Outcome Comparison between Low-Dose Rabbit Anti-Thymocyte Globulin and Basiliximab in Low-Risk Living Donor Kidney Transplantation

The objective of this study was to compare outcomes between basiliximab and low-dose r-ATG in living donor kidney transplantation recipients with low immunological risk. Patients in the low-dose r-ATG group received 1.5 mg/kg of r-ATG for 3 days (total 4.5 mg/kg). Graft survival, patient survival, acute rejection, de novo donor specific antibody (DSA), estimated glomerular filtration rate (e-GFR) changes, and infection status were compared. Among 268 patients, 37 received r-ATG, and 231 received basiliximab. There was no noticeable difference in the graft failure rate (r-ATG vs. basiliximab: 2.7% vs. 4.8%) or rejection (51.4% vs. 45.9%). de novo DSA was more frequent in the r-ATG group (11.4% vs. 2.4%, p = 0.017). e-GFR changes did not differ noticeably between groups. Although most infections showed no noticeable differences between groups, more patients in the r-ATG group had cytomegalovirus (CMV) antigenemia and serum polyomavirus (BK virus) (73.0% vs. 51.9%, p = 0.032 in CMV; 37.8% vs. 15.6%, p = 0.002 in BK), which did not aggravate graft failure. Living donor kidney transplantation patients who received low-dose r-ATG and patients who received basiliximab showed comparable outcomes in terms of graft survival, function, and overall infections. Although CMV antigenemia, BK viremia were more frequent in the r-ATG group, those factors didn’t change the graft outcomes.

Impact of HLA Class I Allele Mismatch on Viral Infection within 100 Days after Cord Blood Transplantation

Introduction: Viral infections occur more frequently in cord blood transplantation (CBT) than in transplantation of other stem cell sources, and they are often fatal. Thus, it is important to determine the predictors of viral infection to improve CBT outcomes. We hypothesized that incompatibility of human leukocyte antigen (HLA) class I can increase susceptibility to viral infections because donor HLA-restricted naïve cytotoxic T cells cannot recognize recipient infected cells properly in the early term after CBT. Herein, we focused on the impact of HLA class I incompatibility on viral infection within 100 days after CBT. Patients and Methods: We retrospectively analyzed 121 patients who underwent 126 CBT procedures at Kyoto University Hospital from February 2003 to January 2019. Viral infection was defined as infection of recipient somatic cells by viruses detected via pathology or molecular biology and confined to those specific for an immunocompromised condition. Cytomegalovirus (CMV) antigenemia was distinguished from viral infections, because in such cases, the infected cells are donor-derived cells. Characteristics were compared between two groups using Fisher's test. The incidences of viral infection, CMV antigenemia, and steroid use for pre-engraftment immune reaction, engraftment syndrome, and acute graft-versus-host disease (aGVHD) together (PIR/ES/aGVHD) were calculated considering death and relapse as competing events, and they were compared using Gray's test. Fine-Gray proportional hazards models were used for univariate and multivariate analyses to evaluate the effects of variables on outcome. Survival was estimated using the Kaplan-Meier method. Non-relapse mortality was estimated using Gray's method. Results: The median patient age was 47 (range, 19-68) years, and 69 patients were male. The underlying diseases were acute myeloid leukemia (n=53), acute lymphoblastic leukemia (n=17), myelodysplastic syndromes (n=17), anaplastic anemia (n=6), non-Hodgkin lymphoma (n=20), and others (n=9). Regarding the CBT protocol, 44 patients received myeloablative conditioning and 83 patients received a calcineurin inhibitor and mycophenolate mofetil for GVHD prophylaxis. We identified 50 virus infections in 42 transplants within 100 days after transplantation, including 7 human herpesvirus 6 infections, 14 CMV infections, 26 BK virus, JC virus, and adenovirus infections, 2 varicella-zoster virus infections, and 1 unknown virus infection. Univariate analysis showed that HLA-A and HLA-C allele mismatches in the GVH direction were associated with a significantly higher incidence of viral infection (mismatch vs. match; HLA-A: 42.7% vs. 25.8%, HR 1.86, P=0.049; HLA-C: 43.9% vs. 17.6%, HR 2.94, P=0.015; Figure 1A). Moreover, 3/6 or more HLA class I allele mismatch in the GVH direction was associated with a significantly higher viral infection incidence (50.0% vs. 26.9%, HR 2.29, P=0.010; Figure 1B), but not with CMV antigenemia (65.8% vs. 70.1%, HR 0.95, P=0.82). These patients with HLA class I mismatches showed no increase in steroid use for PIR/ES/aGVHD (70.4% vs. 64.2%, P=0.53) or prophylactic antiviral drug therapy (62.5% vs. 65.7%, P=0.84). Regarding HLA class II mismatches, HLA-DR mismatch in the GVH direction was not associated with viral infection (34.1% vs. 32.6%, HR 1.13, P=0.72). Univariate analysis showed that lymphoid neoplasm (P<0.01), no use of cytarabine for conditioning (P=0.035), fludarabine and melphalan use for conditioning (P=0.043 and 0.075, respectively), and second or subsequent transplant (P=0.067) were associated with a higher incidence of viral infection. Multivariate analysis showed that HLA class I mismatches and lymphoid neoplasm remained significant factors for viral infection (P=0.035 and <0.01, respectively). Regarding post-CBT outcomes, 5-year overall survival (OS) and non-relapse mortality (NRM) with landmark analysis at 100 days were inferior in patients with viral infection (OS: 66.5% vs. 73.6%, P=0.35; NRM: 14.6% vs. 4.6%, P=0.11). Conclusion: HLA class I allele mismatch, including HLA-C mismatch, was significantly associated with viral infection within 100 days of CBT. Our findings suggest the importance of HLA class I genotype compatibility, including HLA-C compatibility, for CBT. Graft matching can reduce the incidence of viral infection and thus improve outcomes. Figure 1 Disclosures Kanda: Chugai: Honoraria; Otsuka: Honoraria; JCR Pharmaceuticals: Honoraria; Bristol-Meyers Squib: Honoraria; Kyowa Hakko Kirin: Honoraria; NextGeM Incorporation: Patents & Royalties: 2019-011392; MSD: Honoraria; Daiichi Sankyo Company: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Astellas: Honoraria. Takaori-Kondo:Chugai: Research Funding; Janssen: Honoraria; Pfizer: Honoraria; Kyowa Kirin: Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Research Funding; Takeda: Research Funding.

