Long-Term Immune Recovery After Hematopoietic Stem Cell Transplantation for ADA Deficiency: a Single-Center Experience

Abstract

Unconditioned hematopoietic stem cell transplantation (HSCT) is the recommended treatment for patients with adenosine deaminase (ADA)-deficient severe combined immunodeficiency with an HLA-matched sibling donor (MSD) or family donor (MFD). Improved overall survival (OS) has been reported compared to the use of unrelated donors, and previous studies have demonstrated that adequate cellular and humoral immune recovery can be achieved even in the absence of conditioning. Detailed insight of the long-term outcome is still limited. We aim to address this by studying a large single-center cohort of 28 adenosine deaminase-deficient patients who underwent a total of 31 HSCT procedures, of which more than half were unconditioned. We report an OS of 85.7% and event-free survival of 71% for the entire cohort, with no statistically significant differences after procedures using related or unrelated HLA-matched donors. We find that donor engraftment in the myeloid compartment is significantly diminished in unconditioned procedures, which typically use a MSD or MFD. This is associated with poor metabolic correction and more frequent failure to discontinue immunoglobulin replacement therapy. Approximately one in four patients receiving an unconditioned procedure required a second procedure, whereas the use of reduced intensity conditioning (RIC) prior to allogeneic transplantation improves the long-term outcome by achieving better myeloid engraftment, humoral immune recovery, and metabolic correction. Further longitudinal studies are needed to optimize future management and guidelines, but our findings support a potential role for the routine use of RIC in most ADA-deficient patients receiving an HLA-identical hematopoietic stem cell transplant, even when a MSD or MFD is available.

Keywords: ADA SCID; Hematopoietic stem cell transplantation; Primary immunodeficiency; Reduced intensity conditioning.

Fig. 1

Overall survival and event-free survival after HSCT: Censored Kaplan–Meier curves showing OS in relation to donor source (A) and intensity of conditioning (B) and EFS in relation to donor source (C) and intensity of conditioning (D). For OS, n = 28 subjects, overall OS = 85.7%; whereas for EFS, n = 31 HSCT procedures, with 3 of the 28 subjects having received 2 HSCT procedures each, overall EFS = 71%

Fig. 2

Donor chimerism after HSCT: Box plots showing the degree of donor chimerism at last follow-up in peripheral blood (PB), in CD3⁺ cells and CD15⁺ cells: A in relation to donor type for procedures using a MSD, MFD, MUD, or MMUD with n_MSD = 6, n_MFD = 5, n_MUD = 4, and n_MMUD = 3, respectively, in PB and n_MSD = 9, n_MFD = 6, n_MUD = 5, and n_MMUD = 3 in CD3⁺ cells and CD15⁺ cells; B in relation to intensity of conditioning for procedures without conditioning or using RIC or MAC with n_none = 10, n_RIC = 4, and n_MAC = 4, respectively, in PB and n_none = 14, n_RIC = 5, and n_MAC = 4 in CD3⁺ cells and CD15⁺ cells. Significant Kruskal–Wallis test results and (1-tailed) Mann–Whitney test results with p ≤ 0.05 have been indicated*, respectively, at the top and at the bottom of the box plots

Fig. 3

T cell immune recovery after HSCT: A–C Box plots showing levels of absolute T cell counts after HSCT in relation to donor type for procedures using a MSD, MFD, MUD, or MMUD with n_MSD = 9, n_MFD = 6, n_MUD = 3, and n_MMUD = 3 at last follow-up (> 24 months): Absolute counts (× 10⁹/L) of A CD3⁺ T cells, B CD4⁺ T cells, and C CD8⁺ T cells. Differences in cell counts between subgroups were not statistically different. D Proportion of HSCT procedures resulting in CD3⁺ recovery > 1000 cells/mm³ (gray) and CD4⁺ recovery > 300 cells/mm³ (black)

Fig. 4

Humoral recovery after HSCT: A Levels of absolute B cell counts (× 10⁹/L) at 6 and 12 months and at last follow-up (> 24 months) after HSCT in relation to donor type for procedures using MSD, MFD, MUD, or MMUD with n_MSD = 10, n_MFD = 8, n_MUD = 7, and n_MMUD = 3, respectively, at 6 months, and n_MSD = 9, n_MFD = 6, n_MUD = 5, and n_MMUD = 1 at 12 months, and n_MSD = 9, n_MFD = 6, n_MUD = 3, and n_MMUD = 3 at last follow-up (> 24 months). Significant Kruskal–Wallis test results with p ≤ 0.05 have been indicated* at the top of the box plots. B Proportion of patients who have discontinued IgRT at 24 months post-HSCT in relation to donor type and conditioning regimen