Cumulative Incidence Of Cytomegalovirus Reactivation Research Articles

Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation.

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).

Cytomegalovirus (CMV) Reactivation and CMV-Specific Cell-Mediated Immunity After Chimeric Antigen Receptor T-Cell Therapy.

The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood owing to a lack of routine surveillance. We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx recipients and tested plasma samples for CMV before and weekly up to 12 weeks after CARTx. We assessed CMV-specific cell-mediated immunity (CMV-CMI) before and 2 and 4 weeks after CARTx, using an interferon γ release assay to quantify T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves. CMV was detected in 1 patient (1.4%) before and in 18 (25%) after CARTx, for a cumulative incidence of 27% (95% confidence interval, 16.8-38.2). The median CMV viral load (interquartile range) was 127 (interquartile range, 61-276) IU/mL, with no end-organ disease observed; 5 patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir 2 weeks after infusion and recovered to baseline levels by week 4. In adjusted models, BCMA-CARTx (vs CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA-CARTx target and use of corticosteroids for >3 days (46% and 49%, respectively). CMV testing could be considered between 2 and 6 weeks in high-risk CARTx recipients.

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.

Targeted dosing of anti-thymocyte globulin in adult unmanipulated haploidentical peripheral blood stem cell transplantation: A single-arm, phase 2 trial.

Anti-thymocyte globulin (ATG) is widely used in allogeneic hematopoietic stem cell transplantation to prevent severe graft-versus-host disease (GVHD) and graft failure. However, overexposure to ATG may increase cytomegalovirus (CMV), Epstein-Barr virus (EBV) reactivation, non-relapse mortality, and disease recurrence. To investigate the optimal dosing of ATG, we established a targeted dosing strategy based on ATG concentration monitoring for haploidentical peripheral blood stem cell transplantation (haplo-PBSCT). The aim of this phase 2 trial is to evaluate the safety and efficacy of the ATG-targeted dosing strategy in adult unmanipulated haplo-PBSCT. ATG was administered for 4 days (-5 days to -2 days) during conditioning. The ATG doses on -3 days and -2 days were adjusted by our dosing strategy to achieve the optimal ATG exposure. The primary endpoint was CMV reactivation on +180 days. Between December 2020 and January 2022, 66 haplo-PBSCT patients were enrolled and 63 of them were evaluable with a median follow-up of 632 days. The cumulative incidence of CMV reactivation was 36.7% and that of EBV was 58.7%. The 1-year disease-free survival was 82.5%, overall survival was 92.1%, and CD4+ T-cell reconstruction on +100 days was 76.8%. The most common severe regimen-associated toxicities (> grade 3) were infections (51.5%) and gastrointestinal toxicity (25.5%). A total of 102 haplo-PBSCT patients who received the conventional fixed ATG dose (cumulative 10 mg/kg) comprised historical control. The outcomes in historical control were inferior to those of phase 2 trial cohort (CMV reactivation: 70.8%, p < .001; EBV reactivation: 76.0%, p = .024; CD4 + T-cell reconstruction: 54.1%, p = .040). In conclusion, ATG-targeted dosing strategy reduced CMV/EBV reactivation and improved survival without increasing GVHD after haplo-PBSCT. These advantages may be associated with accelerated immune reconstitution.

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.

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

Impact of Cytomegalovirus (CMV) Sero-Conversion Pre Allogeneic Stem Cell Transplant on Post-Transplant Outcomes

