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.

Hematopoietic Cell Transplantation for Adenosine Deaminase Severe Combined Immunodeficiency—Improved Outcomes in the Modern Era

“…However, the consequences of unconditioned HSCT on the long-term quality of immune reconstitution are not known but may result in limited thymopoiesis leading to eventual exhaustion of the T-cell receptor repertoire [6]. In this cohort, patients who received a chemotherapy-conditioned transplant had superior myeloid chimerism and higher rates of immunoglobulin independence compared to unconditioned patients, also recently demonstrated in the large European experience of SCID transplantation, and another single center report of HSCT for ADA deficiency [11,12]. Continued follow-up is required to evaluate if this is sustained and to evaluate the impact of higher levels of myeloid chimerism on long-term cellular and humoral immune function.…”

National experience with adenosine deaminase deficiency related SCID in Polish children

“…Frequency of therapy failure is similar: 10-20% in MSD HSCT and 5-20% in GT, but procedurerelated mortality is 5.6 and 0% respectively (12). Some authors recommend considering GT as a first-line treatment, even if MSD is available, as this procedure abrogates any risk of alloreactivity (17). However, since treosulfan-based conditioning was introduced results for MUD, and Haplo HSCT are comparable with MSD in some centers and therefore recommended when there is no access to GT (18).…”

SARS-CoV-2 Vaccine Non-response among Hematopoietic Stem Cell Transplant Patients: A Systematic Review and Meta-analysis

“…The underlying reasons for this non-responsiveness may be multifactorial. Firstly, the autologous transplant procedure itself may temporarily impair the immune system's ability to mount a robust response to vaccines due to the underlying disease, prior treatments such as chemotherapy, or the conditioning regimen used before the transplant (31)(32)(33). Additionally, autologous transplant patients may have residual immunode ciency or immune dysfunction even after recovery, which can affect their ability to generate an adequate antibody response to vaccines, although, this recovery time may be shorter in autologous HSCT recipients compared to those who had allogeneic transplants (34,35).…”