Early Cytomegalovirus Reactivation Research Articles

Impact of Early Cytomegalovirus Reactivation After Allogeneic Hematopoietic Stem Cell Transplantation on Relapse in Patients With Myelodysplastic Syndrome: A Nationwide Retrospective Study From Adult Myelodysplastic Syndrome Working Group of the JSTCT

Cytomegalovirus (CMV) reactivation is a prominent complication associated with adverse outcomes in allogeneic hematopoietic stem cell transplantation (HSCT). However, CMV reactivation after allogeneic HSCT may be associated with a lower incidence of relapse in some hematological malignancies. This study analyzed the Japanese registry data from 1082 patients with myelodysplastic syndrome (MDS) who underwent their first allogeneic HSCT and survived for 100 days after transplantation without graft failure or disease relapse to investigate this association. Patients who received cord blood transplants, demonstrated in vivo T cell depletion, underwent prophylactic anti-CMV treatment, or diagnosed with secondary MDS were excluded. CMV reactivation measured by pp65 antigenemia within 100 days after allogeneic HSCT was observed in 57.5% of patients, with a median time of 46 days from transplant. The 5-yr overall survival and cumulative incidence of relapse (CIR) in the cohort were 60.5% and 15.6%, respectively. The 5-yr CIR showed no significant difference between patients with and without CMV reactivation (14.4% versus 17.2%; P = .185). Interestingly, CMV reactivation within 100 days was significantly associated with a lower 5-yr CIR (7.6% versus 16.4%; P = .002) in patients with <5% myeloblasts in the bone marrow (BM) just before HSCT. Furthermore, this relevancy confirmed even when excluding patients with Grade II to IV acute GVHD (Hazard ratio: 0.38; 95% confidential intervals: 0.18–0.801; P = .011). Our findings indicate a correlation between early CMV reactivation and MDS relapse, based on the proportion of myeloblasts in the BM. These results may contribute to the development of effective CMV prophylaxis post-HSCT.

Surveillance over cytomegalovirus (CMV) reactivation following hematopoietic stem cell transplantation: a single-center experience

Cytomegalovirus (CMV) infection is widespread and usually asymptomatic in immunocompetent individuals. However, during immune suppression, especially after hematopoietic stem cell transplantation (HSCT), viral reactivation may result in symptomatic infection and end-organ disease. Because there is high incidence of CMV seropositivity in Bulgaria, CMV infection/reactivation is an expected common complication in HSCT recipients which requires frequent monitoring. CMV reactivation monitoring via qRT PCR has a significant role in terms of the moment of initiating pre-emptive therapy in these high-risk patients in order to avoid the development of CMV disease and better clinical management. The aim of this study was to determine and analyze the incidence of CMV reactivation in HSCT recipients in a new transplant center in Bulgaria. The incidence of early CMV reactivation after HSCT in our center is very high (76.7%) most likely related to the high-risk donor/recipient (D/R) profile of our recipients. The mean period from HSCT to the first positive PCR result was quite short, 21.5 days on average. The highest-risk group donor-/recipient+ (D-/R+) experienced the longest and the highest levels of viremia, as well as the highest number of reactivations. The nature of the D/R status most significantly affected the degree of viral load. Our data demonstrate the essential role of monitoring of CMV with reliable and sensitive laboratory methods, such as qRT-PCR to avoid development of CMV disease in high-risk patients.

Haploidentical Donor Transplants with Cytokine Release Syndrome Have Increased Risk of Clinically Significant Early CMV Reactivation Compared with Matched Donor Transplants Receiving Post-Transplant Cyclophosphamide

