This study addresses the clinical and molecular characteristics of myeloid leukemia in patients with Down syndrome, a condition that presents unique challenges due to its complexity and heterogeneity. Through a multifaceted methodological approach, including a systematic literature review, a retrospective cohort study, genetic and molecular analysis, a prospective observational study, and the use of fuzzy cognitive maps, the prognostic and therapeutic implications of this condition were investigated. The results reveal distinctive features of myeloid leukemia in patients with Down syndrome, including a higher incidence, unique genetic profiles (especially GATA-1 mutations), and a differential response to treatments. The analysis identified the subtype of myeloid leukemia, initial response to treatment, and the presence of comorbidities as the most influential variables in the clinical course and prognosis. Personalized management strategies are proposed based on comprehensive genetic characterization, treatment adaptation according to the myeloid leukemia subtype, close monitoring of the initial response, and comprehensive management of comorbidities. These strategies, along with a multidisciplinary approach, show potential to improve clinical outcomes and patients' quality of life. The study provides a solid foundation for developing more effective and personalized treatment protocols, emphasizing the importance of a comprehensive approach that considers the genetic, clinical, and demographic particularities of this population. The need for additional research to validate and optimize these approaches in clinical practice is highlighted.