Rate Of Cytomegalovirus Reactivation Research Articles

Evaluating the efficacy and safety of letermovir compared to valganciclovir for the prevention of human cytomegalovirus disease in adult lung transplant recipients.

Lung transplant recipients are at high risk for severe cytomegalovirus (CMV) disease. Off-label use of letermovir (LET) may avert myelotoxicity associated with valganciclovir (VGCV), but data in lung transplantation are limited. This study aims to evaluate the outcomes of LET prophylaxis among lung transplant recipients. This retrospective, matched cohort study included lung transplant recipients who received LET for primary CMV prophylaxis following VGCV intolerance. Patients were matched 1:1 to historical VGCV controls based on age, serostatus group, and time from transplant. The primary outcome was CMV breakthrough within 1 year post-LET initiation; secondary outcomes included hematologic changes. A total of 124 lung transplant recipients were included per group (32% CMV mismatch, D+R-), with LET initiated a median of 9.6 months post-transplantation. One CMV breakthrough event (0.8%) was observed in the LET group versus four (3.2%) in the VGCV group (p=.370). The median (interquartile range) white blood cell (WBC) count was3.1 (2.1-5.6)at LET initiation which increased to5.1 (3.9-7.2)at the end of follow-up (p <.001). For VGCV controls, WBC was4.8 (3.4-7.2)at baseline and5.4 (3.6-7.2)at the end of follow-up; this difference was not statistically significant (p=.395). Additionally, 98.4% of LET patients experienced ≥1 leukopenia episode in the year prior to LET compared to 71.8% the year after initiation (p <.001). Similar results were observed for neutropenia (48.4% and 17.7%, p <.001). LET prophylaxis was associated with a low rate of CMV reactivation and leukopenia recovery. LET may represent a reasonable prophylaxis option for lung transplant recipients unable to tolerate VGCV.

Application of CMV-IVIg as prophylaxis against cytomegalovirus reactivation in allogeneic hematopoietic stem cell transplantation patients.

Cytomegalovirus (CMV) reactivation remains one of the major and life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Yet, there is still a lack of safe and effective ways to prevent CMV reactivation in allo-HSCT patients. Here, we retrospectively analyzed a cohort of patients who underwent HSCT at our transplant center between 2018 and 2022 to evaluate the efficacy of prophylactic CMV-specific intravenous immunoglobulin (CMV-IVIg) against CMV reactivation. After Propensity Score Matching, the CMV reactivation rate was significantly decreased in the CMV-IVIg group (HR, 2.952; 95% CI,1.492-5.841; P=.002) compared with the control group. Additionally, the time duration of CMV reactivation (P=.001) and bacterial infection rate (P=.013) were significantly lower in the CMV-IVIg group. Moreover, prophylactic CMV-IVIg was more effective in CMV seropositive patients who received ATG as part of GVHD prevention (HR, 8.225; 95% CI,1.809-37.39; P=.006). In conclusion, CMV-IVIg is considered an effective and safe way to prevent CMV reactivation in HSCT recipients, which may be related to the acceleration of immune reconstitution in the early stage after transplantation.

Extended duration letermovir in allogeneic hematopoietic stem cell transplant

ObjectivesDespite the use of antiviral prophylaxis in recipients of allogeneic hematopoietic cell transplants (HCT), cytomegalovirus (CMV) is a common clinically significant infection and is associated with significant morbidity and mortality in this patient population. Based on current approval, letermovir is initiated within 28 days following allogeneic HCT for CMV seropositive recipients and continued through 100 days post-transplant. However, it is unknown whether patients who receive extended duration CMV prophylaxis with letermovir would result in less CMV reactivation and reactivation compared to those who do not. This study aimed to evaluate the efficacy of letermovir prophylaxis in CMV seropositive patients when continued for greater than 100 days post-allogeneic stem cell transplant. MethodsA single-center retrospective chart review was conducted on recipients of allogeneic HCT from November 2017 to July 2021. Patients were eligible for inclusion if they were at least 18 years of age, received an allogeneic HCT, CMV seropositive, and initiated letermovir between days 0–28 post-transplant. The primary endpoint of this study is to compare rates of CMV reactivation in patients who stopped letermovir prophylaxis at 100 days post-transplant (standard duration group) versus those who continued letermovir prophylaxis past day 100 (extended duration group). ResultsA total of 87 patients met the eligibility criteria for inclusion. The median duration of letermovir prophylaxis was 78 days in the standard duration group versus and 132 days in the extended duration group. There were more CMV reactivations in the standard duration group versus the extended duration group, 28% versus 19% respectively. CMV pneumonitis was observed in one of the patients in the standard duration group. All-cause mortality at day 200 post-transplant was similar between the two groups. ConclusionThe results of this study suggest that extended duration letermovir prophylaxis may be associated with less CMV reactivation compared to the standard duration of prophylaxis.

Impact of Early Natural Killer Cell Reconstitution on the Outcomes of T Cell-Replete Allogeneic Hematopoietic Stem Cell Transplantation.

Early immune reconstitution is crucial to successful outcomes after allogeneic stem cell transplantation (allo-HSCT). However, in T cell-replete HSCT, the impact of natural killer (NK) cells on transplantation outcome and the factors influencing early NK cell reconstitution remain unclear. In this retrospective study, we analyzed 128 patients with hematological malignancies who received the first T cell-replete allo-HSCT between May 2019 and September 2021. After application of a conditioning regimen, prophylaxis for graft versus host disease (GVHD), and engraftment, the patients received prevention and treatment procedures for cytomegalovirus (CMV) reactivation. NK cells, T lymphocytes and B lymphocytes in peripheral blood were collected and analyzed at 30, 60, 90, 135 and 180 days after transplantation to observe immune cell reconstitution. Overall survival (OS), relapse-free survival (RFS), minimal residual disease (MRD), relapse, and non-relapse mortality (NRM) were evaluated. SPSS 25.0 and R version 4.2.1 were used for statistical analysis. In patients with rapid NK recovery (NK cell count at 30 days post-HSCT [NK30] >165/μL and 60 days post-HSCT [NK60] >265/μL), we observed lower rates of NRM, CMV reactivation and acute GVHD (aGVHD). Multivariate analysis indicated that a lower NK30 (≤165/μL) was an independent factor associated with inferior OS and RFS. The NK30 and NK60 in patients with CMV reactivation and aGVHD after transplantation were significantly lower than those in patients without these complications. In addition, CD107a expression in NK cells was also significantly lower in patients who experienced aGVHD. Correlation analysis did not find an inhibitory effect of T-lymphocyte subset reconstitution on NK cells in the early stage after transplantation. Rapid NK cell reconstitution early after allo-HSCT had protective effects on NRM and survival. Promoting early NK cell reconstitution represents a new approach to improving the outcomes of allo-HSCT.

