Activated PI3K Delta Syndrome
Conditions
Keywords
Activated PI3K delta syndromes, APDS, Leniolisib
Brief summary
The study would like to compare patient samples at different time points using state-of the art-phenotyping tools. Collection of blood samples of APDS patients undergoing PI3K inhibitor treatment will be collected when feasible according to the standard of care planning (a blood test is supposed to be performed for these patients at M0-M3-M6-M12 then each 6 months for a total period of 2 years from the beginning of the PI3K inhibitor treatment). The whole blood will be processed in order to isolate the peripheral blood mononuclear cells (PBMC) and the plasma. Serum, RNA and DNA extraction will be performed on a separate sample.
Detailed description
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.
Interventions
BIOLOGICALBlood samples
A maximum of 27 ml of blood collected at each visit for metabolic markers analysis
BIOLOGICALUrine samples
One urine sample collected at each visit for enteric virus infection research
BIOLOGICALStool samples
One stool sample collected at each visit for enteric virus infection research
Sponsors
Assistance Publique - Hôpitaux de Paris
URC-CIC Paris Descartes Necker Cochin
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Biomarker | At 0 day, 3 months, 6 months, 12 months, 18 months and 24 months of treatment | Identify new biomarker marker for increased PI3K signaling to monitor the disease severity by mass cytometry, single cell RNA-sequencing, single cell ATAC-sequencing and screening for auto-antibodies |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| activation-induced cytidine deaminase (AID) off-target activity | At 0 day, 3 months, 6 months, 12 months, 18 months and 24 months of treatment | Investigate the possibility of activation-induced cytidine deaminase (AID) off-target activity in memory B cells due to PI3Kdelta inhibitor treatment by NGS panel sequencing |
| Correlation between biological data with the clinical data | At 0 day, 3 months, 6 months, 12 months, 18 months and 24 months of treatment | the analyses results will be correlated with the clinical data collected for the patients enrolled in the trial and receiving PIK3CD inhibitor treatment (early access program) in order to explore a possible correlation between biological data and clinical characteristics. |
| Enteric virus infection research | At 0 day, 3 months, 6 months, 12 months, 18 months and 24 months of treatment | Presence of Chronic enteric virus infection will be investigated by multiplex PCR and if negative by NGS in stools, plasma, urins |
Countries
France
Contacts
CONTACTMichaela SEMERARO, MD, PhD
CONTACTLaure CHOUPEAUX, MSc
STUDY_DIRECTORSven Kracker, PHD
Institut National de la Santé Et de la Recherche Médicale, France
Outcome results
None listed