Prognostic Factors for CMV Reactivation/Infection after Stem Cell Transplantation and Value of Oral Valganciclovir for Preemptive Therapy.
Authors: Graef Thorsten , Bobrikova Tatjana , Adams Ortwin , Fenk Roland , Ruf Leilani , Zohren Fabian , Gattermann Norbert , Haas Rainer , Kobbe Guido 
Published: April 2020

INTRODUCTION: Cytomegalovirus (CMV) infection and disease are major complications of allogeneic stem cell transplantation (SCT). Different strategies have been developed to reduce the risk for CMV-associated disease and death. Before routine use of prophylactic regimens, CMV seropositive allogeneic HCT recipients had a 70 to 80 percent risk of reactivation of this virus, and one-third of these patients developed CMV disease. Preemptive antiviral therapy has markedly reduced the incidence and severity of CMV disease, but in spite of these advances significant morbidity and mortality are associated with CMV.

PATIENTS AND METHODS: In this unicenter retrospective study, we studied 197 adults who received allogeneic HSCT mostly because of myeloid leukaemia between 2000 and 2004. The median age was 46 years (range, 17-68), included were 80 female and 117 male patients. The grafts consisted mainly of PBSC (94%) and in 54% unrelated donors were used. Conditioning regimens included TBI in 42% cases. The CMV-serostatus proportions were D-/P- 34%, D-/P+ 20%, D+/P- 14% and D+/P+ 32%. All patients with ablative regimens received prophylactic i.v. acyclovir starting one day after SCT. After discharge oral CMV-prophylaxis consisted of famciclovir (52%), acyclovir (30%), valacyclovir (8%) or ganciclovir (10%). The prognostic factors for CMV reactivation in recipients were assessed by univariate analyses and Pearson correlations.

RESULTS: CMV seropositive recipients (p=.00001) and donors (p=.03) were significantly associated with a higher rate of CMV reactivations, and also the use of an unrelated donor was a prognostic factor for more frequent CMV reactivations (p=.007). TBI, age and GvHD were not associated with more frequent of CMV reactivations. Famciclovir and acyclovir were associated (p=.0001) with a higher rate of CMV-reactivations in CMV+ recipients, than valacyclovir or ganciclovir. In all, we observed 60 cases (31%) of CMV reactivation/infection (D-/P- 14%, D-/P+ 30%, D+/P- 7% and D+/P+ 49%) after a median of 50 days (range, 9-403). 48 of them (80%) were CMV+ before SCT and 50 of 60 (83%) were successfully treated. In all, 30 patients (7 CMV-, 23 CMV+) were treated with valganciclovir and 30 (5 CMV-, 25 CMV+) received other agents (valacyclovir n=11, foscarnet n=4 or ganciclovir n=15) after a single dose of i.v. IG. 29 of 30 patients who received valganciclovir had a negative PCR result, confirmed by 2 consecutive CMV-PCRs, after a median of 24 days (range, 9 – 365). In the group of the CMV+ recipients, valganciclovir resulted in a statistically superior therapeutic response (p=0.024) when compared to other agents. Oral valganciclovir therapy was well tolerated and toxicity was limitted to manageable cytopenia. 11 of 12 CMV- recipients (91%) were also successfully treated after CMV-infection, with no significant difference between the different therapeutic agents.

CONCLUSION: CMV seropositive recipient is the primary prognostic factors for CMV reactivation after allogeneic SCT. The prophylactic use of valacyclovir and ganciclovir were significantly better in CMV+ recipients, than famciclovir or acyclovir. Valganciclovir resulted in a better therapeutic response in comparison to other agents after CMV reactivation and should be tested as primary preemptive therapy in randomized trials.