Medical Care
Patients with dysgammaglobulinemia or recurrent infections due to X-linked lymphoproliferative (XLP) syndrome may benefit from immunoglobulin replacement therapy. This can be delivered intravenously every few weeks or subcutaneously every week, which is usually performed at home. Other manifestations of dysregulation, such as aplastic anemia or vasculitis, may respond to treatment with corticosteroids or other immunosuppressive agents. [6]
Colitis associated with XLP type 2 (XLP2) is treated symptomatically and with immunosuppression similar to that used for irritable bowel disease. [13]
Epstein-Barr virus infection
If there is evidence of Epstein-Barr virus (EBV)–driven disease, including hemophagocytic lymphohistiocytosis (HLH), treatment with a monoclonal anti-CD20 antibody (rituximab) can be used to deplete the B cell population harboring the virus. This approach is effective at reducing and often clearing the viremia but risks exacerbating long-term hypogammaglobulinemia. [6, 17]
Antiviral agents are poorly effective against EBV but acyclovir has been used in some circumstances. [6]
Successful treatment with combination therapy of rituximab and ganciclovir has been reported. [18]
HLH
Hemophagocytic lymphohistiocytosis is treated according to standardized protocols (HLH 94 and 2004) based on the use of dexamethasone, etoposide, and cyclosporine, with the addition of intrathecal methotrexate and steroids if there is neurological involvement. This is a highly suppressive regime and can be associated with significant toxicity. The protocol follows different stages, starting with an intense period of treatment initially, with reducing doses of steroids and frequency of etoposide over time if a response is seen. Re-intensification of therapy is occasionally required. [19]
Other immunosuppressive agents have been used to control HLH, either in combination with steroids or as rescue therapy, including ATG (anti-thymocyte globulin) in combination with etoposide and the anti-CD52 antibody alemtuzumab (Campath). In addition, newer biologics are now available, and some are being tested in HLH, including the interleukin-6 receptor agonist tocilizumab (Actemra). [20]
Lymphoma
Patients with B-cell lymphomas should be treated with the standard therapy for that disease. Special attention should be paid to the potential infectious complications of these therapies.
Gene therapy
Gene therapy offers the advantages of reduced toxicity from conditioning as, in general, less chemotherapy is required and the use of autologous cells removes the risk of graft versus host disease which causes significant morbidity and mortality post HSCT. [21]
Rivat et al reported a preliminary study in mice in which the immune function defects of XLP syndrome were corrected by lentiviral vector-mediated gene transfer of SH2D1A into autologous hematopoietic stem cells. The transfer of gene-corrected cells led to the restoration of natural killer (NK) and CD8 T cell cytotoxicity, NKT development, as well as GC formation and function upon immunological challenge. [22] However, SAP is a tightly regulated signaling protein that is predominately expressed in T cells, and the use of a ubiquitous human promoter that can drive expression in all hematopoietic cells may not be optimal.
An alternative therapeutic strategy to more directly address the T cell–dependent clinical manifestations of XLP1 is gene correction of the patient's own T cells. Murine studies utilizing gene-modified T cell transfers into mice demonstrated the correction of T follicular helper cell function, the restoration of germinal centers, and the improvement in baseline immunoglobulin levels. In addition, the correction of CD8+ T cell function was shown using an in vivo tumor model. These data support gene therapy as a potentially useful therapeutic option. [6]
Stem Cell Transplantation
Hematopoietic stem cell transplantation (HSCT), which includes the transfer of bone marow, mobilized CD34+ cells from peripheral blood, or umbilical cord–derived CD34+ cells, is currently the only definitive treatment for XLP syndrome. However, success is dependent on the availability of an appropriate donor who is human leukocyte antigen matched. A number of factors must be considered prior to HSCT, including the disease status, previous treatments, and the type of pre-conditioning regimen. An EBV-positive donor is preferred in patients with EBV-driven disease.
Several studies have evaluated the clinical outcomes of patients undergoing HSCT using either myeloablative-conditioning regimens or reduced-intensity-conditioning (RIC) regimens. [5, 23, 24] These studies revealed similar overall post-transplantation survival rates with RIC and myeloablative protocols in XLP1, with both averaging about 80%. [5, 24] The outcomes of allogeneic HSCT for XLP2 are less certain at this time. Early evidence suggests that reduced-intensity conditioning regimens should be considered due to very poor early experience with myeloablative preparative regimens. [24]
Long-Term Monitoring
Close monitoring of EBV viral loads is important in to allow the prevention of recurrent infections, organ damage such as bronchiectasis, and permit early treatment of EBV infection and more serious complications. [6] No formal surveillance guidelines exist; the following are general considerations [13] :
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Blood should be monitored by EBV-PCR for evidence of EBV infection if symptoms of infection or HLH develop.
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Blood counts, hepatic profiles, coagulation studies, and inflammatory markers (ferritin, soluble IL2R) should be monitored as needed based on clinical status for early evidence of HLH.
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IgG levels should also be monitored as needed based on clinical phenotype.
