Early CMV Viral Load Burden Predicts Late Clinically Significant CMV Infections in Patients Receiving Ptcy-Based Hematopoietic Cell Transplantation

Introduction: Cytomegalovirus (CMV) infection is associated with significant morbidity following hematopoietic cell transplantation (HCT) and is increased with the use of post-transplant cyclophosphamide (PTCY)-based graft-versus-host disease (GVHD) prophylaxis. With letermovir prophylaxis, the incidence of serious CMV infections and end-organ disease has decreased, but it remains challenging to predict those patients at highest risk for late CMV infections (defined here as those occurring after D100). Here, we investigated the association between CMV viral loads prior to D100 and the incidence of clinically significant CMV infections occurring between D100 and 1-year post-HCT.

Methods: This single-center retrospective study included 188 adults at risk for CMV infection (CMV recipient and/or donor seropositive) undergoing HCT with PTCy-based GVHD prophylaxis between February 2015 and February 2022 who survived without disease relapse or repeat HCT to D100 post-HCT. Patients were followed for one-year. Letermovir prophylaxis through D100 was used for CMV-seropositive recipients after 2017 per institutional protocol. Clinical information, CMV viremia measurements, and diagnosis of clinically significant CMV infections (CS-CMV; CMV viremia/disease requiring CMV therapy) were extracted from the electronic medical record. CMV burden was captured in all patients who developed viremia as the total area under the curve (AUC) calculated as the sum of the areas of trapezoids formed by plotting the viral load over time from D0 until D100. The first AUC group was comprised of patients with AUC=0 (n=102); 3 other AUC groups were assessed by AUC quartile (Q1, n=23; Q2/Q3, n=42; Q4, n=21) with those in Q2 and Q3 combined for analysis purposes. A landmark analysis was performed to evaluate the impact of AUC on CS-CMVi and non-relapse mortality (NRM) after D100 through one-year post-HCT. For patients with early episodes of CS-CMVi or infections that spanned the D100 timepoint, late CS-CMVi after D100 were recorded only for recurrent episodes following resolution of viremia (2 undetectable viral loads) and cessation of treatment. This study was approved by the Dana-Farber Harvard Cancer Center (DF/HCC) Institutional Review Board.

Results: Of 188 recipients of PTCy-based HCT at risk for CMV infection, the median age at HCT was 60 (19.4 – 78.3) and 57% were male. Acute myeloid leukemia was the most frequent primary disease (38%), followed by myelodysplastic syndrome or myeloproliferative neoplasm (31%), acute lymphoblastic leukemia (16%) and B-cell lymphomas (15%). Donor types included haploidentical (56%), HLA-mismatched unrelated (26%), and HLA-matched unrelated (19%). 115 patients (61%) received letermovir prophylaxis. Patients in Q1 had an AUC >0 and ≤1,904 IU/ml, in Q2-3 had an AUC >1,904 IU/mL and <27,453 IU/mL, and in Q4 had an AUC ≥27,453 IU/mL. Baseline and disease characteristics across quartiles were similar and there was no significant difference in NRM after Day 100. While 7.8% (95% CI 3.7 – 14.1) of those patients who never reactivated CMV prior to Day 100 developed late CS-CMVi; overall a higher CMV AUC prior to D100 was associated with a higher cumulative incidence of late CS-CMVi: Q4, 38.1% (95% CI 17.7 – 58.4); Q2/Q3, 19.0% (95% CI 8.8 – 32.2); Q1, 13.0% (95% CI 3.1 – 30.3) p=0.001.

Discussion: While letermovir has revolutionized the management of HCT recipients at risk of CMV reactivation, almost 30% of patients still develop CS-CMVi, including a significant number of cases after discontinuation of letermovir. Here, we show that patients with the highest burden of CMV viremia in the first 100 days after transplant, had the highest risk of late CS-CMVi after D100, while patients with no viremia in the first 100 days had the lowest risk of late CS-CMVi, demonstrating that in the setting of PTCy-based GvHD prophylaxis including those receiving letermovir prophylaxis, the CMV AUC is an additional tool to stratify patients at risk for late CS-CMVi. In addition, while some studies have suggested that early low-grade viremia is important for establishing CMV-specific immunity and protection from late CMV infections, we did not find that in this cohort of recipients of PTCy-based HCT.