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Background: Outcomes in chronic myeloid leukemia (CML) remain heterogeneous despite effective BCR::ABL1 tyrosine kinase inhibitors (TKIs). Somatic mutations in epigenetic regulators, particularly additional sex combs like 1 (ASXL1), have been implicated in adverse prognosis, but their clinical impact in CML has not been systematically defined. Methods: A systematic review was conducted using CINAHL, EMBASE, MEDLINE Ultimate, and PubMed from inception through August 2025. A total of 1,339 records were identified; after duplicate removal and screening, 11 studies met inclusion criteria and were included in qualitative synthesis and meta-analysis. Eligible studies included adult and pediatric patients with chronic and advanced phase (accelerated or blast) CML with ASXL1 mutation status assessed using validated molecular methods. Outcomes included molecular response, cytogenetic response, survival, and treatment resistance. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CI). Statistical heterogeneity was assessed using the I² statistic. Results: Across included studies, ASXL1 mutations were detected in approximately 16% of patients. At 12 months, ASXL1-mutated patients had significantly lower odds of achieving major molecular response (MMR) compared with ASXL1–wildtype patients (OR 0.29; 95% CI 0.16–0.51; p< 0.0001; I²=30%). No statistically significant difference was observed in complete cytogenetic response (CCyR) (OR 0.30; 95% CI 0.02–5.31; p=0.41; I²=68%). Compared with patients harbouring other non-ASXL1 somatic mutations, ASXL1 mutation was not associated with a significant difference in MMR (OR 0.49; 95% CI 0.23–1.05; p=0.067; I²=0%). Conclusions: ASXL1 mutations are associated with inferior molecular response to TKI therapy in CML, supporting their role as an adverse prognostic biomarker. These findings highlight the potential value of incorporating myeloid mutation profiling into future CML risk-stratification strategies.