Long-term enzyme replacement therapy feasible in ADA-deficient patients
Published Date: 30/8/17Access Full Text Article
medwireNews: Enzyme replacement therapy over the long term could be an option for patients with adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) for whom curative therapies are unavailable, say US researchers who describe a patient who has remained on treatment for 24 years.
He presented at the age of 3.5 months with fever and cough, diarrhoea and oral thrush, where the latter had persisted for 3 months. The patient, who had no family history of immunodeficiency disorders, had severe hypogammaglobulinemia and lymphopenia, with very low B- and T-cell counts.
The investigators report that tests showed “barely detectable” ADA activity in red blood cells and total 2′-deoxyadenosine nucleotides (dAXP) made up 20.6% of total adenine nucleotides, where normal is below 1.0%, thus confirming a diagnosis of ADA-SCID. Molecular analysis revealed the presence of the A179D and R211H missense mutations, both of which have been reported in other ADA-SCID patients.
Treatment with polyethylene glycol-modified (PEG)-ADA at a dose of 30 U/kg twice weekly was initiated alongside prophylactic antibiotics and intravenous immunoglobulin. The patient responded well to enzyme replacement, with a “marked increase” not only in plasma ADA levels, but also B-cell and lymphocyte counts, and a concurrent decrease in dAXP levels.
The prophylactic antibiotics were discontinued when the infant was 9 months old after mitogen lymphoproliferative tests yielded normal results, and intravenous immunoglobulin was withdrawn a month later.
As gene therapy was not available at the time and an HLA-matched donor could not be identified, the patient continued to receive PEG-ADA, remaining on treatment for 24 years, with periodic dose adjustments to account for changes in weight.
The patient’s plasma ADA levels have been acceptable throughout the course of treatment, remaining within the range of 25–101 μmol/h per mL in the first year, 27–211 μmol/h per mL between 1–5 years of age, 63–152 μmol/h per mL between 6–10 years, and 29–101 μmol/h per mL at 11–24 years.
His immunoglobulin levels have also been within normal limits over the 24-year period, “which has not been the case for most patients treated solely with PEG-ADA”, say Sami Bahna, from the Louisiana State University Health Sciences Center in Shreveport, and co-researchers.
The patient has also shown evidence of T-cell recovery, with his total lymphocyte counts rising from 0x103/μL at diagnosis to 0.77×103/μL at the most recent evaluation, while his CD4 counts rose from 13 to 207 cells/μL. Nevertheless, these values remain below normal levels, indicating the presence of mild lymphopenia, the study authors comment.
They also note that the patient has not been completely free of infections during the clinical course. Just before he turned 3 years of age, he was hospitalised for right middle-lobe pneumonia and otitis media of the right ear that “responded well” to intravenous ceftriaxone treatment.
And at the age of 3 years, he contracted meningoencephalitis of unknown aetiology, followed by coagulase-negative Staphylococcus bacteraemia when he was 4-years-old and membranous glomerulonephritis at 18 years of age, but his immune recovery has been “sufficient to prevent frequent or opportunistic infections”, the investigators say.
Furthermore, thus far, the patient has not exhibited any signs of autoimmune or lymphoproliferative disorders, conditions that can develop in individuals receiving enzyme replacement therapy, Bahna et al say in Pediatrics.
Nonetheless, they stress the importance of considering “potentially curative” modalities, such as haematopoietic stem-cell transplantation or gene therapy when possible, given the high financial cost of PEG-ADA therapy and the associated increased risk of autoimmune and lymphoproliferative disorders.
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