Cytomegalovirus Reactivation In Patients Research Articles

Clinical Significance of Cytomegalovirus Reactivation in Patients With Plasma Cell Dyscrasia Who Were Treated With Anti-CD38 Monoclonal Antibody: A Retrospective Analysis in a Single Institution

IntroductionAnti-CD38 monoclonal antibodies (mAbs) have improved the prognosis of patients with plasma cell dyscrasia (PCD), but are also associated with increased infectious adverse events. Cytomegalovirus (CMV) is a common latent pathogen that is reactivated in immunocompromised individuals. Although CMV reactivation has mostly been reported after high-dose chemotherapy followed by stem cell transplantation in patients with PCD, cases of reactivation during anti-CD38 mAb therapy have been reported recently. Due to limited studies, we aimed to determine the frequency and impact of CMV reactivation during anti-CD38 mAb therapy. Patients and MethodsThis retrospective analysis included 154 consecutive patients with PCD who were treated with anti-CD38 mAbs at a single institution. ResultsSeventy-six patients were evaluated for CMV reactivation by CMV pp65 antigen testing, and 29 (38%) patients, including nine with newly diagnosed PCD, showed positive results. Patients who tested positive for the CMV pp65 antigen had substantially lower serum albumin levels than those who tested negative. However, the two groups showed no marked difference in the concurrent anti-PCD medications or baseline absolute lymphocyte count. Although most patients showing positive results in the CMV pp65 antigen test had mild or no symptoms, with fever being the most common symptom, some patients developed CMV end-organ disease. In addition, CMV reactivation interfered with the course of anti-PCD treatment in most patients, necessitating dose reductions, delays, and discontinuation of chemotherapy. ConclusionThis study provides an overview of the clinical impact of CMV reactivation in patients with PCD treated with anti-CD38 mAb-containing regimens.

Cytomegalovirus Reactivations in Allogeneic Hematopoietic Stem Cell Transplantation from HLA-Matched and Haploidentical Donors with Post-Transplantation Cyclophosphamide

Cytomegalovirus (CMV) reactivations cause significant morbidity in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. Graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide (PTCy) is associated with an increased risk of CMV infections. Data are limited comparing HSCT with PTCy performed from matched sibling donors (MSDs), matched unrelated donors (MUDs), and haploidentical (Haplo) donors. In the present study, we aimed to characterize CMV reactivation and recurrence in patients with hematologic malignancies undergoing HSCT from MSD, MUD, and Haplo donors using PTCy as GVHD prophylaxis in the pre-letermovir era. We also analyzed risk factors of CMV reactivation, including GVHD as a time-dependent variable, on the incidence and mortality associated with CMV infections. We analyzed CMV reactivation in patients undergoing HSCT from 160 MSDs, 124 MUDs, and 82 Haplo donors from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus, and mycophenolate mofetil was given irrespective of donor type. Overall, 46% of patients had at least 1 CMV reactivation. The 1-year cumulative incidence of CMV infection was 39% for MSD, 44% for MUD, and 62% for Haplo donors (P < .001), with 96% of reactivations occurring before day +100. Multivariate analysis identified factors associated with the first CMV reactivation, including Haplo donor, positive recipient CMV serology, older patient age, and grade II-IV acute GVHD. The 1-year cumulative incidence of second reactivation from HSCT was 13%. Recipient CMV seropositivity, older patient age, and grade II-IV acute GVHD, but not type of donor, were identified as adverse factors for second CMV reactivation in multivariate analysis. The 1-year cumulative incidence of a third reactivation post HSCT was 4.4%. Ten cases of CMV disease were recorded, with no attributable deaths. Nevertheless, the risk for nonrelapse mortality was greater for patients who experienced CMV reactivation in multivariate time-dependent Cox model analysis. CMV reactivation is frequent in HSCT with PTCy in patients not receiving letermovir prophylaxis. Identified risk factors include the use of a Haplo donor, recipient CMV seropositivity, and grade II-IV acute GVHD. The prevalence of recurrent CMV reactivations is a noteworthy issue, especially after acute GVHD, warranting trials of secondary prophylaxis strategies.