INTRODUCTION: The choice of an ideal allogeneic hematopoietic cell transplantation (allo-HCT) donor depends on numerous parameters, including cytomegalovirus (CMV) sero-status matching. We sought to determine the frequency of observed CMV seroconversions in patients pre allo-HCT and to investigate the impact on post-transplant CMV reactivation and survival outcomes. METHODS: We conducted a retrospective study that included 752 adult patients that underwent allo-HCT at the Princess Margaret Cancer Centre from January 2015 to February 2020, before the adoption of letermovir prophylaxis in high-risk patients. CMV serology was assessed for all patients at consult and pre-transplant assessment. The cohort was divided into 4 groups based on apparent pre-transplant seroconversion: 1) From negative to positive (group1), 2) From positive to negative (group2), 3) Consistently negative (group3), 4) Consistently positive (group 4). We documented the occurrence of CMV viremia in all 4 groups depending on CMV sero-status of the donor, and investigated post-transplant outcomes. Standard routine monitoring for CMV viremia post-transplant was performed using quantitative polymerase chain reaction (PCR). RESULTS: The minimum follow-up of survivors was 2 years. Eighty-nine patients (12%) had sero-converted from negative to positive, 17 (2%) from positive to negative, 151 (20%) were consistently sero-negative and 495 (66%) were consistently sero-positive pre-transplant. Transplant indications were acute myeloid leukemia (AML) in 50%, acute lymphoid leukemia (ALL) in 19% of patients. Median age of the entire cohort was 58 years (range: 18-76), 43% were female, 38% had hematopoietic cell transplant- comorbidity index (HCT-CI) ≥3, 20% had Karnofsky performance status (KPS) <90%, for 23% the disease risk index (DRI) was high or very high. Fully HLA matched donor were 78% of the donors. Haplo-identical donors were 14%, 58% of donors were unrelated and 28% were matched related. Reduced intensity conditioning (RIC) was given to 77% of patients, 89% underwent in-vivo T-cell depletion. No difference was shown between the four CMV sero-status groups regarding overall survival (OS) (p=0.46), cumulative incidence of relapse (CIR)(p=0.76), neutrophil recovery (p=0.20), platelet recovery (p=0.69), grade III-IV acute graft-versus-host disease (GVHD)(p=0.93), moderate/severe chronic GVHD (p=0.57) or graft failure (p=0.28). For the four groups, the cumulative incidence of CMV reactivation at 6 months was 5.6%, 47.1%, 7.9% and 79.4% for group 1,2,3 and 4 respectively (Figure). In multivariable analysis, recipient CMV sero-status pre-transplant was associated with CMV reactivation (Hazard ratio HR=20, 95% CI= 11-34, p<0.0001 for consistently positive CMV sero-status compared to consistently negative, irrespective of donor CMV sero-status). Other parameters influencing CMV reactivation included increasing CD34+ cell dose (HR=1.02, 95% CI=1.004-1.04, p=0.02) and haplo-identical donor status (HR=2.1 in comparison to matched related donors, 95% CI =1.55-2.84, p<0.0001). Considering both donor and recipient CMV sero-status, we separated the cohort into eight groups (Table). In 89 patients that converted CMV serology pre-transplant from negative to positive, 6 patients had CMV reactivation post-transplant (5 of them received stem cells from a CMV positive donor). In 17 patients that converted from positive to negative, 8 (47%) had CMV reactivation post-transplant. In the consistently CMV positive group, the incidence of CMV reactivation was high with either CMV negative (87.5%) or CMV positive (77.2%) donors (Table). CONCLUSION: Allo-HCT patients that demonstrate CMV sero-conversion pre-transplant from negative to positive have a very low risk of CMV reactivation post-transplant. The observed sero-conversion in these patients may be due to passive CMV immunity acquired through the administration of blood-derived products. Patients that sero-converted from positive to negative pre-transplant continue to demonstrate CMV reactivation risk even with a CMV negative donor. Quantitative CMV IgG/IgM pre-transplant may help to differentiate between true sero-conversion and passively transmitted CMV immunoglobulins, which in turn may facilitate determination of CMV reactivation risk as well as donor choice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Relationship between certain HLA alleles and the risk of cytomegalovirus reactivation following allogeneic hematopoietic stem cell transplantation.

Evidence is emerging to support an association between certain human leukocyte antigen (HLA) alleles and the risk of cytomegalovirus (CMV) reactivation following allogeneic hematopoietic stem cell transplant (allo-HSCT). The primary aim of this study was to identify HLA alleles associated with resistance or susceptibility to CMV reactivation. We studied 586 adults who underwent allo-HSCT for high-risk hematological malignancies. High-resolution HLA typing data were available for recipients and donors. HLA class I and II alleles observed at a frequency of >5% in our population were included in the analysis. A CMV viremia level of more than 200 IU/ml on weekly monitoring was considered to be indicative of CMV reactivation. The median follow-up time in surviving patients was 21 months (range 4-74 months). The cumulative incidence of CMV reactivation at 6 months in the entire cohort was 55% (95% confidence interval [CI] 50.8%-59.2%). Mismatched donors, increasing recipient age, occurrence of acute graft versus host disease and recipient CMV seropositivity were associated with an increased risk of CMV reactivation. HLA B*07:02 (hazard ratio 0.59, 95% CI 0.40-0.83) was associated with a decreased risk of CMV reactivation. Patients who developed CMV reactivation had a lower incidence of relapse, higher transplant-related mortality (TRM) and lower overall survival (OS) than those without CMV reactivation. There was an adverse correlation of OS and TRM with increasing numbers of CMV reactivations. We observed that HLA B*07:02 was associated with a decreased risk of CMV reactivation. CMV reactivation was associated with lower relapse post-transplant, but this did not translate into a survival benefit due to higher TRM.