Jejunal diaphragm disease associated with cytomegalovirus infection

Background and study aims Diaphragm disease (DD) is a rare gastrointestinal disease featuring multiple thin, circumferential strictures in the intestine, related to prolonged intake of nonsteroidal anti-inflammatory drugs (NSAIDs). Here, we report a case of DD associated with cytomegalovirus (CMV) infection in a patient not taking NSAIDs. A 72-year-old man was referred to our hospital due to persistent epigastric pain. Push enteroscopy showed extensive mucosal detachment in the upper jejunum. Immunohistochemistry examination of biopsy specimens revealed CMV positivity. In addition, CMV antigenemia was positive. Antiviral treatment with ganciclovir improved his symptoms and the CMV antigenemia became negative. Wireless capsule enteroscopy performed 1 month after antiviral treatment showed regenerated mucosa and multiple diaphragm-like strictures in the jejunum, resulting in capsule retention. Balloon dilatation using double balloon enteroscopy (DBE) was performed and the capsule was retrieved endoscopically. DBE 6 months after antiviral therapy confirmed no recurrence of stenosis or inflammation. The patient had no history of long-term NSAID use. In a case of DD unassociated with NSAIDs, CMV infection should be considered in the differential diagnosis.

CYTOMEGALOVIRUS REACTIVATION IN ADULT RECIPIENTS OF AUTOLOGOUS STEM CELL TRANSPLANTATION: A SINGLE CENTER EXPERIENCE

Introduction: Cytomegalovirus (CMV) reactivation and infection is a well-recognized complication after allogeneic stem cell transplantation (SCT). Yet only few studies have addressed CMV reactivation after autologous SCT (ASCT).Methods: We retrospectively reviewed medical records of 210 adult patients who underwent ASCT for lymphoma or multiple myeloma (MM) at a single center from January 1, 2007 until December 31, 2012. All patients were monitored weekly with CMV antigenemia test till day 42 after transplantation, and for 2 months after last positive test in those who had any positive CMV antigenemia test before day 42.Results: thirty seven (17.6%) patients had CMV reactivation; 23 patients had lymphoma while 14 had MM as the underlying disease. There was no difference in the rate of CMV reactivation between lymphoma and MM patients (20% versus 14.7%, P = 0.32). The majority of the patients were treated with ganciclovir/valganciclovir, all patients had their reactivation resolved with therapy, and none developed symptomatic CMV infection. None of the patients who died within 100 days of transplantation had CMV reactivation. Log rank test showed that CMV reactivation had no effect on the overall survival or the disease-free survival of patients (P values, 0.29 and 0.79, respectively).Conclusion: In our cohort, CMV reactivation rate after ASCT was 17.6%. There was no difference in reactivation rates between lymphoma and MM patients. With the use of preemptive therapy, symptomatic CMV infection was not documented in any patient in our cohort. CMV reactivation had no impact on patients’ survival post ASCT.

Use of Valacyclovir for the Treatment of Cytomegalovirus Antigenemia after Hematopoietic Stem Cell Transplantation