Cytomegalovirus Reactivation in Severe Coronavirus Disease 2019: Case Series from a Tertiary Care Center in the Western State of India

Abstract Introduction: Cytomegalovirus (CMV) reactivation in patients who have been admitted to the intensive care unit (ICU) is linked to higher mortality and health-care costs. There is a dearth of published research on CMV reactivation in patients with severe SARS-CoV-2. Materials and Methods: Objectives: The objective of this study was to describe clinical and laboratory profiles and outcomes of CMV reactivation in patients with severe SARS-CoV-2 illness. In this retrospective study carried out at a tertiary care hospital ICU in the Western state of India, patients with severe SARS-CoV-2 who were admitted from January 1, 2021, to May 31, 2021, and who got CMV viral load testing by reverse transcriptase polymerase chain reaction were analyzed. Results: During the study period, 27 out of 277 admitted patients were subjected to plasma CMV viral load testing, of which 13 patients had detectable viral load giving a prevalence of 4.7%. Patients who tested positive for CMV had significantly higher mortality (P = 0.020) and ventilator support needs (P = 0.004). Both fungal and bacterial bloodstream infections were frequent in CMV-positive patients, but neither was statistically significant (P = 0.065 and P = 0.571, respectively). In this case series, there was no difference in CMV reactivations according to the degree of lymphopenia (P = 0.149), usage of steroids (P = 0.766), or immunomodulatory medications (tocilizumab/bevacizumab, P = 0.926). Conclusions: In SARS-CoV-2 patients with severe illness, CMV reactivation was associated with an increased need for ventilator support, a higher incidence of nosocomial infection (bacterial and fungal), and overall mortality.

Management of cytomegalovirus reactivation in patient with immunotherapy-induced gastritis

Management of cytomegalovirus reactivation in patient with immunotherapy-induced gastritis

Incidence and Outcomes of Cytomegalovirus Reactivation after Chimeric Antigen Receptor T Cell Therapy

