Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort

Lankester, Arjan C.; Neven, Bénédicte; Mahlaoui, Nizar; Asmuth, Erik G J von; Courteille, Virginie; Alligon, Mikael; Albert, Michael H.; Serra, I; Bader, Peter; Balashov, Dmitry; Beier, Rita; Bertrand, Yves; Blanche, Stéphane; Bordon, Victoria; Bredius, R.G.M.; Cant, Andrew J.; Cavazzana, Marina; Heredia, Cristina Diaz de; Doğu, Figen; Ehlert, Karoline; Entz‐Werlé, Natacha; Fasth, Anders; Ferrua, Francesca; Ferster, Alina; Formánková, Renata; Friedrich, Wilhelm; González‐Vicent, Marta; Goździk, Jolanta; Güngör, Tayfun; Hoenig, Manfred; İkincioğulları, Aydan; Kałwak, Krzysztof; Kansoy, Savaş; Küpesiz, Alphan; Lanfranchi, Arnalda; Lindemans, Caroline A.; Meisel, Roland; Gautier, Michel; Miranda, Nuno; Moraleda, José Marı́a; Moshous, Despina; Pichler, Herbert; Rao, Kanchan; Sedláček, Petr; Slatter, Mary; Soncini, Elena; Speckmann, Carsten; Sundin, Mikael; Toren, Amos; Vettenranta, Kim; Worth, Austen; Yeşilipek, M. Akif; Zecca, Marco; Porta, Fulvio; Schulz, Ansgar; Veys, Paul; Fischer, Alain; Gennery, Andrew R.

doi:10.1016/j.jaci.2021.10.017

Cited by 76 publications

(54 citation statements)

References 31 publications

(44 reference statements)

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“…Unfortunately, cross-validation was hard to provide in the case of rare diseases. Nevertheless, our modeling results were interestingly in line with the data from previous cohort studies ( 18 ). Computation reflected, in part, the physiopathology of post-HSCT CD4+ T-cell reconstitution for SCID.…”

Section: Discussionsupporting

confidence: 91%

Bayesian Modeling Immune Reconstitution Apply to CD34+ Selected Stem Cell Transplantation for Severe Combined Immunodeficiency

et al. 2022

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Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. Allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy are curative treatments, depending on the donor's availability and molecular diagnostics. A partially human leukocyte antigen (HLA)-compatible donor used has been developed for this specific HSCT indication in the absence of a matched donor. However, the CD34+ selected process induces prolonged post-transplant T-cell immunodeficiency. The aim here was to investigate a modeling approach to predict the time course and the extent of CD4+ T-cell immune reconstitution after CD34+ selected transplantation. We performed a Bayesian approach based on the age-related changes in thymic output and the cell proliferation/loss model. For that purpose, we defined specific individual covariates from the data collected from 10 years of clinical practice and then evaluated the model's predicted performances and accuracy. We have shown that this Bayesian modeling approach predicted the time course and extent of CD4+ T-cell immune reconstitution after SCID transplantation.

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Section: Discussionsupporting

confidence: 91%

Bayesian Modeling Immune Reconstitution Apply to CD34+ Selected Stem Cell Transplantation for Severe Combined Immunodeficiency

et al. 2022

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“…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.…”

Section: Discussionmentioning

confidence: 59%

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

et al. 2022

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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.

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“…HSCT in the absence of a pretransplant conditioning regimen for IL2RG deficiency is associated with low donor chimerism in the myeloid compartment and poor NK cell engraftment [26][27][28]. This was also observed for UPN1, together with a shortage and decline of naive T cells.…”

Section: Discussionmentioning

confidence: 93%

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

et al. 2022

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The first successful European hematopoietic stem cell transplantation (HSCT) was performed in 1968 as treatment in a newborn with IL2RG deficiency using an HLA-identical sibling donor. Because of declining naive T and natural killer (NK) cells, and persistent human papilloma virus (HPV)-induced warts, the patient received a peripheral stem cell boost at the age of 37 years. NK and T cells were assessed before and up to 14 years after the boost by flow cytometry. The boost induced renewed reconstitution of functional NK cells that were 14 years later enriched for CD56dimCD27+ NK cells. T-cell phenotype and T-cell receptor (TCR) repertoire were simultaneously analyzed by including TCR Vβ antibodies in the cytometry panel. Naive T-cell numbers with a diverse TCR Vβ repertoire were increased by the boost. Before and after the boost, clonal expansions with a homogeneous TIGIT and PD-1 phenotype were identified in the CD27− and/or CD28− memory population in the patient, but not in the donor. TRB sequencing was applied on sorted T-cell subsets from blood and on T cells from skin biopsies. Abundant circulating CD8 memory clonotypes with a chronic virus-associated CD57+KLRG1+CX3CR1+ phenotype were also present in warts, but not in healthy skin of the patient, suggesting a link with HPV. In conclusion, we demonstrate in this IL2RG-deficient patient functional NK cells, a diverse and lasting naive T-cell compartment, supported by a stem cell boost, and an oligoclonal memory compartment half a century after HSCT.

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Hematopoietic cell transplantation in severe combined immunodeficiency: The SCETIDE 2006-2014 European cohort

Cited by 76 publications

References 31 publications

Bayesian Modeling Immune Reconstitution Apply to CD34+ Selected Stem Cell Transplantation for Severe Combined Immunodeficiency

Bayesian Modeling Immune Reconstitution Apply to CD34+ Selected Stem Cell Transplantation for Severe Combined Immunodeficiency

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

T and NK Cells in IL2RG-Deficient Patient 50 Years After Hematopoietic Stem Cell Transplantation

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