Unexpected High Incidence of Human Herpesvirus-6 Encephalitis after Naive T Cell–Depleted Graft of Haploidentical Stem Cell Transplantation in Pediatric Patients

Abstract

The CD45RA T cell depletion (TCD) method has been used to deplete naive T cells, preventing graft-versus-host disease (GVHD) but preserving memory cells, providing immediate functional T cells with anti-infection, antileukemia, and antirejection effects. We describe a series of 25 consecutive high-risk patients with leukemia who received haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with CD45RA TCD. Each patient received 2 cell products: 1 created by CD34 positive selection and the other through CD45RA depletion from the CD34 negative fraction by a CliniMACS device. CD45RA-depleted haplo-HSCT was well tolerated, with rapid engraftment and low risk of severe acute GVHD and chronic GVHD. Although this treatment achieved a good control of viral reactivations, such as cytomegalovirus and adenovirus, we observed an unexpectedly high rate of limbic encephalitis due to human herpesvirus-6 (HHV-6; 8 cases). Characteristically, the infection appeared early in almost all patients, just after the engraftment. Although no patient died from encephalitis, 1 patient showed neuropsychological sequelae, and another experienced secondary graft failure just after the HHV-6 reactivation.

Low incidence of HHV‐6 reactivation in haploidentical hematopoietic stem cell transplantation with corticosteroid as graft‐vs‐host disease prophylaxis compared with cord blood transplantation

“…Based on the two recent pediatric studies of an unexpected high incidence of HHV‐6 reactivation in CD34‐positive selection‐based T‐cell depleted manipulated haplo‐SCT, we observed the lowest incidence of HHV‐6 reactivation in our haplo‐SCT even among various haplo‐SCT including post‐transplant cyclophosphamide method. Although their CD45RA T‐cell depletion method could offer the advantage of preserving the memory T cells beneficial for controlling viral reactivations, such as CMV and HHV‐6, they observed only good control of CMV reactivation, but not HHV‐6 . Conversely, in our unmanipulated haplo‐SCT, which uses neither in vitro T‐cell depletion nor post‐transplant cyclophosphamide, frequent CMV antigenemia developed despite the low incidence of HHV‐6 reactivation, although the underlying mechanism of this opposite incidence remains unclear.…”

“…Despite the use of methylprednisolone and ATG as GVHD prophylaxis and a reduced‐intensity conditioning regimen, respectively, it remains unclear whether the lack of HHV6 reactivation in our reduced‐intensity haplo‐SCT could be interpreted by the difference in graft sources in which donors will have memory T cells against HHV‐6. Based on the two recent pediatric studies of an unexpected high incidence of HHV‐6 reactivation in CD34‐positive selection‐based T‐cell depleted manipulated haplo‐SCT, we observed the lowest incidence of HHV‐6 reactivation in our haplo‐SCT even among various haplo‐SCT including post‐transplant cyclophosphamide method. Although their CD45RA T‐cell depletion method could offer the advantage of preserving the memory T cells beneficial for controlling viral reactivations, such as CMV and HHV‐6, they observed only good control of CMV reactivation, but not HHV‐6 .…”

“…based T-cell depleted manipulated haplo-SCT,24,25 we observed the lowest incidence of HHV-6 reactivation in our haplo-SCT even among various haplo-SCT including post-transplant cyclophosphamide method. Although their CD45RA T-cell depletion method could offer the advantage of preserving the memory T cells beneficial for controlling viral reactivations, such as CMV and HHV-6, they observed only good control of CMV reactivation, but not HHV-6 24,25.…”

Haploidentical transplantation in high‐risk pediatric leukemia: A retrospective comparative analysis on behalf of the Spanish working Group for bone marrow transplantation in children (GETMON) and the Spanish Grupo for hematopoietic transplantation (GETH)

“…In 41 cases, the graft was unmanipulated. In the remaining 151 cases, the ex vivo TCD graft was performed as follows: in 13 cases, peripheral blood stem cells (PBSCs) were highly purified for CD34 + cells; in 82 cases, patients received a combined depletion of donor CD3 + T cells and CD19 + B cells; in 34 cases, patients received a combined depletion of αβ T cells and CD19 + B cells; and in 22 cases, patients received a highly purified CD34 + graft, adding to the graft a product depleted in naïve CD45RA + T cells, using the CliniMACS System as previously described …”

Correlations of cytokine levels in cerebrospinal fluid and peripheral blood with outcome of HHV‐6B encephalitis after hematopoietic stem cell transplantation

“…Th1 immunity is known to play a crucial role in defenses against viruses. Recently, very high incidence of HHV‐6B encephalitis (8 of 25 patients) was reported among pediatric patients who received naïve T cell‐depleted graft of haploidentical stem cell transplantation . IL‐12‐primed Th1 cells derived from naïve T cells may have an essential protective role against the progression of HHV‐6B encephalitis.…”