Abstract
Current treatment for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) includes enzyme replacement therapy (ERT), allogeneic hematopoietic stem cell transplant (HSCT), or ex vivo corrected autologous hematopoietic stem cell gene therapy. Historic data show HSCT survival is superior using unconditioned matched sibling and family compared to matched unrelated and haploidentical donors. Recent improvement in HSCT outcomes prompted us to retrospectively examine HSCT survival and long-term graft function in ADA-SCID transplanted at our center. Thirty-three ADA-deficient patients received HSCT between 1989 and 2020, with follow-up data to January 2021. Chemotherapy conditioning regimens were defined as myeloablative (MAC—busulfan/cyclophosphamide), reduced-toxicity myeloablative (RT-MAC—treosulfan-based, since 2007), or no conditioning. Serotherapy used included alemtuzumab (with or without other conditioning agents) or antithymocyte globulin (ATG). ERT was introduced routinely in 2010 until commencement of conditioning. Median age at HSCT was 3.2 (0.8–99.8) months. Twenty-one (63.6%) received stem cells from unrelated or haploidentical donors. Seventeen (51.5%) received chemotherapy conditioning and 16 (48.5%) received alemtuzumab. Median follow-up was 7.5 (0.8–25.0) years. Overall survival (OS) and event-free survival (EFS) at 8 years were 90.9% (95% CI: 79.7–100.0%) and 79% (55–91%), respectively. OS after 2007 (n = 21) was 100% vs 75% before 2007 (n = 12) (p = 0.02). Three (9.1%) died after HSCT: two from multiorgan failure and one from unexplained encephalopathy. There were no deaths after 2007, among those who received ERT and treosulfan-based conditioning pre-HSCT. Ten (30.3%) developed acute GvDH (3 grade II, 2 grade III); no chronic GvHD was observed. In the modern era, conditioned HSCT with MUD has a favorable outcome for ADA-deficient patients.
Highlights
Adenosine deaminase (ADA) is an enzyme in the purine metabolic pathway that converts adenosine and 2′deoxyadenosine into inosine and 2′deoxyinosine, respectively
Concerns remain that lack of conditioning may impair long-term immune reconstitution, with lower T-cell receptor excision circle (TREC) levels detected in unconditioned hematopoietic stem cell transplant (HSCT) patients suggesting limited thymopoiesis which may lead to eventual exhaustion of the T-cell receptor repertoire [6]
Yrs, years; HSCT, hematopoietic stem cell transplant are comparable to MSD/MFD HSCT, with excellent rates of Overall survival (OS) and event-free survival (EFS), low rates of acute graft versus host disease (GvHD), and no chronic GvHD
Summary
Adenosine deaminase (ADA) is an enzyme in the purine metabolic pathway that converts adenosine and 2′deoxyadenosine into inosine and 2′deoxyinosine, respectively. European guidelines recommended an unconditioned HSCT using a MSD/ MFD, or GT if a MSD/MFD is not available, the recently published guidelines give the option of conditioning for MSD/MFD donors due to the concerns about long-term immunoreconstitution [10]. Outcomes of alternative HSCT donors for ADA-SCID have been disappointing, the data are relatively limited and may improve with further advances in allogeneic HSCT technologies. Concerns remain that lack of conditioning may impair long-term immune reconstitution, with lower T-cell receptor excision circle (TREC) levels detected in unconditioned HSCT patients suggesting limited thymopoiesis which may lead to eventual exhaustion of the T-cell receptor repertoire [6]. In light of the significant recent improvements in transplant care for children with inborn errors of immunity, this retrospective observational study aimed to examine the HSCT survival and long-term graft function in children with ADA-SCID transplanted at a single national center
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