Background: Post-transplant cyclophosphamide (PTCy) enables safe haploidentical stem cell transplantation by reducing graft-versus-host-disease (GVHD) but is associated with an increased risk of reactivation of Cytomegalovirus (CMV). PTCy has more recently been adopted for matched-donor transplants, where early CMV reactivation may also be more common. This suggests that CMV reactivation is a function of PTCy rather than donor source. However, other studies comparing the rates of CMV in transplants using PTCy-based prophylaxis suggested disparity in donor source may contribute to CMV reactivation. Aim: The goal of this single-centre, retrospective study was to determine if donor type had any impact on CMV reactivation in the setting of PTCy-based GVHD prophylaxis. Methods: The Alfred Hospital Bone Marrow Transplantation Unit has used PTCy for GVHD prophylaxis in both haploidentical and matched-donor allogeneic stem cell transplants (alloSCT) since 2015. A local database search identified 119 allogeneic peripheral blood alloSCT recipients receiving PTCy-based GVHD prophylaxis between February 2015 and December 2022. Matched-donor alloSCTs also received cyclosporin from Day +5 while haploidentical alloSCTs also received tacrolimus and mycophenolate from Day +5. One patient was excluded due to CMV viremia at the time of transplant. Recipients who were CMV seropositive received therapeutic dose valganciclovir 900 mg twice daily from the start of conditioning until the day prior to stem cell infusion. Prophylactic valganciclovir (900 mg daily) was planned upon engraftment for seropositive recipients and those receiving stem cells from a seropositive donor. CMV DNA PCR was performed weekly for the first 100 days post-transplant and beyond when clinically indicated. CMV viremia was defined as any positive CMV PCR (&amp;gt; 34.5 copies/mL) within the first 100 days post-transplant. Therapeutic valganciclovir was initiated for CMV viral loads (VL) &amp;gt; 1,000 copies/mL or earlier for rapidly rising VLs. Cytokine release syndrome (CRS) was defined as fever &amp;gt; 38 degrees Celsius between stem cell infusion and PTCy on Day +3 without an alternate explanation and graded according to CTCAE criteria. CMV donor and recipient negative transplants were excluded from the analysis of the impact of donor disparity on CMV reactivation. Statistical analyses included Fisher's Exact test, one-way ANOVA and Binomial Logistic Regression. Results: Transplant characteristics according to donor source were similar apart from conditioning intensity, where recipients of haploidentical stem cells were more likely to receive myeloablative conditioning (Table 1). The cumulative incidence of moderate-severe chronic GVHD was significantly higher in matched sibling transplants but overall, 12-month GVHD-free and relapse-free survival were similar. As previously reported, CRS (overall and grades II-IV) was significantly more common in haploidentical transplants. Day 100 CMV viremia rates were not statistically different between donor groups. However, haploidentical transplants trended for earlier CMV reactivation (p=0.08), and were significantly more likely to rise above 250 copies/mL (Table 1 and Figure 1). Consequently, haploidentical transplant recipients received significantly more anti-CMV therapy (p=0.009). Multivariable analysis identified haploidentical donor as a major risk factor for CMV &amp;gt; 250 (odds ratio, OR 1.24, p=0.011) and &amp;gt; 1,000 copies/mL (OR 1.41, p=0.032) while transplant for AML/MDS was negatively associated with CMV &amp;gt; 250 (OR 0.19, p=0.009) and CMV &amp;gt; 1,000 copies/mL (OR 0.16, p=0.003). CRS was significantly associated with CMV &amp;gt; 1,000 copies/mL (OR 3.33, p=0.032) but this was no longer significant in multivariable analysis due to the association with haploidentical donor transplantation. Conclusion: This single-center retrospective comparison of PTCy-based transplants shows that haploidentical transplants have increased risk of early and clinically significant reactivation of CMV. Potential explanations include increased immunosuppression with mycophenolate and the presence of CRS, where inflammatory cytokines may de-repress the CMV major immediate early promoter. Selecting this high-risk group (haploidentical transplants with CRS) may be a cost-effective use of letermovir, which can be initiated prior to engraftment.

Effect of Early Cytomegalovirus Reactivation on Relapse in Adult Patients with Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation: A Registry Study from the Japan Society for Transplantation and Cellular Therapy (JSTCT)

Background Cytomegalovirus reactivation (CMVR) is a well-known complication contributing to morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Previous studies have demonstrated that CMVR is associated with poor clinical outcomes following HSCT. However, some studies have shown that CMVR following HSCT may have a recurrence-suppressing effect on hematological diseases, including acute myeloid leukemia and acute lymphoblastic leukemia. Conversely, data on the relevance between CMVR and relapse in patients with myelodysplastic syndromes (MDS) following HSCT remain limited and inconclusive. This nationwide retrospective study aimed to examine the association between CMVR and MDS relapse following HSCT. Methods This study was conducted by the Adult Myelodysplastic Syndromes Working Group of the Japan Society for Transplantation and Cellular Therapy (JSTCT). Clinical data were collected by the JSTCT and the Japanese Data Center for Hematopoietic Cell Transplantation employing the Transplant Registry Unified Management Program (TRUMP). Overall, 1,082 patients aged ≥16 years who were diagnosed with de novo MDS, underwent initial allogeneic HSCT between 2010 and 2018, and survived until 100 days post-transplant without disease relapse were examined. Patients who received cord blood transplantation, in vivo T-cell depletion, and prophylactic anti-CMV treatment were excluded. CMVR was defined as the initiation of CMV preemptive or definitive therapy within 100 days post-transplant. Patients underwent pp65 antigenemia monitoring commencing at the time of neutrophil engraftment after HSCT. Preemptive therapy was typically instituted upon the detection of a minimum of 2 CMV pp65 antigen-positive cells per 50,000 white blood cells. In analysis, CMVR and acute/chronic graft-versus-host disease (GVHD) were evaluated as time dependent covariates. This retrospective study was approved by the Data Management Committee of the JSTCT and the ethics committee of the Ehime University School of Medicine. Results Of the 1,082 patients, 622 (57.5%) experienced CMVR. The median time from HSCT to the onset of CMVR was 46 (range, 4-97) days. In contrast, reactivation beyond 100 days after HSCT was observed in 20 patients (1.8%). End-organ disease due to CMV infection was detected in 79 (7.3%) patients with a median of 61 (range, 19-385) days. CMV infections included enteritis (n = 65), retinitis (n = 5), pneumonitis (n = 4), hepatitis (n = 3), and others (n = 3). Of the whole cohort, the 5-year cumulative incidence of relapse (CIR), non-relapse mortality (NRM), disease-free survival, and overall survival (OS) were 15.6%, 26.7%, 57.7%, and 60.5%, respectively. The OS of patients with CMVR was significantly lower than that of patients without CMVR (P = 0.047). A total of 423 patients died at the time of analysis, and no difference in the cause of death was found between patients with and without CMVR. Then, the effect of CMVR on relapse after HSCT was analyzed by patient, disease, and transplant characteristics. Interestingly, in patients with &amp;lt;5% bone marrow blast count at the time of HSCT, CMVR was significantly associated with a lower CIR (5-year CIR, 7.6% vs. 16.4%; P = 0.002). On the contrary, no difference in the CIR was found between patients with and without CMVR in the group with ≥5% bone marrow blast count (5-year CIR, 19.4% vs. 18.0%; P = 0.72). Moreover, the OS of patients with CMVR was significantly lower than that of patients without CMVR in the group with ≥5% bone marrow blast count (P = 0.009). However, the OS of patients with &amp;lt;5% bone marrow blast count was similar between with and without CMVR (P = 0.82). In the multivariate analysis, CMVR was significantly associated with a lower CIR in the group with &amp;lt;5% bone marrow blast count (hazard ratio [HR], 0.40; 95% confidence interval [CI], 0.23-0.70; P = 0.001). Furthermore, in the analysis excluding patients with grade II-IV acute GVHD, CMVR was similarly associated with a lower CIR in the group with &amp;lt;5% bone marrow blast count (HR, 0.38; 95% CI, 0.18-0.80; P = 0.011). Conclusion This study presents that CMVR may have different effects on MDS relapse depending on the bone marrow blast count at the time of HSCT. Although more studies are needed to understand the underlying mechanisms of this association, these findings may serve as a basis for devising effective CMV prophylaxis after HSCT.