Introduction: Cytomegalovirus (CMV) reactivation is a major complication among seropositive allogeneic hematopoietic cell transplantation (HCT) recipients; however, the incidence and outcomes of CMV reactivation in patients undergoing chimeric antigen receptor T (CAR T) cell therapy remain poorly understood. Methods: Single-center retrospective study of 109 adult CMV seropositive patients who received CAR T cell therapy between February 2018 and February 2023. CMV viral load was monitored at the discretion of the treating physician. CMV outcomes were CMV reactivation (any viremia) and clinically significant CMV (viremia or tissue invasive disease requiring antiviral treatment). The study was approved by our institutional review board and conducted consistent with the principles in the Declaration of Helsinki. A p-value of &amp;lt;0.05 was considered statistically significant. Statistical analyses were performed using GraphPad Prism Software, version 10.0.0. Results: During the study period, there were a total of 148 patients who received CAR T cell therapy. Patients who were CMV seronegative, had history of previous allogeneic HCT, or those who received letermovir prophylaxis were excluded. In total, 109 patients who were CMV seropositive met the inclusion criteria. The patient characteristics are presented in Table 1. Of the 109 patients, 69% received Axicabtagene Ciloleucel (Yescarta), 15% received Brexucabtagene Autoleucel (Tecartus), 8% received Tisagenlecleucel (Kymriah), 5% received Idecabtagene Vicleucel (ABECMA), and 3% received Lisocabtagene Maraleucel (Breyanzi). Eighty-four patients (77%) developed any grade of CRS with the median day of CRS onset being 4 days (IQR, 2 to 6). Forty-six patients (42%) developed any grade of ICANS. Among patients who developed CRS, 74 (88%) received tocilizumab, 58 (69%) received dexamethasone, and 9 (11%) received anakinra. For dexamethasone group, the median dosage was 103 mg (IQR, 45 to 160). In those receiving tocilizumab, the median number of doses was 2.5 (IQR, 1 to 4) and the dosage was standard 8 mg/kg. 31 patients (28%) had evidence of CMV reactivation (any viremia) and 10 patients (9%) had clinically significant CMV reactivation requiring treatment. The median time from CAR T cell infusion to CMV reactivation was 19 days (IQR, 9 to 31). Among those with clinically significant CMV reactivation, the median peak viremia was 2388 IU/mL; six of these patients (60%) developed CMV syndrome with none having tissue invasive disease; and 9 (90%) had documented clearance of the virus in response to antiviral therapy. In this group, there were 2 deaths but were not attributed to CMV reactivation. One was due to fungemia while the other patient's death was attributed to CAR T therapy related toxicities causing multiorgan failure. Among those who didn't reactivate CMV, 37 patients (47%) received dexamethasone, at a median dose of 90 mg (IQR, 25 to 145), whereas in the 10 patients with clinically significant CMV reactivation, 100% received dexamethasone (P=0.001) with a median dose of 130 mg (IQR, 74 to 263). Additionally, those who received tocilizumab and anakinra were also at a significantly higher risk for clinically significant CMV reactivation (p=0.027 and p=0.03, respectively). Conclusions: CMV reactivation is a common complication of CAR T cell therapy in CMV seropositive individuals. Although confirmatory studies are needed, our data shows that administration of immunosuppression, in particular steroids, for management of CAR T cell toxicities is a major risk factor for CMV reactivation, and close monitoring for preemptive therapy or antiviral prophylaxis might be indicated in this setting.

2730. Clinically significant cytomegalovirus infection in patients with lymphoma and no prior cellular therapy

Abstract Background Reactivation of cytomegalovirus (CMV) is commonly reported in lymphoma patients who undergo cellular therapy, with often poor outcomes. The risk for CMV reactivation in patients with lymphoma prior to cellular therapy is not well understood. As new alternative immunosuppressive therapies emerge for lymphoma, understanding baseline risk for CMV reactivation is paramount to improve clinical and oncologic outcomes. Our goal was to identify risk factors, and describe outcomes associated with clinically significant CMV infection (CS-CMVi) in lymphoma patients with no prior cellular therapy. Methods We performed a retrospective cohort study for all lymphoma patients who underwent testing for CMV by PCR from blood between 1/2017 and 12/2020. Patients with prior history of transplantation or chimeric antigen receptor therapy were excluded. Patients with and without CS-CMVi were identified for risk factor analysis by univariate analysis. Results A total of 217 lymphoma patients were included in our analysis; CS-CMVi was identified in 41 (19%) patients. When compared to patients without CS-CMVi (control group), lymphoma patients with CS-CMVi were more likely to have history of HIV (5% vs 0%; p= 0.0350), primary central nervous system lymphoma (7% vs 1%; p= 0.0220) and relapsed disease (54% vs 25%; p= 0.0005) (Table 1). CS-CMVi was also more common if testing was done at time of relapse diagnosis (32% vs 10%; p= 0.0007), during work up for infection (98% vs 68%; p &amp;lt; 0.0001) and more often (3 vs 1; p &amp;lt; 0.0001) (table 1). Mortality and remission rates within 1 year of testing were worse in patients with CS-CMVi (table 2 and figure 1). Conclusion CS-CMVi in lymphoma patients is associated with poor outcomes including oncologic outcomes. Further analysis to better define patients with lymphoma at high-risk for CS-CMVi should be studied for future preventative strategies. Disclosures Fareed Khawaja, MBBS, MEDSCAPE: Honoraria|Viracor: Grant/Research Support Roy F. Chemaly, MD/MPH, Eurofins-VViracor: Grant/Research Support|Karius: Advisor/Consultant

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.

