A group from Nantes, France, has published a study that demonstrates HHV-6 reactivation before engraftment to be strongly predictive of graft failure in adult patients following double umbilical cord blood allogeneic stem cell transplantation. In multivariate analysis, HHV-6 reactivation during aplasia (HR=2.63; 95%CI: 1.64-4.17; p<0.001), younger recipient age (<53 years, HR=1.97; 95% CI: 1.16-3.35; p=0.012) and lower HLA matching between the two units (3/6 or 4/6, HR=2.09; 95%CI: 1.22-3.59; p=0.013) were the three factors independently associated with graft failure in this study.
Double umbilical cord blood (UCB) allogeneic stem cell transplantation (allo-SCT) has been used increasingly in recent years for adults lacking suitable related or unrelated donors. The use of two UCB units is needed in adults in order to overcome the traditionally low cellularity of one UCB unit and thus ensure engraftment and decrease non-relapse mortality.
Among the 73 patients monitored for HHV-6A and HHV-6B, all were monitored once a week from transplant while two patients were only monitored after hematopoietic reconstitution. Overall, HHV-6B reactivation was documented in 59 patients out of 73 (81%) after transplant at a median time of 22 days (range: 0-112) post-transplant. No HHV-6A infections were detected. Among 27 patients who reactivated HHV-6 during aplasia (median time of occurrence: day +13 (range: 0-36)), 9 did not engraft (33%). Among the 44 patients who did not reactivate the virus during aplasia, only 6 did not engraft (14%). HHV-6 reactivation during aplasia was the strongest factor significantly and independently associated with graft failure in patients after dUCB allo-SCT.
The authors propose several possible explanations for the interference of HHV-6 reactivation on engraftment in dUCB allo-SCT patients. First, there may be a higher percentage of CD4+ T cells and lower absolute number of plasmacytoid dendritic cells (pDCs) contained in UCB units compared to other sources of graft. CD4+ T cells are the main target cells for HHV-6 infection, and pDCS are professional type 1 interferon-producing cells implicated in the viral defense of organism, thus the pDCs deficit in UCB graft material may explain higher incidence of HHV-6 reactivation after UCB allo-SCT while direct cytolysis of UCB CD4+ T cells by HHV-6B may favor a host-immune system mediated mechanism of graft failure. Second, CD134, a member of the TNF receptor superfamilly, has recently been identified as a specific cellular receptor for HHV6-B. While CD134 expression in CB graft material may favor HHV-6 reactivation and consequently graft cells lysis, further study is required.
No patients were administered a specific treatment for HHV-6 reactivation in this study, even though several trials in Japan have suggested a potential efficacy with foscarnet as a prophylactive and preemptive treatment for these patients. Foscarnet is often used preferentially in HSCT patients because it does not cause bone marrow suppression; it also shows the highest in vitro efficacy among drugs currently used in anti-HHV-6 therapy.
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