Background: Cytomegalovirus (CMV) infection remains a cause of morbidity and mortality in patients who have undergone allogeneic hematopoietic cell transplantation (HSCT) despite pre-emptive antiviral therapy. Available treatments have clinically significant toxic effects. Valacyclovir is well tolerated, and limited evidence suggests that Valacyclovir is effective in preventing CMV disease when given as prophylactic treatment. We investigated the efficacy and safety of high dose Valacyclovir compared with Valganciclovir or Foscarnet in the pre-emptive therapy of CMV antigenemia. Methods: In a retrospective single-center study, 61 allogeneic HSCT recipients with an initial episode of CMV antigenemia received pre-emptive therapy with either Valacyclovir (n=15), Valganciclovir (n=16), or Foscarnet (n=30). Patients were treated with either Valacyclovir at 2 g twice-daily, Valganciclovir at 900 mg twice-daily, or Foscarnet at 90 mg/kg twice-daily, with appropriate renal dose adjustments for each drug. Patients were assessed weekly using the pp65 antigenemia assay. Endpoints analyzed include viremia clearance at day 14 and 28, and rates of recurrent antigenemia. Neutrophil counts and creatinine levels were monitored during treatment. Results: Overall, 60/61 (98%) of cases achieved CMV antigenemia clearance by day 28, and no patient developed CMV disease. Valacyclovir achieved similar clearance of CMV viremia compared to Valganciclovir and Foscarnet, at rates of 93.3%, 77.5%, and 79.5% respectively at 14 days (p=0.054; log rank test). After adjusting for age, sex, CMV serological status, donor type, CMV antigen level, GVHD therapy, and conditioning regimen, there were no significant differences in the odds of viral clearance at day 14 in patients who received Valganciclovir (odds ratio (OR) 0.16, 95% confidence interval (CI) 0.01 to 2.14, p=0.17) and Foscarnet (OR 0.21, 95% CI 0.02 to 2.39, p=0.21), compared to Valacyclovir (assigned OR 1.00). Recurrent CMV antigenemia by day 180 after clearance of the initial episode occurred in 34/61 (56%) of patients. Use of Acyclovir was not associated with an increased odds of CMV recurrence, compared to Valganciclovir or Foscarnet, after adjusting for the same covariates in logistic regression models. Foscarnet significantly increased creatinine levels (p=0.009), while Valganciclovir significantly reduced neutrophil counts (p=0.012). Laboratory evaluation revealed no hematopoietic or renal toxicity in patients on Valacyclovir treatment. Conclusion: Pre-emptive treatment with Valganciclovir, Foscarnet and Valacyclovir led to similar clearance of CMV antigenemia and rates of recurrence. High dose Valacyclovir is a potential alternative for pre-emptive CMV treatment in allogeneic HSCT recipients, with an acceptable safety profile. Table 1.Response to preemptive cytomegalovirus therapyAll(n=61)Valacyclovir(n=15)Valganciclovir(n=16)Foscarnet(n=30)P Median viral load (No. of CMV positive cells per million leukocytes, range)3 (1-750)3 (1-140)3 (2-181)3.5 (1-750)0.772 Clearance, N (%)0.054Cleared by day 735 (58.3)12 (80.0)11 (68.8)12 (41.4)Cleared by day 1414 (23.3)2 (13.3)2 (12.5)10 (34.5)Cleared by day 218 (13.3)1 (6.7)3 (18.8)4 (13.3)Cleared by day 283 (5.0)0 (0)0 (0)3 (10.3) Recurrent antigenemia, N (%)34 (55.8)7 (46.7)11 (68.8)16 (53.3)0.434 Median days to recurrence43.5 (11-173)59 (27-173)42 (14-94)38 (11-163)0.081 Disclosures Off Label Use: Valacyclovir use for CMV pre-emptive therapy in allogeneic HSCT recipients. Goh:Novartis Pte Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jannsen Pharmaceuticals Inc: Research Funding; Bristol-Myres Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hospira Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees.

