The meta-analysis of 20 studies on CLL/SLL patients treated with new-generation BTKis was based on papers selected from "A comprehensive search on PubMed, Embase, Cochrane Library, and ClinicalTrials.gov. up to January 31, 2023". The full study title is Efficacy and safety of new‑generation Bruton tyrosine kinase inhibitors in chronic lymphocytic leukemia/small lymphocytic lymphoma: a systematic review and meta‑analysis
The authors are from the Department of Neuro-Oncology, Cancer Center, Beijing Tiantan Hospital, Capital Medical University, Beijing
Monotherapy studies included in the meta-analysis, were all covalent bonding BTKi drugs; eight acalabrutinib, one tirabrutinib and seven zanubrutinib study reports.
From the abstract pubmed.ncbi.nlm.nih.gov/378...
The pooled ORR for new-generation BTKi was 92%, while the pooled CR rate was 10%.
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Compared to acalabrutinib monotherapy, zanubrutinib monotherapy demonstrated higher ORR/CR rates and 24-month OS/PFS rates. Common grade ≥ 3 AEs included cytopenia and hypertension.
Despite the superior efficacy of BTKi combination therapy compared to monotherapy, its AEs rates are relatively high. Compared to acalabrutinib, Zanubrutinib may be the preferred monotherapy for CLL. However, randomized-controlled studies are still needed. (Note: this is very important, because comparing study results without randomised-control can lead to wrong conclusions due to the influence of patient differences, such as the number of past treatments, inclusion or exclusion of challenging to treat patients, etc., in the study enrollments. In other words, without a head to head comparison of acalabrutinib and zanubrutinib, (as was done between acalabrutinib and ibrutinib), it's difficult to determine the relative performance of the two BTKi drugs. As the article noted, "both acalabrutinib and zanubrutinib have their advantages and disadvantages in terms of AEs, but the incidence of atrial fibrillation is low for both.")
Full review article (PDF) - Open Access
link.springer.com/content/p...
Some snips:
Acalabrutinib monotherapy was reported in eight studies, and the pooled ORR was 87% (95% CI, 81–93%, I2 = 82.23%, P = 0.00). Seven studies used zanubrutinib monotherapy for CLL patients, and the pooled ORR was 93% (95% CI, 89–97%, I2 = 79.48%, P = 0.00). Pooled CR rate in BTKi monotherapy was 7% (95% CI, 4–12%, I2 = 85.85%, P = 0.00), which was 3% (95% CI, 1–6%, I2 = 61.78%, P = 0.00) and 13% (95% CI, 6–22%, I2 = 90.36%, P = 0.00) in acalabrutinib and zanubrutinib sub-group respectively. Only one study evaluated tirabrutinib, and the pooled ORR was 83% (95% CI, 64–94%), while the pooled CR rate was 7% (95% CI, 1–23%).
In the ELEVATE R/R study [16], either acalabrutinib or ibrutinib was randomly assigned to 533 patients who were previously treated high-risk CLL—del (17p) or del (11q). The IRC-assessed ORR was 81.0% (95% CI, 75.8–85.2) for acalabrutinib and 77.0% (95% CI, 71.5–81.6). The median PFS of acalabrutinib (38.4 months in both groups) was non-inferior to ibrutinib. However, compared with ibrutinib, the incidence of atrial fibrillation/flutter (9.4% vs 16%; P = 0.02), hypertension (9.4% vs 23.2%), and bleeding events (38% vs 51.3%) were lower. There are differences in the discontinuation rates caused by AE, with acalabrutinib being 14.7% and ibrutinib being 21.3%. Zanubrutinib or ibrutinib was randomly assigned to 652 patients who had previously received CLL treatment in the ALPINE study [25]. Compared with ibrutinib, zanubrutinib treatment can improve the overall response (86.2% vs 75.7%, P < 0.01) and the 24-month PFS incidence (78.4% vs 65.9%, P = 0.002). Zanubrutinib was associated with a lower cumulative incidence of atrial fibrillation/flutter (5.2% vs 13.3%), but the incidence rate of neutropenia increased (29.3% vs 24.4%), while the infection rate did not increase (71.3% vs 73.1%). Compared to ibrutinib, events leading to discontinuation of medication with zanubrutinib are less common (14.5% vs 22.2%). Based on the results of these studies, zanubrutinib and acalabrutinib are preferred over ibrutinib due to their favorable safety profile, and zanubrutinib has superior efficacy compared with ibrutinib.
Overall, this meta-analysis has confirmed the excellent efficacy and safety of new-generation BTKi for CLL. The efficacy of BTKi combination therapy is superior to BTKi monotherapy, but its incidence of AEs is higher than monotherapy. The increased occurrence of adverse effects is attributed to the combination of multiple drugs, which raises the risk of drug interactions and side effects. Therefore, exploring safer combination treatment strategies is expected to become one of the future research priorities. Among the BTKi monotherapy, we mainly compare acalabrutinib and zanubrutinib. Zanubrutinib may be the preferred choice in monotherapy for CLL compared to acalabrutinib; both acalabrutinib and zanubrutinib have their advantages and disadvantages in terms of AEs, but the incidence of atrial fibrillation is low for both. Toxicity should be monitored by clinicians, and timely prevention and intervention should be provided as well. To verify our findings and establish the impact of new-generation BTKi on CLL, it is crucial to conduct large-scale multicenter studies and RCTs. Additionally, further studies are needed to determine the optimal schedule of BTKi for CLL treatment.
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