Breakthrough CMV Viremia Outcomes of Letermovir Prophylaxis in Haploidentical Stem Cell Transplant with Post-Transplant Cyclophosphamide

Background

Cytomegalovirus (CMV) causes significant morbidity and mortality in patients who have undergone allogeneic transplant with 45-60% mortality rates or end-organ failure related to CMV disease secondary to immunosuppression. The use of post-transplant Cyclophosphamide (PT-Cy), commonly used in haploidentical transplants (haplo-SCT), has been associated with high rates of CMV infection, reported to be 42% based on a CIBMTR analysis performed in 2021.

Letermovir is FDA approved for prevention of CMV infection and disease in adult CMV-seropositive recipients [R+] undergoing allogeneic hematopoietic stem cell transplant (SCT).

Despite the use of letermovir to decrease incidence of CMV, there has been limited literature on the incidence of CMV breakthrough infections in haplo-SCT patients receiving letermovir. We set out to quantify the incidence of breakthrough CMV infections in patients undergoing haplo-SCT with PT-Cy receiving letermovir prophylaxis.

Endpoints

The primary endpoint was to determine the incidence of breakthrough CMV reactivation (single quantifiable viral load of >200 CMV IU/mL of plasma, 2 detectable viral loads of <200 CMV IU/mL of plasma tested 3-4 days apart) both early <100 days post-transplant and late >100 days. Key secondary end points were mortality due to CMV infection, incidence of disease, end organ involvement, duration of CMV treatment, risk factors associated with CMV reactivation (based on age, sex, and seropositive status), and timing of CMV infections after haploidentical transplant.

Methods

This single-center, retrospective, cohort study was performed at OHSU under an IRB approved protocol. Electronic health records of patients from January 2017 to September 2021 were retrospectively reviewed to assess incidence of breakthrough CMV infection. Eligible patients were at least 18 years of age, received a haploidentical hematopoietic stem cell transplant, and received PT-Cy for graft vs host disease (GVHD) prophylaxis. Those discovered to have active CMV infections (defined as..) during conditioning who were later put on letermovir or foscarnet for treatment of their CMV reactivation were excluded. These data have been previously reported. A posthoc analysis was then performed comparing patients who received letermovir prophylaxis with a historical treatment group that underwent haplo-SCT and receive an identical treatment protocol, but did not received letermovir prophylaxis. Patients were matched by age and CMV seropositive status in a 2:1 ratio (letermovir: no letermovir), and analyzed for comparative CMV related outcomes.

Results: A total of 14 eligible study subjects received letermovir prophylaxis (LP) and 7 patients did not receive letermovir prophylaxis (NLP). Overall, median age was 45 years in both groups with LP group being more male (63%) and the NLP being more female (70%) (Table 1). Thirteen of the 21 subjects received myeloablative conditioning. All subjects received PTCy, MMF until D+35 and tacrolimus goal 5-10 until D100. Letermovir was started 5 days post-transplant and stopped 100 days post-transplant. The number of patients that experienced early CMV reactivation (<100 days) was 3/14 (21.4%) and 6/7 (85.7%) in the LP and NLP treatment groups, respectively. Late CMV reactivations were rare, the LP group had 1 patient reactivate past 100 days post-transplant while there were no patients who reactivated past 100 days in the no NLP group. Mean timing of CMV viremia for the LP was significantly longer at 62 days while the NLP group was at 36.5 days. No significant risk factors were associated with age, CMV recipient seropositivity, or sex. Duration of CMV treatment was 23 days for the LP group and 21 days for the NLP group. Importantly, no patients in either cohort died of CMV (Table 2).

Discussion/Conclusion: Overall, we found the LP was associated with significantly less CMV reactivations, indicating that letermovir provides effective CMV prophylaxis for patients undergoing haplo-SCT with PT-Cy. Interestingly, mean timing of CMV viremia was later for the LP group compared to the NLP group. In our cohort, we did observe 1 patient who reactivated CMV late post-transplant. This observation and the results of a study published by L.W.Liu et al. (doi: 10.1016/j.jtct.2022.05.020.) may suggest that letermovir prophylaxis past day 100 post-transplant may be indicated for haplo-SCT patients.

Saultz:IKENA: Research Funding. Chen:Mesolbast: Honoraria; Morphosys: Honoraria. Gandhi:Gamida: Honoraria; CareDx: Consultancy; Orca Bio: Research Funding. Leonard:KiTE: Consultancy; Amgen: Research Funding; AbbVie: Research Funding; Pfeizer: Consultancy; Adaptive: Consultancy; Takeda: Consultancy. Maziarz:CRISPR Therapeutics: Consultancy, Honoraria; Novartis: Other: Support for research on CART; Orca Bio: Other: Support for research analysis and for medical writing; ASTCT: Membership on an entity's Board of Directors or advisory committees; Allovir: Other: Support for research on Allo HCT costs of care of infectious related complications.