Impact of Cytomegalovirus (CMV) Sero-Conversion Pre Allogeneic Stem Cell Transplant on Post-Transplant Outcomes

INTRODUCTION: The choice of an ideal allogeneic hematopoietic cell transplantation (allo-HCT) donor depends on numerous parameters, including cytomegalovirus (CMV) sero-status matching. We sought to determine the frequency of observed CMV seroconversions in patients pre allo-HCT and to investigate the impact on post-transplant CMV reactivation and survival outcomes.

METHODS: We conducted a retrospective study that included 752 adult patients that underwent allo-HCT at the Princess Margaret Cancer Centre from January 2015 to February 2020, before the adoption of letermovir prophylaxis in high-risk patients. CMV serology was assessed for all patients at consult and pre-transplant assessment. The cohort was divided into 4 groups based on apparent pre-transplant seroconversion: 1) From negative to positive (group1), 2) From positive to negative (group2), 3) Consistently negative (group3), 4) Consistently positive (group 4). We documented the occurrence of CMV viremia in all 4 groups depending on CMV sero-status of the donor, and investigated post-transplant outcomes. Standard routine monitoring for CMV viremia post-transplant was performed using quantitative polymerase chain reaction (PCR).

RESULTS: The minimum follow-up of survivors was 2 years. Eighty-nine patients (12%) had sero-converted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently sero-negative and 495 (66%) were consistently sero-positive pre-transplant. Transplant indications were acute myeloid leukemia (AML) in 50%, acute lymphoid leukemia (ALL) in 19% of patients. Median age of the entire cohort was 58 years (range: 18-76), 43% were female, 38% had hematopoietic cell transplant- comorbidity index (HCT-CI) ≥3, 20% had Karnofsky performance status (KPS) <90%, for 23% the disease risk index (DRI) was high or very high. Fully HLA matched donor were 78% of the donors. Haplo-identical donors were 14%, 58% of donors were unrelated and 28% were matched related. Reduced intensity conditioning (RIC) was given to 77% of patients, 89% underwent in-vivo T-cell depletion.

No difference was shown between the four CMV sero-status groups regarding overall survival (OS) (p=0.46), cumulative incidence of relapse (CIR)(p=0.76), neutrophil recovery (p=0.20), platelet recovery (p=0.69), grade III-IV acute graft-versus-host disease (GVHD)(p=0.93), moderate/severe chronic GVHD (p=0.57) or graft failure (p=0.28). For the four groups, the cumulative incidence of CMV reactivation at 6 months was 5.6%, 47.1%, 7.9% and 79.4% for group 1,2,3 and 4 respectively (Figure). In multivariable analysis, recipient CMV sero-status pre-transplant was associated with CMV reactivation (Hazard ratio HR=20, 95% CI= 11-34, p<0.0001 for consistently positive CMV sero-status compared to consistently negative, irrespective of donor CMV sero-status). Other parameters influencing CMV reactivation included increasing CD34+ cell dose (HR=1.02, 95% CI=1.004-1.04, p=0.02) and haplo-identical donor status (HR=2.1 in comparison to matched related donors, 95% CI =1.55-2.84, p<0.0001).

Considering both donor and recipient CMV sero-status, we separated the cohort into eight groups (Table). In 89 patients that converted CMV serology pre-transplant from negative to positive, 6 patients had CMV reactivation post-transplant (5 of them received stem cells from a CMV positive donor). In 17 patients that converted from positive to negative, 8 (47%) had CMV reactivation post-transplant. In the consistently CMV positive group, the incidence of CMV reactivation was high with either CMV negative (87.5%) or CMV positive (77.2%) donors (Table).

CONCLUSION: Allo-HCT patients that demonstrate CMV sero-conversion pre-transplant from negative to positive have a very low risk of CMV reactivation post-transplant. The observed sero-conversion in these patients may be due to passive CMV immunity acquired through the administration of blood-derived products. Patients that sero-converted from positive to negative pre-transplant continue to demonstrate CMV reactivation risk even with a CMV negative donor. Quantitative CMV IgG/IgM pre-transplant may help to differentiate between true sero-conversion and passively transmitted CMV immunoglobulins, which in turn may facilitate determination of CMV reactivation risk as well as donor choice.

Law:Jazz Educational: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara: Research Funding; Incyte Corporation: Research Funding; Sierra: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.