Letermovir Prophylaxis for Cytomegalovirus Infection in Children After Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) infection is one of the major causes of morbidity following hematopoietic cell transplantation (HCT). Allogeneic HCT (allo-HCT) recipients are at the highest risk of clinically significant CMV reactivation. While letermovir has been approved for prophylactic use in CMV seropositive adults, reports on pediatric data are very limited. The objective of the study was to examine the use of letermovir for prophylaxis from CMV infection in children undergoing allo-HCT in a single center. This retrospective matched-pair analysis study included 39 CMV-seropositive pediatric patients undergoing allo-HCT receiving letermovir as a primary prophylaxis for CMV infection on a compassionate-use basis (LMV group, n=13) or not (control group, n=26). There were no differences in basic characteristics between the analyzed groups. Among patients of the study group, 12 received primary prophylaxis with letermovir from day +1 after HCT. One patient, previously treated with ganciclovir received secondary prophylaxis from day +18. Prophylactic dose of letermovir was adjusted to cyclosporine co-administration, varied in between 120-480 mg, and given orally, once daily. No CMV reactivation was observed during administration of letermovir. Cumulative incidence of CMV reactivation was significantly higher for the control group not receiving prophylaxis. Of the 13 patients of the study group, three died; however, deaths were not attributable to CMV infection. We did not observe any toxicities related to letermovir. Our data support letermovir prophylaxis efficacy and safety in pediatric patients after allo-HCT. Compared with the historical group, prophylactic use of letermovir decreased the number of CMV reactivations in children.

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.

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.

CCR6, IL7R, FAS and Madcam-1 Single Nucleotide Polymorphisms Are Associated with Higher Incidence of Infections in Allogeneic Stem-Cell Transplant from a Related Donor after a Reduced Intensity Conditioning Regimen: A Multicenter Experience

INTRODUCTION: Infection complications are important cause of morbidity and non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-SCT), even in HLA-identical sibling donors. Although there are many studies associating single nucleotide polymorphisms (SNPs) and allo-SCT evolution, these are mainly related with graft versus host disease (GVHD) and/or transplant related mortality (TRM), with few focused on post-allo-SCT infections. This multicentric study analyzes the potential implication of SNPs with cytomegalovirus (CMV) reactivation and fungal infection (FI) development in allo-SCT with reduced intensity conditioning (RIC).MATERIALS AND METHODS: We included paired recipient-donor samples from 247 RIC allo-SCT for patients diagnosed of AML (35%), NHL (21%), MDS (16%), MM (10%), CLL (7%), HL (6%), or others (5%) in four centers in Spain. Flu-Bu conditioning was used in 55% of the transplants while Flu-Mel in 42%. A total of 52 SNP were analyzed from 44 different gene loci and genotyping was carried out by Sequenom Mass ARRAY platform. Allele frequencies were estimated by direct counting and compared between groups using Fisher's test. P-value <0.05 was considered to be statistically significant. Log-rank analysis was used to compare differences between survival curves.RESULTS: Patient's characteristics are shown in Table 1. The median follow up for patients was 28 months (1-175), overall survival at 5 years was 45%, while the event-free survival at 5 years was 57%. Cumulative incidence of CMV reactivation at 3 years was 34% and of FI 11%. Transplant related mortality was 17%, and infection related mortality 14%.In univariate analysis, patients with genotype A/A in rs3093023 (CCR6) showed a lower incidence of CMV reactivation (table 2), along with acute GVHD were the variables associated in multivariate analysis.Regarding to FI, recipient genotype A/A in rs1494555 (IL7R), donor C/C in rs1800795 (FAS), and donor G/G in rs2302217 (MAdCAM-1) were associated with higher FI incidence (table 2), being the only variables related in multivariate analysis.CONCLUSION: This data suggest an association between rs3093023 (CCR6), rs1494555 (IL7R), rs1800795 (FAS) and rs2302217 (MAdCAM-1) polymorphisms with higher incidence of post-allo-SCT opportunist infection. Confirmation in larger series is required.FUNDING: RD12/0036/0069, CB16/12/00233 and 00480, PI12/02361 and ERDF, Innocampus; CEI-2010- 1-0010 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

High Incidence of CMV Reactivation after Haploidentical Donor Hematopoietic Cell Transplantation Using High-Dose Post-Transplant Cyclophosphamide, and Its Impact on Transplant Outcomes

