Research Summary:
Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a low-grade B-cell malignancy. Since the introduction of targeted therapies directed at Bruton tyrosine kinase (BTK) and the B-cell lymphoma 2 (BCL2) protein, CLL outcomes have improved. Patients with CLL were historically treated with chemo-immunotherapy regimens, which commonly resulted in high response rates, but also toxicity, refractory disease, and mortality. In addition, while first-generation covalent BTK inhibitors (BTKi) showed promise in terms of efficacy, they ultimately showed safety and tolerability issues stemming from alternative-target effects, such as atrial fibrillation, hypertension, gastrointestinal symptoms, myalgias/arthralgias, nail and hair changes, and sudden death. These issues limited long-term use of first-generation therapies. Second-generation covalent BTKis, including acalabrutinib, were introduced with improved selectivity and pharmaceutical properties to reduce toxicity, decrease therapy discontinuation, and improve patient outcomes. Furman et al1 provided a final analysis of data from the phase 1/2 ACE-CL-001 trial.
In the phase 1/2, open-label, multicenter ACE-CL-001 trial, researchers demonstrated the efficacy and tolerability of acalabrutinib (100 mg twice daily) for patients aged ≥18 years with a diagnosis of treatment-naïve (TN) (n=99) or relapsed/refractory (R/R) (n=134) CLL/SLL. Eligible patients met ≥1 of the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria for treatment, had adequate organ function, and had an Eastern Cooperative Oncology Group performance status score of 0 to 2.
Median follow-up was 73.7 months in the TN cohort and 52.6 months in the R/R cohort. At the data cut-off, 70.7% of patients with TN CLL and 30.6% of those with R/R CLL remained on acalabrutinib. Adverse events (AEs) and disease progression were reported as the primary reasons for treatment discontinuation.
A total of 99.7% of patients experienced at least 1 treatment-emergent AE (TEAE) during the study, and 71.7% experienced a grade ≥3 AE. There were no unexpected late-term AEs through extended long-term follow-up. The most common TEAEs in the TN cohort were arthralgia (55.6%), diarrhea (53.5%), contusion (50.5%), upper respiratory tract infection (49.5%), headache (48.5%), nausea (34.3%), increased weight (33.3%), and cough (32.3%). Over time, the incidence of the most common AEs decreased. The most common grade ≥3 TEAEs were hypertension (12.1%), weight increase (8.1%), pneumonia (8.1%), neutropenia (8.1%), diarrhea (6.1%), syncope (6.1%), and headache (5.1%).
In the R/R cohort, the most common TEAEs were diarrhea (53.7%), headache (50.7%), upper respiratory tract infection (41.0%), fatigue (36.6%), nausea (35.1%), cough (35.1%), arthralgia (35.1%), and contusion (31.3%). Similarly to the TN cohort, the incidence of TEAEs generally decreased over time in the R/R cohort. The most common grade ≥3 TEAEs were neutropenia (15.7%), pneumonia (15.7%), hypertension (11.2%), anemia (7.5%), and syncope (6.0%).
The rate of serious TEAEs was 49.5% in the TN cohort and 63.4% in the R/R cohort. In the TN cohort, the most common serious TEAEs were pneumonia (6.1%), squamous cell carcinoma of the skin (4.0%), and influenza (3.0%). In the R/R cohort, the most common serious TEAEs were pneumonia (14.2%), acute kidney injury (3.7%), anemia (3.0%), atrial fibrillation (3.0%), diarrhea (3.0%), and hypercalcemia (3.0%).
At the final data cutoff, the overall response rate (ORR) was 97.0% in the TN cohort and 94.8% in the R/R cohort. Among patients with high-risk features in the TN cohort, the ORRs were 100% each for those with del(17p) (n=9), TP53 mutation (n=9), unmutated IGHV (n=57), and complex karyotype (n=12). In the R/R cohort, ORR rates were 87.1% (n=27/31) for patients with del(17p), 81.3% (n=13/16) for TP53 mutation, 90.1% (n=73/81) for unmutated IGHV, and 85.0% (n=17/20) for complex karyotype.
Median progression-free survival (PFS) was not reached in the TN cohort and was 66.1 months (range: 0.4–87.8 months) in the R/R cohort. The 72-month PFS rates were 86.7% (95% confidence interval [CI]: 77.0–92.5%) in the TN cohort and 45.1% (95% CI: 35.6–54.1%) in the R/R cohort. The median PFS in the del(17p) subgroup for the TN cohort was 57 months (95% CI: 15.2–77.5 months) vs not reached (95% CI: not estimable [NE]) in patients without del(17p). The median PFS in the del(17p) subgroup for the R/R cohort was 33.1 months (95% CI: 17.5–43.5 months) vs not reached (95% CI: 71.8 months–NE) in those without del(17p). At 72 months in the TN cohort, the PFS rates were 84.7% in patients with unmutated IGHV and 91.1% in patients with mutated IGHV. In the R/R cohort, 72-month PFS rates were 37.3% in patients with unmutated IGHV and 60.0% in patients with mutated IGHV.
Median event-free survival (EFS) was 79.1 months (95% CI: 79.1 months–NE) and 53.8 months (95% CI: 44.1–66.1 months) in the TN and R/R cohorts, respectively. At 72 months, the EFS rates in the TN and R/R cohorts were 78.1% (95% CI: 68.0–85.3%) and 37.4% (28.9–45.9), respectively. The most common EFS event in both cohorts was treatment discontinuation due to AEs.
The findings from the ACE-CL-001 trial suggest the long-term efficacy and safety of acalabrutinib in TN and R/R CLL/SLL, including among patients at higher risk of relapse.
References
- Furman RR, Wierda WG, Patten PEM, et al. Final phase 2 study results of acalabrutinib in treatment-naive and relapsed/refractory chronic lymphocytic leukemia. Blood Adv. 2026;10(11):3931–3941.