The Effect Of CMV Reactivation On Relapse and Survival In Patients With AML and MDS After Allogeneic Stem Cell Transplant (allo-HCT)

Introduction The effect of CMV reactivation after allo-HCT on relapse and overall survival (OS) in patients with acute myeloid leukemia (AML) and myelodysplatic syndrome (MDS) is controversial (Green et al blood 2013, Elmaagacli et al Blood 2011, and Erard et al Hematologica 2006). Methods We retrospectively analyzed the effect of CMV reactivation on OS and cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) in AML and MDS patients older than > 18 years who had received allo-HCT between 2005-2011 and had not died within 30 days of receiving allo-HCT at MD Anderson Cancer Center. The effect of any CMV antigenemia on allo-HCT outcomes was evaluated by comparing any CMV antigenemia with no CMV antigenemia. Because of potential immunomodulatory effect of CMV infection, the effect of prolonged antigenemia (defined as CMV antigenemia with duration more than 12 days, the median duration of antigenemia for the cohort) on transplant outcomes was analyzed by comparing patients with prolonged antigenemia with patients with no CMV antigenemia or CMV antigenemia with ≤ 12 days. All patients underwent surveillance by pp65 antigenemia test. Preemtive therapy was initiated for > 3 pp65 Ag cells/million WBC's. Kaplan-Meier survival curves were used to estimate OS and the log-rank test was used to assess group differences. CIR and NRM were determined using the competing risks method; competing risk for CIR was death and for NRM was relapse. Group differences in CIR and NRM were assessed using Gray's test. Results Table 1 shows baseline characteristics. Comparing R+/D+, R-/D-, R-/D+, and R+/D- groups, the incidence of any CMV antigenemia after HCT was 48%, 16.7%, 13.5%, and 50.9%, respectively (p<0.0001) and the incidence of CMV disease was 1.0%, 1.9%, 2.7%, and 4.5%, respectively (p = 0.05). When any CMV antigenemia was compared with no CMV antigenemia post allo-HCT, CMV reactivation had no effect on OS (p > 0.15) and CIR (p > 0.61) in all cohort as well as AML and MDS subgroups. Comparing any antigenemia vs. no antigenemia, CIR at 3 years was 34.6% vs. 35.2% in all cohort, 36.7% vs. 36.6% in AML patients, and 29.5% vs. 30.0% in MDS patients, respectively. In patients with CMV antigenemia, duration of antigenemia ranged from 1 to 535 days (median 12 days). We then investigated the effect of prolonged CMV antigenemia on transplant outcomes. Patients with CMV antigenemia > 12 days compared with combined group of ≤ 12 days or no CMV antigenemia had a lower cumulative incidence of relapse and a higher NRM, resulting in a similar OS (Fig. 1). Such a difference was seen in AML but not in MDS subgroup. We then investigated the effect of duration of CMV antigenemia in patients with CMV reactivation. Comparing 1-12 days of antigenemia vs. more than 12 days of antigenemia, CIR at 3 years was 41.9% vs. 26.7% (p = 0.003) in all cohort, 45.8% vs. 26.4% (p = 0.001) in AML patients, and 32.1% vs. 27.4% (p = 0.68) in MDS patients, respectively. Conclusion Prolonged CMV antigenemia is associated with decreased relapse in patients with AML, but not in MDS. Lower relapse is offset by increased NRM resulting in no change in OS. In contrast with published data, lower rate of relapse was not found when any antigenemia was compared with no antigenemia. Disclosures: No relevant conflicts of interest to declare.

