Beyond FAScinating: advances in diagnosis and management of autoimmune lymphoproliferative syndrome and activated PI3 kinase δ syndrome

Refractory autoimmune mutilineage cytopenias can present in childhood associated with chronic nonmalignant lymphoproliferation (splenomegaly, hepatomegaly, and/or lymphadenopathy). Cytopenias due to peripheral destruction and sequestration have been well recognized since the 1950s and are often lumped together as eponymous syndromes, such as Evans syndrome and Canale-Smith syndrome. Though their clinical and genetic diagnostic workup may appear daunting, it can provide the basis for early intervention, genetic counseling, and empirical and targeted therapies. Autoimmune lymphoproliferative syndrome (ALPS), activated phosphatidylinositol 3-kinase delta syndrome (APDS), and many other related genetic disorders are otherwise collectively known as inborn errors of immunity (IEI). They present in early childhood as refractory autoimmune cytopenias due to immune dysregulation leading to lymphadenopathy, splenomegaly, and increased susceptibility to lymphoma. More recently, controlled clinical trials have shown that some of these immune system disorders with hematological manifestations might be more readily amenable to specific targeted treatments, thus preventing end-organ damage and associated comorbidities. Over the last 20 years, both rapamycin and mycophenolate mofetil have been successfully used as steroid-sparing long-term measures in ALPS. Current therapeutic options for APDS/PASLI (phosphoinositide 3-kinase [PI3K]-associated senescent T lymphocytes, lymphadenopathy, and immunodeficiency) include the orally bioavailable PI3Kδ inhibitor, leniolisib, which was licensed by the US Food and Drug Administration (FDA) in 2023 for use in individuals older than 12 years as a targeted treatment. Paradigms learned from patients with rare genetic disorders like ALPS and APDS may help in exploring and streamlining molecular therapy strategies in the wider group of IEIs presenting with refractory cytopenias and lymphoproliferation.