Low Incidence of Human Herpesvirus 6 Reactivation in Unmanipulated HLA-Haploidentical Related Stem Cell Transplantation with Corticosteroid As Graft-Versus-Host Disesase Prophylaxis

Human leukocyte antigen (HLA)-mismatced/haploidentical stem cell transplantation (SCT) is a known risk factor for human herpesvirus 6 (HHV-6) infection. High plasma HHV-6 DNA loads in peripheral blood have been associated with the development of HHV-6-associated encephalitis. However, previous results have been obtained in patients who underwent HLA-matched SCT or combined populations, including a small number of HLA-mismatched SCTs.

To prevent life-threatening encephalitis associated with HHV-6 reactivation following SCT, we weekly examined plasma HHV-6 DNA loads using real-time quantitative-polymerase chain reaction methods until five weeks post-SCT in 11 unrelated umbilical cord blood transplantation (CBT) and 42 unmanipulated HLA-mismatched/haploidentical related SCT (haplo-SCT).

CBT recipients were conditioned with cytarabine 12 g/m², cyclophosphamide 120 mg/kg, and total body irradiation (TBI) 12 Gy as a myeloablative regimen and fludarabine 200 mg/m², cyclophosphamide 50 mg/kg, and TBI 3 Gy for a reduced-intensity regimen. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine A, with mycophenolate mofetil (MMF) or a short course of methotrexate (sMTX).

Haplo-SCT recipients were conditioned with fludarabine 120 mg/m², cytarabine 8 g/m², cyclophosphamide 120 mg/kg, and TBI 8–12 Gy for a myeloablative regimen and fludarabine 180 mg/m², rabbit ATG 8 mg/kg (Fresenius, Munich, Germany) or 4 mg/kg (Genzyme, Tokyo, Japan), and busulfan 8 mg/kg or melphalan　for a reduced-intensity regimen. Bone marrow and peripheral blood stem cells were infused freshly without T-cell depletion. GVHD prophylaxis against myeloablative and reduced-intensity haplo-SCT was performed with tacrolimus, sMTX, MMF, and methylprednisolone 2 mg/kg, and tacrolimus and methylprednisolone 1 mg/kg, respectively.

Compared to all of 11 CBT recipients (100%), plasma HHV-6 DNA was detected in 3 of 42 haplo-SCT recipients (7.1%) despite methylprednisolone use for graft-versus-host disease prophylaxis. As preemptive therapy, 8 CBT and 3 haplo-SCT recipients were administered foscarnet or ganciclovir at a median of four days (range, 0 to 9) after detection of HHV-6 DNA, followed by its rapid resolution except for one CBT recipient who had repeatedly positive results. The remaining 3 CBT recipients were administered foscarnet before detection of plasma HHV-6 DNA. Despite HHV-6 reactivation, no patients developed HHV-6-associated encephalitis.

In the present observations both HLA disparity, and the use of methylprednisolone and antithymocyte globulin was not necessarily a risk factor for development of HHV-6 reactivation in our haplo-SCT fashion. Furthermore, preemptive or prophylactic administration of antivirals potentially prevents HHV-6-associated encephalitis by suppression of HHV-6 reactivation at an early stage of SCT.