Haploidentical donor hematopoietic cell transplantation (HaploHCT) using high-dose post-transplant cyclophosphamide (PTCy) has been increasingly used in patients with hematologic disorders with promising results. However, limited data is available on the incidence, pattern, and risk factors for cytomegalovirus (CMV) reactivation after HaploHCT with PTCy. Furthermore, the impact of CMV reactivation on HaploHCT outcomes has not been well understood in these patients. In this retrospective study we evaluated 119 consecutive patients undergoing HaploHCT for hematological diseases using PTCy between January 2008 and December 2016 at City of Hope under the IRB approved protocol. CMV reactivation was monitored by our institutional PCR assay (quantitative detection limit: 500gc/ml, qualitative limit: 250gc/ml) at least once a week for 100 days post-HCT, with preemptive anti-CMV therapy for positive PCR according to the institutional guidelines.The median age of the cohort was 43 years (range: 2 to 71 years); 47 patients were female and 72 were male. CMV serostatus of donor/recipient was D-R- in 7, D+R- in 6, D-R+ in 23, and D+R+ in 82 patients. Patients received fully ablative (n=46) or reduced-intensity/non-myeloablative conditioning (n=73) followed by peripheral blood stem cell (n=81) or bone marrow (n=38) graft from sibling (n=42) or non-sibling Haplo donor (n=77). Graft versus host disease (GVHD) prophylaxis was PTCy plus tacrolimus/mycophenolate mofetil. Diagnoses of these patients were acute leukemia (n=80), bone marrow failure (n=15), lymphoma (n=11), chronic leukemia (n=6), hemoglobinopathies (n=5), and multiple myeloma (n=2). The HCT-comorbidity index was more than 2 in 42% (n=50) of the patients.Cumulative incidence (CI) of CMV reactivation for the entire cohort was 69.2% (95%CI: 59.8-76.8%) at 100-days, with the median time to reactivation at 35 days (Figure 1a). While for seropositive recipients (n=105), cumulative incidence of CMV reactivation was 76.5% (95%CI: 66.9-83.6%) with the median onset at 33 days. The median CMV PCR values at onset was 624 gc/ml (range: <500 - 9,930) while the median peak PCR value during the 100-day period was 2965 gc/ml (range: <500 - 221,125). The median duration of CMV reactivation was 21 days and 28% (n=33) of patients had recurrent CMV reactivation during the first 100 days post-HCT. In our cohort there was no patient who developed CMV disease.In univariate analyses the only significant risk factor for CMV reactivation was recipient serostatus (HR=0.06, 95%CI: 0.01 to 0.40 for R- compared to R+, p<0.001) (Figure 1b). Acute GVHD (aGVHD) was not associated with CMV reactivation when analyzed as a time-dependent variable partly due to lower incidence and later onset of aGVHD (100 days incidence: 36.7%; median onset day was not reached, range= 18 to 88) than CMV reactivations (median: 33 days, range= 7 to 54).We then evaluated the impact of CMV reactivation in a landmark analysis of 101 patients who were relapse free for 100 days. The median follow up duration in this subgroup was 12.3 months (range: 3.4 to 99.1). In univariate analysis, CMV reactivation was not associated with overall survival (OS), relapse-free survival (RFS), relapse incidence, or non-relapse mortality (NRM). Similarly, the high-peak CMV reactivation or prolonged CMV reactivation (total duration or total episodes) was not predictive of poor outcomes in this cohort. Interestingly, the risk of chronic GVHD was greater in patients who had no CMV reactivation than those who developed prolonged/recurrent CMV reactivations (56.0% vs. 20.5%, p= 0.048, Figure 2).In conclusion, HaploHCT with PTCy was associated with a high rate of CMV reactivations in seropositive recipients. However, due to pre-emptive therapy approach, CMV reactivation did not translate into higher rate of CMV disease. Despite many patients requiring a long course of preemptive anti-CMV therapy, there was no obvious association between CMV reactivation and survival outcomes. The observed association between CMV reactivation and reduced risk of chronic GVHD warrant further clinical and correlative immunologic studies. [Display omitted] DisclosuresNademanee:seattle Genetics: Speakers Bureau.

Timing of Induction Treatment for Reactivation of Cytomegalovirus Impacts Overall Survival in Pediatric Allogeneic Hematopoietic Cell Transplant

Background Despite significant advances in viral detection and treatment, reactivation of cytomegalovirus (CMV) remains a major complication following allogeneic hematopoietic cell transplant (allo-HCT). Methods to decrease the risk of CMV reactivation and long-term sequelae of CMV disease include controlling for known risk factors and administering appropriate antiviral treatments. Although they are shown to be effective, these treatments carry considerable adverse effects that may limit their use. The optimal timing to initiate induction treatment remains unclear, especially in the pediatric population. Design We performed a retrospective analysis of patients who received initial conventional or ex-vivo T-cell depleted (TCD) allo-HCT on the pediatric service from January 2010 – June 2018 at Memorial Sloan Kettering Cancer Center. CMV reactivation was defined as ≥ 1 CMV PCR >500 in whole blood or >137 in plasma within 180 days post-transplant. Induction treatment was typically initiated for CMV PCR ≥ 1000 in whole blood, ≥ 300 in plasma, or rising viremia from baseline. Hospital databases and medical records were utilized to identify patients and collect clinical data. Time-dependent Cox models and multi-state models to account for competing risks were used. This study was approved by Institutional Review Board. Results Our study consisted of 227 patients (54 days - 27 years old) who underwent allo-HCT for malignant (N=143) and non-malignant (N=84) diseases. TCD represented 76% of all allografts. CMV donor (D) and recipient (R) serostatus were: D+/R+ N=90, D+/R- N=29, D-/R+ N=38, D-/R- N=70. Cumulative incidence of CMV reactivation was 24.8% and 15 patients (27%) developed CMV disease. Median time to CMV reactivation was 24 days (IQR 14-33). Of the 56 patients who reactivated, 41 (73%) patients received induction treatment. The median time from CMV reactivation to induction treatment was 6 days (IQR 1-15). D+/R+ serostatus was a predictor for CMV reactivation when compared to D-/R+ (HR=2.1, [95% CI 1.1 - 4, P Conclusions A short interval between CMV reactivation and initiation of induction treatment was significantly associated with improved OS in TCD HCT. Earlier treatment did not translate into improved outcomes, which may be confounded by high-risk patients receiving induction therapies earlier. Further evaluation into CMV prophylaxis and prompt initiation of induction treatment on additional CMV outcomes will help optimize treatment options and improve clinical outcomes.

