Introduction: Chronic Myeloid Leukemia (CML) is categorized as a myeloproliferative neoplasm, with a global annual incidence of approximately 1 case per 100,000 individuals, accounting for 15% of leukemia cases in adults. The National Comprehensive Cancer Network (NCCN) advocates the use of second-generation Tyrosine Kinase inhibitors as the first-line treatment for patients with chronic CML who exhibit a high disease risk score, to achieve a molecular response. Asciminib, a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, offers a targeted alternative, providing a highly specific and potent early molecular response with reduced side effects. This meta-analysis compares Asciminib with second-generation TKIs in the treatment of newly diagnosed Chronic Phase CML.

Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines. A comprehensive literature search was executed across the PubMed, Scopus, Embase, and Google Scholar databases up to July 2025, focusing on studies that compared outcomes between Asciminib and second-generation TKIs. Data analysis was performed using RevMan 5.4.1, and pooled risk ratios (RRs) were calculated employing the Mantel-Haenszel method. A Fixed Effects Model was selected based on the characteristics and quantity of the studies. Statistical significance was determined at p < 0.05. The risk of bias was evaluated using the RoB 2.0 tool.

Results:Two randomized controlled trials including 868 patients (484 receiving asciminib and 384 receiving second-generation TKIs) were included. At 12 weeks, early molecular response (BCR::ABL1 <10%) was achieved in 90% of patients on asciminib compared to 82% in the 2G-TKI group (RR 1.11, 95% CI 1.04–1.17; I²=0). Complete molecular response (BCR::ABL1 ≤1%) was seen in 74.5% of asciminib-treated patients versus 60.7% with 2G-TKIs (RR 1.19, 95% CI 0.95–1.48; I²=84%). At 48 weeks, major molecular response (MMR) was achieved in 34% of asciminib patients versus 23% with 2G-TKIs (RR 1.56, 95% CI 0.76–3.20; I²=90%), while deep molecular responses (MR⁴ and MR⁴.⁵) occurred in 12.5% and 6% of asciminib patients versus 7.8% and 3.6% with 2G-TKIs, respectively (MR⁴ RR 2.07, 95% CI 0.65–6.55; I²=69%; MR⁴.⁵ RR 2.23, 95% CI 0.44–11.38; I²=59%). Treatment discontinuation due to adverse events occurred in 5.1% of asciminib-treated patients versus 11.5% in the 2G-TKI group (RR 0.46, 95% CI 0.29–0.75; I²=0%). Grade ≥3 adverse events occurred in 30.4% of asciminib patients compared to 38.0% with 2G-TKIs (RR 0.74, 95% CI 0.62–0.89; I²=0%), while all-grade adverse events occurred in 85.7% versus 90.1% (RR 0.93, 95% CI 0.89–0.98; I²=0%). Dose modifications due to adverse events were required in 30.6% of asciminib patients compared to 39.1% with 2G-TKIs (RR 0.70, 95% CI 0.54–0.91; I²=56%). Specific adverse events including rash (10.3% vs 17.7%, RR 0.55, 95% CI 0.39–0.78; I²=0%), increased ALT (4.8% vs 14.1%, RR 0.32, 95% CI 0.20–0.51; I²=0%), and arterial occlusive events (0.8% vs 2%, RR 0.39, 95% CI 0.11–1.32; I²=0%) were less frequent with asciminib. Thrombocytopenia rates were comparable between groups (20.5% vs 19.3%, RR 0.94, 95% CI 0.72–1.23; I²=16%).

Discussion:The meta-analysis indicates that asciminib achieves superior early molecular response rates (BCR:ABL1 <10%), nearly doubling the rate compared to second-generation TKIs. These findings, coupled with a consistently favorable safety profile, suggest its potential for long-term efficacy as a treatment option for CML. Notably, there were significantly lower incidences of any-grade adverse events, grade ≥ 3 adverse events, adverse events necessitating dose adjustments, and specific side effects such as rash and thrombocytopenia, supporting its enhanced tolerability. These results were consistent across studies, exhibiting low heterogeneity, and achieved statistical significance. Although MMR, MR⁴, and MR⁴.⁵ at 48 weeks numerically favor asciminib, the differences are not statistically significant and exhibit high heterogeneity across studies, complicating the ability to draw definitive conclusions. While the current evidence remains in its early stages, asciminib demonstrates promising outcomes. Consequently, long-term studies are necessary to ascertain the sustainability of these results.

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2025
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