontinued therapy, most commonly because of adverse events (AEs; n=6) and second primary cancers (n=4).

All patients eventually transitioned to twice-daily acalabrutinib 100 mg following observed improvements in trough BTK occupancy with twice-daily dosing. The median BTK occupancy of 97% to 99% was found during twice-daily dosing at steady-state on days eight and 28 at trough. This was considered better than that observed using 200 mg once-daily dosing (100 mg twice daily vs. 200 mg once daily: trough day eight [p=0.0034] and day 28 [p=0.0003]).

The overall response rate to acalabrutinib was 97%, which included a partial response rate of 90% and a complete response rate of 7%. At four years, the estimated progression-free survival (PFS) and event-free survival (EFS) were 96% and 90%, respectively. While median duration of response (DOR) was not reached during the study, the estimated 48-month DOR was 97%.

In patients with del17p and/or mutated TP53 (n=12), the estimated 48-month PFS was 82% and the estimated 48-month EFS was 75%. Among patients with complex karyotype (n=12), the respective estimated 48-month PFS and EFS rates were 91% and 83%.

Up to 38% of patients experienced a serious AE. Events that necessitated treatment discontinuation in 6% of patients included second primary cancers (n=4) and infection (n=2). Grade ≥3 AEs of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%).

Two patients died during the study. One death was a result of multiple organ dysfunction in the context of pneumonia and grade 4 sepsis. The other patient experienced cardiac failure during an ongoing lung infection and atrial fibrillation.

This trial is limited by its inclusion of patients predominantly treated at academic centers in the U.S., which may limit the generalizability of the results across larger patient groups treated in other health care systems.

Study authors report relationships with Acerta Pharma, which sponsored this trial.


Byrd JC, Woyach JA, Furman RR, et al. Acalabrutinib in treatment-naïve chronic lymphocytic leukemia [published online ahead of print, 2021 Mar 30]. Blood. doi: 10.1182/blood.2020009617.