Acalabrutinib Shows Higher Tolerability Versus Ibrutinib in CLL

John C. Byrd, MD, discusses the early results and adverse events observed in the ELEVATE-RR trial in patients with chronic lymphocytic leukemia.

John C. Byrd, MD, professor and chair of the University of Cincinnati College of Medicine Department of Internal Medicine, the D. Warren Brown Chair of Leukemia Research, and Distinguished University Professor at The Ohio State University, discusses the early results and adverse events observed in the ELEVATE-RR trial (NCT02477696) in patients with chronic lymphocytic leukemia (CLL).

Ibrutinib (Imbruvica) and acalabrutinib (Calquence) are Bruton tyrosine kinase inhibitors used to treat CLL. Investigators in the phase 3 ELEVATE-RR trial believed that acalabrutinib may have a better tolerability profile than ibrutinib. There were 268 participants who received acalabrutinib and 265 who received ibrutinib. Of those patients, 45.2% had a deletion 17p mutation, while 64.2% had a deletion 11q, both of which are high-risk prognostic factors for CLL.

The primary end point was progression-free survival (PFS) in each arm, while secondary end points included incidence of grade 3 or higher adverse events (AEs), incidence of Richter transformation and atrial fibrillation, and overall survival (OS). According to Byrd, in early results, PFS of acalabrutinib was non-inferior to ibrutinib, while atrial fibrillation, Richter transformation, and grade 3 or higher AEs were lower, though not significantly so. In addition, there were fewer discontinuations of treatment in the acalabrutinib group. The hazard ratio was 0.82 in favor of acalabrutinib (95% CI, 0.59-1.15).


0:08 | Atrial fibrillation was significantly higher with ibrutinib, as compared to acalabrutinib. And then there were other secondary end points that were examined, including infections, Richter transformation, and OS. Those all favored acalabrutinib in terms of safety and outcome, but they were not significant.

Moving forward to looking at other AEs between the 2 drugs, there was a plethora of additional AEs, some that were problematic to patient outcome, including hypertension, grade 3 and 4 [AEs], but also things that are irritating to patients: diarrhea, bruising, rash, and interstitial pneumonitis—things that would cause patients to go off of therapy. And indeed, therapy discontinuations were higher in the ibrutinib arm than in the acalabrutinib arm. Acalabrutinib itself had some distinct AEs from ibrutinib: headache was more common; cough was more common. The headache that occurs with this [acalabrutinib] generally did not lead to treatment cessation.

In sum, when we looked at everything, PFS was the same. The AEs for the most part were more common with ibrutinib as compared to acalabrutinib. And something that we really care about when we look at outcome, [is] not only how long our patients stay in remission, but what's their survival? The OS was not significantly different with acalabrutinib than ibrutinib, but the hazard ratio favored acalabrutinib, with a hazard ratio of 0.82.