Acalabrutinib Effective, Safe for Patients With CLL Who Are Intolerant to Ibrutinib


A phase 2 trial found that acalabrutinib may present a potential therapeutic option for patients with chronic lymphocytic leukemia who discontinued ibrutinib treatment.

For patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who are intolerant to ibrutinib (Imbruvica), acalabrutinib (Calquence) is a tolerable and effective option to treat the disease, according to data published in Haematologica.

“The results of this study demonstrate that acalabrutinib is a safe and effective option for patients with relapsed/refractory CLL who were not able to tolerate ibrutinib,” wrote the investigators. “Acalabrutinib is an important therapeutic option in this population and will allow more [patients with CLL] to benefit from BTK inhibitor treatment.”

Treatment with acalabrutinib is already approved for use in patients with CLL. Since ibrutinib is not always tolerated well by patients, acalabrutinib has positioned itself as an effective alternative treatment option. However, a dedicated trial for examining acalabrutinib in patients who are intolerant of ibrutinib therapy had not been previously conducted.

A total of 60 patients with CLL who discontinued ibrutinib treatment were enrolled in the phase 2 trial (NCT02717611) between March 23, 2016, and August 2, 2017. The median age of this population was 69.5 years (range, 43-88 years), with a median number of prior therapies of 2 (range, 1-10).

The overall response rate for patients receiving acalabrutinib was observed at 73% (95% CI, 60%-84%), with 3 patients experiencing a complete response (CR) to treatment. The median progression-free survival (PFS) and overall survival (OS) end points were not reached at a median 35-month follow-up, but the 24-month follow-up estimates were recorded at 72% (95% CI, 58%-82%) and 81% (95% CI, 68%-89%), respectively.

Common adverse events (AEs) observed in patients treated with acalabrutinib included diarrhea (53% of patients), headache (42%), contusion (40%), dizziness (33%), upper respiratory tract infection (33%), and cough (30%).

At a median follow-up of 35 months, 48% of patients remained on acalabrutinib treatment. For those patients who discontinued acalabrutinib treatment, the reasons cited included progressive disease (23%) and AEs (17%).

“This rate of discontinuation due to AEs is low considering that 100% of patients had discontinued ibrutinib due to AEs, suggesting that acalabrutinib is tolerable in a large proportion of patients who are intolerant of ibrutinib,” explained the investigators.

When compared with ibrutinib, acalabrutinib is a more selective BTK inhibitor, and the limited off-target effects of the drug may account for the improved safety profile.

“Clinical strategies for patients with ibrutinib intolerance, such as switching to alternative kinase inhibitors or combining different therapeutic agents, have been evaluated,” wrote the investigators. “Real-world data have suggested that ibrutinib-intolerant patients could be treated successfully with an alternative kinase inhibitor.”

The most significant limitation of the research, according to the study investigators, was the inability to “prospectively or rigorously capture” the ibrutinib experience. This means that several patient responses to ibrutinib are unknown, and every AE resulting from ibrutinib treatment was not captured in detail.

More, it is possible that some low-grade ibrutinib AEs occurred at a higher grade on acalabrutinib treatment, but this data is unknown due to the “subjective reporting of AEs by patients prior to enrollment.”

“This phase 2 study of acalabrutinib in patients who were ibrutinib intolerant demonstrated that acalabrutinib is effective and tolerable in a large proportion of this population,” wrote the investigators.


Rogers KA, Thompson PA, Allan JN, et al. Phase 2 study of acalabrutinib in ibrutinib-intolerant patients with relapsed/refractory chronic lymphocytic leukemia. Haematologica. March 18, 2021. doi:10.3324/haematol.2020.272500

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