Cytomegalovirus reactivation under pre-emptive therapy following allogeneic hematopoietic stem cell transplant: Pattern, survival, and risk factors in the Republic of Korea.

Pre-emptive therapy for cytomegalovirus (CMV) reactivation has been used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). It is unclear if this strategy has poorer clinical outcomes in CMV-endemic areas and if more aggressive prophylaxis is required. We retrospectively analyzed the patterns and survival after CMV reactivation in patients undergoing pre-emptive therapy following allo-HSCT and assessed high-risk patients who could benefit from aggressive CMV prophylaxis in endemic areas. Of the 292 patients who underwent allo-HSCT, 70.5% (donor+ or recipient+) were CMV seropositive. CMV reactivation occurred in 139 patients (47.6%), with a median of 31.5 days from day 0 of allo-HSCT. The overall survival of patients with CMV reactivation who received pre-emptive therapy did not differ from those without reactivation. Of the 139 patients with CMV reactivation, 78 (56.1%) underwent ≥2 rounds of pre-emptive therapy. In multivariate analysis, the risk of CMV reactivation was higher in patients with multiple myeloma, with CMV seropositivity of the recipient and donor, administered with a higher dose of anti-thymocyte globulin (ATG), and with acute graft-versus-host disease (aGVHD) ≥ grade 2. Although half of the patients with allo-HSCT were administered with pre-emptive therapy for CMV, CMV reactivation did not affect their survival, indicating the advantages of pre-emptive therapy, even in CMV-endemic areas. The cost-effectiveness of more aggressive CMV prophylaxis should be re-evaluated in patients at a high risk for CMV reactivation.

P11.78.A BIUXX

Abstract BACKGROUND Glioblastoma (GBM) is a tumor with dismal prognosis and the definition of novel therapeutic targets is a pressing matter in neuro-oncology. Several groups reported the presence of Cytomegalovirus (CMV) in GBM. This virus establish a life-long infection in the host and is able to induce the hallmarks of cancer. Thus, antiviral therapy targeting CMV may represent a valid therapeutic option for patients with GBM. Over the last 15 years we treated more than 150 patients with GBM at Karolinska Universiy Hospital with the antiviral drug valganciclovir as an add-on to standard therapy. We compared retrospectively survival of these patients with contemporary controls with similar clinical and demographic characteristics treated only with standard therapy and found that patients receiving the antiviral seemed to survive longer. In addition to the direct oncomodulatory effect of CMV in GBM cells, its reactivation may affect negatively fragile individuals such as patients with GBM. Indeed patients serologically positive for CMV survives shorter time compared to serologically negative patients. Also Goerig et al. showed that CMV may also be reactivated during irradiation of the brain and cause life threating encephalitis in as many as 48% IgG positive patients with brain tumors. This was linked to encephalopathy and to early mortality risk. Thus, a successful therapeutic strategy would be to start antiviral therapy before or concomitantly radio-chemotherapy since antiviral drugs could prevent CMV reactivation before the virus would be able to cause neurologic deterioration. MATERIAL AND METHODS we analyzed by prospectively collected serological data (IgG and IgM) for CMV of 42 patients with GBM treated with valganciclovir (n=22) or placebo (n=20) in a double blind setting before, during and after radio-chemotherapy and at 6 and 12 months follow ups. We built contingency table and performed Fisher´s exact test. RESULTS At the end of radiation therapy, 5 of 12 (41.6%) IgG positive patients in the placebo group were also IgM positive, showing an active/recent infection, while none of the 16 patients were IgM positive in the valganciclovir treated group (p=0.0067). Three of the 5 patients with CMV reactivation in the placebo group experienced also neurological deterioration and developed an early recurrence at just 3 months while none developed early recurrence in VGCV group. CONCLUSION Valgancicovir prevented CMV reactivation in patients with GBM undergoing chemo-radiotherapy in a prospective, randomize setting. Prophylactic antiviral treatment may therefore be used to prevent encephalopathy and to early mortality risk linked to CMV reactivation. The clinical value of these results will need to be confirmed in larger studies. In this regard, a randomized trial evaluating anti-CMV therapy in 220 patients with GBM (the VIGAS 2, NCT04116411) is currently ongoing at our institution.

