Report of the Italian Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome in the Target Therapy Era

J Clin Immunol. 2024 Dec 23;45(1):58. doi: 10.1007/s10875-024-01835-1.

Abstract

Background: Activated Phosphoinositide 3-Kinase (PI3K) δ Syndrome (APDS), an inborn error of immunity due to upregulation of the PI3K pathway, leads to recurrent infections and immune dysregulation (lymphoproliferation and autoimmunity).

Methods: Clinical and genetic data of 28 APDS patients from 25 unrelated families were collected from fifteen Italian centers.

Results: Patients were genetically confirmed with APDS-1 (n = 20) or APDS-2 (n = 8), with pathogenic mutations in the PIK3CD or PIK3R1 genes. The median age at diagnosis was 15.5 years, with a median follow-up of 74 months (range 6-384). The main presenting symptoms were respiratory tract infections alone (57%) or associated with lymphoproliferation (17%). Later, non-clonal lymphoproliferation was the leading clinical sign (86%), followed by respiratory infections (79%) and gastrointestinal complications (43%). Malignant lymphoproliferative disorders, all EBV-encoding RNA (EBER)-positive at the histological analysis, occurred in 14% of patients aged 17-19 years, highlighting the role of EBV in lymphomagenesis in this disorder. Diffuse large B-cell lymphoma was the most frequent. Immunological work-up revealed combined T/B cell abnormalities in most patients. Treatment strategies included immunosuppression and PI3K/Akt/mTOR inhibitor therapy. Rapamycin, employed in 36% of patients, showed efficacy in controlling lymphoproliferation, while selective PI3Kδ inhibitor leniolisib, administered in 32% of patients, was beneficial on both infections and immune dysregulation. Additionally, three patients underwent successful HSCT due to recurrent infections despite ongoing prophylaxis or lymphoproliferation poorly responsive to Rapamycin.

Conclusions: This study underscores the clinical heterogeneity and challenging diagnosis of APDS, highlighting the importance of multidisciplinary management tailored to individual needs and further supporting leniolisib efficacy.

Keywords: APDS; Activated phosphoinositide 3-kinase δ syndrome; Leniolisib; Lymphoma; Lymphoproliferation; PI3Kδ inhibitor, EBV.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Class I Phosphatidylinositol 3-Kinases* / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Cohort Studies
  • Female
  • Humans
  • Infant
  • Italy
  • Lymphoproliferative Disorders / diagnosis
  • Lymphoproliferative Disorders / etiology
  • Lymphoproliferative Disorders / genetics
  • Lymphoproliferative Disorders / therapy
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Mutation
  • Primary Immunodeficiency Diseases* / diagnosis
  • Primary Immunodeficiency Diseases* / therapy
  • Young Adult

Substances

  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human
  • Class Ia Phosphatidylinositol 3-Kinase
  • PIK3R1 protein, human

Supplementary concepts

  • Activated PI3K-delta Syndrome