The role of allogeneic hematopoietic stem cell transplantation in the treatment of rare inherited bone marrow failure syndromes with cancer predisposition

Abstract

Introduction. Inherited bone marrow failure syndromes (IBMFS) caused by germline pathogenic variants in hematopoietic genes are associated with a high risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment for most of these disorders; however, the optimal indications and timing of transplantation for different genetic subtypes have not yet been fully established. Aim: to evaluate the role of allo-HSCT in the management of patients with rare IBMFS caused by germline variants in GATA2, GATA1, TP53, DDX41, and CBLB, and to define the indications for transplantation. Materials and methods. The study included 33 patients with IBMFS evaluated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) between 2021 and 2025. All the patients underwent comprehensive molecular genetic testing. Clinical manifestations, molecular and cytogenetic characteristics, indications for allo-HSCT, and treatment outcomes were analyzed. Results. The largest subgroup consisted of patients with GATA2 variants (51.5%) who demonstrated a high incidence of clonal evolution and progression to MDS. The main indications for allo-HSCT were clonal evolution, transformation to MDS, and transfusion dependence. The most favorable outcomes were observed in patients with GATA1-associated cytopenias, whereas patients with TP53-associated syndromes had the poorest prognosis. Our findings indicate that performing allo-HSCT before the development of advanced clonal evolution and malignant transformation is associated with improved long-term outcomes. Conclusion. Molecular genetic testing plays a pivotal role in determining the indications and optimal timing of allo-HSCT in patients with inherited bone marrow failure syndromes. A personalized approach based on the underlying genetic defect, clinical disease course, and evidence of clonal evolution allows for timely transplantation and improves patient outcomes.