Primary Immunodeficiency with the PI3K Delta Activation: Clinical Features and Prospective Therapy

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Abstract

Primary immunodeficiency (PID) constitute a polymorphic group of genetic life-threatening disorders. APDS (activated phosphoinositide 3-kinase δ) represents a rare PID caused by monoallelic gain of function defects in the PIK3CD gene, or monoallelic loss of function defects in the PIK3R1 and PTEN genes. Disease symptoms usually manifest early in life and include recurrent bacterial infections, non-malignant and malignant lymphoproliferation, persistent herpes virus infections and a whole spectrum of autoimmune manifestations. Immunological features include T and B lymphocytes defects. APDS treatment including immunoglobulin substitution and immunosuppression does not always lead to complete remission of the disease. Hematopoietic stem cell transplantation is a curative option leading to disease resolution in 75–80% of the patients. In 2023 FDA approved leniolisib — selective PI3Kδ inhibitor — for APDS treatment. In the clinical trial the preparation demonstrated safety and efficacy for the patients with APDS ages 12 and above. Approval of the drug created specifically to treat this rare variant of PID opens a new era of the targeted treatment for the patients with this orphan disease.

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About the authors

Ekaterina Yu. Selina

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Author for correspondence.
Email: selina-katya1998@yandex.ru
ORCID iD: 0009-0003-6545-1435

MD

Россия, Moscow

Anna Yu. Shcherbina

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Email: shcher26@hotmail.com
ORCID iD: 0000-0002-3113-4939
SPIN-code: 6759-0031

MD, PhD, Professor of the RAS

Россия, Moscow

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2. Fig.1. Schematic representation of mutations in the genes encoding the catalytic p110δ and regulatory p85α subunits of PI3-kinase, leading to the development of APDS (the most common variants are highlighted in red) [2]

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3. Fig.2. Distribution of primary diagnoses in patients with APDS [2], %. Note. CVID - common variable immune deficiency; ALPS - autoimmune lymphoproliferative syndrome; X-AG - X-linked agammaglobulinemia; CIN - combined immune deficiency.

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