Bacterial, Fungal and Viral Infections in Patients with Hematological Malignancies: Investigation of CMV Reactivation as a Risk Factor

Reactivation of latent viruses such as human cytomegalovirus (CMV), as well as opportunistic infections associated with bacterial and fungal agents, cause serious clinical consequences in patients with hematological malignancies, which are characterized by both immunosuppressive drug use and functional and numerical disorders of immune system cells. In this study, it was aimed to investigate the association between CMV reactivation and the frequency of various simultaneous infections in adult patients with hematological malignancies. All CMV-DNA test results reported in the medical microbiology laboratory between November 2016 and February 2022 were retrospectively reviewed and the study group consisting of 270 adult patients with hematological malignancies was created. CMV-DNA follow-up results and clinical evaluations of these patients were examined and cases with CMV reactivation were determined. In the final stage, the possible association between CMV reactivation and the frequency of other infections identified by microbiological examination of patients' samples and radiological and clinical evaluations was investigated. Of 270 adult patients with hematological malignancies in the study group, 175 (64.8%) were male and 95 (35.2%) were female, and the mean age of the patients was 50.98 (±17.6). It was determined that 35.9% (97/270) of the patients had CMV reactivation during the follow-up period. The presence of 139 bacterial agents in 99 patients, 63 viral agents in 58 patients, and 56 fungal agents in 50 patients were determined. Bacterial infections were as follows according to the systems; 108 bacteremia (most frequently detected agent Escherichia coli; n=31, 28.7%), 21 urinary tract infections (most common cause E. coli; n=13, 61.9%), and 10 other bacterial infections. Fungal infections were as follows according to the systems; 36 respiratory tract infections (most common Aspergillus spp.; n=23, 63.9%), 6 fungemia (all Candida spp.), 14 other fungal infections (Candida spp.; n=11, and mucormycosis; n= 3). Viral infections were as follows, in order of frequency; hepatitis B (anti-HBc IgG seropositivity in 30 patients), COVID-19 (Coronavirus Disease-2019) in 14 patients, herpes simplex virus in 11 patients, herpes zoster in four patients, BK virus in three patients, and parvovirus B19 in one patient. CMV reactivation rates were found to be significantly higher in patients with fungal pneumonia, non-CMV viral reactivation, and bacterial bloodstream infection, p=0.046, p=0.003, and p=0.038, respectively. In the literature, CMV reactivation, risk factors associated with reactivation, and adverse clinical outcomes of CMV reactivation in patients with hematological malignancies have been investigated from many different aspects. However, additional pressures of CMV on the immune system and its negative effects on innate and adaptive immune responses and possible contributions of this situation to the development of other infections have not yet been studied in detail. We think that determining the possible effects of CMV reactivation on the development of opportunistic infections by comprehensive prospective studies may change antimicrobial therapy strategies in the management of CMV infections.

Letermovir Prophylaxis for CMV Reactivation in Allogeneic Stem Cell Recipients: A Retrospective Single Center Analysis.

Cytomegalovirus (CMV) reactivation is one of the most clinically significant complications in allogeneic stem cell recipients and a frequent cause for transplantation related mortality. Letermovir is a newly available and recently approved drug for CMV prophylaxis. In a retrospective single center analysis, we investigated the benefit of letermovir as CMV prophylaxis in allogeneic stem cell recipients. We included 48 CMV-seropositive transplant recipients from January 2017 to August 2020 from our department. We compared the rate of CMV reactivation in patients who received letermovir as prophylaxis from day 0 after allogeneic stem cell transplantation (alloSCT) with a control group that did not receive CMV prophylaxis. The primary endpoint was CMV reactivation and was defined as an increase of CMV copies over 1250 Ul/ml in the peripheral blood; secondary endpoints were overall survival (OS) up to 180 days, engraftment and all-cause mortality. We included 21 patients in the control group and 27 patients in the letermovir group. Letermovir treatment led to a significantly reduced incidence of CMV reactivation after alloSCT (33.3% in the letermovir group versus 76.2% in the control group, p<0.001). The OS at day 180 was 80.9% in the control group versus 92.6% in the letermovir group (p<0.05). The median duration of letermovir prophylaxis was 192±104 days. Our results indicate that letermovir prophylaxis is associated with a significant lower risk of CMV reactivation and improved overall survival in CMV-seropositive stem cell recipients. Moreover, a prolonged use of letermovir prophylaxis might be a survival benefit.

