Description:
There are over 400 monogenic disorders of the immune system, which predispose to infection, immune dysregulation/autoimmunity and malignancy. In the most recent International Union of Immunological Societies (IUIS) classification of inborn errors of immunity (primary immunodeficiencies and immune dysregulatory diseases, PIDDs), there are 45 genes associated with immune dysregulation and 43 genes associated with bone marrow failure syndromes, besides another 124 genes associated with combined immunodeficiencies (T and B cell), with or without syndromic features. These diseases present a broad spectrum of clinical phenotypes, including autoimmune cytopenias and/or hematopoietic defects. Though these are germline defects, several of them are diagnosed in adulthood or if diagnosed earlier, persist into and through adulthood. There have been several advances in management of adult and pediatric patients with PIDDs, especially in the last few years. For approximately three decades, allogeneic hematopoietic cell transplantation has been considered ‘standard of care’, and the major therapeutic option for children with inherited primary immunodeficiencies and immune dysregulatory disorders (PIDDs). Early allo-HCT is particularly important in infants or children presenting with serious or life-threatening infections, as without definitive treatment, patients with severe forms of PID, such as severe combined immune deficiency (SCID), rarely survive beyond 1 year of age.

While early allo-HCT is preferred for PIDDs, this is often not possible. An initial milder clinical phenotype, delayed diagnosis, late presentation, lack of a genetic diagnosis or an inability to identify a suitable stem cell donor may result in patients surviving to adulthood without having undergone allo-HSCT. Recent evidence has demonstrated that carefully selected adults with PIDDs can achieve equivalent outcomes following HCT compared to that routinely achieved in pediatric cohorts. Therefore, adult and pediatric hematologists need to be aware of the diagnosis of these diseases, their clinical spectrum, treatment options and the role of HCT in management of these diseases.

Dr. Abraham’s talk will focus on the diagnostic laboratory evaluation of immune dysregulatory, combined immunodeficiencies and bone marrow failure syndromes with specific case-based examples with discussion of basic and advanced testing for evaluation of specific immune pathways. Though the case examples will focus on adult patients, the overall discussion will cover the age spectrum of patients affected with inborn errors of immunity (primary immunodeficiencies).

Dr. Seidel’s talk will focus on the relevance of a molecular diagnosis in developing personalized treatment plans for patients with autoimmune cytopenias and immune dysregulation. He will discuss the role of immunophenotypic biomarkers in contributing to therapeutic decision-making, and share data from a prospective study on severe immune cytopenias in treatment stratification.

Dr. Morris’ talk will focus on HCT for these disorders, and discuss specific issues, which make transplanting adult PIDD patients particularly challenging, including: understanding the natural history of rare diseases and predicting outcome with conservative management alone; optimal timing of transplant; conditioning regimens; donor selection; pre, peri- and post-transplant management; and late effects. The role of gene therapy and or gene editing approaches as an alternative to allo-HCT in high risk, monogenic PIDDs will also be discussed.