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International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome

Dimitrova, Dimana, Nademi, Zohreh, Maccari, Maria Elena, Ehl, Stephan, Uzel, Gulbu, Tomoda, Takahiro, Okano, Tsubasa, Imai, Kohsuke, Carpenter, Benjamin, Ip, Winnie, Rao, Kanchan, Worth, Austen J. J., Laberko, Alexandra, Mukhina, Anna, Néven, Bénédicte, Moshous, Despina, Speckmann, Carsten, Warnatz, Klaus, Wehr, Claudia, Abolhassani, Hassan, Aghamohammadi, Asghar, Bleesing, Jacob J., Dara, Jasmeen, Dvorak, Christopher C., Ghosh, Sujal, Kang, Hyoung Jin, Markelj, Gasper, Modi, Arunkumar, Bayer, Diana K., Notarangelo, Luigi D., Schulz, Ansgar, Garcia-Prat, Marina, Soler-Palacín, Pere, Karakükcü, Musa, Yilmaz, Ebru, Gambineri, Eleonora, Menconi, Mariacristina, Masmas, Tania N., Holm, Mette, Bonfim, Carmem, Prando, Carolina, Hughes, Stephen, Jolles, Stephen, Morris, Emma C., Kapoor, Neena, Koltan, Sylwia, Paneesha, Shankara, Steward, Colin, Wynn, Robert, Duffner, Ulrich, Gennery, Andrew R., Lankester, Arjan C., Slatter, Mary and Kanakry, Jennifer A. 2022. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome. Journal of Allergy and Clinical Immunology 149 (1) , pp. 410-421. 10.1016/j.jaci.2021.04.036

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Background Activated phosphoinositide 3-kinase (PI3K) delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). Objective We sought to characterize HCT outcomes in APDS. Methods Retrospective data was collected on 57 APDS1/2 patients (median age 13 years, range 2-66) who underwent HCT. Results Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With 2.3 years median follow-up, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 vs 2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mTOR inhibitors (mTORi) were used in the first year post-HCT, compared to 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential non-immunologic roles of PI3K not correctable through HCT. Conclusions Graft failure, graft instability and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: This is an open access article under the CC BY-NC-ND license (
Publisher: Elsevier
ISSN: 0091-6749
Date of First Compliant Deposit: 2 June 2021
Date of Acceptance: 30 April 2021
Last Modified: 11 May 2023 12:44

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