Low-Dose ATG Has the Same Risk of CMV Reactivation after Allogeneic PBSCT As Ptcy, but Letemovir Is Effective in Preventing CMV Reactivation

[Introduction] Allogeneic peripheral blood stem cell transplantation (allo-PBSCT) is a curative treatment for hematological malignancies but has a risk of a chronic graft-versus-host disease (GVHD) compared to other donor sources. Post-transplant cyclophosphamide (PTCY) has been spread rapidly worldwide from HLA haploidentical-SCT (Haplo-SCT) to HLA matched-SCT. Although PTCY was theoretically thought to preserve non-alloreactive T cells which can contribute to fight infection, recent studies showed that PTCY was associated with the increased incidence of cytomegalovirus (CMV) infection. Letermovir (LTV), a novel anti-CMV agent, was useful for the prevention of CMV reactivation after SCT including Haplo-SCT using PTCY. On the other hand, low-dose antithymocyte globulin (ATG) is an alternative and useful option for GVHD prophylaxis in allo-PBSCT and often used in Japan. However, the risk of post-transplant CMV reactivation and the protective effect of LTV when using low-dose ATG remain to be elucidated. [Methods] We retrospectively analyzed 222 recipients who received allo-PBSCT using PTCY or low-dose ATG at Hokkaido University Hospital from January 2013 to July 2021. Of the 121 patients who underwent PBSCT with PTCY, 69 (all patients underwent Haplo-PBSCT) were without LTV prophylaxis and 52 (34 patients, Haplo-PBSCT) were with LTV. On the other hand, of the 101 patients who underwent PBSCT with low-dose ATG, 66 (12 patients, Haplo-PBSCT) were without LTV and 35 (2 patients, Haplo-PBSCT) were with LTV. LTV was administered on the day 0 at a dosage of 480 mg daily. All patients were monitored for CMV reactivation by using the anti-CMV pp65 monoclonal antibody HRP-C7 assay at least weekly from neutrophil engraftment to discharge and after discharge monthly until day 180 after SCT. CMV reactivation was defined as the start of CMV preemptive therapy, generally initiated when there are 2 or more CMV antigen positive cells per 50000 white blood cells. Moreover, CMV disease was defined by organ dysfunction attributable to CMV. [Results] Baseline characteristics of the patients are summarized in Table 1. Although more patients in ATG group compared to PTCY group received myeloablative conditioning regimen significantly, there was no significant difference between the groups in terms of sex, age, underlying disease, disease risk at SCT, and CMV serostatus. GVHD prophylaxis in PTCY consisted of CY (40-50 mg/kg on day 3 and 4), tacrolimus (from day 5), and mycophenolate mofetil (from day 5), whereas that in ATG consisted of ATG at a total dose of 2-3 mg/kg around day -2, tacrolimus (from day -1) and short-term methotrexate. LTV prophylaxis significantly reduced the cumulative incidence of CMV reactivation at 180 days after SCT in PTCY group (69.6% without LTV vs. 22.4% with LTV, p&amp;lt;0.001) and ATG group (62.6% without LTV vs. 18.9% with LTV, p&amp;lt;0.001; Figure 1.). Importantly, although CMV disease were occurred in 2 patients in PTCY (1 gastritis and 1 retinitis) and 8 focuses in 7 patients (3 pneumoniae, 3 enteritis, 1 retinitis, and 1 glossitis) in ATG without LTV prophylaxis, none of the patients receiving LTV developed CMV disease in both group. Moreover, LTV did not affect overall survival, the cumulative incidence of non-relapse mortality, relapse, acute GVHD, and engraftment of neutrophil and platelet. Interestingly, the cases of early CMV reactivation within 100 days after SCT under LTV prophylaxis was significantly more frequent in ATG than in PTCY (p=0.0345). [Conclusion] CMV reactivation occurred with similar frequency after allo-PBSCT with low-dose ATG as after that with PTCY. LTV was effective for prevention of CMV reactivation in both GVHD prophylaxis methods. CMV breakthrough reactivation may be likely to occur in PBSCT with low-dose ATG compared to that with PTCY even under LTV prophylaxis, and careful CMV monitoring may be required.

Time-dependent analysis of the impact on early cytomegalovirus reactivation of HLA mismatch and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation from related donors in acquired aplastic anemia.

