Monitoring CMV-Specific CD8+ T-Cell Responses After Allogeneic Stem Cell Transplantation: A New Way of Guiding Anti-Viral Therapy

CMV reactivation after allo-SCT is usually monitored by CMV-PCR. We present the results of a pilot study looking at the additional use of Multimers for monitoring CMV-specific CD8+ T-cells at different intervals after allo-SCT.

10 patients (4 males) that underwent allo-SCT from HLA-identical siblings (n=4) or HLA-matched unrelated (n=6) donors between May 2010 and May 2012 were enrolled. The diagnosis was acute leukemia (n=6), lymphoproliferative disorders (n=2) and myelodysplastic syndromes (n=2). All patients and 8 donors were CMV seropositive. All patients were positive for the HLA-A*0201 allele. Pentamers (Proimmune, UK) and Streptamers (Gottingen GmbH, Germany) were directed against the epitope NLVPMVATV of the pp65_495-503 protein of CMV in the context of HLA-A*0201. Samples were obtained from engraftment at 30-day intervals until day +180 and 2-monthly thereafter.

The median follow-up was 12.6 (4-21) months after SCT. Engraftment occurred in all patients at a median of 21.2 (15-27) days. Acute GVHD was diagnosed in 4 patients at a median of 63.3 (25-92) days. One patient developed acute GVHD following infusion of donor lymphocytes for the treatment of mixed chimerism on day +323.

Three patterns were observed. In 2 patients no CMV-specific CD8+ T-cells could be detected after SCT despite several episodes of CMV-PCR reactivation requiring prolonged antiviral treatment. In 5 patients CMV-PCR reactivation triggered a rapid increase of CMV-specific CD8+ T-cells (median 112.2 x 10⁵/L, range 1.3-279.7 x 10⁵/L). However, the CMV-PCR became immediately negative and antiviral treatment was stopped in all reactivations within 2 weeks. Subsequent CMV-PCR reactivations also lasted under 2 weeks in this group. Finally, 3 patients showed an early immune reconstitution with CMV-specific CD8+ T-cells detected (median 1.3 x 10⁵/L, range 0.3-2.3 x 10⁵/L) at a median of 21 (17-33) days post-SCT. No CMV-PCR reactivation was observed in this group.

We conclude that monitoring CMV-specific T-cell immunity after allo-SCT in combination with CMV-PCR may be able to distinguish patients at higher risk of CMV reactivation and in need of prolonged antiviral therapy. Patients with CMV-specific CD8+ T-cells detectable at the time of CMV-PCR reactivation may only need a short course of antiviral therapy, while those with early and persistent CMV-specific CD8+ T-cells may be at a very low risk of developing CMV disease in the long-term.