Ganciclovir in the Prevention of Cytomegalovirus Reactivation in Allogeneic Hematopoietic Stem Cell Transplantation: Non-Eliminative Reduction of Viral Load

Objective: Objective: Allogeneic hematopoietic stem cell transplantation (HCT) is used to treat various hematological disorders with a significant risk of treatment-related morbidity and mortality. During long immunosuppressed status, reactivation of cytomegalovirus (CMV) is a challenging complication with its diagnosis, treatment, and toxicity. In our study, we aimed to evaluate the effectiveness of ganciclovir to prophylaxis with valacyclovir in patients who have undergone allogeneic HCT. Material and Methods: Data of 82 patients were analyzed in a retrospective manner. Patients were grouped as patients receiving valacyclovir alone or ganciclovir plus valacyclovir. CMV-DNA levels were monitored weekly. Reactivation and alterations of viral DNA levels were recorded and compared in both prophylaxis regimes. Results: Mean age of patients was 44.85 years (19-69 years). The 31 patients were female (37,8%) and 51 were male (62,2%). All recipients were CMV seropositive before allogeneic HCT, and only 2 donors were CMV seronegative (2,4%). Forty-one of the patients received valacyclovir (50%), while 41 received ganciclovir plus valacyclovir (50%). Reactivation was not observed in 32 patients (39%). The 33 of the 41 patients receiving ganciclovir plus valacyclovir and 18 of the 41 patients on valacyclovir alone developed CMV reactivation. Although the inclusion of ganciclovir to valacyclovir was not related with decreased rates of CMV reactivation, the level of CMV DNAemia was relatively lower in patients on ganciclovir plus valacyclovir than in valacyclovir treatment alone. Conclusion: Inclusion of ganciclovir to valacyclovir in allogeneic HCT patients did not decrease the rate of CMV reactivation, and did not shorten the duration but reduced the degree of CMV DNAemia

Early Cytomegalovirus Reactivation after Allogenic Bone Marrow Transplantation Is Associated with the Loss of Recipient-Derived Humoral Immunity and Is Reduced By IL-6 Inhibition

Background:Interleukin-6 (IL-6) promotes the differentiation of pathogenic T cells and represents a dominant pathway of cytokine-dysregulation and graft-versus-host disease (GVHD). Cytomegalovirus (CMV) reactivation is a common and life-threatening infectious complication following allogenic bone marrow transplantation (BMT). The role of T cell immunity is long-established, and our group recently demonstrated that CMV strain-specific immunoglobulins (Ig) are critical in preventing CMV reactivation in preclinical models (Martins JP et al, Science 2019).Methods and Results:In a phase I/II clinical trial (Kennedy GA et al, Lancet Onc. 2014), we observed unexpectedly low rates of CMV reactivation following IL-6 receptor (IL-6R) blockade with tocilizumab (TCZ) compared to historical control (8/35 vs 20/43, P < 0.05). We used our preclinical models of murine CMV (MCMV) reactivation to pursue the mechanisms. We transplanted bone marrow (BM) and T cells from naïve B6 donors into CMV-latently infected B6D2F1 recipients and monitored MCMV reactivation. Ablation of IL-6R in donor T cells (using B6 CD4 cre x IL-6R fl/fl transgenic mice; IL-6R -/-) significantly reduced MCMV reactivation 5 weeks after BMT, as measured by plasma viremia and infectious viral loads in the liver (Fig 1A).Next, we examined the contribution of donor T and B cells to the suppression of MCMV reactivation by IL-6R inhibition. At 2 - 3 weeks after BMT and prior to MCMV reactivation, cytokine (IFNɣ/TNF) secretion from CD4 + T cells (in response to MCMV infected DC) was not detectable; MCMV m38 tetramer + CD8 T cells were present at very low frequencies (< 0.1% of CD8 T cells) which were not altered by IL-6R ablation. The frequency of CXCR-5 +PD-1 + T FH cells was comparable or lower in IL-6R -/- vs wild-type (WT) T cells after BMT. Transplant of BM from B6.μMT mice (unable to generate mature B cells and plasma cells) did not increase MCMV viremia (Fig 1B), excluding a role for donor B cells. Thus, early MCMV reactivation in the presence of IL-6 is independent of MCMV-specific T cells and donor B cells.To study the effects of IL-6 on recipient-derived humoral immunity we quantified MCMV-specific IgG in plasma after BMT and found that levels were significantly higher in recipients of IL-6R -/- T cells (Fig 1C). Furthermore, MCMV-IgG levels in plasma correlated with MCMV viremia (r = - 0.72, P < 0.0001) and viral loads in liver (r = - 0.68, P < 0.0001). MCMV-IgG2a, which can only be generated by B6D2F1 recipients, was significantly higher in recipients of IL-6R -/- T cells, confirming that differences in humoral responses were of recipient-origin. To define relevant mechanisms, we examined the kinetics of IgG after BMT by monitoring the loss of murine IgG (transferred on day 0) in plasma (Fig 1D). Recipients of IL-6R -/- T cells showed significantly slower loss of IgG than recipients of WT T cells, with or without GVHD prophylaxis with cyclosporine (CSA). Thus, ablation of IL-6 signaling in donor T cells is associated with reduced loss of recipient IgG and protection from MCMV reactivation, an outcome which seems independent of the effects of IL-6 on GVHD.We correlated our findings with data from a recent randomized, placebo-controlled, double-blind phase III clinical trial of TCZ administration on Day -1 of BMT (Kennedy GA et al, Blood 2021). TCZ reduced CMV reactivation in at risk seropositive BMT recipients of volunteer unrelated donor grafts regardless of acute GVHD (all at risk recipients, TCZ vs. control: 12/26 vs 21/28, P = 0.03; at risk without grade 2-4 GVHD, TCZ vs control: 6/18 vs 9/13, P = 0.03). TCZ did not alter the frequency of B cells or the frequency and function of HCMV-specific CD8 + T cells, quantified by HCMV-pMHC tetramer-staining and HCMV peptide-specific cytokine (IFNγ/TNF) secretion. In contrast, levels of HCMV-specific IgG at day +30 in HCMV-seropositive recipients were significantly higher in the TCZ versus control group (Fig 1E). Consistent with our preclinical studies, the level of HCMV-IgG significantly and inversely correlated with early HCMV reactivation (within 35 days) after transplant.Conclusion:These data confirm the importance of recipient-derived humoral immunity in controlling early CMV reactivation in clinical BMT recipients. Critically, we demonstrate the ability of IL-6R blockade to maintain protective humoral responses until effective donor-derived adaptive immunity can be generated. [Display omitted] DisclosuresBoeckh: Merck: Consultancy, Research Funding; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; GSK: Consultancy. Hill: Generon corporation: Consultancy; NapaJun Pharma: Consultancy; Compass Therapeutics: Research Funding; Syndax Pharmaceuticals: Research Funding; Applied Molecular Transport: Research Funding; iTeos Therapeutics: Consultancy, Research Funding; Roche: Research Funding; Neoleukin Therapeutics: Consultancy.