Cytomegalovirus (CMV) reactivation is an important issue in allogeneic hematopoietic cell transplantation (HCT). The incidence of early CMV reactivation is notably high in HLA-mismatched HCT. However, the interactions between HLA mismatch and acute graft-versus-host disease (aGvHD), a time-dependent event, make it methodologically challenging to evaluate the independent impact on CMV reactivation of the two variables. We retrospectively analyzed 355 patients with acquired aplastic anemia who received related donor transplants using a unified antithymocyte globulin-based platform. Patients were divided into group 1 (6/6 HLA match), group 2 (1-2/6 HLA allelic mismatch), and group 3 (3/6 HLA allelic mismatch). The impact of covariates was analyzed through two models: (1) time-dependent Cox and (2) dynamic landmarking analysis. The time-dependent Cox model showed that the HLA mismatch of 3/6 alleles (hazard ratio (HR) =1.852, P = .004) and aGvHD (HR = 1.009, P = .019) were independent risk factors for CMV reactivation. With the dynamic landmarking analysis, a higher HLA disparity correlated to increased early CMV reactivation (HR = 1.606, P = .001) at all time points. Developing aGvHD following HCT was generally associated with a higher incidence of CMV reactivation (HR = 1.623, P = .013), though its impact decreased with successive later landmark time points. In conclusion, our data suggest that the higher HLA disparity and aGvHD increases susceptibility to early CMV reactivation. In particular, the dynamic landmarking analysis demonstrated the time-varying effect of aGvHD on CMV reactivation, and HLA mismatch showed a profound impact over time following HCT.

Early Cytomegalovirus Reactivation in Renal Recipients Is Associated with High Levels of B Cell Maturation Antigen Transcript Expression Prior to Transplantation.

Cytomegalovirus (CMV) infection is the most frequent infection episode in kidney transplant (KT) recipients. Reactivation usually occurs in the first three months after transplantation and is associated with higher cellular and/or antibody-mediated rejection rates and poorer graft performance. CMV induces the expression of BAFF (B-cell-activating factor, a cytokine involved in the homeostasis of B cells), which communicates signals for survival and growth to B cells and virus-specific plasma cells via the R-BAFF (BAFF receptor), TACI (the calcium modulator, the cyclophilin ligand interactor), and BCMA (B cell maturation antigen) receptors. These molecules of the BAFF system have also been suggested as biomarkers for the development of alloantibodies and graft dysfunction. This prospective study included 30 CMV-IgG seropositive KT recipients. The expression levels of the genes BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA) in peripheral blood leukocytes (PBL) pre-KT were determined using qPCR. qPCR was also used to monitor CMV reactivation in the first three months following KT. The remainder of the KT recipients were classified as CMV- reactivation, and those with more than 500 copies/mL in at least one sample were classified as CMV+ reactivation. There were no discernible variations in the BAFF-R and TACI transcript expression levels. In the CMV+ group, we examined the relationship between the transcript levels and peak viremia. Peak viremia levels and BCMA transcript levels showed a strong correlation. BAFF-R and TACI expressions showed no measurable differences. In patients with early CMV reactivation, high BCMA receptor expression was associated with increased plasmablast, lymphocyte B cell class-switched levels (LBCS), and viral load. Our findings demonstrate that pre-KT BCMA transcript levels increased in KT recipients with early CMV reactivation. These transcript levels positively correlate with peak viremia and weakly with plasmablast and LBCS levels in PBLs.

Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation.

The kinetics of early and late cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin inhibitor plus posttransplantation cyclophosphamide (PTCy; n= 44), mycophenolate mofetil (MMF; n= 414), or methotrexate (MTX; n= 322). Transplantation occurred between 2007 and 2018; CMV monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load and areas under the curve (AUC) within 1 year were calculated. PTCy and MMF were associated with an increased risk of early (day ≤100) CMV reactivation ≥250 IU/mL after multivariate adjustment. The viral load AUC at 1 year was highest with MMF (mean difference= 0.125 units vs MTX group) and similar between PTCy and MTX (mean difference= 0.016 units vs MTX group). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1 year posttransplant. Although different mechanisms of immunosuppressive agents may affect CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.

Antiviral therapy defiant mixed viral retinitis post hematopoietic allogeneic stem cell transplant

Cytomegalovirus (CMV) retinitis is an uncommon presentation post allogeneic transplant and can be vision-threatening. Our case demonstrates the occurrence of polymerase chain reaction (PCR) proven mixed viral retinitis (cytomegalovirus and varicella zoster virus) post allogeneic stem cell transplant despite multiple prophylactic antiviral therapies, including letermovir, and in the documented absence of CMV DNAemia. A 21-year-old female with acute myeloid leukemia presented with mixed viral retinitis (cytomegalovirus and varicella zoster virus) post allogenic transplant. This presentation occurred despite ongoing standard prophylaxis for both of these viruses, as well as following two courses of treatment for CMV viremia, with a documented negative CMV PCR in the blood prior to the presentation with retinitis. The patient was treated with intravenous ganciclovir and subsequently transitioned to oral valganciclovir with durable resolution of the retinitis. We report a rare case of mixed viral retinitis occurring despite multiple antiviral prophylaxes including letermovir and with PCR-documented absence of preceding CMV viremia, in a post-allogeneic stem cell transplant patient, with PCR of the aqueous fluid demonstrating two viral populations. With very little existing literature on either mixed viral retinitis or CMV retinitis during letermovir prophylaxis, this case expands the literature on both topics. CMV retinitis is an uncommon potentially vision threatening presentation post hematopoietic stem cell transplant, and can occur due to early CMV reactivation, low CD4 count, and delayed CD4 lymphocyte recovery. Letermovir has poor CNS and retinal penetration. This case highlights the need for more research on secondary prophylaxis with letermovir.

