Issue Archive

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a congenital immunodeficiency syndrome associated with infections, lymphoproliferation, pulmonary and gastrointestinal complications, risk of lymphoma, and early mortality. It is caused by mutations in either subunit of the PI3Kδ heterodimer, leading to increased PI3Kδ signaling. In this Plenary Paper, Rao et al report on a randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib in 31 patients with APDS. Despite the small cohort, reflecting the rarity of this disorder, the agent reduces adenopathy and splenomegaly and improves immune cell profiles.

Fakhouri and colleagues present their diagnostic and therapeutic approach to atypical hemolytic uremic syndrome, a potentially devastating thrombotic microangiopathic disease resulting from dysregulation of the alternative complement pathway. Using 2 illustrative cases, the authors discuss their approach to diagnosis, which is largely one of exclusion, as well as management with C5 blockade and parameters for discontinuing complement inhibitor therapy.

BRAF V600E mutation is present in 90% of hairy cell leukemia (HCL). Targeted therapy with BRAF inhibitors is effective in relapsed/refractory HCL, but relapses are frequent. Kreitman and colleagues report that combined therapy with the BRAF inhibitor dabrafenib and trametinib, which targets downstream MEK, is highly effective, resulting in 89% response and 65.5% complete response, with an overall 24-month progression-free survival rate of over 94%.

X-linked chronic granulomatous disease is caused by mutations in the CYBB gene, encoding a subunit of the nicotinamide adenine dinucleotide phosphate oxidase complex. It is a target for gene therapy; however, current lentiviral vectors have limited success in reconstituting oxidase activity. Wong et al used bioinformatics to define enhancer elements and create a novel lentiviral vector that mimics physiologic regulation of CYBB. In preclinical studies, the vector showed improved gene transfer and reconstitution of oxidase activity.

Large granular lymphocyte leukemia (LGLL) is most commonly Tαβ LGLL in type. LGLL associated with γδ T cells (Tγδ LGLL) is less studied and had previously been reported to have a similar natural history and prognosis. Barilà et al present a multicenter retrospective review of 137 patients with Tγδ LGLL, reporting that they have the same prevalence of STAT3 mutations but are more frequently symptomatic, largely from cytopenias, respond best to cyclosporine A, and have reduced survival compared to Tαβ LGLL.

Heparin-induced thrombocytopenia (HIT) is associated with antibodies that recognize platelet factor 4/heparin (PF4/H) complexes and activate platelets. However, not all PF4/H antibodies are platelet activating (PA), and the development of HIT correlates with PA antibodies. Zhu et al cloned platelet-activating and nonactivating antibodies from 6 patients with HIT and identified 2 immunoglobulin heavy-chain motifs that characterize PA antibodies, providing potential new approaches to PF4/H analysis to improve HIT diagnosis.

Yu and colleagues delineate the role of receptor-interacting protein kinase (RIPK) 3 in driving gastrointestinal (GI) graft-versus-host disease (GVHD). The authors report that RIPK3 cooperates with RIPK1 to drive GI tract GVHD through the triggering release of T-cell-recruiting chemokines and major histocompatibility complex class II molecules that sustain an alloreactive T-cell response. They describe a novel RIPK1 inhibitor that arrests murine GI tract GVHD without impairing graft-versus-leukemia reactivity, suggesting a novel nonimmunosuppressive therapeutic option.