The effect of donor cytomegalovirus serological status on the outcome of allogeneic stem cell transplantation

Objective: Donor cytomegalovirus (CMV) serological negative status may have an adverse effect on the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT), while there is inadequate data for Chinese people. This study is to explore the impact of donor CMV serological status on the outcome of CMV seropositive patients receiving allo-HSCT. Methods: Our study retrospectively analyzed 16 CMV seropositive patients with hematological malignancies receiving allogeneic grafts from CMV seronegative donors (antibody IgG negative) at Peking University People's Hospital from March 2013 to March 2020, which was defined as D-/R+ group. The other 64 CMV seropositive patients receiving grafts from CMV seropositive donors at the same period of time were selected as matched controls through a propensity score with 1∶4 depending on age, disease state and donor-recipient relationship (D+/R+ group). Results: Patients in D-/R+ group developed CMV DNAemia later than patients in the D+/R+ group (+37 days vs. +31 days after allo-HSCT, P=0.011), but the duration of CMV DNAemia in D-/R+ group was longer than that of D+/R+ group (99 days vs. 34 days, P=0.012). The rate of CMV reactivation 4 times or more in D-/R+ group was 4/16, significantly higher than that of D+/R+ group (4.7%, 3/64, P=0.01). The incidences of refractory CMV DNAemia (14/16 vs. 56.3%, P=0.021) and CMV disease (4/16 vs. 4.7%, P=0.01) in D-/R+ group were both higher than those in D+/R+ group. In addition, the application of CMV-CTL as the second-line antiviral treatment in D-/R+ group was more than that in D+/R+ group. Univariate analysis and multivariate analysis suggested that CMV serological negativity is an independent risk factor for refractory CMV DNAemia and the duration of CMV infection. The cumulative incidence of aGVHDⅡ-Ⅳ, cGVHD, 3-year probability of NRM, overall survival, and the cumulative incidence of relapse were all comparable in two groups. Conclusions: Although there is no significant effect on OS and NRM, the incidence of refractory CMV DNAemia, the frequency of virus reactivation, and the development of CMV disease in D-/R+ group are higher than those in controls. Therefore, CMV seropositive donors are preferred for CMV seropositive patients.

Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation

AbstractReactivation of cytomegalovirus (CMV) is a common complication following allogeneic stem cell transplantation. Genetic determinants in the host and donor that may influence the rate of reactivation are currently unknown. Viral replication is controlled by T cells and natural killer (NK) cells and these share expression of killer immunoglobulin-like receptors (KIRs). We analyzed whether activatory KIRs carried by the donor influenced the subsequent rate of CMV reactivation in the patient. In transplantations involving siblings where both donor and recipient were CMV seropositive, donors with more than one activating KIR gene were associated with a 65% reduction in CMV reactivation. Multivariate analysis confirmed a significantly reduced risk of CMV reactivation in sibling transplantations where the donor had more than one activating KIR. Reduced-intensity transplantation and graft-versus-host disease grade 2 or higher were associated with an increased risk of CMV reactivation. This observation indicates that activating KIRs play an important role in the cellular control of CMV reactivation.

Real-World Experience Using Letermovir for CMV Prophylaxis in High-Risk Allogeneic Hematopoietic Stem Cell Patients in the Setting of Using T-Cell Depletion As Gvhd Prophylaxis and the Impact on CMV Reactivation, 1-Year Overall Survival, and 1-Year Gvhd-Free-Relapse-Free Survival

Background: Cytomegalovirus (CMV) is a major cause of morbidity in allogeneic hematopoietic stem cell transplant (HSCT) patients. Marty et al. 2017 showed that letermovir is effective in preventing CMV reactivation in high-risk HSCT patients, though only 16% were haplo-identical. Recently, Karam et al. 2019 showed decreased rates of CMV reactivation in haplo-identical HSCT using letermovir in unselected high-risk patients. The effects of letermovir on other transplant-related outcomes including overall survival (OS), relapse free survival (RFS), and Graft-versus-host-disease (GVHD)-free-/relapse-free survival (GRFS), however, are not as well-known. With the increased use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis in all transplant types, letermovir use may need to be broadened as those that are T-cell depleted are also at increased risk of CMV reactivation. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 18) who received allo-HSCT from 2018 to 2020. Recipients who were CMV positive, received T-cell depleting therapies such as PTCy for GVHD prophylaxis and/or ATG in the conditioning regimen, and those who fulfilled the criteria in Marty et al. 2017 were categorized as high-risk. Patients were considered to have CMV reactivation if they had clinically significant serum CMV viremia or organ involvement by day+100. Letermovir was initiated on day+21 for high-risk patients. The primary end-point assessed was day+100 CMV reactivation. Secondary end-points included 1-year OS, 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HSCT period. Results: A total of 116 adult HSCT recipients were reviewed. 51% were male and 49% were female. The donor sources comprised of 27% match related, 28% match-unrelated, and 49% haplo-identical. Most common diseases included AML (38%), ALL (38%) and MDS (8%). 64% received myeloablative conditioning regimens while 36% received reduced intensity regimens. Furthermore, 92% of patients received peripheral blood with 8% receiving bone marrow. 70% of patients at time of transplant were in CR1 or had stable disease. 61% of patients received letermovir prophylaxis (n=71), all high-risk, and 39% did not (n=45). 13 high-risk patients did not receive letermovir due to insurance limitations and were included in the non-letermovir group. 85% (n =60) received T-cell depleting therapies in the letermovir group compared to 51% (n=23). 90% (n=64) were CMV positive in the letermovir group and 64% (n= 29) were positive in the non-letermovir group. Both groups were similar in regard to the incidence of GVHD. The only factors significantly associated with CMV reactivation were haplo-HSCT, CMV recipient positivity, use of PTCy as GVHD prophylaxis and/or ATG in conditioning regimen, risk status, and GVHD (p = 0.054, p = .017, p = 0.003, p = 0.050, and p = 0.024 respectively). In a subset analysis of all high-risk patients, CMV reactivation was 32% in the letermovir group and 69% in the non-letermovir group (p = 0.03). All other factors were not significantly associated with outcomes. CMV reactivation in the letermovir group was (32%) compared to the non-letermovir group (29%). 1-year OS, 1-year TRM, 1-year RFS, and 1-year GRFS were 85%, 13.2%, 87%, and 60% respectively in the letermovir group compared with 88%, 10%, 90%, and 56% in the non-letermovir group, though not statistically significant. Discussion: Our study confirms improved CMV reactivation outcomes with use of letermovir in high-risk patients. Furthermore, all end-points were similar between both groups, despite increased usage of myeloablative conditioning overall and more high-risk patients in the letermovir group, indicating improved 1-year OS, TRM, and GRFS compared with historical outcomes. Although the primary and secondary end-points were not statistically significant, it may be clinically meaningful, as our center has demonstrated similar outcomes amongst those who were high-risk and received letermovir and those who were low-risk and did not. This suggests broadened use of letermovir may be needed in the prevention of CMV reactivation and the improvement in overall outcomes. Further studies using letermovir in low risk patients may be necessary to investigate improved outcomes in the allo-HSCT setting. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

