Research Summary
Patients with chronic lymphocytic leukemia (CLL) and higher-risk genomic features, such as unmutated immunoglobulin heavy chain variable (IGHV), del(17p) and/or TP53 mutations, and complex karyotype (CK), traditionally have a poorer prognosis, compared to patients without such features. Acalabrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, has shown efficacy in treating patients with higher-risk CLL, including both those who had not undergone prior treatment and those with relapsed/refractory (R/R) disease. In this study, Davids et al1 completed a pooled analysis of five clinical trials to assess the efficacy and safety of acalabrutinib in treatment-naïve (TN) and R/R patients with higher-risk CLL. Their findings are summarized below.
Data on TN patients from the ACE-CL-001, ACE-CL-003, and ELEVATE-TN trials were analyzed. Data on R/R patients from the ACE-CL-001, ACE-CL-003, ELEVATE-RR, and ASCEND trials were analyzed. Patients were treated with twice-daily acalabrutinib 100mg; some patients in the ACE-CL-001 and ACE-CL-003 trials initially received a 200mg dose. In the ACE-CL-003 trial and in one arm of the ELEVATE-TN trial, patients were also treated with six cycles of obinutuzumab.
In total, 808 patients were included for analysis, 488 in the R/R cohort and 320 in the TN cohort. Unmutated IGHV was highly prevalent in both groups (R/R: 87%, TN: 90%). Del(17p)/TP53 mutation were present in 45 percent of R/R patients and 20 percent of TN patients. The rates of CK overall and CK without del(17p)/TP53 mutation were 33 and 15 percent, respectively, in the R/R cohort and 25 and 14 percent, respectively, in the TN cohort. Efficacy analyses included data from 155 patients with lower-risk CLL and 320 patients with higher-risk CLL in the TN cohort and data from 86 patients with lower-risk CLL and 468 with higher-risk CLL, all of whom only received acalabrutinib monotherapy, in the R/R cohort.
The overall response rate (ORR) was high in the TN cohort in both the higher-risk (95.0%) and lower-risk (92.3%) subgroups. Overall, the higher-risk subgroup showed comparable 48-month progression-free survival (PFS) to the lower-risk subgroup with acalabrutinib-based therapy (86% and 88%, respectively). Further analysis showed that PFS did not significantly differ between lower-risk patients and patients with unmutated IGHV, CK overall, or CK without del(17p)/TP53 mutation. However, patients with del(17p)/TP53 mutation experienced shorter PFS, compared to lower-risk patients. The 48-month overall survival (OS) for acalabrutinib-based therapy was 93 percent in both the higher-risk and lower-risk subgroups. There was no significant difference in OS between lower-risk patients and those with del(17p)/TP53 mutation.
In the R/R cohort, ORR was 87.2 percent in the higher-risk subgroup and 84.9 percent in the lower-risk subgroup. Patients with higher-risk genomic features experienced favorable PFS with acalabrutinib monotherapy, though 36-month PFS was significantly longer in the lower-risk subgroup (76%), compared to the overall higher-risk subgroup (65%). However, PFS was similar between lower-risk patients and patients with CK without del(17p)/TP53 mutation. OS outcomes were favorable for the higher-risk subgroup, but compared to the lower-risk subgroup, OS was significantly shorter in the overall higher-risk subgroup. Patients with del(17p)/TP53 mutation also had shorter a OS, compared to lower-risk patients.
Patients with del(17p)/TP53 mutation had an ORR of 90.6 percent in the TN cohort and 86.0 percent in the R/R cohort. The 48-month PFS and OS rates were 76.9 and 88.6 percent, respectively, in the TN cohort. In the R/R cohort, 36-month PFS and OS rates were 54.4 and 72.5 percent, respectively. PFS was significantly decreased in patients with del(17p)/TP53 mutation, compared to those without del(17p)/TP53 mutation, in the TN and R/R cohorts. OS was significantly different between those with and without del(17p)/TP53 mutation in the R/R cohort, but not in the TN cohort.
In the TN and R/R cohorts, ORR was 95.8 and 87.3 percent, respectively, among patients with unmutated IGHV. The TN cohort had a 48-month PFS rate of 85.6 percent and 48-month OS rate of 93.5 percent. PFS and OS were not significantly different between patients with unmutated or mutated IGHV in the TN cohort. The 36-month PFS and OS rates were 64.6 and 82.0 percent, respectively, in the R/R cohort. Patients with unmutated IGHV had significantly shorter PFS in the R/R cohort, compared to patients with mutated IGHV, but OS did not significantly differ.
Patients with CK had an ORR of 91.1 percent in the TN cohort and 83.6 percent in the R/R cohort. In the TN cohort, 48-month PFS and OS rates were 84.1 and 90.6 percent, respectively. There were no significant differences in PFS or OS between patients with or without CK in the TN cohort. The R/R cohort demonstrated a 36-month PFS rate of 68.4 percent and a 36-month OS rate of 77.4 percent. In the R/R cohort, patients without CK had significantly longer PFS and OS, compared to those with CK.
Among higher-risk patients, the rate of treatment discontinuation due to treatment-emergent adverse events (TEAEs) was 13.8 percent in the TN cohort and 16.6 percent in the R/R cohort. The rates of Grade 3 or higher atrial fibrillation/flutter, hypertension, and hemorrhage were low.
These findings showed that acalabrutinib-based treatment is effective in patients with CLL with higher-risk genomic features, regardless of prior treatment status.
Reference
- Davids MS, Sharman JP, Ghia P, et al. Acalabrutinib-based regimens in frontline or relapsed/refractory higher-risk CLL: pooled analysis of 5 clinical trials. Blood Adv. 2024;8(13):3345–3359.