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Multicenter Study
. 2024 Dec 23;45(1):58.
doi: 10.1007/s10875-024-01835-1.

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

Federica Barzaghi  1   2 , Mattia Moratti  3   4 , Giuseppina Panza  2   5 , Beatrice Rivalta  6   7 , Giuliana Giardino  8 , Antonio De Rosa  8 , Lucia Augusta Baselli  9 , Matteo Chinello  10 , Antonio Marzollo  11 , Davide Montin  12 , Maddalena Marinoni  13 , Giorgio Costagliola  14 , Silvia Ricci  15   16 , Lorenzo Lodi  15   16 , Baldassarre Martire  17 , Cinzia Milito  18 , Antonino Trizzino  19 , Alberto Tommasini  20   21 , Marco Zecca  22 , Raffaele Badolato  23 , Caterina Cancrini  6   24 , Vassilios Lougaris  25 , Claudio Pignata  26 , Francesca Conti  3   27
Affiliations
Multicenter Study

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

Federica Barzaghi et al. J Clin Immunol. .

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.

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Conflict of interest statement

Declarations. Compliance with Ethical Standards: The study was conducted in strict adherence to the Helsinki Declaration: participants or their parents provided written informed consent for the collection and publication of any data included in this article, which was approved by the local ethical committee of each centre. Competing Interests: Authors V.L., C.C., F.C., A.To., A.Tr., R.B., M.Z., F.B., C.P. received an honorarium from Pharming Group N.V. to participate in the APDS advisory board. The other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Clinical and molecular diagnosis of APDS cohort: gene variants (A), diagnostic delay (B) and clinical signs at onset (C). Abbreviations: ABD, Adaptor-binding domain; BH, Bcl-2 homology domain; cSH2, C-terminal SH2; nSH2, N-terminal SH2; RBD, Ras-binding domain; SH, Src homology domain; VUS, Variant of Uncertain Significance; APDS, Activated PI3K-kinase Delta Syndrome; IEI, Inborn Errors of Immunity
Fig. 2
Fig. 2
Malignant lymphoproliferation in the APDS cohort. Abbreviations: APDS, Activated PI3K-kinase Delta Syndrome; AL, Anaplastic lymphoma; DLBCL, Diffuse Large B Cell Lymphoma; EBER, EBV-encoded RNA; EBV, Epstein-Barr virus; HL, Hodgkin Lymphoma; NHL, Non-Hodgkin Lymphoma; NLPHL, Nodular lymphocyte-predominant Hodgkin Lymphoma. Adapted from Rivalta B et al. Case Report: EBV Chronic Infection and Lymphoproliferation in Four APDS Patients: The Challenge of Proper Characterization, Therapy, and Follow-Up. Front Pediatr. 2021 Aug 27;9:703853. 10.3389/fped.2021.703853. PMID: 34540765; PMCID: PMC8448282
Fig. 3
Fig. 3
Clinical phenotype of APDS patients receiving leniolisib prior to treatment and after initiation. The graph represent the variation of clinical signs before (dark grey) and after (light grey) starting leniolisib
See this image and copyright information in PMC

References

    1. Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2020;59(3):323–33. 10.1007/s12016-019-08738-9. - PubMed
    1. Angulo I, Vadas O, Garçon F, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71. 10.1126/science.1243292. - PMC - PubMed
    1. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605–35. 10.1016/j.cell.2017.07.029. - PMC - PubMed
    1. Lucas CL, Kuehn HS, Zhao F, et al. Dominant-activating, germline mutations in phosphoinositide 3-Kinase p110δ cause T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97. 10.1038/ni.2771. - PMC - PubMed
    1. Nguyen T, Lau A, Bier J, et al. Human PIK3R1 mutations disrupt lymphocyte differentiation to cause activated PI3Kδ syndrome 2. J Exp Med. 2023;220(6): e20221020. 10.1084/jem.20221020. - PMC - PubMed

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