Risk Factors for Recurrent CMV Reactivation in CMV Seropositive Recipients Following T Cell Depleted Haematopoietic Stem Cell Transplantation

Introduction:Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). Seropositive status and the use of T cell depleted grafts are major risk factors for CMV reactivation due to delayed immune reconstitution. However, not all recipients of T cell depleted grafts experience CMV reactivation. Indeed some recipients only experience one reactivation episode, while others show persistent or recurrent CMV reactivation.

Aim: To identify additional risk factors which contribute towards recurrent CMV reactivation in the first 100 days in CMV seropositive recipients following T cell depleted grafts.

Patients and Methods:A retrospective study was performed from January 2004 to February 2014 at University Hospital of Wales, UK. CMV viral load was determined by real time PCR and T cell recovery was determined by flow-cytometry. Non-normal distribution data were expressed as median values (range). Chi-square test was used to compare differences between groups of categorical data. All statistical analyses were performed using SPSS 20 software (Chicago, IL).

Results: During the study period a total of 296 patients received allogeneic transplants of whom 124 (42%) were CMV seropositive. Recipient seropositive / donor seropositive (R+/D+) were 53% while 46% were recipient seropositive / donor seronegative (R+/D-). The median age was 56 years (range 19-72) and 64 (51%) were male. All patients received T cell depletion with either Campath-1H (111 patients 90%) or rabbit ATG (13 patients 10%). 32% had a sibling (SIB) donor and 68% a matched unrelated donor (MUD). 21% had no CMV reactivation during the first 100 days, 31.5% had one reactivation episode and 42.5% had a median of 2 episodes (range 2-5). A CD4 count at day + 100 of <50 cell/ul was the most significant risk factor in predicting CMV reactivation p=0.002. We then assessed associated factors that may predict for failure of recovery of CD4 count at day + 100. We found that patients who were refractory to first and/or second line of chemotherapy but subsequently responded to salvage therapy achieving either CR or PR showed significant correlation with recurrent CMV reactivation and low CD4 count at day + 100 following transplant (p=0.031) when compared with those who achieved CR to first line of chemotherapy. Also AML as the underlying disease was associated with both failure of recovery of CD4 count and an increased risk of recurrent CMV reactivation p=0.001 compared with all other disease groups. On the other hand, we didn't find any significant association with low CD4 count and other factors like recipient age (p=0.489), time from diagnosis to transplant (p=0.203), conditioning regimens (p=0.093), presence of acute GVHD (p=0.410) and concomitant fungal infection (p=0.675).

Conclusion: Failure of response to first and/or second line therapy and underlying diagnosis of acute myeloid leukaemia are associated with a lower CD4 count at day + 100 and increased risk of recurrent CMV reactivation in CMV seropositive recipients following T cell depleted graft.