Reduced risk of chronic GVHD by low-dose rATG in adult matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies

The optimal rabbit anti-thymocyte globulin (rATG) graft-versus-host disease (GVHD) prophylaxis regimen in matched sibling donor peripheral blood stem cell transplantation (MSD-PBSCT) remains to be elucidated. In this prospective study, we used low-dose rATG for GVHD prophylaxis in patients or donors aged ≥ 40 years with hematological malignancies receiving MSD-PBSCT. rATG was administered to 40 patients at an intravenous dose of 5 mg/kg divided over day 5 and day 4 before graft infusion. No graft failure occurred. Median times to leukocyte engraftment and platelet engraftment were 11.0 days and 13.9 days. The cumulative incidence of grades 2–4 and grades 3–4 acute GVHD at day +100 was 30.0% and 2.6%. The 2-year cumulative incidence of extensive chronic GVHD and severe chronic GVHD was 11.4% and 14.7%. 93.5% (29/31) of patients had discontinued immunosuppressive medication within 3 years after transplantation. The 2-year cumulative incidence of transplant-related mortality (TRM) and relapse was 14.0% and 22.6%. The cumulative incidence of cytomegalovirus reactivation, Epstein–Barr virus reactivation, and fungal infection was 22.3%, 12.9%, and 12.5%. Kaplan–Meier estimates for overall survival, disease-free survival, and GVHD-free and relapse-free survival 3 years after transplantation were 68.9%, 68.9%, and 54.0%. rATG for GVHD prophylaxis is tolerable and efficacious at a 5 mg/kg total dose administered over 2 days (days −5 to −4) in patients receiving allogeneic MSD-PBSCT.

CMV-Seropositive Recipients Are at Higher Risk of CMV Reactivation and NRM after Haploidentical-SCT with PT-Cy

