Cerebral Lymphoma in an Adenosine Deaminase–Deficient Patient With Severe Combined Immunodeficiency Receiving Polyethylene Glycol–Conjugated Adenosine Deaminase

Abstract

ABSTRACT. Polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) provides an alternate therapy to mismatched stem cell transplantation for patients with ADA-deficient severe combined immunodeficiency. Although replacement therapy with PEG-ADA is effective in preventing infections, immune function does not return to normal, and most patients remain lymphopenic. Information is limited regarding the prognosis of patients on long-term ADA-replacement therapy. Here we present a case of a 10-year-old child who was diagnosed with ADA-severe combined immunodeficiency at 4 weeks of age after contracting pneumonia. Treatment with PEG-ADA was begun, the biochemical markers of ADA deficiency normalized, and his clinical progress was very good without significant infections. Lymphoproliferative disorders, usually related to Epstein-Barr virus (EBV), may develop in individuals with certain types of primary immunodeficiencies, including SCID. Polyethylene glycol-conjugated bovine ADA (PEG-ADA) is a replacement therapy for ADA deficiency. 3,4 PEG prolongs the half-life of the ADA enzyme by reducing its catabolism. By greatly reducing the levels of toxic metabolites, PEG-ADA therapy has been successful in preventing infections, although restoration of immune function is only partial. Information regarding the long-term prognosis of patients receiving PEG-ADA is limited. Here we report the case of a boy who received PEG-ADA for 10 years with effective control of infections but ultimately developed cerebral lymphoma. CASE REPORTA 10-year-old white male who was being followed at our allergy/immunology clinic for ADA-SCID and had been doing well on PEG-ADA (Adagen; Enzon, Inc, Piscataway, NJ) therapy presented to his pediatrician because of a 6-week history of headache, eye deviation, and weakness. The headache was increasingly severe, constant, and localized to the left frontotemporal area. There was no aura, and the pain was unrelated to positional change. Increasing dose and frequency of nonsteroidal antiinflammatory drugs had been ineffective for pain relief. For the previous few weeks, he had a decreased appetite and an ϳ10-lb weight loss. One week before presentation, his right eye appeared medially deviated, and his right upper and lower extremities became weak. His pediatrician noticed no fever or nuchal rigidity and transferred him to our hospital.He was the family's firstborn as a term infant. At 4 weeks of age, he developed severe pneumonia, and an immunologic evaluation at another academic institution revealed ADA-SCID with red-cell ADA activity of 0.5 nmol/hour per mg protein (ϳ1% of normal). His ADA genotype was Ala833 Asp in exon 4 of one allele and a 5Ј splice junction mutation ϩ 1 Gly3 Ala in exon 5 of his second ADA allele. 5 A matched bone marrow transplant (BMT) donor could not be found, and the patient's family declined mismatched BMT, preferring ADA-replacement therapy. With the initiation of PEG-ADA therapy, plasma ADA activity increased by ϳ100-to 1000-fold, and the level of erythrocyte deoxyadenosine n...

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

“…Remarkably, the number of CD4 and CD8 lymphocytes continued to increase until the last measurement at 6 months after ELA–ADA was initiated, reaching absolute numbers that were higher than in our three previous patients treated with ADAGEN. The number of CD3 + T cells in our patient (2·17 × 10 9 /l) was also higher than the number of such cells in many other ADA–SCID patients reported previously . Whether the differences in T cell recovery reflect individual variation or are caused by better immune reconstitution with ELA–ADA will need to be determined through larger prospective studies.…”

Ex vivo gene therapy with lentiviral vectors rescues adenosine deaminase (ADA)–deficient mice and corrects their immune and metabolic defects

“…43 On the other hand, tumors of donor origin may result from an intrinsic susceptibility of ADA-deficient cells or an ineffective immunologic surveillance, as hypothesized for lymphomas developing in ADA-SCID patients receiving PEG-ADA. 2,45 Importantly, we found no evidence of insertional mutagenesis induced by LV integrated at high copies in these tumors. Nevertheless, in-depth studies in a larger group of animals will be required to specifically address the safety of LV gene transfer in the ADA-deficient mouse model.…”

A 24-Year Enzyme Replacement Therapy in an Adenosine-deaminase-Deficient Patient

“…12 It seems that PEG-ADA therapy can provide adequate immune restoration, but the risk of developing lymphoproliferative disorders remains. ADA deficiency can cause pulmonary alveolar proteinosis and inflammatory liver disease, which may respond to PEG-ADA therapy.…”