Efficacy of letermovir in HLA-haploidentical hematopoietic transplantation with posttransplant cyclophosphamide.

Cytomegalovirus reactivation (CMV-R) is a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HCT), especially in human leukocyte antigen-haploidentical transplantation (haplo-HCT) with posttransplant cyclophosphamide (PTCy). Prophylactic letermovir (LTV) prevents CMV-R in patients undergoing allo-HCT. However, evidence regarding its use in haplo-HCTs with PTCy is limited. Therefore, we aimed to investigate the efficacy of prophylactic LTV in haplo-HCT with PTCy. We retrospectively analyzed 52 patients seropositive for CMV who underwent haplo-HCT with PTCy at our institution between January 2015 and June 2021 and compared patients who received LTV prophylaxis (LTV group: n = 29) with those who did not receive prophylaxis for CMV (control group: n = 23). The primary endpoint was the 100-day cumulative CMV-R incidence. We used Gray's test and the Fine and Gray test to compare the two groups. The 100-day cumulative CMV-R incidence was lower in the LTV group than in the control group (17.2% vs 81.8%, p < 0.001). Multivariate analysis revealed that prophylactic LTV reduced the 100-day cumulative CMV-R incidence (hazard ratio: 0.17, 95% confidence interval: 0.06-0.44, p < 0.001). Prophylactic LTV effectively prevents CMV-R in patients undergoing haplo-HCT for PTCy.

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.

Prognostic outcomes of cytomegalovirus reactivation after autologous stem cell transplantation.

Background: Cytomegalovirus (CMV) reactivation is a common complication in patients undergoing allogeneic stem cell transplantation. However, the incidence of CMV reactivation is low after autologous stem cell transplantation (auto-SCT), and the prognostic value of CMV reactivation remains controversial. Moreover, reports on late CMV reactivation after auto-SCT are limited. We aimed to analyze the association between CMV reactivation and survival outcomes and develop a predictive model for late CMV reactivation in patients undergoing auto-SCT. Methods: Data of 201 patients who underwent SCT at the Korea University Medical Center from 2007 to 2018 were collected. We analyzed prognostic factors for survival outcomes after auto-SCT and risk factors for late CMV reactivation using a receiver operating characteristic curve. Then, we developed a predictive risk model for late CMV reactivation based on results of the risk factor analysis. Results: Early CMV reactivation was significantly associated with better overall survival (OS) (hazard ratio [HR], 0.329; P = 0.045) in patients with multiple myeloma; however, no significant differences were observed in patients with lymphoma. For late CMV reactivation, a serum lactate dehydrogenase level greater than the upper limit of normal (HR, 2.251; P = 0.027) and late CMV reactivation (HR, 2.964; P = 0.047) were independent risk factors for poor OS, while lymphoma diagnosis (vs. multiple myeloma; HR, 0.389; P = 0.016) was an independent risk factor for good OS. In risk factor analysis for late CMV reactivation, T-cell lymphoma diagnosis (odds ratio [OR], 8.499; P = 0.029), ≥ two prior chemotherapies (OR, 8.995; P = 0.027), failure to achieve complete response (CR) after transplantation (OR, 7.124; P = 0.031), and early CMV reactivation (OR, 12.853; P = 0.007) were significantly associated with late CMV reactivation. To develop the predictive risk model for late CMV reactivation, a score (1 to 1.5) was assigned for each of the above-mentioned variables. The optimal cutoff value (1.75 points) was calculated using the receiver operating characteristic curve. The predictive risk model showed good discrimination, with an area under the curve of 0.872 (standard error, 0.062; P < 0.001). Conclusions: Late CMV reactivation was an independent risk factor for inferior OS, whereas early CMV reactivation was associated with better survival in patients with multiple myeloma. This risk prediction model could be helpful in identifying high-risk patients who require monitoring for late CMV reactivation and potentially benefit from prophylactic or preemptive therapy.

