Acalabrutinib/Obinutuzumab Prolongs PFS vs Ibrutinib and Venetoclax Combos in CLL, Meta-Analysis Says

A systemic review and network meta-analysis investigated 3 trials and determined that acalabrutinib/obinutuzumab up front prolongs progression-free survival for patients with chronic lymphocytic leukemia vs other regimens.

The use of acalabrutinib (Calquence) with obinutuzumab (Gazyva) prolonged progression-free survival (PFS) in patients with chronic lymphocytic leukemia (CLL) compared with other regimens such as ibrutinib (Imbruvica)/obinutuzumab and venetoclax (Venclexta)/obinutuzumab, according to the results of a meta-analysis published in Clinical Lymphoma, Myeloma, and Leukemia.

In terms of PFS, when investigators utilized a fixed-effect analyses to compare ibrutinib/obinutuzumab with venetoclax/obinutuzumab (relative risk [RR], 1.52; 95% CI, 0.82-2.81), acalabrutinib with ibrutinib/obinutuzumab (RR, 0.87; 95% CI, 0.47-1.61), and acalabrutinib with venetoclax/obinutuzumab (RR, 0.57; 95% CI, 0.32-1.01). In all instances the RR did not exceed the 1.0 value, translating to a lack of notable difference in PFS for ibrutinib/obinutuzumab, venetoclax/obinutuzumab, and acalabrutinib. However, the combination of acalabrutinib and obinutuzumab was found to improve PFS vs other regimens such as ibrutinib/obinutuzumab (RR, 0.43; 95% CI, 0.22-0.87) and venetoclax/obinutuzumab (RR, 0.29; 95% CI, 0.15-0.56)

Investigators assessed 3 trials for this analysis: the phase 3 ILLUMINATE (NCT02264574), the phase 3 ELEVATE-TN (NCT02475681), and the phase 3 CLL14 (NCT02242942) studies. The studies had a cumulative total of 1191 patients who received a number of therapies, including ibrutinib/obinutuzumab (ILLUMINATE trial; n = 113), and venetoclax/obinutuzumab (CLL14 trial; n = 216), acalabrutinib/obinutuzumab (ELEVATE-TN trial; n = 179), and acalabrutinib monotherapy (ELEVATE-TN trial; n = 179). Across the studies, the control arm was commonly comprised of chlorambucil/obinutuzumab (n = 504).

The 3 studies also included patients with genetic aberrations such as TP53 (P = .96), 11q deletion (P = .30), and unmutated IGHV (P = .46). Within these studies, the patients’ cumulative illness rating score of over 6 was higher in the CLL14 trial by (86.1%) vs ILLUMINATE (32.7%), and ELEVATE-TN (single agent arm, 11.7%; combination arm, 16.8%) (P < .0001).

The investigators also assessed the impact of targeted agents on overall response rate (ORR). There was no difference found between the different targeted agents, including venetoclax/obinutuzumab compared with ibrutinib/obinutuzumab (RR, 0.98; 95% CI, 0.61-1.59), acalabrutinib compared with ibrutinib/obinutuzumab (RR, 0.90; 95% CI, 0.55-1.48), and acalabrutinib compared with venetoclax/obinutuzumab (RR, 0.92; 95% CI, 0.60-1.40). However, the investigators were not able assess overall survival due to a lack of data from the ILLUMINATE trial.

There were no differences observed in adverse effects (AEs) when investigators compared venetoclax /obinutuzumab with ibrutinib/obinutuzumab (RR, 1.00; 95% CI, 0.63-1.58), acalabrutinib with ibrutinib/obinutuzumab (RR, 1.01; 95% CI, 0.62-1.53, and acalabrutinib plus ibrutinib/obinutuzumab compared with venetoclax/obinutuzumab (RR, 1.01; 95% CI, 0.68-1.52).

When the analysis was restricted to events that were of grade 3 or 4, investigators identified the following results: venetoclax/obinutuzumab vs ibrutinib/obinutuzumab (RR, 1.05; 95% CI, 0.64-1.73), acalabrutinib vs ibrutinib/obinutuzumab (RR, 0.73; 95% CI, 0.43-1.24), and acalabrutinib compared with venetoclax/obinutuzumab (RR, 0.69; 95% CI, 0.44-1.09).

The median times of continuous treatment for ibrutinib was 29.3 months and 27.7 months for acalabrutinib. The median time for time-limited venetoclax was 11.1 months. The 3 distinct studies did not allow for the analysis of Bruton tyrosine kinase inhibitor or relevant AEs.

Patients with TP53 mutations (n =60) had a comparable risk of progression across the different targeted agent regimens, including venetoclax/obinutuzumab vs ibrutinib/obinutuzumab (RR, 3.18; 95% CI, 0.66-15.38), acalabrutinib vs ibrutinib/obinutuzumab (RR, 2.09; 95% CI, 0.43-10.25), and acalabrutinib vs venetoclax/obinutuzumab (RR, 0.66; 95% CI, 0.17- 2.49).

Additionally, investigators performed an analysis for unmutated IGHV (n = 306) venetoclax-obinutuzumab vs ibrutinib-obinutuzumab (RR, 1.47; 95% CI, 0.63-3.39), acalabrutinib vs ibrutinib/obinutuzumab (RR, 0.73; 95% CI, 0.33-1.61), and acalabrutinib vs venetoclax/obinutuzumab (RR, 0.50; 95% CI, 0.23-1.07).

11q deletion (n = 80) was similarly assessed in patients who were treated with venetoclax/obinutuzumab vs ibrutinib/obinutuzumab (RR, 0.85; 95% CI, 0.12-5.91), acalabrutinib vs ibrutinib/obinutuzumab (RR, 0.54; 95% CI, 0.08-3.60), and acalabrutinib vs venetoclax/obinutuzumab (RR, 0.64; 95% CI, 0.11-3.65).

Patients who had a TP53 mutation or 11q deletion did not have an improvement in PFS with after being treated with venetoclax/obinutuzumab or ibrutinib/obinutuzumab. However, it was found that those with unmutated IGHV had a better PFS with acalabrutinib/obinutuzumab than venetoclax/obinutuzumab (RR, 0.36; 95% CI, 0.15-0.90).


Molica S, Giannarelli D, Montserrat E. Comparison between venetoclax-based and Bruton tyrosine kinase inhibitor-based therapy as upfront treatment of chronic lymphocytic leukemia (CLL): A Systematic Review and Network Meta-analysis. Clinical, Lymphoma, Myeloma, and Leukemia. 2021;21(4):216-223. doi:10.1016/j.clml.2020.10.012