Specific features of hematologic tumors in children with hereditary genetic syndromes

Abstract

Hereditary genetic syndromes are a significant risk factor for development of oncohematological diseases in childhood. Specifically, Down syndrome is associated with a 500-fold increased risk of acute megakaryoblastic leukemia and a 20-fold increased risk of acute lymphoblastic leukemia compared to the general population. The pathogenesis of leukemia in various hereditary syndromes involves three key mechanisms: impaired DNA repair (as seen in Fanconi anemia, Bloom syndrome), congenital genomic instability (characteristic of ataxia-telangiectasia, Li–Fraumeni, Nijmegen breakage syndrome), and constitutive activation of proliferative signaling pathways (RAS/MAPK pathway in Noonan syndrome and neurofibromatosis type 1). Specificities of pathogenesis explain therapeutic responses and recommended options in this group of patients. For patients with genomic instability syndromes and bone marrow failure syndromes a 50 % dose reduction of chemotherapeutic agents, complete avoidance of alkylating agents, and exclusion of radiotherapy are recommended. Allogeneic hematopoietic stem cell transplantation remains the only curative treatment option but requires modified conditioning regimens. Contemporary fludarabine-based hematopoietic stem cell transplantation protocols achieve 83 % 5-year survival in Fanconi anemia patients. Emerging innovative therapies (PARP inhibitors, JAK-kinase inhibitors, blinatumomab, tisagenlecleucel) represent promising strategies to enhance treatment efficacy while reducing toxicity.