Long-Term Outcome of Adenosine Deaminase-Deficient Patients—a Single-Center Experience

Scott, Olive; Kim, Vy Hong-Diep; Reid, Brenda; Pham‐Huy, Anne; Atkinson, Adelle; Aiuti, Alessandro; Grunebaum, Eyal

doi:10.1007/s10875-017-0421-7

Cited by 25 publications

(17 citation statements)

References 45 publications

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“…4 HSCT was performed as previously described. 5 ERT using Adagen (Sigma-Tau Pharmaceuticals, Gaithersburg, Md) was administered in accordance with the manufacturer's instructions. Patient 12 received GT in Italy under a phase I/II clinical trial conducted at San Raffaele Hospital, Milan, using a Moloney murine leukemia virus-derived vector encoding ADA.…”

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confidence: 99%

“…4 Unique clinical features of particular genetic subtypes of SCID, such as increased sensitivity to radiation and alkylating chemotherapy in patients with Artemis/DCLRE1C deficiency, impact outcome following allogeneic hematopoietic cell transplantation (HCT) including survival, immune reconstitution, and late effects. 1,5 The Primary Immune Deficiency Treatment Consortium (PIDTC) 6901 Prospective Study has been enrolling patients with SCID disorders in the United States and Canada since August 2010. PIDTC 6901 is a prospective study approved by the institutional review boards of each center and performed in accordance with the Declaration of Helsinki (NCT01186913).…”

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confidence: 99%

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Neutropenia among patients with adenosine deaminase deficiency

Kim

Pham‐Huy

Grunebaum

2019

Journal of Allergy and Clinical Immunology

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(ADA) is a ubiquitous enzyme important for the degradation and salvage of adenosine (Ado) and deoxyAdo (dAdo). Autosomal-recessive defects that severely disrupt the function of ADA lead to accumulation of purine metabolites, which are toxic for rapidly proliferating cells, such as lymphocytes. 1 Most ADA-deficient patients present in the first year of life with profound T-and B-cell defects, leading to severe combined immunodeficiency (SCID). In addition, ADA-deficient patients frequently suffer from liver, lungs, bone, and other tissues abnormalities. 1 Management of ADA deficiency includes supportive care with antimicrobials such as trimethoprim/ sulfamethoxazole (TMP-SMZ) and immunoglobulins. Enzyme replacement therapy (ERT) with polyethylene-glycol-conjugated ADA can improve purine homeostasis and may serve as a ''bridge'' until patients undergo allogeneic hematopoietic stem cell transplantation (HSCT) or gene therapy (GT). HSCT using healthy HLA-matched or mismatched family-related or unrelated donors can correct the immune and some of the systemic abnormalities. 2 Myelodysplasia has previously been reported among ADA-deficient patients; however, because most patients were after unsuccessful HSCT or GT, the role of the metabolic abnormality was not clear. 3 Here, we tested the hypothesis that ADA deficiency could be directly associated with myeloid abnormalities and neutropenia. We analyzed data from all 20 patients diagnosed at our center

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Neutropenia among patients with adenosine deaminase deficiency

Kim

Pham‐Huy

Grunebaum

2019

Journal of Allergy and Clinical Immunology

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“…On the other hand, retroviral vector GT with autologous CD34+ cells transduced with ADA has emerged as a safe and efficacious therapeutic strategy for patients lacking HLA-identical sibling donor ( 26 , 30 – 33 ). Noteworthy, in comparison with clinical trials conducted on other primary immunodeficiencies (SCIDX1, CGD, and WAS), no lymphoproliferative disorders or aberrant clonal expansion have been observed in more than 40 patients treated worldwide with an available follow-up of more than one decade in some of them ( 34 ).…”

