International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome
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: Journal of Allergy and Clinical Immunology (2021)

BackgroundActivated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT).ObjectivesThis study sought to characterize HCT outcomes in APDS.MethodsRetrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT.ResultsPre-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.ConclusionsGraft 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. Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). This study sought to characterize HCT outcomes in APDS. Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. 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. 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.