Incidence of CMV Replication and the Role of Letermovir Primary/Secondary Prophylaxis in the Early Phase After Allogeneic Hematopoietic Stem Cell Transplantation - A Single Centre Study.

Cytomegalovirus (CMV) replication may cause life-threatening complications after allogeneic haematopoietic stem cell transplantation (allo-HSCT). The aim of the study was to characterize CMV events, and the outcome of letermovir (LTV) CMV prophylaxis. In this retrospective analysis of patients treated with an allo-HSCT between 2010 and 2020, we determined plasma CMV events, as well as associated risk factors. We identified 423 patients who had undergone allo-HSCT between 2010 and 2020. CMV DNAemia was found in 130/423 (30.7%) of patients. CMV reactivation rate was significantly higher in patients with acute graft-versus-host disease, HLA mismatch, and CMV IgG seropositivity of donors and recipients. Among 42 patients receiving LTV prophylaxis those, 5 (11.9%) showed CMV DNAemia under LTV versus 87/353 (24.6%) in a control group. Despite the development of better approaches with weekly monitoring and early treatment initiation, CMV reactivations play an important role after allo-HSCT.

Real World Outcomes of Letermovir Prophylaxis in Unselected High Risk CMV Seropositive Hematopoietic Stem Cell Transplant Recipients

Introduction: Cytomegalovirus (CMV) is a leading cause of morbidity following allogenenic hematopoietic stem cell transplant (HSCT). Letermovir (LTV), an orally available antiviral drug which inhibits the CMV-terminase complex, was recently approved for CMV prophylaxis in CMV-seropositive HSCT recipients due to its ability to significantly reduce the risk of clinically significant CMV infection and its favorable toxicity profile. In the pivotal phase 3 study, subgroup analysis suggested increased benefit of LTV in patients at higher risk for CMV infection (i.e. unrelated or haploidentical donor (HID) vs. matched related donor), however HID transplants represented only 16% of the study population1. Therefore, we conducted a retrospective analysis of CMV reactivation rates, before and after the initiation of routine LTV prophylaxis, to determine the real-world safety and efficacy of LTV in an unselected group of CMV-seropositive high risk HSCT recipients, including a large number of HID transplants. Methods: We conducted a retrospective review of 106 consecutive CMV-seropositive high risk allogeneic HSCT recipients between 2017 and 2019. We compared the incidence of CMV infection immediately prior to the initiation of routine LTV prophylaxis in high risk transplant recipients (pre-LTV) (n=41) to that occurring after the initiation of LTV prophylaxis (post-LTV) (n=63). HSCT recipients were considered high risk if they had received at least one of the following: transplant from a haploidentical donor, matched unrelated donor, umbilical cord blood donor source or received anti-thymocyte globulin. CMV infection was defined as the need for pre-emptive therapy or documented CMV disease. The cumulative incidence (CI) of CMV infection at 100 days and 180 days were calculated to accommodate death as a competing risk. We used the Wald test to compare the CI at 100 and 180 days between the two cohorts. Results: Baseline characteristics of the pre- and post-LTV cohorts were similar, with HID transplants making up the majority of HSCTs in both groups, 65% and 64% respectively. We found a significantly lower CI of CMV infection at both 100 and 180 days in the post-LTV cohort when compared to the pre-LTV cohort (19.4% vs. 68.3% and 27.6% vs. 71% respectively; p&lt;0.001) (Fig. 1). Despite lower CMV incidence following LTV prophylaxis, there was no significant difference in median time to CMV infection when compared to patients not receiving LTV prophylaxis (median [range] 40 [10, 243] vs. 36 [10, 180] days, p=0.72). The CI of CMV disease was 1.6% in the post-LTV cohort vs. 7.3% in the pre-LTV cohort (p=0.186). No significant differences were observed in any other outcome variable including overall survival, non-relapse mortality, relapse, acute graft-versus-host disease (GVHD) or time to neutrophil or platelet recovery. A preplanned subset analysis limited to HID transplant recipients (Fig. 2) again demonstrated a significant decrease in CMV infection in the post-LTV cohort at 100 and 180 days (27.9% vs. 80.8% and 34.6% vs. 84.6% respectively; p&lt;0.001). Conclusion: This single center analysis confirms the benefit of LTV prophylaxis in reducing the risk of clinically significant CMV infection in unselected high risk CMV-seropositive HSCT patients, including a substantial number of HID transplant recipients. We found no significant impact of LTV prophylaxis on any other transplant outcome including hematologic engraftment, GVHD, relapse or mortality. In contrast to the pivotal phase 3 study, we saw few CMV infections occurring past day 100 after discontinuation of LTV prophylaxis. Future planned analyses will include comparisons of antiviral usage and associated toxicities (i.e. cytopenias), overall treatment charges and hospitalization/resource utilization. Disclosures LaPorte: Merck: Speakers Bureau.