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confidence: 99%

First Occurrence of Plasmablastic Lymphoma in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Disease Patient and Review of the Literature

et al. 2018

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Adenosine deaminase-deficient severe combined immunodeficiency disease (ADA-SCID) is a primary immune deficiency characterized by mutations in the ADA gene resulting in accumulation of toxic compounds affecting multiple districts. Hematopoietic stem cell transplantation (HSCT) from a matched donor and hematopoietic stem cell gene therapy are the preferred options for definitive treatment. Enzyme replacement therapy (ERT) is used to manage the disease in the short term, while a decreased efficacy is reported in the medium-long term. To date, eight cases of lymphomas have been described in ADA-SCID patients. Here we report the first case of plasmablastic lymphoma occurring in a young adult with ADA-SCID on long-term ERT, which turned out to be Epstein–Barr virus associated. The patient previously received infusions of genetically modified T cells. A cumulative analysis of the eight published cases of lymphoma from 1992 to date, and the case here described, reveals a high mortality (89%). The most common form is diffuse large B-cell lymphoma, which predominantly occurs in extra nodal sites. Seven cases occurred in patients on ERT and two after haploidentical HSCT. The significant incidence of immunodeficiency-associated lymphoproliferative disorders and poor survival of patients developing this complication highlight the priority in finding a prompt curative treatment for ADA-SCID.

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“…ADAGEN was found to have reduced immunogenicity, which further helped to extend its circulating life . ADAGEN was shown to rapidly correct the metabolic, immune and systemic abnormalities in ADA‐deficient patients , and recent guidelines recommend administering ADAGEN to all newly diagnosed ADA–SCID . In mice lacking ADA [ADA‐knock‐out (KO) mice], which recapitulate many of the features observed in the human condition including profound T and B cell deficiency, ADAGEN can correct the metabolic, immune and non‐immune abnormalities when treatment is initiated at an early age .…”

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confidence: 99%

Comparison of elapegademase and pegademase in ADA-deficient patients and mice

Murguía-Favela

Min

Loves

et al. 2020

Clinical and Experimental Immunology

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The absence of adenosine deaminase (ADA) causes severe combined immune deficiency (SCID), which has been treated with PEGylated bovineextracted ADA (ADAGEN). ADAGEN was recently replaced by a PEGylated recombinant bovine ADA, expressed in Escherichia coli (elapegademase, ELA-ADA). Limited information on ELA-ADA is available. ADA enzymatic activity of ELA-ADA and ADAGEN was assessed in vitro at diverse dilutions. ADA activity and immune reconstitution in an ADA-SCID patient treated with ELA-ADA were compared with age-matched patients previously treated with ADAGEN. ADA activity and thymus reconstitution were evaluated in ADA-deficient mice following ELA-ADA or ADAGEN administered from 7 days postpartum. In vitro, ADA activity of ELA-ADA and ADAGEN were similar at all dilutions. In an ADA-SCID patient, ELA-ADA treatment led to a marked increase in trough plasma ADA activity, which was 20% higher than in a patient previously treated with ADAGEN. A marked increase in T cell numbers and generation of naive T cells was evident following 3 months of ELA-ADA treatment, while T cell numbers increased following 4 months in 3 patients previously treated with ADAGEN. T cell proliferations stimulation normalized and thymus shadow became evident following ELA-ADA treatment. ADA activity was significantly increased in the blood of ADA-deficient mice following ELA-ADA compared to ADAGEN, while both treatments improved the mice weights, the weight, number of cells in their thymus and thymocyte subpopulations. ELA-ADA has similar in-vitro and possibly better in-vivo activity than ADAGEN. Future studies will determine whether ELA-ADA results in improved long-term immune reconstitution.

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Long-Term Outcome of Adenosine Deaminase-Deficient Patients—a Single-Center Experience

Abstract: ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.

Cited by 25 publications

References 45 publications

Neutropenia among patients with adenosine deaminase deficiency

Neutropenia among patients with adenosine deaminase deficiency

First Occurrence of Plasmablastic Lymphoma in Adenosine Deaminase-Deficient Severe Combined Immunodeficiency Disease Patient and Review of the Literature

Comparison of elapegademase and pegademase in ADA-deficient patients and mice

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