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Lookup NU author(s): Professor Andrew Cant
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Copyright: © 2025 Upton et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare, underrecognized inborn error of immunity. This study aimed to identify outcomes important in evaluating APDS treatment effectiveness and percent change in specific outcomes indicating a clinically meaningful benefit. METHODS: In this e-Delphi panel study, 28 globally based APDS experts used a 5-point Likert scale (Strongly Disagree to Strongly Agree) to indicate level of agreement that an outcome was an important measure of APDS treatment effectiveness in adult and pediatric patients at 3 and 6 months after treatment initiation. A threshold of ≥75% responding with "Agree" or "Strongly Agree" was considered consensus. Percent meaningful improvement in 6 outcomes was assessed and applied to APDS trial data (NCT02435173). RESULTS: Twenty-four panelists participated; e-Delphi rounds 1-5 were completed by 23, 21, 18, 17, and 16 panelists, respectively. Outcomes with the highest degree of consensus included lymph node size/volume, clinician overall impression of disease activity, antibiotic use, patient/caregiver-reported social outcomes and patient quality of life, hospitalizations, thrombocytopenia, spleen volume, lymphopenia, and anemia. Panelists indicated within-patient clinically meaningful improvements in adult patients ranged from median values of 20%-25% in lymph nodes, naïve B-cell to total B-cell ratio, spleen volume, hemoglobin, platelets, and lymphocytes at 3 months, and 25%-30% at 6 months. Panelists indicated within-patient clinically meaningful improvements in pediatric patients ranged from median values of 20%-27.5% at 3 months and 22.5%-45% at 6 months in the same 6 outcomes. In an application of responder thresholds, treatment with leniolisib resulted in significant and meaningful improvements in disease hallmarks, including lymph node size, spleen volume, and naïve B-cell ratio. CONCLUSION: This study provides expert consensus on outcomes important in assessing APDS treatment effectiveness and improvement thresholds in 6 treatment outcomes indicative of a clinically meaningful benefit. These outcomes may help optimize APDS treatment in the clinic.
Author(s): Upton JEM, Williams KW, Cant A, Santos A, Bana e Costa J, Bradt J, Harrington A, Gwaltney C
Publication type: Article
Publication status: Published
Journal: PLoS One
Year: 2025
Volume: 20
Issue: 10
Online publication date: 15/10/2025
Acceptance date: 09/09/2025
Date deposited: 27/10/2025
ISSN (electronic): 1932-6203
Publisher: Public Library of Science
URL: https://doi.org/10.1371/journal.pone.0333341
DOI: 10.1371/journal.pone.0333341
Data Access Statement: All relevant data for the e-Delphi study are included in the manuscript and its supporting information files. Data used for the practical application of the e-Delphi responder definitions are from a randomized controlled phase 3 trial (NCT02435173, Rao, VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kd inhibitor leniolisib for activated PI3Kd syndrome. Blood. 2023;141:971-983); individual patient datasets are not publicly available. Reasonable requests for specific data fields or variables can be sent to Pharming Healthcare, Inc. at publication.inquiries@pharming.com.
PubMed id: 41091701
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