Incidence and Predictive Risk Factors of Infective Events in Patients With Multiple Sclerosis Treated With Agents Targeting CD20 and CD52 Surface Antigens.

ObjectiveMonoclonal antibodies (MAbs) directed against the CD20 and CD52 antigens are used increasingly in patients with multiple sclerosis (MS). Several life-threatening opportunistic infections have been reported in postmarketing case series. The aim of this study was to investigate the incidence of infections and associated prognostic factors during the first year of treatment in patients receiving anti-CD20 (ocrelizumab or rituximab) or anti-CD52 MAbs (alemtuzumab).MethodsA retrospective study was conducted in patients with MS referring to the Neurodegenerative Diseases Center at the University of Naples Federico II who received MAbs between November 2015 and June 2018.ResultsA total of 163 patients were enrolled. Approximately 40% of patients experienced lymphocytopenia during treatment. Eighty-six infective events were reported in 67 patients (41%). Bacterial infections were significantly more frequent with anti-CD20, whereas viral infections prevailed with alemtuzumab. Cytomegalovirus reactivation rates were significantly higher in the alemtuzumab group than in patients on anti-CD20 (51% vs 6%, P < .001). The overall annualized infection rate was 1.1 per patient-year, higher in patients on anti-CD52 versus those on anti-CD20 regimens (1.5 vs 0.8 per patient-year). Alemtuzumab treatment, prior exposure to ≥2 MS drugs, and iatrogenic immune impairment significantly and independently predicted an infection event (adjusted hazard ratio [aHR], 2.7; P = .013; aHR, 1.7; P = .052; and aHR, 2.9; P = .004; respectively).ConclusionsGiven their considerable infection risk, MS patients receiving MAbs should undergo timely follow up and tailored preventive interventions. Anti-CD52–based treatment, prior exposure to MS drugs, and on-treatment immune impairment are significant predictive factors of infection and their evaluation could help clinicians to stratify a patient’s risk of infection.

Letermovir for primary and secondary cytomegalovirus prevention in allogeneic hematopoietic cell transplant recipients: Real-world experience.

Cytomegalovirus (CMV) is associated with significant morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) patients. We evaluated the efficacy of letermovir as primary and secondary prophylaxis in 53 CMV-seropositive hematopoietic stem cell transplant recipients. 70% of patients were at high risk for CMV reactivation and disease (primarily ex vivo T-cell-depleted HCT [n=18; 34%] or haploidentical T-replete HCT [n=12; 23%]). This was a retrospective, single-center study which identified patients transplanted between January 2018 and June 2018. Patients were followed through September 2018. The primary outcome was the incidence of clinically significant CMV infection (CMV viremia requiring preemptive treatment or CMV disease). Primary letermovir prophylaxis started at a median of 7days (range, 7-40) after allo-HCT. The median duration of primary letermovir prophylaxis was 116days (range, 12-221). With primary prophylaxis in 39 patients, the observed CMV reactivation rate was 5.1%. Twenty-nine patients continued primary prophylaxis beyond 14weeks with a reactivation rate of 3.4%. No recurrent reactivation was seen with secondary prophylaxis of an additional 14 patients. Our experience demonstrates the efficacy of letermovir in a real-world setting for CMV prevention for the first 14weeks and continued efficacy when given longer than 14weeks after allogeneic stem cell transplantation or as secondary prophylaxis.

PS1270 HIGH INCIDENCE OF CYTOMEGALOVIRUS (CMV) REACTIVATION IN HEMATOLOGICAL PATIENTS TREATED WITH BENDAMUSTINE BASED CHEMOTERAPY REGIMENS

Background:Bendamustine (BENDA) alone or in combination with other drugs is being increasingly used in the treatment of chronic lymphocytic leukaemia (CLL), non‐Hodgkin lymphomas (NHL), and multiple myeloma (MM) due to its safety and efficacy. Variable infection rates both in BENDA monotherapy and in BENDA‐containing regimens have been documented. Limited data are available on cytomegalovirus (CMV) reactivations and infections in patients with hematologic malignancies undergoing BENDA therapy.Aims:We retrospectively analysed for CMV reactivation 120 consecutive patients who underwent therapy with BENDA alone (6%), combined with rituximab (81.5%) and combined with rituximab and dexamethasone. Our cohort included 95 B‐NHL (49 indolent e 46 aggressive B‐LNH), 5 T‐NHL, 18 CLL and 2 HL with a median age of 72 years (range 47–88) and a female to male ratio of 0.67 (female/male: 48/72). BENDA was used as first line therapy in 94 patients (78%) and as a salvage therapy in 26 patients (22%).Methods:CMV monitoring was performed on plasma samples by a real‐time TaqMan CMV‐DNA polymerase chain reaction (PCR) assay, according to the manufacturers’ recommendations (Roche). Quantitative CMV DNA was detected every 3 weeks before starting the next BENDA cycle, while CMV DNA monitoring was performed once a week in cases of CMV reactivation defined by plasma CMV DNA levels higher than 137 IU/ml.Results:CMV reactivation was detected in 29 patients (24%) among the 120 patients analysed for CMV‐DNA, with a median CMV peak viral load of 1835 UI/ml. Reactivation occurred after 55 days (range: 11–313 days) since the first BENDA administration in 27 B‐LNH (10 aggressive and 17 indolent B‐LNH), 1 T‐LNH and 1 CLL.Reactivation rates were different in each BENDA protocols: 1/7 (14.3%) in patients treated with BENDA, 21/98 (28.6%) in patients treated with R‐BENDA and 7/15 (46.7%) in patients treated with RD‐BENDA. All patients showed a deep lymphocytopenia at the time of CMV reactivation with a median of 345 lymphocytes/mm3.We furthermore analyzed potential risk factors for CMV reactivation during a BENDA containing treatment such as: age of the patients, diagnosis, type of BENDA regimen used, CMV‐specific IgG levels, nadir of total lymphocytes and total IgG during treatment, T CD4+ lymphocytes levels.The nadir of total lymphocytes and total IgG resulted significantly associated to CMV reactivation in a multivariate analysis (P‐value = 0.0001 and P‐value = 0.0008, respectively).Summary/Conclusion:Using these variables, we built a risk score for CMV reactivation which can help the physician to assess the risk of CMV reactivation in each patient and eventually start CMV‐DNA monitoring, prophylaxis or preemptive therapy.This single‐center study provides further evidence that BENDA regimens for lymphoproliferative diseases are associated with a high CMV reactivation rate and therefore a strict surveillance for CMV is required during their use.

