Acalabrutinib Shows Better Safety, Tolerability Than Ibrutinib in Relapsed/Refractory CLL

John Seymour, MD, discusses the safety of acalabrutinib vs ibrutinib in patients with chronic lymphocytic leukemia, and what findings from post-hoc analyses of the ELEVATE-RR trial mean for clinical practice.

Acalabrutinib (Calquence) was found to have a lower incidence of cardiovascular-related toxicities and a lower toxicity burden compared with ibrutinib (Imbruvica) in patients with chronic lymphocytic leukemia (CLL), according to John Seymour, MD, who added that because of these data, the former BTK inhibitor may be the preferred option in clinical practice.

Data from the head-to-head phase 3 ELEVATE-RR trial (NCT02477696), presented during the 2021 ASH Annual Meeting,1 showed that exposure-adjusted incidence and exposure-adjusted time with events like atrial fibrillation, hypertension, and bleeding were 1.5- to 4.1 times higher with ibrutinib vs acalabrutinib. Additionally, other generally lower-grade adverse effects (AEs) such as diarrhea, arthralgias, back pain, muscle spasm, or dyspepsia, were 1.4- to 13.1 times higher with ibrutinib.

“My interpretation of these data is that for the typical patient with CLL, acalabrutinib is substantially better tolerated,” Seymour said. “In my practice, it is the preferred BTK inhibitor, given its more favorable cardiovascular and musculoskeletal toxicity profile.”

In an interview with OncLive®, Seymour, clinical hematologist, associate director of Clinical Research, the Peter MacCallum Centre and director of the integrated Haematology Department, the Peter MacCallum Cancer Centre & the Royal Melbourne Hospital, Melbourne, Australia, further discussed the safety of acalabrutinib vs ibrutinib in patients with CLL, and what findings from post-hoc analyses of the ELEVATE-RR trial mean for clinical practice.

OncLive®: What were the key objectives of the post-hoc analysis of the phase 3 ELEVATE-RR trial?

Seymour: This was a randomized study [in which we compared the use of] acalabrutinib vs ibrutinib, both [given] orally [and] continuously, in patients with relapsed or refractory CLL and the molecular features of del(17p) or del(11q).

The primary end point of this study was noninferiority by [independent review committee (IRC)]–assessed progression free survival [PFS]—and that was met. The treatments were felt to be equivalent in efficacy, with a median PFS of 38.4 months in each arm. Given that equivalence of disease control, an important focus was on patient tolerance and AEs.

We know with long-term chronic therapies that both the duration and intensity of these AEs, particularly some of the lower-grade musculoskeletal and cardiovascular AEs, have significant impacts on quality of life [QoL] and tolerance. We wanted to look [at this] in greater detail, to try to better describe the overall toxicity burden of these 2 similarly effective treatments in patients with relapsed CLL.

Could you expand on the design of the study?

The design of the study was a non-blinded, 1:1 randomization. Both are oral medications, [with] acalabrutinib taken at 100 mg twice daily and ibrutinib at 420 mg once daily. The primary end point [of the research] was noninferiority by IRC-assessed PFS.

[The trial had] several prespecified secondary end points, [and] particularly important [among them was] the incidence of any-grade atrial fibrillation or flutter; that is a recognized toxicity with this class of drugs.

We had 2 separate analyses. In 1, we looked at the toxicity burden, accounting for the duration of time on the drug, which was slightly longer with acalabrutinib, at 38.3 months compared with 35.5 months with ibrutinib.We expressed these by exposure-adjusted event rates. [We also] included an assessment of the duration that the patient had the toxicity—an exposure-adjusted time with the event. These were expressed as event rates per 100 patient months of treatment, or the number of months expected, where an AE was present, on average, per 100 months of treatment time with each of these drugs.

[We also analyzed] Q-TWiST, [which is] quality-adjusted time without symptoms or toxicity, where the treatment period on drug is partitioned into time with toxicity, time with relapse of disease, or the time with neither of those, [meaning] the time where the patient has neither disease progression nor [experienced] toxicity from treatment. This measures a utility of QoL over each of these periods. These are the methods that we used to better assess the tolerance and toxicity of these 2 drugs.

What were the key findings from the analyses?

Overall, what both analyses revealed in greater detail [compared with what was reported] in the primary publication [of ELEVATE-RR] was that acalabrutinib is a generally better tolerated BTK inhibitor in the relapsed/refractory CLL setting based on the overall lower cardiovascular-related toxicity burden.

In general, the exposure-adjusted time with events for these cardiovascular toxicities were, on average, 2- to 4-fold higher with ibrutinib than with acalabrutinib, particularly for hypertension and atrial fibrillation. This was [found] regardless of the age of the patient or number of prior therapies [received], and as well as in patients without a prior history of these events.

Some of the other generally lower-grade AEs, such as diarrhea, arthralgias, back pain, muscle spasm, or dyspepsia, were 1.4- to 13-fold higher in their exposure-adjusted incidence and exposure-adjusted time with these events with ibrutinib compared with acalabrutinib.

The muscle cramps are the AE that best illustrates the utility of this in our method of analysis; the overall incidence was 6% vs 13%. The higher rate with ibrutinib is moderately different. Yet, if we factor in the time with these events, that was 0.8 with [acalabrutinib] per 100 patient months of treatment, an expectation of less than 1 per 100 months of treatment, vs 10 months with ibrutinib, where roughly 10% of the time, a typical patient would be expected to have some of that toxicity.

That illustrates the greater precision that we get by factoring in this exposure adjustment. Two toxicities, with this adjustment, were more frequent and [had] a greater time with acalabrutinib [vs ibrutinib]. They were headache and cough—that had a 1.1- to 1.6-fold higher exposure-adjusted incidence than with ibrutinib.

The Q-TWiST analyses generally showed similar trends, where, depending on how we defined the utility of the toxicity burden, the time without toxicity or relapse was numerically higher for acalabrutinib vs ibrutinib. That achieved statistical significance if we looked at the total time with grade 2 to 4 toxicities, reflecting the frequent, relatively low-grade, often musculoskeletal toxicities that we see with these BTK inhibitors.

What should be taken away from these data?

These abstracts are relatively dense, with several tables where the data are presented in detail, but the takeaways are that we are fortunate that we have several effective treatments for CLL. The class of drugs, the BTK inhibitors, is very effective.


Seymour JF, Byrd JC, Hillmen P, et al. Characterization of Bruton tyrosine kinase inhibitor (BTKi)-related adverse events in a head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia (CLL). Blood. 2021;138(suppl 1):3721. doi:10.1182/blood-2021-146228