Determining the Genetic Drivers of Diffuse Large B Cell Lymphoma 30 Years After Gamma Retroviral Gene Therapy for Severe Combined Immunodeficiency due to Adenosine Deaminase Deficiency

In 1993, a newborn with adenosine deaminase–deficient severe combined immunodeficiency (ADA-SCID) received investigational gene therapy with autologous cord blood cells transduced with a gammaretroviral ADA vector infused without conditioning (PMCID: PMC3013367). Low-level engraftment ensued, but without clinical benefit, and the patient was maintained on chronic ADA enzyme replacement therapy. At age 30 years, they developed diffuse large B cell lymphoma (DLBCL) that has been studied to determine whether insertional mutagenesis contributed to clonal proliferation. ADA-SCID was diagnosed prenatally due to a positive family history; cord blood was harvested at delivery and transduced with LASN gammaretroviral vector, with cells reinfused at four days of age. The patient received IVIG until age 19 years and ADA enzyme replacement therapy (ERT, Adagen followed by Revcovi) for 27 years, when they chose to discontinue treatment. At 30 years, they resumed ERT, but presented with pancytopenia, sepsis, liver and lung granulomas, cholestasis, and lymphadenopathy. To address persistent lymphopenia, ERT was increased, but signs of hemophagocytic lymphohistiocytosis ensued, after which metastatic DLBCL was diagnosed. Despite remission with chemotherapy, the patient developed multiorgan dysfunction, elected hospice care and died within a few months. At 5 years of age, the patient had maintained detectable gene marking in 1% of PBMC, 0.01-0.1% of monocytes and granulocytes, 1% of T cells, and 0.1% of B cells (PMCID: PMC3777239). With the recent diagnosis, analysis of bone marrow and lymph node, both with high proportions of malignant cells, revealed low transgene copy number (0.05 and 0.11/cell, respectively). Insertion site sequencing showed no vector incorporation near genes previously implicated in malignancy in gene therapies. Capture-based next-generation sequencing of 529 cancer genes revealed pathogenic mutations in ARID1A, NFKBIE, GNA13, and DUSP2, all associated with DLBCL, but not found among the patient’s insertion sites. Thus, our patient’s lymphoma was not a result of insertional mutagenesis but could reflect an intrinsic cancer diathesis in ADA deficiency and/or defective immune surveillance, recurrent infections, and impaired organ function. Patients with ADA-SCID require long-term monitoring for immune status and malignancy regardless of whether primary treatment is with chronic enzyme replacement, allogeneic transplantation, or gene therapy.