Cytomegalovirus Reactivation in Children with Hemoglobinopathies Who Undergo Hematopoietic Cell Transplantation with Distal Alemtuzumab

Introduction Cytomegalovirus (CMV) viremia after allogeneic hematopoietic cell transplant (HCT) is associated with substantial morbidity. In vivo T cell depletion with alemtuzumab is a known risk factor for CMV reactivation. After observing very early CMV viremia in patients who received distal alemutuzumab in preparation for HCT for hemoglobinopathies, we implemented a quality improvement project to decrease the burden of CMV in this population. Objective To describe patterns of CMV reactivation before and after changing our CMV prophylaxis and surveillance strategies. Methods We reviewed medical records of children undergoing HCT for sickle cell disease (SCD) or beta thalassemia at Children`s Hospital of Philadelphia between 2007-2018, who received distal alemtuzumab containing conditioning regimens. Patients received alemtuzumab (48 mg, starting ∼22 days before transplant) with fludarabine and melphalan. Beginning in February 2014, CMV seropositive (CMV+) patients received prophylaxis with valganciclovir from completion of alemtuzumab through day -1 and foscarnet starting on day 0, as well as weekly CMV surveillance beginning with alemtuzumab administration. Rates of CMV reactivation, as well as balancing metrics [time to engraftment and rate of acute kidney injury (AKI) within 100 days post-HCT] were evaluated before and after implementation of this preventive approach. Results Twenty-nine children were included in the analysis. The median age was 11.1 (range: 3.1 to 17.3) years at HCT; 22 (75.9%) patients had SCD and 8 (24.1%) had beta thalassemia. All patients received bone marrow grafts, 22 (75.9%) from HLA-identical siblings and 7 (24.1%) from unrelated donors. Prior to HCT, 13 patients were CMV+. Of those, 11 (84.6%) developed CMV reactivation (7/7 pre-intervention and 4/6 post-intervention). Time from alemtuzumab start to CMV reactivation, regardless of prophylactic strategy, is shown in Figure 1. CMV reactivation occurred at a median of 4 (range: -11 to +13) days after planned HCT. During the post-intervention period, CMV reactivation was identified in 2 patients prior to the start of the proximal cytotoxic phase of conditioning and HCT was delayed until viremia cleared. One CMV seronegative patient developed CMV viremia 47 days post-HCT. Median time to engraftment was similar before and after the intervention (12.5 versus 13 days), as was the proportion of patients with AKI (3/7 versus 1/6). Conclusion In this cohort, rates of CMV viremia were high and CMV reactivation often occurred very early in the transplant course. In two cases, CMV reactivation was identified prior to transplant day, necessitating a delay in HCT. Consideration should be given to implementing a program of screening or prophylaxis beginning as early as the start of alemtuzumab administration in CMV+ patients. Further research is needed to determine the optimal prophylactic strategy.

Impact of Post-Transplant High-Dose Cyclophosphamide and Donor Sources on CMV Reactivation.

Introduction Cytomegalovirus (CMV) reactivation remains a common cause of morbidity and mortality following allogeneic hematopoietic cell transplant (HCT) despite attempts at prophylaxis. Following transplantation, surveillance of the peripheral blood CMV viral load with early aggressive treatment is commonly employed and has been an effective strategy at preventing overt infection. While a matched related donor (MRD) is often the preferred transplant type, the use of alternative donors including matched unrelated donors (MUD), mismatched unrelated donors (MMUD) and haploidentical (HI) transplants, has greatly increased over the past several years. The data regarding CMV infection among these alternative donor types is scarce. Objectives To better characterize the extent and risk factors for CMV reactivation among patients who received an allogeneic HCT for hematologic malignancies, particularly among HI transplant recipients and those who received post-transplant high-dose cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis. Methods A retrospective analysis was performed on 88 adults with hematologic malignancies who received an allogeneic HCT at our institution from 2012-2017. Only cases with CMV seropositive donors and/or recipients were included. We compared donor types/sources, conditioning regimens, GVHD prophylaxis regimens, and assessed for CMV reactivation utilizing the peripheral blood polymerase chain reaction (PCR) values that are monitored in post-transplant clinic visits. Results Nineteen (22%) patients received MRD transplants, while the remainder received alternative donor sources, including 17 (19%) HI transplants. Overall, the rate of CMV reactivation was 27% with a significant difference noted between donor sources (p= Conclusion HI HCT transplant recipients are at high risk for CMV reactivation. The use of myeloablative conditioning regimens or PTCy did not affect the rate of CMV reactivation.