Cytomegalovirus Reactivation in Patients with Solid Malignancies: A Case Series and Literature Review

Cytomegalovirus Reactivation in Patients with Solid Malignancies: A Case Series and Literature Review

Cytomegalovirus Reactivation in Patients With Acute Lymphoblastic Leukemia in Non-transplant Setting.

Acute lymphoblastic leukemia is predominately a childhood disease and around two third of cases are of B-cell phenotype. Cytomegalovirus is an important cause of morbidity and mortality in allogeneic hematopoietic progenitor cell transplant; however, it is rare in patients with B-cell acute lymphoblastic leukemia in non-transplant settings. In this study, we evaluated 72 patients of acute precursor (pre) B-cell acute lymphoblastic leukemia at Shaukat Khanum Memorial Cancer Hospital and Research Center, out of which three were positive for Cytomegalovirus.

491. Characterizing the Association of Pre-Existing Cytomegalovirus (CMV)-specific Humoral Immunity with CMV Reactivation Risk after Hematopoietic Cell Transplantation (HCT)

Abstract Background There is renewed interest in CMV-specific humoral immune protection due to recent murine data suggesting that strain-specific antibodies may inhibit CMV cell-to-cell spread (Science. 2019; 363:288). To characterize the nature of antibody protection against CMV after HCT, we tested pre-HCT sera in a cohort of CMV D-R+ allogeneic HCT recipients from the pre-letermovir era using VirScan, a technology that measures pathogen-specific humoral immunity (IgG) at the epitope level. Methods Patients (age 0-70 years) who received 1st, myeloablative, HCT for acute leukemia or myelodysplastic syndrome and who underwent PCR surveillance and preemptive therapy were included. VirScan was used on sera collected pre-HCT. Cumulative incidence curves and multivariable Cox regression analyses were used to determine the association of pre-HCT CMV antibody epitopes scores with CMV reactivation (any, &amp;gt;150 IU/mL, &amp;gt;500 IU/mL) in the first 8 weeks post-HCT. Results 170 CMV D-R+ HCT recipients were tested a median of 26 days (range 7-37 days) prior to HCT and had a median of 37 CMV antibody epitopes (IQR 29-50 epitopes, range 14-77 epitopes). The cumulative incidence of CMV reactivation was higher in patients with greater pre-HCT CMV antibody epitopes at each evaluated PCR threshold (Figure 1) and the effect appeared more pronounced in adults (Figure 2). High (≥ 4th quartile vs. 1st quartile), pre-HCT CMV antibody epitopes were associated with an increased risk of any CMV reactivation (adjusted Hazard Ratio [aHR]=4.1, 95% confidence interval [CI] 2.1-7.7, p&amp;lt; 0.001) and at &amp;gt;150 IU/mL (aHR=3.0, 95% CI 1.4-6.5 p=0.006) after adjusting for age, HLA-matching, and pre-HCT T-cell depletion ( &amp;gt;150 IU/mL only). Figure 1Figure 2 Conclusion We observed a paradoxically increased risk of CMV reactivation in patients with high pre-HCT CMV VirScan scores. It is possible that pre-HCT CMV-specific humoral immunity as measured by VirScan is reflective of the burden of latent CMV or that CMV-specific antibodies may mediate antibody-dependent enhancement after HCT and thus facilitate reactivation. Future studies are needed to validate our findings in diverse cohorts and to elucidate the underlying mechanism of increased VirScan scores and associated risks of CMV reactivation. Disclosures Rachel A. Bender Ignacio, MD, MPH, Abbvie: Advisor/Consultant|SeaGen: Advisor/Consultant Joshua A. Hill, MD, Allovir: Advisor/Consultant|Allovir: Grant/Research Support|Covance/CSL: Advisor/Consultant|CRISPR: Advisor/Consultant|Deverra: Grant/Research Support|Gilead: Grant/Research Support|Karius: Advisor/Consultant|Karius: Grant/Research Support|Merck: Grant/Research Support|Octapharma: Advisor/Consultant|OptumHealth: Advisor/Consultant|Oxford Immunotec: Grant/Research Support|Pfizer: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Advisor/Consultant Geoffrey Hill, M.D., FRACP, FRCPA, Applied Molecular Transport: Grant/Research Support|Compass Therapeutics: Grant/Research Support|Generon Corporation: Advisor/Consultant|Heat Biologics: Grant/Research Support|iTeos Therapeutics: Advisor/Consultant|iTeos Therapeutics: Grant/Research Support|Laevoroc Oncology: Grant/Research Support|NapaJen Pharma: Advisor/Consultant|Neoleukin Therapeutics: Advisor/Consultant|Serplus Technology: Grant/Research Support|Syndax Pharmaceuticals: Grant/Research Support Michael J. Boeckh, MD PhD, Allovir: Advisor/Consultant|Amazon: Grant/Research Support|Ansun Biopharma: Grant/Research Support|EvrysBio: Advisor/Consultant|Gates Ventures: Grant/Research Support|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Helocyte: Advisor/Consultant|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|Kyorin Pharmaceuticals: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support|Moderna: Advisor/Consultant|Moderna: Grant/Research Support|Regeneron: Grant/Research Support|ReViral: Advisor/Consultant|Symbio: Advisor/Consultant|Takeda: Grant/Research Support|Vir Biotechnology: Advisor/Consultant|Vir Biotechnology: Grant/Research Support.

