CMV-Replication After Allogeneic Stem Cell Transplantation Is Associated with a Gvhd-Independent Reduced Relapse Risk in Lymphoma

We have previously showed that a CMV- reactivation after allogeneic HSCT is associated with a reduced risk for leukemic relapse and improved overall survival in patients with AML (Elmaagacli et al Blood 2011). Further, experimental data in a lymphoma mice model reported from Erlach et al. showed that coinfection with murine CMV revealed a strong anti-lymphoma effect by induction of apoptosis in lymphoma cells and improving rate of overall survival in mice after transplant.

This prompted us to investigate the influence of early replicative CMV infection in 94 (median age [years]: 45, 18 – 70) patients with lymphoma, who received transplants from unrelated (n=67) or related (n=27) donors. Patients were transplanted from HLA-identical (n=74), HLA-mismatched (n=20). 13 patients were transplanted for indolent lymphoma (FL n=11, CLL n=2), 67 patients for aggressive lymphoma (B-lineage n=35, T-lineage n=27, transformed n=5), 11 patients for MCL and 3 patients for HD. The disease stages of patients at HSCT were CR in 20 patients, PR in 40 patients, refractory in 30 patients and untested in 2 patients. 55 patients (59%) received previous autograft and 82 patients (87%) were treated prior to transplant with at least 3 chemotherapy lines. The hematopoietic cell transplantation specific comorbidity index (HCT-CI) were 0–2 in 76 patients (81%) and 3+ in 18 patients (19%). Myeloablative preparative regimen was applied in 60 patients (64%) while 34 patients (36%) received a RIC. Sixty-eight % of patients (n=48) were at risk for CMV reactivation based on either patient or donor pretransplant CMV serostatus. CMV replication as detected by pp65 antigenemia assay occurred in 34 patients (36%).

Taking all competing risks into account, the cumulative incidence of progressive free survival (PFS) at 5 years after alloSCT was 38 % (95 % confidence limit [95 % CL]: 31 – 45) in patients without as compared to 20 % (95 % CL: 9 – 31) in patients with early pp65 antigenemia (p<0.018). In multivariate analysis including parameters as grades II-IV acute graft-versus-host disease (GvHD), chronic GvHD, disease stage, chemorefractory, previous chemotherapy lines and pp65 antigenemia, CMV replicative status was confirmed as a strong independent predictor of PFS (hazard ratio [HR]: 0.29, 95 % CL: 0.08 – 1.00, p<0.049) together with chronic GvHD (HR: 0.32, 95 % CL: 0.13 – 0.80, p<0.016), and chemorefractory HR: 3.3, 95 % CL: 1.28 – 8.4, p<0.013). The anti-lymphoma effect was detectable across all lymphoma subsets and was most pronounced in patients with chemotherapy refractory lymphoma or refractory disease of lymphoma. However, Overall survival rate did not differ in both groups (51.9% for patients with CMV-replication versus 50.7% without n.s.)

This is the first report which demonstrates a strong and independent effect of early CMV replication on the PFS in patients with lymphoma. This effect deserves further and more comprehensive studies with regard to its clinical relevance and the underlying anti-lymphoma mechanisms.

Cumulative incidence of progression-free survival (PFS) stratified by posttransplant HCMV pp65-antigenemia and cell type of aggressive lymphoma.

No relevant conflicts of interest to declare.