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

Abstract

BACKGROUND:

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).

OBJECTIVES:

This study sought to characterize HCT outcomes in APDS.

METHODS:

Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.

RESULTS:

Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure-free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 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 nonimmunologic roles of phosphoinositide 3-kinase 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.

• Authors: Dimana Dimitrova, Zohreh Nademi, Maria Elena Maccari, Stephan Ehl, Gulbu Uzel, Takahiro Tomoda, Tsubasa Okano, Kohsuke Imai, Benjamin Carpenter, Winnie Ip, Kanchan Rao, Austen J J Worth, Alexandra Laberko, Anna Mukhina, Bénédicte Néven, Despina Moshous, Carsten Speckmann, Klaus Warnatz, Claudia Wehr, Hassan Abolhassani, Asghar Aghamohammadi, Jacob J Bleesing, Jasmeen Dara, Christopher C Dvorak, Sujal Ghosh, Hyoung Jin Kang, Gašper Markelj, Arunkumar Modi, Diana K Bayer, Luigi D Notarangelo, Ansgar Schulz, Marina Garcia-Prat, Pere Soler-Palacín, Musa Karakükcü, Ebru Yilmaz, Eleonora Gambineri, Mariacristina Menconi, Tania N Masmas, Mette Holm, Carmem Bonfim, Carolina Prando, Stephen Hughes, Stephen Jolles, Emma C Morris, Neena Kapoor, Sylwia Koltan, Shankara Paneesha, Colin Steward, Robert Wynn, Ulrich Duffner, Andrew R Gennery, Arjan C Lankester, Mary Slatter, Jennifer A Kanakry
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 149 Issue 1 Pg. 410-421.e7 (01 2022) ISSN: 1097-6825 [Electronic] United States
• PMID: 34033842 (Publication Type: Journal Article, Multicenter Study, Research Support, N.I.H., Intramural)
• Copyright: Published by Elsevier Inc.

Chemical References

• MTOR Inhibitors
• Class I Phosphatidylinositol 3-Kinases

Topics

• Adolescent
• Adult
• Aged
• Child
• Child, Preschool
• Class I Phosphatidylinositol 3-Kinases
• Female
• Graft Rejection
• Hematopoietic Stem Cell Transplantation
• Humans
• Kaplan-Meier Estimate
• MTOR Inhibitors (therapeutic use)
• Male
• Middle Aged
• Phosphatidylinositol 3-Kinases (genetics)
• Primary Immunodeficiency Diseases (mortality, therapy)
• Retrospective Studies
• Transplantation, Homologous
• Treatment Outcome
• Young Adult