Risk factors associated with cytomegalovirus reactivation in patients receiving immunosuppressive therapy for rheumatic diseases: a retrospective study

Immunosuppressive treatment is a common cause of cytomegalovirus (CMV) reactivation. However, there is no consensus regarding the risk factors for CMV reactivation in rheumatic diseases. Therefore, this study aimed to elucidate the risk factors associated with CMV reactivation. We retrospectively collected the data of 472 patients with rheumatic diseases whose CMV pp65 antigen (C7-HRP) titer was measured. We divided the patients into those with and those without C7-HRP. We retrospectively collected data on age, sex, primary condition and organ involvement, and blood test results. We also investigated the use of immunosuppressants and the maximum and cumulative doses of prednisolone (PSL). We performed univariate and multivariate analyses to identify risk factors for CMV reactivation. Multivariate analysis showed that higher age (71.2 vs. 64.4 years, p = 0.0022), hypoalbuminemia (2.9 vs. 3.4 g/dL, p = 0.0104), higher creatinine level (1.2 vs. 0.9 mg/dL, p = 0.0026), cyclosporine use (8.2 vs. 3.6%, p = 0.0101), and higher maximum (552.4 vs. 243.3 mg, p < 0.0001) and cumulative (2785.9 vs. 1330.5 mg, p < 0.0001) doses of PSL were associated with CMV reactivation. Older age, hypoalbuminemia, higher creatinine level, cyclosporine use, and higher maximum and cumulative doses of PSL were significant risk factors for CMV reactivation in rheumatic diseases.

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.

Efficacy of Cytomegalovirus Specific Immunoglobulins to Reduce CMV Reactivation in Pediatric Hematopoietic Stem Cell Transplant Recipients.

