Authored by Dr. Brian Koffman
Bottom Line:
Acalabrutinib has a low risk of sudden death and ventricular arrhythmias in chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL) patients.
Who Performed the Research and Where Was it Presented:
Dr. Jeff Sharman was the principal investigator of the abstract: “Analysis of Ventricular Arrhythmias and Sudden Death with Acalabrutinib from 5 Prospective Clinical Trials” that was presented at the American Society of Hematology (ASH) Annual Meeting in December 2023 held in San Diego, CA.
Background:
The introduction of ibrutinib, the first BTK inhibitor approved in CLL / SLL, dramatically improved outcomes for patients. However, it is associated with an increased risk of sudden death (SD) that is generally thought to be caused cardiac irregularities, and with ventricular arrythmias (VA), dangerous irregular heart rhythms, plus hypertension and other side effects.
Acalabrutinib is a second generation, more selective BTK inhibitor that has been shown in head to head comparison to be better tolerated than ibrutinib.
This study was designed to assess the risk of SD and VA in CLL patients taking acalabrutinib compared to other therapies.
Methods and Participants:
Data were aggregated from five different prospective clinical trials that compared acalabrutinib to standard of care (SOC) to assess the relative risk of SD and VA in CLL patients. SOC included ibrutinib, bendamustine plus rituximab, chlorambucil plus obinutuzumab, and idelalisib plus rituximab.
Results:
- The five pooled studies included 1,299 chronic lymphocytic leukemia / small lymphocytic lymphoma patients who received acalabrutinib for a total cumulative exposure of 4,568.4 patient-years.
- There were also 585 representing 941.3 patient-years who received SOC therapies which formed the comparator group.
- Using raw data extraction from the five trials, it was found that five (0.4%) and three (0.5%) patients had a fatal VAs and SD event in the acalabrutinib and comparator groups, respectively.
- However, after an adjudication by manual review of the cases, only two of five patients in the acalabrutinib group and two of three patients in the comparator group were ultimately determined to have had a fatal VA or cardiac-related SD.
- Looking at risk per 100 patient-years, fatal VAs and SDs were fewer for acalabrutinib versus SOC but the difference was not statistically significant.
- Nonfatal potentially serious VAs were reported in two patients in each group (acalabrutinib, 0.2%; comparator, 0.3%)
- Again, although the acalabrutinib group had a lower exposure-adjusted event rate per 100 patient-years of nonfatal VA than the SOC group, the difference was not statistically significant.
- Leaving out ibrutinib as a comparator did not change the results.
Conclusions:
The risk of a fatal cardiac event was low at approximately one per thousand patient-years for acalabrutinib compared to three per thousand patient-years for the comparators. If only the adjudicated fatal cases were included, the rate dropped further to 0.44 per thousand patient-years for acalabrutinib compared to two per thousand patient-years for the comparators. While none of these differences were statistically significant, and any chance of sudden death is important to reduce to a minimum, the overall risk is low.
The results raise questions about whether increased cardiac issues are inherent with all BTK inhibitors and all that can be done is to lower risk, but it can never be fully eliminated. Although the median age of the patients was not stated in the abstract, complicating these speculations is that we know that CLL patients tend to be elderly and therefore already at a higher risk for a fatal cardiac event. Perhaps long-term real-world data will offer future guidance.
Links and Resources:
Watch my monologue here:
To read the entire ASH abstract and see the detailed table of results, click on Analysis of Ventricular Arrhythmias and Sudden Death with Acalabrutinib from 5 Prospective Clinical Trials.
Stay strong. We are all in this together.
Brian Koffman, MDCM (retired), MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society
