Calquence (acalabrutinib) led to fewer treatment-related heart toxicities and an otherwise similar safety profile compared with Imbruvica (ibrutinib) when used to treat patients with chronic lymphocytic leukemia (CLL). These results were seen regardless if patients had cardiovascular disorders at the start of treatment, according to recent research.
Data presented at the 2023 International Workshop on CLL demonstrated that the exposure-adjusted incidence rates of cardiac disorder events observed were consistently lower in the Calquence group compared with the comparator arms across the three individual trials regardless of grade. Although no distinct trend was noted among patients who presented with one or more baseline cardiovascular disorders, the number of events in this subgroup was limited.
In the pooled comparator group (585 patients), incidence of any grade of cardiac disorder events were approximately twice as high to the pooled Calquence group (599 patients).
Analysis of cardiac disorder events in patients who switched from other treatments to Calquence in the phase 3 ELEVATE-TN trial (72 patients) demonstrated a lower incidence of any-grade cardiac disorder events during the post-crossover period with Calquence compared with the pre-crossover period with comparator treatment.
“This analysis does not suggest an increased risk of cardiac treatment-emergent adverse effects and outcomes in (Calquence)-treated patients, regardless of the presence of baseline cardiovascular disorders,” Dr. Rupal O’Quinn, of Perelman School of Medicine, and colleagues wrote in a poster presentation on the data.
Although the first-generation BTK inhibitor Imbruvica has shown significant efficacy in the treatment of patients with CLL, it is associated with notable cardiac toxicity, including cardiac arrhythmias, cardiac failure and sudden death.
In contrast, the next-generation BTK inhibitor Calquence offers a more favorable cardiovascular safety profile with fewer atrial fibrillation events compared with Imbruvica due to its selectivity. Given that the CLL patient population is inherently at higher risk for cardiac events due to factors like advanced age, polypharmacy, substantial comorbidities and pre-existing cardiac conditions, a comprehensive evaluation of cardiac toxicities associated with CLL therapies is imperative.
In this longitudinal review, investigators conducted a comprehensive assessment of cardiac outcomes with Calquence compared to active comparator drugs, such as Imbruvica in patients with and without cardiovascular disorders at baseline. The analysis evaluated how CLL therapies affect cardiac health.
Safety data were gathered from 3 randomized phase 3 studies: ELEVATE-RR, ELEVATE-TN, and ASCEND. Regarding patients’ treatment regimen, those on ELEVATE-RR received Calquence or Imbruvica, those on ELEVATE-TN were treated with Calquence with or without Gazyva (obinutuzumab) vs Gazyva plus chlorambucil, and patients in ASCEND received Calquence vs Zydelig (idelalisib) plus Rituxan (rituximab) or bendamustine plus Rituxan.
A total of 1,362 patients who experienced 3,672 treatment-related side effects were identified from the clinical trial database. Demographic and baseline characteristics were similar between the Calquence and comparator arms in all three trials. Across all trials, 404 patients (29.7%) presented with at least one baseline cardiovascular disorder. The distribution of these baseline cardiovascular disorders was also comparable between the Calquence and comparator arms across the various studies. Specifically, 599 patients received Calquence monotherapy, 178 were treated with Calquence plus Gazyva, and 585 were treated with various comparators, including Imbruvica and other anticancer agents.
Within the ELEVATE-TN and ASCEND trials, 72 patients who initially received Gazyva plus chlorambucil and 80 patients who were treated with Zydelig plus Rituxan or bendamustine plus Rituxan later transitioned to Calquence monotherapy. Notably, the median duration of exposure to BTK inhibitors administered continuously exceeded that of the comparator treatments across all studies.
Regarding the incidence for baseline cardiac disorder events in patients without any baseline cardiovascular disorders, the results varied by trial. In ELEVATE-RR, the incidence associated with Imbruvica was two-times higher than that observed with Calquence (0.67 vs. 0.34).
Meanwhile, the EAIR in ELEVATE-TN was numerically lower for both Calquence plus Gazyva (0.28) and Calquence monotherapy (0.25) vs chlorambucil plus Gazyva (0.59). In the ASCEND trial, Calquence demonstrated a numerically lower incidence (0.28) vs Zydelig plus Rituxan (0.44) and bendamustine plus Rituxan (0.54).
These findings suggest a potentially favorable cardiovascular safety profile associated with Calquence.
Pooled analysis revealed that the incidence of any-grade cardiac disorder events among patients without any baseline cardiovascular disorders was numerically lower in the pooled Calquence group (0.29) vs the comparator group (0.62). Patients in the pooled Calquence group with a baseline number of one, two or three or more cardiovascular disorders experienced any-grade incidence of 0.16, 0.05 and 0.05, respectively. Corresponding any-grade incidence in the pooled comparator arm were 0.22, 0.07 and 0.04.
The most frequently occurring any-grade cardiac disorder in both groups was atrial fibrillation (Calquence group, 0.20; comparator group, 0.41). Other common any-grade PTs included palpitations (0.08; 0.12), cardiac failure (0.04; 0.08), tachycardia (0.04; 0.08), angina pectoris (0.06; 0.05), sinus tachycardia (0.01; 0.05), chronic cardiac failure (0.01; 0.04), myocardial ischemia (0.01; 0.04), acute myocardial infarction (0.01; 0.03), arrythmia (0.02; 0.03) atrial flutter (0.01; 0.03), cardiac arrest (0.00; 0.03), coronary artery disease (0.00; 0.03), mitral valve incompetence (0.00; 0.03), myocardial infarction (0.01; 0.03), pericarditis (0.00; 0.03) and sinus bradycardia (0.03; 0.03)
Notably, the incidence of fatal events within the cardiac disorder category was three- to four-times higher in the pooled comparator group vs the pooled Calquence group. However, the incidence of fatal events did significantly increase in patients with one or more baseline cardiovascular disorder compared with those without baseline cardiovascular disorders (0.01 vs 0.06). Within the subgroup of patients without baseline cardiovascular disorders, the incidence of fatal events was three-times higher in the pooled comparator group compared with the pooled Calquence group. The overall incidence of fatal events remained low.
In the ELEVATE-TN trial (72 patients), the incidence of grade 3 or greater (moderate to severe) events remained similar pre- and post-crossover, and only one fatal event occurred during the post-crossover period. However, among patients with no cardiovascular disorders at baseline, the incidence were similar pre- and post-crossover (0.44 vs 0.40). Conversely, the incidence among those who had one or more any-grade cardiovascular disorder at baseline was higher pre- vs post-crossover. Those with one, two and three or more events before crossover had an incidenceof 0.67, 0.0 and 0.0 vs 0.13, 0.09 and 0.0, respectively, after crossover.
In the ASCEND trial (80 patients) the incidence of any-grade cardiac disorder events remained low both before and after the crossover to Calquence. Although the incidence of grade 3 or greater effects numerically increased post- vs pre-crossover (0.18 vs 0.19), no fatal effects were reported. For those with baseline cardiovascular effects, results were consistent regardless of the number of cardiovascular disorders present. Prior to crossover, patients with one, two or three or more events at baseline had incidences of 0.0, 0.0 and 0.10. The corresponding incidences for all three categories after crossover was 0.06.
“The results may help to inform treatment decisions for patients with CLL, particularly if they also have heart disease or are at higher risk of heart disease,” study investigators concluded.
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