Although cytomegalovirus (CMV) infection has been identified as one of the primary causes of morbidity and mortality after allogeneic stem cell transplantation (SCT), very little is known about the characteristics of this disease after reduced-intensity stem cell transplantation (RIST). Junghanss et al1 recently reported that the onset of CMV disease was significantly delayed after nonmyeloablative transplantation (NST) compared with myeloablative SCT. They speculated that host T cells, which remained after NST, help to protect recipients from CMV disease in the early phase of SCT. Their “true” NST-conditioning regimen consisted of low-dose (2 Gy) total body irradiation with or without fludarabine (Flu), which may allow most host cells to survive to provide overlapping immunity against CMV infection along with engrafted donor-derived cells. In our RIST study framework using Flu (180 mg/m2) or cladribine (0.66 mg/kg) plus busulfan (8 mg/kg), with or without antithymocyte globulin (ATG), achievement of donor T-cell chimerism was delayed when ATG was omitted.2 In this situation, we evaluated the correlation between the induction of T-cell chimerism and CMV infection by analyzing the medical records of 63 CMV-seropositive patients who underwent RIST between September 1999 and November 2001 from an HLA-matched (n = 49) or -mismatched (n = 14) related donor. Twenty-four patients underwent RIST without ATG, whereas 39 underwent RIST with ATG. T-cell donor-host chimerism analysis was performed with CD3+ cells by the polymerase chain reaction (PCR)–based amplification of polymorphic short tandem repeat (STR) regions, as previously described.2 Mononuclear cells (MNCs) were separated by the Ficoll-Hypaque method and then by magnetic cell sorting (MACS), using anti-CD3 monoclonal antibody combined with immunomagnetic beads, to give CD3+ and CD3− cells as final products. CMV infection was monitored at least once a week after engraftment by a commercially available kit using the monoclonal antibody HRP-C7 (Teijin, Tokyo, Japan) as previously described.3 The initially published data3 were updated and follow-up chimerism analysis showed that host T cells were present up to day 60 after RIST without ATG, but eventually disappeared by day 90. Positive CMV antigenemia was observed in 14 patients (58%) after RIST without ATG, and in 21 patients (54%) with ATG (P = .57, log-rank test). However, there was a significant difference in the median number of days to show positive antigenemia between RIST with and without ATG (P = .01, Mann-Whitney U test).
Thus, the data obtained with this more homogenous cohort, in terms of the cytoreductive regimen and CMV seropositivity, appear to further support the impact of residual host T-cell immunity against CMV, as suggested by Junghanss et al. Nevertheless, this still needs to be clarified in a future study. In contrast to the findings of Junghanss et al, in this series of high-risk patients who were managed with our preemptive therapy,3 only 2 patients developed CMV disease. Hence, our experience highlights the importance of close monitoring of CMV antigenemia even to the late phase after RIST, as suggested by Junghanss et al.
Risk of cytomegalovirus infection after transplantation with nonmyeloablative and reduced-intensity conditioning regimens
Nakai et al report cytomegalovirus (CMV) results in a cohort of hematopoietic stem cell transplant (HSCT) recipients who received HLA-matched or -mismatched related grafts following a reduced-intensity conditioning with fludarabine or cladribine and busulphan with and without antithymocyte globulin (ATG). Similar to our results, Nakai et al report persistence of host T-cell chimerism in the early posttransplantation period. There seemed to be a difference in the incidence of CMV antigenemia between regimens that did and did not contain ATG. Patients who received ATG had a prolonged time to clearance of CMV antigenemia. This is in line with our data, in which a trend toward a shorter time to CMV clearance was observed in nonmyeloablative recipients compared with myeloablative recipients without mixed donor-host T-cell chimerism.1-1 Nakai et al raise the question whether the observed effects in nonmyeloablative HSCT recipients are due to persistent host immunity or due to donor-derived lymphocytes. Our data in non–T-cell–depleted patients suggest that persistent host immunity is the likely reason because controlling for donor CMV serostatus did not change the results.1-1 However, in T-cell–depleted patients the situation may be different. Data in myeloablative recipients who received T-cell–depleted grafts indicate that donor serostatus is an important parameter of posttransplantation CMV risk.1-2 This suggests that CMV-specific donor T cells may be important in this setting. We agree that more laboratory studies are needed to define the relative impact of host and donor immunity in nonmyeloablative transplant recipients who are conditioned with regimens with and without in vivo T-cell depletion. Recently developed technology should be helpful to perform these experiments.1-3 1-4
Nakai et al also show incidence estimates of 3% for CMV disease using a preemptive therapy approach and conclude that this figure is lower than that reported in our study. The time of follow-up was not reported in the letter. In our study, the incidence of CMV disease in CMV-seropositive HSCT recipients was 6% (2/34 recipients) during the first 100 days after transplantation with a similar preemptive therapy approach.1-1 Recently we updated the data on CMV disease among related HLA-matched donor nonmyeloablative HSCT recipients.1-5 In this update, no new cases of CMV disease had occurred, resulting in an overall incidence of CMV disease of 4% (2/51 recipients) among CMV-seropositive HSCT recipients during the first 100 days after transplantation. Thus, the results appear to be similar. We also described an increasing incidence of late CMV disease among nonmyeloablative transplant recipients and emphasized that weekly CMV surveillance and preemptive therapy should be continued for at least 1 year in patients who had graft-versus-host disease and/or CMV reactivation before day 100.1-1 Thus, the risk for late CMV disease appears to be similar to that observed after myeloablative transplantation,1-6 and similar prevention strategies should be applied.