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.

Differences in Patterns of Infections Among Allogeneic Hematopoietic Cell Transplant Patients Receiving Letermovir Prophylaxis for Cytomegalovirus

Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic- cell transplantation (HCT) with a significant increase in morbidity and mortality among patients who acquire such infection. Pre-emptive prophylaxis in which antiviral agents are started based on detection of CMV in the blood to prevent clinical disease has been the standard practice for many years. This approach was limited by the toxicity of available anti-CMV medications and increased complications among patients who activate CMV(1, 2). Letermovir, an antiviral agent that inhibits replication by binding to components of the terminase complex (UL51, UL56, or both) was approved in 2017 for prevention of CMV infection and disease among HCT recipients(3). Letermovir has been shown to delay polyfunctional CMV-specific cellular immune reconstitution as well as cause a decrease in absolute polyfunctional CD8+ T cell responses(4). The impact of such delayed immune reconstitution on infections other than CMV has not been widely described especially in the setting of post-transplant cyclophosphamide as GVHD prophylaxis. To study the impact of Letermovir on non-CMV infections during the first 6 months post HCT and to assess its effect on other transplant endpoints including OS, DFS, NRM, relapse, acute and chronic GVHD, we analyzed 409 consecutive patients who received their HCT at our center between 2016 and June of 2021. Letermovir prophylaxis was started at our center in January 2018 and is given to patients receiving MUD or haploidentical transplant and are either CMV+ or donor is CMV+. The final dataset included 321 subjects with the following characteristics: Median age 54 years (19-80); disease AML/ALL/MDS 81%, NHL/HD/Other 19%; donor type haplo (69%), MUD 31%; Cell Source PBSC 88%; Myeloablative conditioning 38% ; Donor/Recipient +/+ 50%, +/- 12%, -/+ 38% . The median follow up for survivors was 31.2 (11.5-52.6) months for letermovir group versus 66.2 (53.1-76.9) months for no letermovir group. Patients in the letermovir group were less likely to have received a reduced intensity regimen (22% vs 33%, p=0.05) and to have received a marrow graft (8% vs 16%, p=0.02). The survival endpoints at 3 years were OS (72.7% vs 68.8% p=0.5), DFS (64.4% vs 58.0% p=0.27), relapse (21.2% vs 28.6% p=0.08) and non-relapse mortality NRM (14.5% vs 13.5% p=0.5) for letermovir compared to no letermovir . The cumulative incidences for grade II-IV acute and moderate-severe chronic GVHD were 50.7% vs 40.2%, p=0.08 and 24.3% vs 24.1%, p=0.85 for Letermovir and no letermovir respectively The cumulative incidence of CMV reactivation was significantly lower for letermovir 24.4% compared to 57.1% for letermovir (p<0.001) figure 1, whereas non-CMV infections were similar between both groups with a trend towards lower infections for letermovir recipients 75.2% vs 83% p=0.07, figure 1. When assessing the difference in non-CMV infections per infection, there was no difference in the mean number of infections at 6 months post-HCT where patients in both groups had a mean of 2.5 infections. When looking at different types of infections between Letermovir and no letermovir groups, there was no difference in mean number of bacterial infections (1.58 vs 1.43), viral infections (0.90 vs 0.95) and fungal infections (0.16 vs 0.22), P =NS for all. Our data shows that in a large cohort of allogeneic HCT recipients, mostly haploidentical with Post-transplant cyclophosphamide, letermovir significantly decreases CMV reactivation without changing the pattern or incidence of non-CMV infections. 1. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38. 2. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711-9. 3. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. The New England journal of medicine. 2017;377(25):2433-44. 4. Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood. 2021;138(1):34-43. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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

