High Incidence but Low Morbitiy of Early Cytomegalovirus (CMV) Infections Following Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation with Alemtuzumab and Ganciclovir Prophylaxis.

Background: IThe CD52 monoclonal antibody Alemtuzumab appears to be of great promise when incorporated as a lymphocyte depleting agent in RIC stem cell transplants. However the degree of functional immunosuppression produced by this antibody in this application has not yet been well characterized. As a surrogate functional marker, we have studied the incidence and pattern of CMV infection following RIC transplantation regimens with a regimen incorporating this antibody.

Methods: We analyzed CMV infections and risk factors in 49 patients who underwent allogeneic stem cell transplantation with a RIC regimen consisting of Fludarabine (120mg/m²), total body irradiation (450 cGy), antithymocyte globulin (40mg/kg), (n=11) or Alemtuzumab (40mg), (n=38) with or without CD45 monoclonal antibodies for various malignant disorders. Donors were HLA identical (related, n=20; unrelated, n=20) or one antigen mismatched (n=9). Ganciclovir was used as prophylaxis starting at engraftment or on recovery from cytopenias. CMV antigenemia and polymerase chain reaction based assays were performed on peripheral blood twice a week till day 100 and then on each clinic visit.

Results: The cumulative incidence of CMV reactivation at 1 year post-transplant with Alemtuzumab, in patients at risk, was 60% (95% CI, 45%–78%). Median time to reactivation of 24 days (range, 5– 95 days). Fifty seven percent (12/21) of the reactivations occurred before day 30. Recurrence of CMV reactivation occurred in 38% (8/21) of patients with a median number of recurrences of 2 (range, 1–6) and they extended beyond day 100. Only one patient developed CMV colitis and fully recovered with treatment. There was no CMV related mortality. The overall non-relapse mortality was 16% and overall survival in CMV reactivators and non-reactivators was not statistically different. Risk factors for CMV reactivation analyzed were patients age, sex, acute graft vs host disease, Alemtuzumab use, Ganciclovir use before day 30 and absolute lymphocyte count at day 30. In univariate analysis, use of Alemtuzumab (P= 0.001) and starting Ganciclovir after day 30 (P= 0.002) were significantly associated with CMV reactivation but in multivariate analysis only starting Ganciclovir after day 30 was statistically significant, P= 0.009 (95% CI, 1.5%–17%).

Conclusions: RIC stem cell transplantation using Alemtuzumab is associated with a particularly high incidence of early CMV reactivation, and is also associated with recurrent reactivation extending beyond day 100. Although the incidence of CMV disease was low, the high frequency of viral reactivation with Alemtuzumab is likely an indicator of profound post transplant immune suppression, suggesting that despite the “reduced intensity” of the conditioning, these patients require early, comprehensive and prolonged pre-emptive/prophylactic therapy for opportunistic infections.