Established and emerging non-cellular therapies in inherited bone marrow failure syndromes

Abstract

Inherited bone marrow failure syndromes (IBMFs) are a molecularly heterogeneous group of genetically-determined syndromes with a wide spectrum of clinical abnormalities and risk of hematopoietic neoplasia and reduced life expectancy. The prevalence is not well established but is growing due to the advent of genetic diagnostics. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative modality in eligible IBMF patients but the indications are individualized due to significant transplant-related morbidity, including secondary cancer. HSCT indications and practices are also impacted by the gradual introduction of gene therapies for IBMFs, but that remains developmental at the moment. Medical non-transplant therapies have played an important role in several IBMFs for decades. Their impact vary from nearly curative treatment in Diamond–Blackfan Anemia (DBA), through supportive interventions, to experimental treatment aimed at impacting the natural course of the disease. This may be subject to change, because of the description of new syndromes or new pathomechanisms of the established syndromes. While their impact might be diminishing due the progress in gene therapy, there might be some new clinically useful interventions due to new medical technologies and the progress in drug-repurposing. The medical therapies can be used as a mainstay of therapy, bridge therapy to transplantation, peri-or post-transplantation aiming at amelioration of the hematological and non-hematological phenotype, improved growth and development, diminishing the risk of myeloid neoplasm or other cancer. Disease-and therapy-specific risks of these interventions must be actively addressed in patients. We present state-of-the-art and developmental applications of non-cellular therapies in IBMFs.