Bone Marrow Transplantation (2011) 46, 18–19 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11
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COMMENTARY
Reduced-intensity SCT for chronic active EBV infection: excellent outcomes should trigger future investigations on how EBV-positive recipient cells are eradicated Bone Marrow Transplantation (2011) 46, 18–19; doi:10.1038/bmt.2010.258; published online 18 October 2010 Kawa et al.1 report in this issue on their experience of using hematopoietic stem cell transplantation (HSCT) to treat T- or NK-cell chronic active Epstein–Barr virus infection (CAEBV). EBV is a ubiquitous latent gamma herpes virus, infecting 490% of the world’s population.2 Primary infection usually occurs through the oropharynx, where mucosal epithelial cells and/or B cells become productively infected. During primary infection, EBV establishes lifelong latency in the memory B cells. Latently, infected cells traffic from blood to the oropharyngeal lymphoid tissue where it is thought that periodic reactivation of EBV into the lytic cycle leads to shedding of virus and infection of new B cells, perpetuating the infection.3 During acute infection healthy individuals mount a vigorous humoral and cellular immune response. Although antibodies to the viral membrane proteins neutralize viral infectivity, the cellular immune response is required for controlling primary and latent EBV infected cells.4,5 Latent EBV infection is associated with a heterogeneous group of diseases.6,7 These diseases often have unique geographic distributions, implying that genetic as well as environmental factors have an important role in addition to EBV in their pathogenesis.7 Although rare in the Western hemisphere T- and NK-cell CAEBV is most commonly seen in Japan. CAEBV patients do not have an underlying immunodeficiency and its etiology remains poorly understood.8–12 In CAEBV, EBV resides in T or NK cells and the pattern of lymphocyte infection is distinct from patients with hemophagocytic lymphohistiocytosis.11 In addition, most CAEBV patients have evidence of clonal expansion of their EBV-positive T or NK cells.8,10 As patients are at great risk of developing fatal lymphoma, leukemia or hemophagocytic syndrome, aggressive treatment strategies have been advocated to eradicate EBV-positive T or NK cells.8,12–14 Current treatment protocols rely on chemotherapy followed by HSCT similar to therapeutic strategies developed for hemophagocytic lymphohistiocytosis.8,13–15 Kawa et al.1 report in this issue on 29 CAEBV patients, who had received hemophagocytic lymphohistiocytosis type therapy (prednisone, VP-16, cyclosporine) and intensive combination chemotherapy before HSCT. While 11 patients received a myeloablative stem cell transplant (MAST), 18 received a reduced-intensity stem cell transplant (RIST). RIST recipients had a lower treatment-related mortality
in comparison to MAST recipients (5.6 vs 45%) resulting in a superior 3-year OS rate (95.0 vs 54.5%; P ¼ 0.016). MAST and RIST groups had similar patient characteristics; in particular there was no difference in regards to disease status at the time of transplant. Gotoh et al.16 had previously reported on the outcome of 14 CAEBV patients, who engrafted after HSCT. In their series, 4 patients received a MAST and 10 patients a RIST regimen. While only one MAST recipient survived long-term, six RIST recipients did. Taken together, both studies strongly suggest that use of a RIST regimen significantly improves OS of CAEBV patients by reducing treatment-related mortalities. One concern of RIST regimens is engraftment failure and recurrent disease. In regard to engraftment failure, there were two graft rejections. Both patients were successfully grafted with subsequent reduced-intensity transplants. Only 1 of 18 RIST recipients developed recurrent CAEBV early after transplant and achieved a complete response with a second reduced-intensity transplant. It is noteworthy that seven RIST recipients received unrelated umbilical cord blood as a stem cell source, which does not contain EBV-specific T cells raising the question of how residual EBV-positive T or NK cells are eliminated by the incoming graft? Clearly, these cells are resistant to conventional therapies, as few cures have been reported without HSCT. Of interest, none of the umbilical cord blood products was a 6/6 match, arguing that alloreactivity might have contributed to the elimination of residual EBV-positive recipient cells. Future studies are clearly needed to elucidate which cellular component of umbilical cord blood products is responsible for eradicating EBV-positive T or NK cells. These studies might not only pave the way to improve current adoptive immunotherapy approaches,17,18 but also contribute to our current understanding of the etiology of CAEBV.
Conflict of interest The author declares no conflict of interest.
Acknowledgements The author was supported by grants from the National Institutes of Health (P50 CA126752), and a SCOR grant from the Leukemia and Lymphoma Society (R7016-09).
Commentary
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S Gottschalk Departments of Pediatrics and Immunology, Center for Cell and Gene Therapy, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA E-mail:
[email protected]
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