New Biomarker-based Strategy to Screen and Monitor for Activated Phosphoinositide 3-kinase δ Syndrome

Activated PI3K delta syndromes (PI3Kδ) (APDS type 1 and type 2) are combined immunodeficiencies with variable clinical manifestations caused by heterozygous gain-of-function mutations of the PIK3CD gene. APDS is a very young onset disease, most clinical manifestations appear in pediatric age. Patients may experience severe, disabling, and life-threatening clinical manifestations. Additionally, they may exhibit autoimmunity in addition to immune deficiency. APDS patients present a high risk of developing tumors especially B lymphomas. Hematopoietic stem cell transplantation (HSCT) is the only curative option and, given the risks, may be considered for patients with severe APDS (including those who have developed lymphoma). HSCT is curative, but carries a 10 to 20% mortality risk and cannot guarantee reversibility of organ damage. Positive data from the phase II/III study of the PI3Kδ selective inhibitor leniolisib met the co-primary criteria of reduced lymph node size and increased percentage of B naïve cells in patients with APDS. In addition, safety data from the study showed that leniolisib was well tolerated by participants. The drug is also under review by the European Medicines Agency and a marketing authorization for APDS patients older than 12 years old will be soon available. In the meantime the access to this drug is available by compassionate use for patients older than 12 years old.

In this context, it will be interesting to evaluate the clinical and biological profile of these patients before and after leniolisib treatment in order to identify useful biomarkers for the follow up of the disease. In addition, carful long-term monitoring of patients under PI3Kδ inhibitors is mandatory to detect adverse effects of iatrogenic overinhibition of the PI3K pathway.

Inclusion criteria

Group 1:

• Patients with genetic diagnosis of APDS type 1 or type 2 and planned to be treated by PI3Kδ selective inhibitor leniolisib
• Primary immunodeficient patients with new disease-causing variants in the PIK3CD gene or PIK3R1 gene
• Minimum age 12 years old
• Patients or holders of parental authority do not oppose participation in this research.
• Patients affiliated to a Health Insurance scheme or beneficiaries

Group 2 :

• Patients with genetic diagnosis of APDS type 1 or type 2 already treated by PI3Kδ selective inhibitor leniolisib in the last 2 years
• Patients whose pre-treatment samples are available/analyzable
• Minimum age 12 years old
• Patients or holders of parental authority do not oppose participation in this research.
• patients affiliated to a Health Insurance scheme or beneficiaries

Exclusion criteria

• Bone marrow transplantation
• Refusal to participate to the study.