Background: Cytomegalovirus (CMV) reactivation still represents a common complication after allogeneic stem cell transplantation and is associated with increased non-relapse mortality (NRM) and reduced overall survival (OS). Patients receiving T cell-replete haploidentical stem cell transplantation (haplo-SCT) with high dose post-transplant cyclophosphamide (PT-Cy) are considered at higher risk of developing CMV reactivation due to their particular immuno-suppressed status. Letermovir was recently shown to significantly reduce the frequency of CMV reactivation in a phase 3 clinical trial. We decided to perform a retrospective analysis among patients treated with haplo-SCT with PT-Cy in order to identify whether every patients should receive CMV prophylaxis with letermovir or it is possible to identify a particular subgroup that may benefit more of prophylactic treatment. Methods: We retrospectively analyzed 513 consecutive patients receiving Haplo-SCT with PT-Cy at our institutions between April 2009 and December 2018. Median age was 56 years old (range 15-77), main diagnosis was represented by acute myeloid leukemia (31%), Hodgkin lymphoma (22%), non-Hodgkin lymphoma (21%) and myelodisplastic syndrome (12%). Donor/recipient CMV serostatus was as follows: neg/neg (G1) 16%, pos/pos (G2) 50%, pos/neg (G3) 12% and neg/pos (G4) 22%. Conditioning regimen was non-myeloablative/reduced intensity in 90% of the cases, graft source was represented by bone marrow for 25% of the patients. Results: With a median follow-up of 35 months, 3-year OS was 57%, 3-year NRM 24% and 3-year graft-versus-host-disease (GVHD)/relapse free survival (GRFS) 43%. 180-days cumulative incidence of grade 2-4 acute GVHD was 23% and 2-year moderate-severe chronic GVHD was 9%. Median day of CMV reactivation was 41 days (range 10-275), 100-days and 1-year cumulative incidence of CMV reactivation was 43% and 48%, respectively. Cumulative incidence of CMV reactivation was more common among seropositive recipients: G1 1% vs G2 60% vs G3 32% vs G4 67% (Table I, p&lt;0.001). Recipient CMV positive serostatus and increasing patient age (hazard ratio (HR): 1.01, p=0.033) were the only variables associated with increased risk of CMV reactivation. 3-year OS, 3-year progression-free survival (PFS) and 3-year GRFS were worse among seropositive recipients, and consistently 3-year NRM was higher for G2 and G4 (Table I). By a time-dependent analysis we investigated the impact of CMV reactivation on main outcomes. Only 180-day cumulative incidence of grade 2-4 acute GVHD, and none of the other analyzed outcomes, was more frequent after CMV reactivation (HR 2.064, p=0.001). By time-dependent multivariable analysis, positive recipient CMV serostatus, was an independent predictor of increased NRM (G2: HR 2.47 and G4 HR: 2.61, p=0.007) and worse GRFS (G2: HR 1.71, p=0.003 and G4 HR 1.32, p=0.183). Pre-transplant active disease and hematopoietic cell transplant comorbidity index (HCT-CI) ≥3 were the other independent variables affecting OS, NRM, PFS and GRFS by multivariable analysis. Based on landmark analysis at day 100, patients experiencing CMV reactivation had a higher NRM rate compared with those without reactivation (18% vs 10%, p=0.034) and a tendency for lower OS (72% vs 78%, p=0.065) and GRFS (50% vs 55%, p=0.061). Moreover, by multivariable analysis, CMV reactivation and increasing donor age were the main independent predictors of grade 2-4 acute GVHD: HR 2.21, (p=0.01) and 1.01 (p=0.016), respectively. Conclusion: Recipient positive CMV serostatus is associated with increased risk of CMV reactivation, increased rate of NRM and worse GRFS. CMV reactivation is associated with increased risk of developing grade 2-4 acute GVHD and higher NRM. We conclude that also in the platform of haplo-SCT with PT-Cy, letermovir prophylaxis should be given not to all patients, but mainly to CMV seropositive recipients, that probably may benefit the most in terms of CMV reactivation, acute GVHD incidence and NRM. Disclosures Chabannon: Gilead: Other: speaker's fees, hospitalities; Sanofi SA: Other: research support, speaker's fees, hospitalities; Novartis: Other: speaker's fees; Celgene: Other: speaker's fees; Terumo BCT: Other: speaker's fees; Miltenyi Biotech: Other: research support; Fresenius Kabi: Other: research support; EBMT: Other: Working Party Chair, Board member. Carlo-Stella:Boehringer Ingelheim: Consultancy; Rhizen Pharmaceuticals: Research Funding; Celgene: Research Funding; Genenta Science srl: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Novartis: Consultancy, Research Funding; MSD: Honoraria; Sanofi: Consultancy, Research Funding; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; BMS: Honoraria; Janssen: Other: Travel, accommodations; Takeda: Other: Travel, accommodations. Santoro:Bayer: Consultancy, Speakers Bureau; MSD: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Consultancy, Speakers Bureau; BMS: Consultancy; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Arqule: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; Abb-Vie: Speakers Bureau; Roche: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau. Blaise:Pierre Fabre medicaments: Honoraria; Molmed: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria.

Letermovir Prophylaxis Is Effective for Cytomegalovirus Reactivation after Allogeneic Hematopoietic Cell Transplantation: Single Center Real-World Data

Background: Morbidity and mortality after allogeneic hematopoietic cell transplantation (alloHCT) are still essentially affected by reactivation of cytomegalovirus (CMV). Letermovir is the first drug approved for prophylaxis of CMV reactivation in seropositive patients who have undergone alloHCT. Letermovir shows neither myelo- nor nephrotoxicity, and significantly reduced the incidence of CMV reactivation in a pivotal phase III trial (NEJM 2017;377:2433). Therefore, we have adopted letermovir prophylaxis according to the label as standard policy in our institution in March 2018: in seropositive recipients letermovir is given from engraftment until day +100 or CMV reactivation. The purpose of this study was to investigate if the positive trial results could be reproduced under real-world conditions. Methods: The study cohort contained the first seropositive 82 patients who received letermovir prophylaxis at our institution (between March 2018 and March 2019). These were compared with a control cohort comprising another 82 patients who underwent alloHCT at our institution between January 2017 and March 2018 immediately before the introduction of letermovir. Quantitative PCR was used to monitor CMV viremia twice a week during the inpatient period and weekly thereafter. Patients reactivating CMV prior to engraftment were not considered as event in both groups. Results: Both cohorts were matched for underlying disease, CMV donor/recipient sero-status, use of ATG, and donor type. No higher grade adverse effects of letermovir intake were observed. With altogether 11 reactivation events, the cumulative incidence of CMV reactivation on day +100 was 13% (95%CI 6-21%) in the letermovir cohort which was significantly lower than in the control group (34 events, d +100 cumulative incidence 41% (95%CI 31-52%); HR 0.32 (95%CI 0.24-0.44); p&lt;0.0001). Two hospitalizations for foscavir administration occurred in the letermovir group compared to 9 hospitalizations in the control group. The cumulative number of days on valganciclovir before d +100 was 373d for the 82 letermovir patients vs 1082d for the 82 control patients. There were 5 deaths before d +100 in the letermovir group (three NRM, two PD) and 7 deaths in the control group (four NRM, three PD). Conclusions: This observational study proves in a real-world setting the efficacy and safety of letermovir for the prophylaxis of CMV reactivation after alloHCT. Letermovir lowered the incidence of CMV reactivation to the same extent as observed in the approval trial. In terms of health economics, letermovir reduced hospitalization needs and costs for therapeutic anti-CMV agents. Longer follow-up will be needed to assess the impact of letermovir prophylaxis on non-relapse and overall mortality. Disclosures Derigs: MSD: Honoraria. Müller-Tidow:MSD: Membership on an entity's Board of Directors or advisory committees. Luft:Neovii: Research Funding; JAZZ: Research Funding. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; Neovii, Riemser: Research Funding; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau. Schmitt:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; Therakos Mallinckrodt: Other: Financial Support.

