Epstein-Barr virus (EBV) reactivation in allogeneic stem-cell transplantation:: Relationship between viral load, EBV-specific T-cell reconstitution and rituximab therapy

Background. Monitoring of Epstein-Barr virus (EBV) reactivation after allogeneic hematopoietic stem-cell transplantation, markedly improved with quantitative real-time polymerase chain reaction amplification of EBV DNA and visualization of EBV-specific CD8(+) T cells with peptide-human leukocyte antigen (HILA) class I tetramers. We decided to combine these methods to evaluate posttransplant EBV reactivation and rituximab therapy. Methods. We followed 56 patients treated with an HLA-genoidentical sibling (n=32), an HLA-matched unrelated donor (MUD, n=19), or an unrelated cord-blood transplant (n=5). EBV DNA was quantified in plasma and in peripheral blood mononuclear cells (PBMC). Patient CD8(+) T cells were stained with a panel of eight tetramers. Results. EBV DNA was detected in half of the patients, mainly in the MUD group (17/19). In 19 patients, viral DNA was detected only in the cellular compartment. All patients who controlled reactivation without rituximab and despite a viral load of greater than 500 genome equivalents (gEq)/150,000 PBMC mounted an EBV-specific CD8(+) T-cell response in greater than 1.4% of CD3(+)CD8(+) T cells. Plasmatic EBV genome was found in nine patients preceded by a high cellular viral load. Three of these patients controlled the reactivation before or without the introduction of rituximab, and they all developed a significant and increasing EBV-specific T-cell response. Patients with EBV-specific T cells at the onset of reactivation controlled viral reactivation without rituximab. Conclusion. This study emphasizes the benefit of an early and close monitoring of EBV reactivation and CD8(+)-specific immune responses to initiate rituximab only when necessary and before the immune response becomes overwhelmed by the viral burden.