Background Cytomegalovirus (CMV) causes significant morbidity and mortality in patients who have undergone allogeneic transplant with 45-60% mortality rates or end-organ failure related to CMV disease secondary to immunosuppression. The use of post-transplant Cyclophosphamide (PT-Cy), commonly used in haploidentical transplants (haplo-SCT), has been associated with high rates of CMV infection, reported to be 42% based on a CIBMTR analysis performed in 2021. Letermovir is FDA approved for prevention of CMV infection and disease in adult CMV-seropositive recipients [R+] undergoing allogeneic hematopoietic stem cell transplant (SCT). Despite the use of letermovir to decrease incidence of CMV, there has been limited literature on the incidence of CMV breakthrough infections in haplo-SCT patients receiving letermovir. We set out to quantify the incidence of breakthrough CMV infections in patients undergoing haplo-SCT with PT-Cy receiving letermovir prophylaxis. Endpoints The primary endpoint was to determine the incidence of breakthrough CMV reactivation (single quantifiable viral load of >200 CMV IU/mL of plasma, 2 detectable viral loads of <200 CMV IU/mL of plasma tested 3-4 days apart) both early <100 days post-transplant and late >100 days. Key secondary end points were mortality due to CMV infection, incidence of disease, end organ involvement, duration of CMV treatment, risk factors associated with CMV reactivation (based on age, sex, and seropositive status), and timing of CMV infections after haploidentical transplant. Methods This single-center, retrospective, cohort study was performed at OHSU under an IRB approved protocol. Electronic health records of patients from January 2017 to September 2021 were retrospectively reviewed to assess incidence of breakthrough CMV infection. Eligible patients were at least 18 years of age, received a haploidentical hematopoietic stem cell transplant, and received PT-Cy for graft vs host disease (GVHD) prophylaxis. Those discovered to have active CMV infections (defined as..) during conditioning who were later put on letermovir or foscarnet for treatment of their CMV reactivation were excluded. These data have been previously reported. A posthoc analysis was then performed comparing patients who received letermovir prophylaxis with a historical treatment group that underwent haplo-SCT and receive an identical treatment protocol, but did not received letermovir prophylaxis. Patients were matched by age and CMV seropositive status in a 2:1 ratio (letermovir: no letermovir), and analyzed for comparative CMV related outcomes. Results: A total of 14 eligible study subjects received letermovir prophylaxis (LP) and 7 patients did not receive letermovir prophylaxis (NLP). Overall, median age was 45 years in both groups with LP group being more male (63%) and the NLP being more female (70%) (Table 1). Thirteen of the 21 subjects received myeloablative conditioning. All subjects received PTCy, MMF until D+35 and tacrolimus goal 5-10 until D100. Letermovir was started 5 days post-transplant and stopped 100 days post-transplant. The number of patients that experienced early CMV reactivation (<100 days) was 3/14 (21.4%) and 6/7 (85.7%) in the LP and NLP treatment groups, respectively. Late CMV reactivations were rare, the LP group had 1 patient reactivate past 100 days post-transplant while there were no patients who reactivated past 100 days in the no NLP group. Mean timing of CMV viremia for the LP was significantly longer at 62 days while the NLP group was at 36.5 days. No significant risk factors were associated with age, CMV recipient seropositivity, or sex. Duration of CMV treatment was 23 days for the LP group and 21 days for the NLP group. Importantly, no patients in either cohort died of CMV (Table 2). Discussion/Conclusion: Overall, we found the LP was associated with significantly less CMV reactivations, indicating that letermovir provides effective CMV prophylaxis for patients undergoing haplo-SCT with PT-Cy. Interestingly, mean timing of CMV viremia was later for the LP group compared to the NLP group. In our cohort, we did observe 1 patient who reactivated CMV late post-transplant. This observation and the results of a study published by L.W.Liu et al. (doi: 10.1016/j.jtct.2022.05.020.) may suggest that letermovir prophylaxis past day 100 post-transplant may be indicated for haplo-SCT patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

B-Cell Reconstitution After Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis.

Background and ObjectivesAutologous hematopoietic stem cell transplantation (aHSCT) is increasingly used to treat aggressive forms of multiple sclerosis (MS). This procedure is believed to result in an immune reset and restoration of a self-tolerant immune system. Immune reconstitution has been extensively studied for T cells, but only to a limited extent for B cells. As increasing evidence suggests an important role of B cells in MS pathogenesis, we sought here to better understand reconstitution and the extent of renewal of the B-cell system after aHSCT in MS.MethodsUsing longitudinal multidimensional flow cytometry and immunoglobulin heavy chain (IgH) repertoire sequencing following aHSCT with BCNU + Etoposide + Ara-C + Melphalan anti-thymocyte globulin, we analyzed the B-cell compartment in a cohort of 20 patients with MS in defined intervals before and up to 1 year after aHSCT and compared these findings with data from healthy controls.ResultsTotal B-cell numbers recovered within 3 months and increased above normal levels 1 year after transplantation, successively shifting from a predominantly transitional to a naive immune phenotype. Memory subpopulations recovered slowly and remained below normal levels with reduced repertoire diversity 1 year after transplantation. Isotype subclass analysis revealed a proportional shift toward IgG1-expressing cells and a reduction in IgG2 cells. Mutation analysis of IgH sequences showed that highly mutated memory B cells and plasma cells may transiently survive conditioning while the analysis of sequence cluster overlap, variable (IGHV) and joining (IGHJ) gene usage and repertoire diversity suggested a renewal of the late posttransplant repertoire. In patients with early cytomegalovirus reactivation, reconstitution of naive and memory B cells was delayed.DiscussionOur detailed characterization of B-cell reconstitution after aHSCT in MS indicates a reduced reactivation potential of memory B cells up to 1 year after transplantation, which may leave patients susceptible to infection, but may also be an important aspect of its mechanism of action.

Low absolute neutrophilic and lymphocytic counts in children with CMV reactivation following HSCT

Introduction: Cytomegalovirus (CMV) infection is one of the commonest infections after hemopoietic stem cell transplantation (HSCT) and it may lead to significant morbidity, mortality and can lead increased healthcare costs. Aim: The aim of this work was to evaluate the relation between neutrophilic and lymphocytic count recovery in children with CMV reactivation following HSCT. Method: The study included 30 patients with CMV reactivation who underwent allogenic hematopoietic stem cell transplantation for non-malignant diseases in Abo El-Reesh Al Mounira Pediatric Hospital, Cairo University. Pre- and post-transplant clinical and laboratory data were collected. Results: The 30 patients developed 69 episodes of CMV reactivation. 66.6% and 53.5% of the reactivation episodes were associated with low absolute lymphopenic and neutrophilic respectively. The early CMV reactivation episodes were associated with severe low absolute lymphocytic and neutrophilic counts with p value (0.003, 0.006) respectively. Conclusion: Neutrophilic and lymphocytic count recovery is an important factor associated with reactivation. Importance of close monitoring of viral load among lymphopenic and neutropenic patients for strong surveillance and early detection of CMV reactivation and proper management.

