Acalabrutinib Induces Durable Response in Patients With Waldenström Macroglobulinemia

In a phase II study of patients with Waldenström macroglobulinemia (WM), treatment with the highly selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib led to an overall response rate (ORR) of 93 percent, with 27 months of follow-up. The efficacy was observed across patients with both treatment-naïve and relapsed/refractory disease, according to results presented at the 2018 ASCO Annual Meeting.

“Ibrutinib is an approved BTK inhibitor with demonstrated activity in WM, yet treatment with ibrutinib has been associated with toxicities such as bleeding and atrial fibrillation,” said lead author Roger Owen, MRCP, MRCPath, MD, of St. James’ University Hospital in Leeds, U.K. “Acalabrutinib is a highly selective BTK inhibitor with minimal off-target activity.”

The phase II trial enrolled adults with WM without prior BTK inhibitor exposure or significant cardiovascular disease; patients who had prior or concurrent atrial fibrillation were permitted in the study.

Among the 116 patients (n=14 treatment-naïve and n=92 relapsed/ refractory) enrolled as of February 13, 2018, the median patient age was 69 years (range = 39-90 years). In the relapsed/ refractory group, patients had received a median of two prior therapies (range = 1-7 therapies), the most common of which was rituximab.

Patients received acalabrutinib 100 mg twice-daily in 28-day cycles until disease progression or intolerance; six patients received acalabrutinib 200 mg once-daily and later switched to 100 mg twice-daily.

At a median follow-up of 27.4 months (range = 4.6-40.7 months), 72 percent of patients remained on treatment: 50 percent of treatment-naïve (n=7) and 75 percent of relapsed/refractory patients (n=69).

“Treatment discontinuation due to adverse events (AEs) was low,” Dr. Owen noted, at 21 percent (n=3) and 4 percent (n=4) in the treatment-naïve and relapsed/ refractory cohorts, respectively. Other causes for discontinuation were disease progression (0 and 9 [10%]), investigator decision (2 [14%] and 4 [4%]), and death (1 [7%] and 3 [3%]).

The primary endpoint of ORR (defined as a minor response or better) was 93 percent (n=13) in the treatment-naïve cohort and 94 percent (n=86) in the relapsed/refractory group. The ORR was consistent across prespecified subgroups, including age ≥65 years (93.4%) and ≥3 prior therapies (95.5%).

Median durations of response, progression-free survival, and overall survival were not reached in either cohort. See TABLE for 24-month survival rates and other efficacy outcomes.

Treatment Response

The most common any-grade treatmentrelated AEs were headache (39%), diarrhea (31%), contusion (29%), and dizziness (25%). The most common grade 3/4 AEs were neutropenia (16%), pneumonia (7%), anemia (5%), increased alanine transaminase (5%), and hyponatremia (5%).

Three patients reported experiencing atrial fibrillation, including one grade 3 event. More than half of patients (56%) experienced bleeding events, most commonly contusion and epistaxis; four of these were grade 3/4 events, but none led to treatment discontinuation. There were five grade 5 AEs (pneumonia, glioblastoma multiforme, esophageal carcinoma, myocardial ischemia, and intracranial hematoma).

Of the nine participants who discontinued acalabrutinib due to AEs (3 in the treatment-naïve cohort and 6 in the relapsed/ refractory cohort), three developed a secondary malignancy during treatment.

“We observed rapid and sustained reductions in immunoglobulin, which was mirrored by substantial and sustained improvements in hemoglobin,” Dr. Owen added. While he noted that acalabrutinib appears to be “a highly effective treatment for WM with durable responses and limited toxicity,” the study’s findings are limited by its lack of a comparator arm and the small number of patients in the treatment-naïve cohort.

The authors report financial relationships with AstraZeneca, the manufacturer of acalabrutinib.


Owen R, McCarthy H, Rule S, et al. Acalabrutinib in patients (pts) with Waldenström macroglobulinemia (WM). Abstract #7501. Presented at the 2018 American Society of Clinical Oncology Annual Meeting, June 3, 2018; Chicago, IL.