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

Dimitrova, D.; Nademi, Z.; Maccari, M.E.; Ehl, S.; Uzel, G.; Tomoda, T.; Okano, T.; Imai, K.; Carpenter, B.; Ip, W.; Rao, K.; Worth, A.J.J.; Laberko, A.; Mukhina, A.; Neven, B.; Moshous, D.; Speckmann, C.; Warnatz, K.; Wehr, C.; Abolhassani, H.; Aghamohammadi, A.; Bleesing, J.J.; Dara, J.; Dvorak, C.C.; Ghosh, S.; Kang, H.J.; Markelj, G.; Modi, A.; Bayer, D.K.; Notarangelo, L.D.; Schulz, A.; Garcia-Prat, M.; Soler-Palacin, P.; Karakukcu, M.; Yilmaz, E.; Gambineri, E.; Menconi, M.; Masmas, T.N.; Holm, M.; Bonfim, C.; Prando, C.; Hughes, S.; Jolles, S.; Morris, E.C.; Kapoor, N.; Koltan, S.; Paneesha, S.; Steward, C.; Wynn, R.; Duffner, U.; Gennery, A.R.; Lankester, A.C.; Slatter, M.; Kanakry, J.A.

doi:doi:10.1016/j.jaci.2021.04.036

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...Show moreBackground: 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.Show less

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