Risk Factors for Early Cytomegalovirus Reactivation and Impact of Early Cytomegalovirus Reactivation on Clinical Outcomes after T Cell-Replete Haploidentical Transplantation with Post-Transplantation Cyclophosphamide

Risk factors for cytomegalovirus (CMV) reactivation and the impact of CMV reactivation on patient outcomes have been extensively investigated after matched related or unrelated donor transplantation, but little is known in the setting of haploidentical stem cell transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), in which recipients are considered more severely immunocompromised. We retrospectively analyzed a cohort of 554 consecutive patients undergoing Haplo-SCT with PT-Cy at 3 different centers. Early CMV reactivation (occurring within the first 120 days post-transplantation) occurred in 242 patients, for an estimated cumulative incidence of 44%. Among those patients, 74 (30%) had recurrent CMV and 20 (8%) had CMV disease. On multivariable analysis, positive recipient CMV serostatus (hazard ratio [HR] >2.5; P < .001), disease histology (lymphoid versus myeloid: HR, 0.66; P=.003) and increasing recipient age (HR, 1.01; P=.015) were independent predictors of CMV reactivation. At a 4-month landmark analysis, CMV reactivation was associated with higher 1-year and 5-year cumulative incidence of nonrelapse mortality (NRM) relative to patients without reactivation: 13% versus 5% and 22% versus 9%, respectively (P < .001). On multivariable analysis, CMV reactivation was an independent negative predictor of NRM (HR, 2.69; P < .001) and was close to statistically significant for overall survival (HR, 1.38; P=.062). Our results suggest that CMV reactivation plays an important role at determining NRM. Because patient CMV serostatus is the main predictor of CMV reactivation, it should be considered when evaluating strategies for preventing CMV reactivation. 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

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.

Letermovir Is Effective for Prevention of Cytomegalovirus Reactivation in HLA-Haploidentical Peripheral Blood Stem Cell Transplantation with Post-Transplant Cyclophosphamide

[Introduction] Cytomegalovirus (CMV) infection is a common viral infection in recipients of allogeneic hematopoietic stem cell transplantation (allo-SCT). Early CMV reactivation after allo-SCT is associated with worse non-relapse mortality (NRM) and overall survival (OS). Recently, T-cell replete HLA-haploidentical SCT using post-transplant cyclophosphamide (PTCy-haplo SCT) has been developed and spread rapidly worldwide. Rationale of this strategy is assumed to be selective and cytotoxic depletion of alloreactive T cells which are responsible for graft-versus-host disease (GVHD), while preserving non-alloreactive T cells which can contribute to fight infections. However, recent studies showed that PTCy-haplo SCT was associated with the increased incidence of CMV infection. Letermovir (LET), a novel anti-CMV agent, which inhibits the CMV DNA terminase complex, was approved for the prevention of CMV reactivation in allo-SCT recipients in 2018 in some countries including Japan based on the result of a phase 3 trial. Our facility performs LET prophylaxis in allo-SCT recipient if either donor or recipient is seropositive CMV. Although LET is effective for the prevention of CMV reactivation in allo-SCT recipients, the clinical effectiveness of LET prophylaxis in PTCy-haplo SCT is not well elucidated. Based on these things, we retrospectively evaluated the efficacy of LET prophylaxis in PTCy-haplo SCT.[Methods] We retrospectively analyzed consecutive 99 recipients who received PTCy-haplo SCT at Hokkaido University Hospital from March 2013 to March 2021. We compared the cumulative incidence of CMV reactivation between the LET prophylaxis group (LET group, 33 patients) and LET non-prophylaxis group (non-LET group, 66 patients). LET was initiated on the day 0 at a dosage of 480mg daily. All patients were monitored for CMV reactivation by using the anti-CMV pp65 monoclonal antibody HRP-C7 assay at least once a week from the time of engraftment. CMV reactivation was defined as the detection of CMV antigen positive cells per 50000 white blood cells, whereas CMV disease was defined by organ dysfunction attributable to CMV.[Results] As baseline patient's characteristics were summarized in Table1, there were no difference between LET and non-LET group in terms of age, sex, underlying disease, disease risk at transplantation, prior transplantation, conditioning intensity, and CMV serostatus. All patients received peripheral blood stem cell transplantation. GVHD prophylaxis consisted of Cy (40-50 mg/kg on day 3 and 4), tacrolimus (from day 5), and mycophenolate mofetil (from day 5). The cumulative incidence of CMV reactivation at 150 days after transplantation in LET group was significantly lower than that in non-LET group (30.3% versus 69.7%; P <.001, Figure1A). Importantly, CMV disease were occurred in three patients without LET prophylaxis (gastritis, enteritis, and retinitis), but not in the patients with LET prophylaxis. The cumulative incidence of NRM at 1 year was similar between the patients with and without LET prophylaxis (17.6% versus 9.2%; P=0.366, Figure1B), as was OS at 1 year (71.5% versus 69.4%; P=0.801, Figure1C). Neutrophil engraftment was achieved in 32 patients (97%) at a median of 15 days in LET group and 64 patients (97%) at a median of 14.5 days in non-LET group (P=0.243). Furthermore, platelet engraftment was achieved in 26 patients (79%) at a median of 34 days in LET group and 57 patients (86%) at a median of 31 days in non-LET group (P=0.282). These findings suggest that LET does not affect engraftment. Interestingly, the length of hospitalization in the LET group was significantly shorter than that in non-LET group (the median, 59.5 days versus 71 days; P=0.0488), suggesting that LET suppresses CMV reactivation leading to early discharge.[Conclusion] To our best knowledge, this is the largest retrospective study about the efficacy of LET in PTCy-Haplo SCT. LET is effective for prevention of CMV reactivation in PTCy-haplo SCT. Further studies focused on the long term effect of LET prophylaxis in PTCy-haplo SCT, such as the incidence of relapse and chronic GVHD, is warranted. [Display omitted] DisclosuresNakagawa: AbbVie GK: Research Funding; Takeda Pharmaceutical Company: Research Funding. Teshima: Gentium/Jazz Pharmaceuticals: Consultancy; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Research Funding; CHUGAI PHARMACEUTICAL CO., LTD.: Research Funding; Fuji pharma CO.,Ltd: Research Funding; Takeda Pharmaceutical Company: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis International AG: Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; TEIJIN PHARMA Limited: Research Funding; Astellas Pharma Inc.: Research Funding; Bristol Myers Squibb: Honoraria; Janssen Pharmaceutical K.K.: Other; Kyowa Kirin Co.,Ltd.: Honoraria, Research Funding; Sanofi S.A.: Research Funding.