Efficacy and Pharmacoeconomic Impact of Letermovir for CMV Prophylaxis in Allogeneic Hematopoietic Cell Transplant Recipients

Cytomegalovirus (CMV) seropositivity and early CMV reactivation after hematopoietic-cell transplantation (HCT) remain associated with increased mortality. Those at high risk include CMV seropositive recipient/donor pairs (CMV R+ or D+) and those on escalated immunosuppression (prednisone ≥ 20mg/kg) for graft versus host disease (GVHD). Historically, our institutional CMV reactivation rate (RR) was 63% in our high risk cohort, similar to national average. Prophylaxis with letermovir, a new CMV-antiviral therapy, significantly reduced the incidence of CMV reactivation and viremia in a prospective trial (Marty FM, et al. NEJM 2017). The purpose of this study was to assess CMV reactivation, defined as CMV viral load > 500 IU/mL, with letermovir prophylaxis and its pharmacoeconomic impact in an outpatient transplant program. This was a retrospective review of adult HCT patients receiving letermovir from December 2017-August 2018 at Vanderbilt University Medical Center. Use of letermovir was standardized at a program level. Therapy was used in high risk patients, undergoing HCT with matched-unrelated donor (MUD), cord blood donor or haploidentical donor transplants with no active CMV reactivation prior to initiation and no anti-CMV treatment post-HCT. Primary endpoint compared CMV RR to historical controls utilizing a two-sided t-test. Secondary outcomes evaluated logistics and cost impact. 30 patients met entry criteria (26 CMV R+, 21 D+), RR was significantly lower than our historical control (20% vs 63%; p = 0.0003). Median time to reactivation was 38 days post-HCT (29-58). 4 of the 6 patients with reactivation received induction therapy with ganciclovir (50%), valganciclovir (25%), or letermovir (25%, peak viral load 740 IU/mL) for ∼40 days (31-52). All were CMV R-/D+ with AML and received HCT from MUD (75%) or haploidentical donors (25%). The remaining 2 patients (CMV R+/D+) had low level reactivation (137-500 IU/mL) and continued letermovir through day 100 without additional CMV treatment. Patients started letermovir by day 14 post-HCT (5-65) with a median 83 days (7-158) of prophylaxis. 3 patients received letermovir as secondary prophylaxis due to prior CMV reactivation or escalated immunosuppression for GVHD. Of those patients, reactivation occurred in 1 patient (AML MUD transplant; CMV D-/R+) who had 2 reactivations while on foscarnet therapy. No letermovir resistance was observed. Letermovir copay was between $10 and $360/month. 76% of prescriptions required prior authorization, 19% monetary grant, 18% patient assistance. Majority had private insurance (49%) and Medicare/Medicaid (36%) with a median of 3 days for approval and 5 days from prescription submission to patient medication pick-up. Primary prophylaxis with letermovir is associated with significantly lower RR compared to historical controls and is financially feasible with dedicated pharmacy services.

Post Transplant Prophylaxis with High Dose Valacyclovir through Day 100 Versus Day of Post Transplant Hospital Discharge Decreases Cytomegalovirus Reactivation in Adult Umbilical Cord Blood Transplant Recipients

Abstract Background: Cytomegalovirus (CMV) infection remains an important cause of morbidity and cost following umbilical cord blood transplantation (UCBT). While the introduction of letermovir represents a novel approach to CMV prophylaxis, optimal CMV management strategies remain controversial. An intensive strategy to prevent CMV disease including one week of pre-transplant ganciclovir followed by high-dose acyclovir or high-dose valacyclovir through day 100 reduced post-transplant CMV reactivation (Milano et al, Blood 2011), but this approach is costly and potentially challenging to administer. Insurance approval for outpatient high-dose valacyclovir is variable, and the pill burden of high-dose acyclovir for post-transplant patients may be unmanageable. A recent study demonstrates that the removal of pre-transplant ganciclovir does not decrease CMV reactivation rates (Hill et al, BBMT 2018). At our center we have attempted to implement the high intensity strategy described above, but for patients who are unable to obtain high-dose valacyclovir at hospital discharge, we have transitioned to standard dose 800 mg acyclovir twice daily. Additionally, in November 2016, we discontinued pre-transplant ganciclovir. To examine the efficacy of these approaches, we compared CMV outcomes among these patients. Methods: All consecutive adult CMV seropositive (CMV R+) patients who received their first double UCBT from December 2009 to January 2018 were reviewed. Patients were excluded if they had initial CMV reactivation prior to day 0 or after day 100, graft failure, death or relapse before day 100, or participated in a CMV prophylaxis trial. Starting the day of transplant, CMV R+ patients received either valacyclovir 2 grams orally 3 times daily or acyclovir 500 mg/m2 intravenously every 8 hours until able to tolerate oral medication. At hospital discharge, patients for whom valacyclovir was authorized by insurance received valacyclovir 2 grams orally 3 times daily through day 100. All others received acyclovir 800 mg orally twice a day through day 100. No patients received anti-thymocyte globulin with conditioning. All patients transplanted prior to November 2016 received pre-transplant ganciclovir, after which pre-transplant ganciclovir was discontinued. CMV reactivation was defined as any detectable PCR positive whole blood sample (checked twice weekly through day 100). Thresholds for treatment with ganciclovir or foscarnet evolved over time, but required high initial copies levels, persistent or rising DNAemia, or evidence of end-organ involvement. Acute graft-versus-host-disease (aGVHD) treatment was based on institutional guidelines and uniform for all patients. Results: Demographics of the 101 patients studied are provided in table 1. Forty-one patients received prophylaxis with high-dose valacyclovir until post-transplant discharge only (median 23 days) and 60 received valacyclovir through day 100. Between day 0 and day 100, fewer patients in the high-dose valacyclovir group (n= 20, 36%) had CMV reactivation compared to those in the acyclovir group (n= 23, 57%), p= 0.025 (figure 1). Nine patients (9%) in the acyclovir group and 6 (6%) in valacyclovir group received CMV directed treatment (p= 0.1). Patients who did or did not received pre-transplant ganciclovir had similar rates of CMV reactivation (p= 0.55 in acyclovir arm, p= 0.15 in valacylcovir arm). Overall survival (p= 0.64), neutrophil and platelet engraftment time, and incidence of grade 2-3 (p= 0.7) and grade 3-4 aGVHD (p= 0.3) were comparable between groups. Conclusions: High-dose valacyclovir through day 100 post-transplant as compared to through the day of hospital discharge post-transplant reduced CMV reactivation rates. While threshold for treatment will vary according to institutional protocol, high-dose valacyclovir through day 100 likely reduces treatment episodes. One week of pre-transplant ganciclovir does not reduce CMV reactivation rates. These data provide important baselines for future comparisons of outcomes following letermovir prophylaxis in this population. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees.