Acalabrutinib Safe, Effective in Ibrutinib-Intolerant CLL/SLL

Farrukh T. Awan, MD

The investigational BTK inhibitor acalabrutinib was shown to be well-tolerated and effective in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL) who display intolerance to ibrutinib (Imbruvica), according to recent findings presented at the 58th Annual Meeting of the American Society of Hematology (ASH) held in San Diego, CA.

In the ACE-CL-001 study, only one-third of patients who were ibrutinib-intolerant and subsequently treated with acalabrutinib had a recurrent adverse event, reported Farrukh T. Awan, MD, who presented the study at the ASH Annual Meeting. In addition, acalabrutinib had promising activity in ibrutinib-intolerant patients, with an overall response rate (ORR) of 79%.

“Based on these preliminary findings, we feel that acalabrutinib has promising activity in this group of patients, and safety, and it’s effective very quickly and it appears at least in the early follow-up to have durability,” said Awan, associate professor, division of hematology, department of internal medicine, Ohio State University.

The findings support an ongoing phase II trial of acalabrutinib in ibrutinib-intolerant patients, said Awan.

Although ibrutinib has dramatically improved progression-free survival (PFS) and overall survival (OS) in CLL patients compared with conventional therapies, a subset of patients experience intolerable adverse events such as diarrhea, rash, myalagias/arthralgias, atrial fibrillation, and bleeding, leading to treatment discontinuation or dose reduction.

Acalabrutinib is a highly selective, potent BTK inhibitor shown to minimize off-target activity in preclinical studies. The clinical activity of the agent as a monotherapy has been demonstrated in patients with previously untreated or relapsed or refractory CLL, including those with del17p.

The study included 33 patients with confirmed CLL and intolerance to ibrutinib. They were treated with acalabrutinib, 100mg twice daily (n=30) or 200mg daily (n=3), until disease progression or discontinuation for another reason. The primary objective of this analysis was to evaluate safety, including the frequency, severity, and attribution of adverse events in this cohort. Secondary objectives were assessment of ORR, duration of response, and PFS. Ninety-one percent of the patients enrolled had ibrutinib as their last prior therapy. Eighty-one percent had unmutated IVGH, 31% had del11q, and 38% had del17p.

The adverse events experienced by patients that resulted in discontinuation of ibrutinib included rash in 7 (21%), arthralgia in 6 (18%), diarrhea in 5 (15%), fatigue in 4 (12%), hemorrhage in 4 (12%), myalgia in 3 (9%), atrial fibrillation (AF) in 2 (6%), erythema nodosum in 2 (6%), and hematoma in 2 (6%). Nine of the patients had grade-3 adverse events, including 2 with rash, 2 with arthralgia, 2 with diarrhea, 1 with fatigue, 1 with hemorrhage, and 1 with myalgia.

The median time from ending ibrutinib to starting acalabrutinib was 47 days, and the median time on acalabrutinib was 12.2 months. Nine of the 33 (27%) patients discontinued treatment with acalabrutunib, 3 (9%) for progressive disease, 3 (9%) for adverse events (hemorrhagic stroke, fungal infection, and metastatic endometrial cancer), 1 (3%) was physician decision in a patient with a history of hemophilia, and 2 (6%) for other reasons. Twenty-four (73%) remain on acalabrutinib.

“Acalabrutinib was fairly well tolerated. There were very few grade-3 or higher adverse events, and those were primarily hypertension, fevers, and myalgia,” said Awan. “The majority of the events were grade 1, and those were most commonly diarrhea and headache.”

A total of 12 (36%) patients experienced 16 recurrent adverse events. Fourteen of the 16 recurrent adverse events either decreased in severity or remained unchanged in severity on acalabrutinib compared with on ibrutinib.

“Only 2 events were worse as compared to when they were on ibrutinib, and those were the confusion and the fatigue,” said Awan. “No patient discontinued acalabrutinib because of recurrence of an ibrutinib-related adverse event.”

Of the 2 patients who had an AF event while on acalabrutinib, 1 grade-2 event was a recurrence of previous AF on ibrutinib in a patient who discontinued flecainide, who had no further recurrence when flecainide was restarted. The other AF episode was a grade-3 event that occurred in the setting of pseudomonal infection and pleural effusion, and resolved after 2 days.

Of 29 patients evaluable for response, best response was a complete response (CR) in 1 patient (3.4%), a partial response (PR) in 15 (51.7%), PR with lymphocytosis (PRL) in 7 (24.1%), and stable disease (SD) in 6 (20.7%). The overall response rate (ORR) when including only CR plus PR was 55.2%, and was 79.3% when including PRL in the ORR definition. All evaluable patients achieved at least SD. The median time to PRL or better was 1.9 months.

“This is an early follow-up but responses seem to be durable, and 81% of the patients have a duration of response in excess of 12 months,” Awan said.

The median PFS had not been reached at data cut-off on September 1, 2016.

Awan FT, Schuh A, MD PhD, Brown JR, et al. Acalabrutinib monotherapy in patients with ibrutinib intolerance: Results from the phase 1/2 ACE-CL-001 clinical study. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 638.

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The 2 grade-5 events that occurred while patients were on acalabrutinib—stroke and disseminated systemic fungal infection&mdash;were both deemed unrelated to study drug.