Research Summary
Bruton tyrosine kinase (BTK) inhibitors have improved the treatment landscape of chronic lymphocytic leukemia (CLL). Acalabrutinib is a second-generation, highly selective, covalent BTK inhibitor that has demonstrated a high overall response rate (ORR) in relapsed/refractory CLL, including among patients with high-risk features. Acalabrutinib has minimal off-target effects, which suggests that it might result in less off-target adverse effects (AEs). Park et al1 conducted a meta-analysis to evaluate the efficacy and safety of acalabrutinib in relapsed/refractory CLL. Their findings are summarized below.
The authors searched PubMed, Embase, and Cochrane databases for relevant studies on acalabrutinib monotherapy in relapsed/refractory CLL. Case reports, letters to the editor, and systematic reviews were ineligible for inclusion. Studies describing the use of acalabrutinib in combination therapy and studies that included treatment-naïve patients with CLL or patients with other B-cell malignancies (eg, mantle cell lymphoma) were excluded. The primary endpoint was ORR, and secondary endpoints were complete response (CR), mortality rate, mortality rate due to pneumonia, mortality rate due to CLL progression, rate of Grade 3 or greater AEs, and atrial fibrillation. I2 was utilized to evaluate heterogeneity between studies, with an I2 of 60 percent or greater indicating high evidence of heterogeneity.
Data from 12 studies including a total of 797 patients with relapsed/refractory CLL were included for analysis. Among studies with available data, the majority of patients had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1 or less. Less than half of patients had bulky disease of 5cm or larger in most studies reporting on this variable. Across all studies with del(17p) information, the majority of patients lacked del(17p), and in all but one study with del(11q) information, most patients lacked del(11q). The prevalence of unmutated immunoglobulin heavy chain variable (IGHV) ranged from 73 to 82.1 percent in studies that reported on this feature.
ORR was evaluated in seven studies including a total of 531 patients. The majority of studies utilized the standard of care dosage, which is 100mg twice daily, but some patients received 200mg twice daily. ORR was found to be 82 percent (I2: 81.96%, p<0.01). The varying population sizes between trials might have impacted the weight-based proportions, which therefore might explain the high heterogeneity. Five studies including a total of 315 patients assessed CR rate, which was found to be four percent (I2: 0.00%; p=0.99).
The overall mortality rate was 12 percent (I2: 87.23%, p<0.01), which is an acceptable mortality rate. The varying population sizes and varying median numbers of prior therapies across studies might have contributed to high heterogeneity. The mortality rate due to AEs was seven percent (I2: 67.67%, p=0.01), and the rate of mortality due to pneumonia was two percent (I2: 0.00%, p=0.43). There was a four-percent mortality rate due to CLL progression (I2: 61.03%, p=0.04).
The incidence rate of Grade 3 or greater neutropenia was 18 percent (I2: 0.00%, p=0.70). The rate of Grade 3 or greater anemia was calculated to be nine percent (I2: 36.93%, p=0.18), and the rate of Grade 3 or greater thrombocytopenia was seven percent (I2: 54%, p=0.09). There was high heterogeneity in the incidence of any-grade atrial fibrillation and pneumonia, with occurrence rates of seven percent (I2: 80.13%; p=0.00) and 10 percent (I2: 66.37%, p=0.02), respectively. These findings showed that acalabrutinib monotherapy was a tolerable treatment option for patients with relapsed/refractory CLL.
Exploratory meta-regression analyses of the primary and secondary endpoints were conducted to determine the impact of high-risk features on heterogeneity. Unmutated IGHV, del(17p), and del(11q) had coefficients of –7.88, –7.24, and –5.26, respectively, for ORR, indicating that these variables significantly impacted the heterogeneity of ORR (p=0.028, p=0.01, and p<0.01, respectively). Thus, a 10-percent increase in del(17p) and del(11q) was correlated with a 0.7- and 0.5-percent decrease in ORR, respectively, and unmutated IGHV was associated with a 7.88-percent decrease in ORR. Meta-regression analyses were not significant for CR or mortality rate.
When examining atrial fibrillation, male sex had a coefficient of 4.43 (p=0.013), thereby suggesting that male sex was associated with a 4.43-percent increase in the incidence of atrial fibrillation. ECOG PS of 1 or less significantly affected the heterogeneity of pneumonia, with a coefficient of 3.50 (p=0.004). The heterogeneity of thrombocytopenia was impacted by del(17p), as a 10-percent elevation in del(17p) was associated with a 0.079-percent increase in thrombocytopenia (p=0.03).
Limitations of this meta-analysis included the lack of certain patient characteristics in some studies and the inability to conduct multivariate analyses. NOTCH1 mutation and del(13q) could not be evaluated due to an insufficient number of data points. Additionally, progression-free survival analysis was not conducted due to the lack of standardized data reporting.
These findings illustrated that acalabrutinib therapy was efficacious in the treatment of relapsed/refractory CLL, with a tolerable safety profile. Acalabrutinib demonstrated efficacy in patients with high-risk features as well.
Reference
- Park D, Chan-Golston AM, Yan Y, et al. Meta-analysis of the efficacy and adverse effects of acalabrutinib in the management of relapsed/refractory chronic lymphocytic leukemia. J Chemother. 2025;37(3):256–267.