Cytomegalovirus (CMV) infection is a serious complication of pediatric hematopoietic stem cell transplant (HSCT). To date, antiviral therapy has been the mainstay of prophylaxis, with conflicting results regarding the benefits of CMV-specific immunoglobulins (CMV-Ig). After introducing prophylactic CMV-Ig to HSCT recipients at risk (seropositive recipient and/or donor), we conducted a single-center retrospective study comparing the incidence and severity of CMV infection with and without CMV-Ig. We identified 49 'at risk' recipients from 76 consecutive HSCTs over 3.5 years, in addition to standard antiviral prophylaxis, 10 patients received CMV-Ig and 39 did not. There was no significant difference in donor type, cell source, conditioning, or CMV status between the groups. We observed a potential trend toward reduction of incidence of CMV reactivation in patients exposed to CMV-Ig (30%) compared with those who weren't (38.4%). Besides, no symptomatic or lethal infection was observed in the CMV-Ig group, and time to recovery seemed shorter (21 [±7] vs 51.4 [±55] days) and peak titers lower (4578 [±4788] vs 24131 [±49257]) with CMV-Ig. No adverse events were noted. The statistical significance of the results was limited by the small sample size. These data raise interest in prophylactic CMV-Ig as a safe way of potentially reducing the severity and duration of CMV reactivation in HSCT.

Low Graft Invariant Natural Killer T-Cell Dose Is a Risk Factor for Cytomegalovirus Reactivation After Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) reactivation is common after allogeneic hematopoietic cell transplantation (HCT) and may result in fatal CMV disease. Invariant natural killer T (iNKT) cells are potent modulators of the immune system preventing graft-versus-host disease while promoting graft-versus-leukemia effects. It is thought that iNKT cells selectively influence mediators of both innate and adaptive immunity. Here, we investigated the impact of graft iNKT cells on CMV reactivation in patients undergoing allogeneic HCT. We found a significantly decreased cumulative incidence of CMV reactivation in patients with higher numbers of iNKT cells in the allograft. Therefore iNKT-cell–enriched grafts or adoptive transfer of iNKT cells are compelling cytotherapeutic strategies to improve outcomes after allogeneic HCT.

Risk Factors of Cytomegalovirus Reactivation in Ulcerative Colitis Patients: A Meta-Analysis.

Cytomegalovirus (CMV) infection is associated with exacerbation of disease activity in patients with ulcerative colitis (UC). However, the risk factors for CMV reactivation in this population remain debatable. This meta-analysis was performed to identify the risk factors for CMV reactivation in UC patients. PubMed, Cochrane Library, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched from the inception of these databases to 31 August 2021, with the aim of identifying studies that investigated the risk factors of CMV reactivation in UC patients. A quality assessment of the included studies was performed with the Newcastle-Ottawa Scale. The publication bias was assessed respectively via a funnel plot and Egger’s regression asymmetry test. The robustness and reliability of each outcome were evaluated by sensitivity analysis. Twenty studies were included in the final meta-analysis, comprising a total of 2099 patients with UC. A significantly higher risk of CMV reactivation was observed in patients with severe UC (OR = 1.465, 95% CI: 1.107 to 1.939, p = 0.008), pancolitis (OR = 2.108, 95% CI: 1.586 to 2.800, p = 0.0001), older age of UC onset (MD = 6.212, 95% CI: 2.552 to 9.971, p = 0.001), as well as use of glucocorticoids (OR = 4.175, 95% CI: 3.076 to 5.666, p = 0.001), immunosuppressants (OR = 1.795, 95% CI: 1.289 to 2.501, p = 0.001), and azathioprine (OR = 1.444, 95% CI: 1.012 to 2.061, p = 0.043). However, infliximab treatment was observed not to increase the occurrence of CMV reactivation in patients who suffered from UC. In contrast, 5-aminosalicylic acid (OR = 0.674, 95% CI: 0.492 to 0.924, p = 0.014) was associated with a lower risk of CMV reactivation. Patients with UC should be closely monitored for risk factors of CMV reactivation in order to provide timely diagnosis and antiviral treatment.