Carolina Dagli-Hernandez

Objectives: To provide a comprehensive analysis regarding the safety profile of bispecific antibodies (BsAbs), focusing on the prevalence of cytokine release syndrome (CRS) in patients with non-Hodgkin lymphoma (NHL). Methods: We performed a meta-analysis of phase 1 to 3 clinical trials with different BsAbs approved for commercialization (mosunetuzumab, glofitamab, odronextamab, and epcoritamab), administered as monotherapy or in combination with other anticancer therapies, both in first-line and in cases of relapsed/refractory disease, as well as in different NHL subtypes. Results: This meta-analysis provides pooled data from 40 clinical trial cohorts totaling information from 3,653 patients and 1,577 events on the safety of BsAbs (anti-CD20/CD3) in the treatment of NHL. The median age of participants was 64.4 years. The pooled prevalence of CRS of all grades and grade ≥3 was 43% and 7%, respectively. Stratification by treatment regimen (monotherapy versus combination therapy) showed that CRS of all grades was estimated at 47% (95% CI: 41–54%) in monotherapy and 35% (95% CI: 27–45%) in combination therapy, based on the included studies. However, the pooled prevalence estimates of severe CRS (grade ≥3) were similar between groups, with 7% (95% CI: 5–9%) in monotherapy and 6% (95% CI: 3–11%) in combination therapy. Conclusion: This meta-analysis provides a comprehensive descriptive synthesis of CRS prevalence among patients with NHL treated with bispecific antibodies (BsAbs). CRS of any grade was frequently reported, whereas severe events (grade ≥3) remained uncommon, particularly in the context of relapsed/refractory disease, which represented 90.61% of the included cohort. Given the clinical and methodological heterogeneity across trials and the non-comparative nature of the pooled estimates, these findings should be interpreted as descriptive evidence rather than direct comparative evidence of safety. Future research should focus on optimizing dosing strategies, incorporating prophylactic measures, standardizing CRS reporting, and improving toxicity management to better balance tolerability and efficacy of BsAbs in patients with NHL.

Background/Objectives: Lung cancer has a high mortality rate worldwide, with non-small cell lung cancer (NSCLC) being the most prevalent. Carboplatin and paclitaxel are key treatments for NSCLC; however, adverse drug reactions (ADRs) pose significant challenges. This study examined the impact of genetic variations in ABCB1 and ABCC2 genes on the incidence of ADRs and survival in NSCLC patients treated with carboplatin and paclitaxel. Methods: Variants were identified using RT-PCR, and ADRs classified according to the Common Toxicity Criteria for Adverse Events, Version 4.03. Results: The ABCB1 rs1128503 (c.1236C>T) CC genotype was associated with a higher chance of nausea (OR: 3.5, 95% CI 1.367–9.250, p = 0.0093), vomiting (OR: 13.553, 95% CI 1.705–107.723, p = 0.0137), and a higher risk of death in CT or TT genotypes (HR: 1.725, 95% CI 1.036–2.871, p = 0.0361). The ABCC2 rs717620 (c.-24C>T) TT genotype was associated with increased ALP levels (OR: 14.6, 95% CI 1.234–174.236, p = 0.0335). The ABCB1 rs2032582 non-CC genotypes (TT+AA+TA+CA+CT) were associated with an increased risk of death (HR: 1.922, 95% CI 1.093–3.377, p = 0.0232). Patients with hypocalcemia (HR: 2.317, 95% IC 1.353–3.967, p = 0.022), vomiting (HR: 3.047, 95% IC 1.548–5.997, p = 0.0013), and diarrhea (HR: 2.974, 95% IC 1.590–5.562, p = 0.0006) were associated with lower overall survival. Conclusions: The data suggest that ABCB1 variants may influence gastrointestinal ADRs and patient survival, highlighting the importance of pharmacogenomics in predicting ADRs and drug resistance. This approach offers more precise pharmacotherapy, reduces ADRs, and enhances the patients’ quality of life and survival.

