Lymphoproliferative disorders not uncommon in ADA-SCID patients

Lymphoproliferative disorders not uncommon in ADA-SCID patients

Published Date: 18/4/18

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medwireNews: There is a “significant” incidence of lymphoma among individuals with adenosine deaminase deficient-severe combined immunodeficiency (ADA-SCID), say investigators who identified eight such cases in the literature in addition to their report of a patient with plasmablastic disease.

They note that patients who develop this complication have poor survival, which highlights the importance of “finding a prompt curative treatment for ADA-SCID.”

Alessandro Aiuti (San Raffaele Telethon Institute for Gene Therapy, Milan, Italy) and study authors describe a female patient with ADA-SCID who developed plasmablastic lymphoma at the age of 18 years.

She was diagnosed with ADA deficiency at 3 months of age and was initially treated with polyethylene glycol-modified-ADA, which led to some improvement in immune function and clinical symptoms, but her lymphocyte counts remained low. As a matched bone marrow donor was unavailable, the patient was given infusions of autologous peripheral blood T lymphocytes transduced with a gammaretroviral vector expressing wild-type ADA, leading to improvements in T-cell counts and function. But systemic detoxification remained suboptimal and enzyme replacement therapy was restarted and continued.

When the patient was 18 years old, she was admitted to a hospital with a persistent fever and multiple lymphadenopathies. Blood tests revealed high levels of Epstein–Barr virus (EBV) DNA as well as antibodies against the EBV early and nuclear antigen. And histopathology confirmed the diagnosis of EBV-related plasmablastic B-cell lymphoma. Chemotherapy was initiated, but within 12 days the patient died as a result of haemorrhagic alveolitis.

Of the nine incidences of lymphoma in ADA-SCID patients reported thus far, five have been associated with EBV infection, which could be because EBV seems to have an effect on lymphocyte proliferation via “suppression of T-cell surveillance and modulation [of] apoptosis and cytokine balance in B-cells”, say Aiuti et al.

That said, “[t]he pathogenesis of lymphomas in ADA-SCID patients remains still unclear”, they add, explaining that the lack of functional ADA would be expected to reduce the oncogenic risk as “the accumulation of adenosine and purine metabolites in ADA-deficient patients leads to increased apoptosis in T and B cells.”

However, “[s]ince all patients described here were either under PEG-ADA treatment or received [haematopoietic stem cell transplantation], one can speculate that in these patients adenosine metabolites were adequately detoxified.”

As the patient described in the report had received peripheral blood gene therapy, Aiuti and team investigated whether there was a link between the treatment and the development of malignancy. T cells isolated from the patient’s bone marrow, peripheral blood and lymph nodes were “highly positive” for the vector, whereas B cells had low levels, which “rule[s] out the possibility that the lymphoproliferative event originated from the infused transduced cells”, they write in Frontiers in Immunology.

The researchers continue: “It is likely that, despite being polyclonal, the T-cell repertoire of the transduced T cells, which were ex vivo cultured, was not sufficiently broad to survey and control the B cell transformation induced by the EBV infection.”

The prognosis of ADA-SCID patients who develop lymphomas remains poor – all but one of the nine patients in the case series died, despite receiving multiple lines of treatment. Only one patient, who had Burkitt’s lymphoma, achieved complete remission at 20 months from the onset of the malignancy.

“Attending physicians must be [made] aware that the delay of a definitive treatment could expose these fragile patients to multiple severe complications, including aggressive lymphoproliferative disorders”, Aiuti and colleagues conclude.

© 2020 Springer Healthcare Ltd

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