Quantifying Cytomegalovirus-Specific T Cell Responses Prior to Hospital Discharge Allows Risk Stratification for Late Viral Reactivation after Allogenic Hematopoietic Cell Transplantation

Background Cytomegalovirus (CMV) infection remains a significant complication after allogenic hematopoietic cell transplantation (HCT). In the first three months after HCT, close monitoring of patients associated with prophylactic or preemptive administration of ganciclovir effectively prevents CMV-related complications. However, once patients are discharged from cancer centers around day 100 after HCT their risk of late CMV reactivation remains high. Since virus-specific T cells are capable of controlling CMV replication, we assessed whether their quantification shortly before hospital discharge allows risk-stratification for late CMV reactivation. Methods Allogeneic HCT recipients of all ages at the Fred Hutchinson Cancer Research Center who were CMV-seropositive or had a CMV-seropositive donor and participated in a prospective immune monitoring study were analyzed if they received at least 50% of weekly scheduled viral load (VL) PCR tests between days 100 and 180 after transplantation. CMV-specific cellular immunity was quantified via interferon-gamma ELISpot assay from cryopreserved peripheral blood mononuclear cells (PBMC) that were collected around day 90 after HCT. Cells were stimulated with peptide pools spanning the entire IE-1 and pp65 proteins (15mers with 11 amino acid overlap). Univariate Cox regression analysis was performed to determine hazard ratios (HR) for developing CMV reactivation at ≥50 IU, ≥500, ≥1000 IU/mL using different threshold levels (10, 50, or 100 spot-forming units (SFU) per 200,000 PBMC) for IE-1 and pp65. Results 13 out of 69 patients (18.8%) in this cohort showed clinically significant viral reactivation between days 100 and 180 after HCT, defined as having a viral load ≥1000 IU/ml at least once during the observational period (this level is commonly used to start preemptive treatment in the late setting). The best separation of risk was achieved by using a threshold of 10 SFU for both antigens: Individuals with less than 10 SFU for IE-1 or pp65 had an increased risk for CMV reactivation (HR 8.49, 95% CI, p=0.04) compared to patients with at least 10 SFU for both antigens. Correspondingly, the cumulative incidence of CMV reactivation was significantly higher in the group of patients with Conclusions Quantification of CMV-specific cellular immune responses around day 100 can help identify patients that are at risk for developing clinically significant late CMV reactivation. Both IE-1 and pp65 are useful for predicting CMV reactivation. Further studies with larger cohorts should be performed to confirm the suggested threshold levels of immune protection.

Prophylactic Pretransplant Ganciclovir to Reduce Cytomegalovirus Infection after Hematopoietic Stem Cell Transplantation