Gefitinib is a selective inhibitor of the epidermal growth factor receptor that is used to treat advanced and metastatic non-small cell lung cancer (NSCLC). Dermatological adverse reactions are most commonly associated with gefitinib treatment. The cause of adverse reactions in individuals is multifactorial. Pharmacogenetics is an effective tool to detect such adverse reactions. This case report describes a female patient with NSCLC who was administered gefitinib at a dose of 250 mg/day. However, due to severe adverse dermatological reactions, the treatment was interrupted for 15 d and antibiotic therapy was administered to manage the skin rashes, maculopapular rashes, and hyperpigmentation. Treatment adherence was adequate, and no drug interactions were detected. A pharmacogenetic analysis revealed homozygosity in the ATP-binding cassette (ABC)-B1 rs1128503 (c.1236A>G), heterozygosity in ABCG2 rs2231142 (c.421G>T) and rs2622604 (c.-20+614T>C), and a non-functional variant of the cytochrome P450 family 3, subfamily A, member 5 (CYP3A5). The relationship between altered genetic variants and the presence of adverse reactions induced by gefitinib is still controversial. Overall, this case report highlights the importance of continuing to study pharmacogenetics as predictors of adverse drug reactions.

Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy.

Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase, a key enzyme in cholesterol biosynthesis, that are highly effective in reducing plasma low-density lipoprotein (LDL) cholesterol and decreasing the risk of cardiovascular events. In recent years, a multitude of variants in genes involved in pharmacokinetics (PK) and pharmacodynamics (PD) have been suggested to influence the cholesterol-lowering response. However, the vast majority of studies have analyzed the pharmacogenetic associations in populations in Europe and the USA, whereas data in other populations, including Brazil, are mostly lacking. This narrative review provides an update of clinical studies on statin pharmacogenomics in Brazilian cohorts exploring lipid-lowering response, adverse events and pleiotropic effects. We find that variants in drug transporter genes (SLCO1B1 and ABCB1) positively impacted atorvastatin and simvastatin response, whereas variants in genes of drug metabolizing enzymes (CYP3A5) decreased response. Furthermore, multiple associations of variants in PD genes (HMGCR, LDLR and APOB) with statin response were identified. Few studies have explored statin-related adverse events, and only ABCB1 but not SLCO1B1 variants were robustly associated with increased risk in Brazil. Statin-related pleiotropic effects were shown to be influenced by variants in PD (LDLR, NR1H2) and antioxidant enzyme (NOS3, SOD2, MTHFR, SELENOP) genes. The findings of these studies indicate that statin pharmacogenomic associations are distinctly different in Brazil compared to other populations. This review also discusses the clinical implications of pharmacogenetic studies and the rising importance of investigating rare variants to explore their association with statin response.

Anticoagulant and antiplatelet drugs effectively prevent thrombotic events in patients with cardiovascular diseases, ischemic stroke, peripheral vascular diseases, and other thromboembolic diseases. However, genetic and non-genetic factors affect the response to antithrombotic therapy and can increase the risk of adverse events. This narrative review discusses pharmacogenomic studies on antithrombotic drugs commonly prescribed in Brazil. Multiple Brazilian studies assessed the impact of pharmacokinetic (PK) and pharmacodynamic (PD) gene variants on warfarin response. The reduced function alleles CYP2C9*2 and CYP2C9*3, and VKORC1 rs9923231 (c.-1639G>A) are associated with increased sensitivity to warfarin and a low dose requirement to prevent bleeding episodes, whereas CYP4F2 rs2108622 (p.Val433Met) carriers have higher dose requirements (warfarin resistance). These deleterious variants and non-genetic factors (age, gender, body weight, co-administered drugs, food interactions, and others) account for up to 63% of the warfarin dose variability. Few pharmacogenomics studies have explored antiplatelet drugs in Brazilian cohorts, finding associations between CYP2C19*2, PON1 rs662 and ABCC3 rs757421 genotypes and platelet responsiveness or clopidogrel PK in subjects with coronary artery disease (CAD) or acute coronary syndrome (ACS), whereas ITGB3 contributes to aspirin PK but not platelet responsiveness in diabetic patients. Brazilian guidelines on anticoagulants and antiplatelets recommend the use of a platelet aggregation test or genotyping only in selected cases of ACS subjects without ST-segment elevation taking clopidogrel, and also suggest CYP2C9 and VKORC1 genotyping before starting warfarin therapy to assess the risk of bleeding episodes or warfarin resistance.

Aim: Functional analysis of PCSK9 3′UTR variants and mRNA–miRNA interactions were explored in patients with familial hypercholesterolemia (FH). Materials & methods: PCSK9 3′UTR variants were identi...