Early cytomegalovirus reactivation after heart transplantation: A case report and literature review

Reactivation of cytomegalovirus is one of the most significant morbidities in solid organ transplant recipients. Reports describing the risk factors for cytomegalovirus reactivation in heart transplantation are scarce. We present a case in which viral reactivation 9 days after heart transplantation resulted in cytomegalovirus enterocolitis. Before transplantation, the patient received extracorporeal membrane oxygenation. Cytomegalovirus reactivation occurred under prophylactic medication with valganciclovir and progressed to cytomegalovirus enterocolitis, complicated by ischemia and a small bowel perforation. The patient died of repeated septic shock, severe gastrointestinal tract complications, and cytomegalovirus hepatitis. A review of 70 heart transplant recipients at our hospital from 2005 to 2020 revealed that cytomegalovirus reactivation occurred more frequently in those who received pretransplantation extracorporeal membrane oxygenation than in those who did not (36.4% vs. 6.8%, P = 0.018). This finding suggests that early diagnosis and prompt management of cytomegalovirus reactivation in patients receiving extracorporeal membrane oxygenation as a bridge to heart transplantation is crucial.

Relapse Protection Following Early Cytomegalovirus Reactivation after Hematopoietic Stem Cell Transplantation Is Limited to HLA-C Killer Cell Immunoglobulin-Like Receptor Ligand Homozygous Recipients

Although the risk for nonrelapse mortality (NRM) associated with early cytomegalovirus (CMV) reactivation (CMVR) after allogeneic hematopoietic stem cell transplantation (HSCT) is well established, debate is ongoing on whether CMVR may reduce the risk of primary disease relapse. The aim of this study was to evaluate relapse protection following early CMV reactivation after HSCT in the context of the recipient HLA-C killer cell immunoglobulin-like receptor ligands (KIRLs). In this retrospective bicentric study, 406 matched related or unrelated donor transplantations for acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) were stratified by HLA-C KIRL group (homozygous versus heterozygous) and analyzed separately for the impact of early CMVR on the cumulative incidences of relapse, NRM, and acute and chronic graft-versus-host-disease (GVHD) using landmark and multistate analyses. By landmark analysis of patients alive and relapse-free at 45 days post-HSCT, HLA-C KIRL homozygous recipients (C1/1 or C2/2) had a lower risk of subsequent relapse if CMVR occurred before this landmark (subhazard ratio [sHR], 0.36; P=.002). In contrast, in HLA-C KIRL heterozygous (C1/2) recipients, early CMVR had no impact on subsequent relapse (sHR, 0.88; P=.63). NRM (sHR, 3.31; P < .001) and grade III-IV acute GVHD (sHR, 2.60; P=.04) were significantly increased after early CMVR in the homozygous cohort, but not in the heterozygous cohort (NRM: sHR, 1.23; P=.53; grade III-IV acute GVHD: sHR, 1.40; P=.50). Multivariable landmark analyses and a multistate model confirmed the limitation of the relapse-protective effect of early CMVR to the homozygous cohort. Chronic GVHD and overall survival were not influenced in neither cohort. An antileukemic effect of early CMVR after HSCT for AML/MDS was significant but strictly limited to recipients homozygous for HLA-C KIRL. However, particularly in this cohort, CMVR had an adverse impact on aGVHD and NRM.

Comparison of Cytomegalovirus-Specific Immune Cell Response to Proteins versus Peptides Using an IFN-γ ELISpot Assay after Hematopoietic Stem Cell Transplantation.

Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality following hematopoietic stem cell transplantation (HSCT). Measuring CMV-specific cellular immunity may improve the risk stratification and management of patients. IFN-γ ELISpot assays, based on the stimulation of peripheral blood mononuclear cells with CMV pp65 and IE-1 proteins or peptides, have been validated in clinical settings. However, it remains unclear to which extend the T-cell response to synthetic peptides reflect that mediated by full-length proteins processed by antigen-presenting cells. We compared the stimulating ability of pp65 and IE-1 proteins and corresponding overlapping peptides in 16 HSCT recipients using a standardized IFN-γ ELISpot assay. Paired qualitative test results showed an overall 74.4% concordance. Discordant results were mainly due to low-response tests, with one exception. One patient with early CMV reactivation and graft-versus-host disease, sustained CMV DNAemia and high CD8+ counts showed successive negative protein-based ELISpot results but a high and sustained response to IE-1 peptides. Our results suggest that the response to exogenous proteins, which involves their uptake and processing by antigen-presenting cells, more closely reflects the physiological response to CMV infection, while the response to exogenous peptides may lead to artificial in vitro T-cell responses, especially in strongly immunosuppressed patients.