Introduction Cytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic stem cell transplantation (HCT) occurring in 35-55% of HCT recipients. CMV reactivation can lead to adverse outcomes including end-organ damage and graft failure. Objective To reduce the incidence of CMV reactivation and disease by using prophylactic ganciclovir pretransplant. Methods We conducted a retrospective analysis of all recipient or donor CMV seropositive patients who received their first allogeneic HCT between 2012 and 2017. Ganciclovir was administered pretransplant (5 mg/kg twice daily IV from day −8 to day −2). Patients received valacyclovir or acyclovir starting day 0 until one-year posttransplant. Patients were monitored weekly with serum CMV PCR through Day 100 posttransplant. CMV reactivation was defined as a CMV viral load of more than 135 IU/ml, and was treated with preemptive therapy. All patients received GVHD prophylaxis with calcineurin inhibitor. Results Seventy-nine consecutive patients were treated. The median age was 58 years (range 20 to 72). The most common diagnoses were acute myeloid leukemia (49%) and acute lymphocytic leukemia (14%). Graft sources were matched related donor (30%), matched unrelated donor (35%), haploidentical (5%) and cord blood (29%). 43 patients (55%) received myeloablative conditioning. 36 patients (45%) received fludarabine based reduced intensity/nonmyeloablative conditioning. 24 patients (30%) had CMV reactivation with median time of reactivation of 47 days posttransplant (range 27 to 229). 22 out of the 24 (88%) patients required treatment for CMV reactivation with a median treatment duration of 37 days (range 14 to 315) and were treated with ganciclovir or foscarnet. The cumulative incidence of CMV reactivation at day 100 posttransplant was 27% with a 95% CI (18%-37%) depicted in Figure 1. There were no patients with biopsy proven CMV disease or deaths attributed to CMV reactivation or disease. The median time-to neutrophil recovery (≥500 K/ul) was 18 days and the median time to platelet recovery (≥20,000 K/ul) was 19 days. The incidence of acute GVHD Grades II-IV was 25 %. The incidence of significant kidney injury (Creatinine >2.5 mg/dL) was 2.4%. Conclusions The incidence of CMV reactivation, in this high-risk patient population, by day 100 of 27% with pretransplant ganciclovir may be improved compared to historical controls of 35-55%. The use of pretransplant ganciclovir was associated with no CMV disease and was safe, with low incidence of kidney damage. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation should be considered regardless of graft source. Future prospective randomized trials are needed to evaluate strategies for CMV prophylactic regimens.

Donor NKG2C Copy Number: An Independent Predictor for CMV Reactivation after Double Cord Blood Transplantation

Cytomegalovirus (CMV) is a member of the herpesviridae family and remains latent in the host cells after primary infection. The virus reactivates in the immunosuppressed host and is a leading cause of morbidity following allogeneic hematopoietic stem cell transplant (allo-HSCT). Natural killer (NK) cells provide the first-line defence against viruses and a subset of NK cells expressing NKG2C have been shown to play a role in the immune surveillance of human CMV. Deletion of the NKG2C gene has been reported as a risk factor for viral infections including CMV and HIV, but current data on the influence of NKG2C gene-copy number variations in the donor graft on the risk of CMV reactivation after allo-HSCT is limited. Following cord blood transplantation (CBT), where the T-cell compartment is functionally naïve, the NKG2C genotype may have an even more pronounced impact on the risk of CMV reactivation. Therefore, we studied NKG2C copy number in the donor graft and the risk of CMV reactivation after double umbilical cord blood transplantation (DUCBT) in 100 CMV seropositive DUCBT recipients and their corresponding cord blood grafts (n=200). The gene encoding NKG2C is present at different copy numbers in the genomes of different individuals, with possible genotypes including 2 copies (wt/wt), 1 copy due to heterozygous deletion (wt/del) or 0 copies due to homozygous deletion (del/del). Among the donor CB units, approximately 2/3 had both copies of the gene (wt/wt), 1/3 had only one copy (wt/del) and only a minority of units had 0 copies with both alleles deleted (del/del). In the setting of DUCBT, the combined graft may contain 0 to 4 functional copies of NKG2C gene. In our cohort, patients whose combined grafts contained only 1 or 2 NKG2C gene copies had a significantly higher probability of CMV reactivation than patients whose combined grafts had 3 or 4 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the 4 groups was 100%, 92.9%, 60.5% and 55.9% respectively (p=0.005). No patient received a graft with zero gene copies. For the rest of the analysis we divided the patients into two groups, namely the 84 patients who received a combined graft with 3 or 4 NKG2C copies and the 16 patients who received two units with 1 or 2 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the two groups was 58.4% and 93.7% respectively (p=0.0003). In a multivariate analysis, receiving a combined graft with low NKG2C copy number (1 or 2 copies) (HR=2.72, CI=1.59-4.64; p<0.0001) and reduced intensity conditioning (RIC) (HR=0.59, CI=0.35-0.99, p=0.046) were the only independent predictors for CMV reactivation. Interestingly, the NKG2C copy number of the dominant cord was not predictive for CMV reactivation, suggesting that both cord blood units contribute to the antiviral response early post-DUCBT. Our study points to an important role for donor NKG2C in protection against CMV reactivation after DUCBT. If confirmed in larger numbers of CBT recipients, NKG2C genotyping of the CB graft may be a useful biomarker for predicting the risk of CMV infection after CBT, thus guiding the intensity of CMV prophylaxis for individual patients. Moreover these novel findings may provide a compelling rationale for considering NKG2C genotype as a criterion in the algorithm of CB selection for DUCBT. DisclosuresOran:ASTEX: Research Funding; AROG pharmaceuticals: Research Funding; Celgene: Consultancy, Research Funding. Champlin:Sanofi: Research Funding; Otsuka: Research Funding. Shpall:Affirmed GmbH: Research Funding.