Prospective Weekly Multiple Viral Monitoring in Blood Using Multiplex PCR Assay Early After Hematopoietic Stem Cell Transplantation

Abstract 1954 Backgrounds: Viral infections remain serious complications after hematopoietic stem cell transplantation (HSCT), despite a remarkable progress of the prophylactic and treatment strategies. Detection of the early stage of viral reactivation and infection was extremely important as CMV antigenemia monitoring and pre-emptive therapy. In this study, we performed a prospective PCR-guided viral monitoring for 13 species and evaluate the association with actual onset of viral disease. Patients and methods: Adult patients aged ≥ 16 years old who were scheduled for allogeneic or autologus HSCT were eligible for this study. Informed consent was obtained from all patients. From a week before transplantation to the 8 weeks after, the DNA quantity of 13 viral species was weekly measured using in-house multiplex PCR assays, which enable to simultaneously determine the amount of herpes simplex virus-1 (HSV-1), human simplex virus-2 (HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) humanherpesvirus 6 (HHV-6), humanherpesvirus 7(HHV-7), humanherpesvirus 8 (HHV-8), parvovirus B19, hepatitis B virus (HBV), JC virus (JCV), BK virus (BKV), and adenovirus (ADV). As antiviral prophylaxis for HSV/VZV and HHV-6 diseases, oral acyclovir and intravenous foscarnet in all recipients and exclusively in those receiving unrelated cord blood, respectively, whereas antigenemia-guided preemptive therapy against CMV disease with ganciclovir or foscarnet was performed in allo-transplant settings. Results: A hundred patients who underwent HSCT at Toranomon Hospital from May to December 2010 were enrolled for this study. Median age was 52 (16–71) years old. Six patients who underwent autologous transplantation were included. In a total of 821 peripheral specimens obtained during the study period, HHV-6 was detected in 69.6%, CMV in 37.7%, BK in 13.2% and ADV in 7.7% of 471 PCR positive samples, and the detection rate of other virus was lower than 3.1%. The cumulative incidences of positive viral load due to HHV-6, CMV, BKV, ADV during the study period were 88.5%, 54.3%, 24.1%, and 11.6%. During the study period, 31 patients developed any viral infections with a cumulative incidence of 34.0%, at a median of 18 (-1-56) days after HSCT. Ten patients had 2 or more episodes of different viral infections, and a total of 45 infectious episodes were documented. HHV-6 encephalitis accounted for 33.3% of all viral infections during prophylactic foscarnet administration. Other common viruses included ADV 22.2 % (dissemination in 8, hemorrhagic cystitis (HC) in 2), and BKV 35.6 % (HC in all 22 patients). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were analyzed for common virus such as ADV, BKV and HHV-6. CMV was excluded CMV antigenemia-guided pre-emptive therapy successfully suppressed the onset of diseases. The sensitivity, specificity, PPV, and NPV for diagnosing ADV infections were 85.7%, 100.0%, 100.0% and 98.9%. These data suggest ADV monitoring is a useful strategy for predicting the onset of disease. The sensitivity, specificity, PPV, and NPV for diagnosing BKV associated HC were 61.1%, 86.6%, 50.0% and 91.0%, whereas those of the PCR assay with use of a threshold of 10000 copies/ml were 46.6%, 71.8%, 29.1% and 88.4% for diagnosing HHV-6 encephalitis. Conclusion: Our multiple viral monitoring system using multiplex PCR assay was useful for detecting viral load kinetics for 13 species early after HSCT. As for ADV, viral load in blood detected in our assay had a high sensitivity and specificity for developing ADV infectious diseases. The sensitivity and specificity level for HHV-6 and BK was not as high as ADV because definite threshold level was not determined yet and HHV-6 encephalitis might be suppressed due to prophylactic foscarnet, these findings suggested that the multiplex PCR assay could be applied to the routine monitoring for viral infections in the early period after HSCT. Disclosures: No relevant conflicts of interest to declare.