Letermovir reduces chronic GVHD risk in calcineurin inhibitor-free GVHD prophylaxis after hematopoietic cell transplantation

Among major unmet needs in allogeneic stem cell transplantation (HSCT), the identification of a suitable donor, the control of infection complications (where cytomegalovirus [CMV] is paradigmatic), and the reduction of both disease relapse and graft-versus-host disease (GVHD) represent 4 key challenges. Originally developed in the setting of haploidentical HSCT,1 posttransplantation cyclophosphamide (PTCy) is now an established GVHD-prophylaxis platform, preventing the risks of acute and chronic GVHD (aGVHD and cGVHD) after HLA-mismatched as well as HLA-matched unrelated and related HSCT.(2-8) Despite this, the issue of high-rate infections is still a major concern.(9-13) A recent CIBMTR (Center for International Blood and Marrow Transplant Research) study showed how PTCy was associated with a higher incidence of CMV infection, regardless of donor type. Moreover, CMV reactivation was associated with the abrogation of cGVHD protection in the PTCy platform.14Herein, we aimed to investigate how the introduction of letermovir, a recently approved CMV-specific DNA-terminase inhibitor for CMV prophylaxis, could represent a turning point in real-life experience. We analyzed all adult patients undergoing HSCT for hematologic malignancies in our center between February 2016 and February 2021. Details on conditioning regimens are shown in supplemental Table 1. GVHD prophylaxis was calcineurin-inhibitors (CNI)-free and predominantly based on PTCy with sirolimus alone for matched related donor HSCT, or in combination with mycophenolate mofetil in case of a mismatched related or unrelated donor, in accordance with local guidelines.8 Median time on GVHD prophylaxis in patients surviving more than 3 months was 189 days (interquartile range [IQR], 164-240) in the letermovir cohort and 183 days (IQR 134-230) in the no-letermovir cohort (P 5 .26). Population description is shown in Table 1. Letermovir-based CMV prophylaxis has been introduced in the center guidelines from 1 March 2019 on, at the daily dose of 480 mg from Day 0 to Day +100, as recommended for CMV-seropositive patients not receiving cyclosporine. Moreover, all patients received antiviral prophylaxis with acyclovir. CMV monitoring on whole peripheral blood was done every week until Day +100 and then every 2 weeks until immunosuppressive therapy withdrawal. All HSCT survivors received regular lifelong assessments. In the case of aGVHD or cGVHD, first-line systemic treatment consisted of steroids (methylprednisolone 2 mg/kg per day for aGVHD; prednisone 1 mg/kg per day for cGVHD). Agents beyond the first-line included calcineurin inhibitors, methotrexate, extracorporeal photopheresis, ruxolitinib, and ibrutinib. The local guidelines for GVHD treatment did not change from 2016 onward. The primary endpoint of our analysis was to compare the cumulative incidence of clinically relevant CMV phylaxis and 105 patients from a letermovir-free historical cohort. Secondary endpoints included