Long-Term Data Support Acalabrutinib Use Up Front in CLL

September 2020 Vol 11, No 9

A targeted therapy used to treat non-Hodgkin lymphoma has demonstrated durable remissions in treatment-naive chronic lymphocytic leukemia (CLL), according to data presented at the ASCO20 Virtual Scientific Program.

Long-term results of the phase 2 study of acalabrutinib monotherapy showed an overall response rate of 97% in previously untreated patients with CLL. Importantly, responses were durable, with 86% of patients still on treatment after almost 2.5 years. The treatment was also well tolerated, with no long-term safety issues. Lead author of the study, John Byrd, MD, said that, collectively, these data support the use of acalabrutinib up front in CLL.

“Acalabrutinib monotherapy produced a very high and durable response, regardless of high-risk genomic characteristics seen in previously untreated CLL,” said Dr Byrd, Distinguished University Professor of Medicine at The Ohio State University Comprehensive Cancer Center. “The toxicity associated with acalabrutinib was generally mild, with only a small subset of patients discontinuing therapy due to adverse events.”

As Dr Byrd reported, targeted inhibition of Bruton’s tyrosine kinase, or BTK, has improved clinical outcomes in patients with relapsed/refractory and treatment-naive CLL. Acalabrutinib is a selective BTK inhibitor that has demonstrated less off-target activity in nonhuman studies compared with other BTK inhibitors, such as ibrutinib. In late 2019, acalabrutinib was approved in patients with treatment-naive and relapsed/refractory CLL and small lymphocytic lymphoma based on 2 complementary phase 3 studies.

Dr Byrd reported mature results from CLL-001, the first phase 2 study of acalabrutinib in patients with treatment-naive CLL. In the expansion of the study, 99 patients with treatment-naive disease were enrolled and received acalabrutinib until disease progression or unacceptable toxicity.

Patients were initially enrolled at either a dose of 100 mg twice daily or 200 mg once daily. Later in the study, when it was identified that twice-daily dosing was potentially better, all patients were converted to 100 mg twice daily. In addition to assessing tolerability, efficacy end points included investigator-assessed response, time to response, duration of response, and event-free survival.

Demographics of patients matched most CLL trials that have been performed, said Dr Byrd, who reported that enrolled patients had a median age of 64 years, and nearly half had Rai stage III or IV disease. In addition, 10% of patients had deletion 17p, a rare genomic aberration, and almost two-thirds had IgVH-unmutated CLL.

After a median follow-up of 53 months, 86% of patients still remained on therapy with acalabrutinib. Fourteen patients discontinued treatment, 6 of these due to adverse events; 3 patients had progressive disease. Of the 6 patients who discontinued due to adverse events, 4 were due to secondary cancers, and 2 were due to infections, said Dr Byrd.

The most common adverse events of any grade were diarrhea, headache, upper respiratory tract infection, arthralgia, and contusion or bruising. Most of these adverse events were grade 1/2, said Dr Byrd, who noted that adverse events with acalabrutinib generally went away as time progressed on therapy.

Serious adverse events were reported in 38% of patients, with pneumonia and sepsis being the only ones that occurred in 2 or more patients. Two deaths were reported on study, one due to multiorgan dysfunction in the setting of pneumonia and the other due to cardiac failure, but both of these were considered unrelated to acalabrutinib therapy.

“High-grade hematologic adverse events were very uncommon, and no patients discontinued acalabrutinib due to hypertension, bleeding events, or atrial fibrillation,” said Dr Byrd.

Finally, the results of the study showed an overall response rate of 97%, including 7% complete response and 90% partial response. Notably, the median time to response was 3.7 months.

“Median duration of response and event-free survival median response have not yet been reached with extended follow-up, and the estimated 48-month duration of response is 97%,” Dr Byrd concluded.

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Last modified: August 10, 2023

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