Developed CMV Disease Research Articles

Cell-mediated Immunity to Guide Primary Prophylaxis for CMV Infection in Organ Transplant Recipients: A Multicenter Single-arm Prospective Study.

There are few interventional studies using CMV cell-mediated immunity (CMI) to guide antiviral prophylaxis. We assessed the Quantiferon-CMV (QTF-CMV) assay to guide CMV prophylaxis duration in high-risk organ transplant recipients. A single-arm, multicenter, prospective interventional study including high-risk kidney, pancreas, liver, and heart transplant recipients who were either donor CMV-seropositive, recipient-seronegative (D+/R-) or recipient-seropositive with antithymocyte globulin (R+/ATG) induction. CMI testing was performed using the QTF-CMV assay at months 3, 4, 5, and 6 posttransplant. Prophylaxis was discontinued for a positive CMI but continued for a negative result up to a maximum of 6 mo. The primary endpoint was CMV viremia ≥1000 IU/mL up to 1 y posttransplant. One hundred eight patients were included, comprising kidney (n = 89), kidney-pancreas (n = 7), liver (n = 10), and heart (n = 2) transplants. Eighty-nine patients (82.4%) completed the study protocol (n = 39 D+/R- and n = 50 R+/ATG). In the D+/R- group, only 1 of 39 patients (2.6%) had a positive QTF-CMV result. In the R+/ATG group, 33 of 50 patients (66%) had a positive QTF-CMV result before 6 mo, allowing for early discontinuation of prophylaxis (28 at month 3, 4 at month 4, and 1 at month 5). During the follow-up, CMV viremia ≥1000 IU/mL occurred in only 4 of 33 patients (12.1%) who discontinued prophylaxis early compared with 6 of 17 patients (35.3%) with negative QTF-CMV results and continued prophylaxis (hazard ratio 0.31; 95% confidence interval, 0.09-1.09; P = 0.07). No R+ patient developed CMV disease. QTF-CMV-guided prophylaxis appears useful in R+ patients who may benefit from a tailored duration of prophylaxis. This strategy does not appear to be useful in D+/R- patients.

Abatacept-Prophylaxis Based Haploidentical Transplantation May Allow Sustained Engraftment and Offset Gvhd in Non-Malignant Disorders

Introduction: Non-malignant disorders (NMD) derive no benefit from graft-versus-host disease (GVHD) after allogeneic hematopoietic transplantation (HCT). Transplantation designed to optimize engraftment and immune reconstitution while minimizing GVHD and organ toxicities is desirable. Post-transplant cyclophosphamide (PTCy) decreases severe chronic GVHD risk in radiation-containing regimens for NMD when combined with serotherapy (anti-thymocyte globulin) (PMID: 22955919; PMID: 30500440). Abatacept effectively offsets GVHD following unrelated donor (URD) HCT (PMID: 33449816; PMID: 32813873). Based on these reports, NCT03128996 was developed for haploidentical transplantation in NMD after radiation-free reduced intensity conditioning (RIC) combining PTCy + Abatacept for GVHD prophylaxis. Serotherapy does not contribute to GVHD prophylaxis in this RIC approach. Outcomes focused on safety and GVHD- free donor engraftment in children with NMD and no better donor options. Method: Conditioning included alemtuzumab (day -22 to -19), fludarabine (day -8 to -4), melphalan (day -3) and thiotepa (day -4) as previously published (hydroxyurea prior to RIC was used in proliferative marrow disorders) (PMID: 32813873). Stem cell source was bone marrow (BM) or CD34-selected peripheral blood cells with a fixed CD3 cell dose of 1x10^6/kg recipient weight. GVHD prophylaxis included tacrolimus (day -1, with wean beginning 6-9 months post-HCT), PTCy on days +3 and +4, mycophenolate mofetil until day +28, and monthly abatacept doses until 13 months post-HCT. Survival, safety, donor chimerism, GVHD incidence, and incidence of post HCT infection were primary outcome measures. Results: Eleven patients 6 to 24 years old (median 9 years) underwent HCT for adrenoleukodystrophy ( 2), sickle cell disease (SCD) ( 6), aplastic anemia ( 1), second transplant for severe combined immunodeficiency ( 1) and STAT 5B gain-of-function mutation ( 1). Eight were trial participants and 3 treated according to trial guidelines. All patients tolerated abatacept infusions and engrafted with neutrophil recovery (>500/cu mm) at a median of 17 days (range 15-24 days). As of 7/31/2023, median follow up is 411 days (range 83-1979 days). The mean myeloid and T-cell chimerisms at D100 (n=10) and 1 year (n=6) were 97.8%+/- 5.3 and 96.3% +/- 6.4 and 98.6% +/- 3.3 and 95% +/-8.7, respectively. One patient with SCD has low myeloid engraftment (24%) at 7 months post-HCT (lymphoid 91%); a stem cell boost is planned after immune suppression with fludarabine/Cytoxan/ATG (PMID: 35798858). Viral reactivation was noted in 4 patients, none developed CMV disease or EBV post-transplant lymphoproliferation. One patient developed grade 1 acute GVHD. Of 6 evaluable patients, one developed localized chronic skin GVHD. This patient remains on systemic immune suppression beyond 13 months (ruxolitinib). The overall and GVHD-free survival at 1-year post HCT in evaluable patients (N=6) is 100 % and 83%, respectively. Conclusion: Promising preliminary results in this cohort support continuation of the trial with longer term follow-up. The effective suppression of GVHD without serious infectious complications in the first year post-HCT is encouraging. Virus reactivation was however noted early post-HCT and requires monitoring and prophylaxis. Incorporating abatacept into GVHD prophylaxis was successful in achieving desired outcomes; the phase 1 portion of the study is completed and the phase 2 trial and follow-up are ongoing.

B-267 Validation of a New Molecular Test to Quantify Plasma Cytomegalovirus Load

Abstract Background Cytomegalovirus (CMV) is a DNA virus that often causes severe disease in immunosuppressed or immunocompromised patients. With the expanding indications for immune-modulating agents and transplant patients, the number of patients at risk for developing CMV disease is increasing. Test results are used to determine active CMV disease, risk of developing active disease, response to therapy, risk of relapsed infection, and/or appropriate time to discontinue therapy. For this purpose, molecular assays are attractive because of their broad linear range and low limits of detection. CerTest Biotec has developed a quantitative real time PCR assay for the detection and quantification of cytomegalovirus in plasma samples. Methods Plasma-EDTA samples characterized as positive or negative and quantified by IU/ml were selected. The selected samples were collected from both male and female adults (except 1 sample of an infant) between July 2016 and December 2020. Two CE-marked molecular reference assays were used for the comparative analysis: RealStar® CMV PCR Kit 1.0 (Altona), using the CFX96™ Real-Time PCR Detection System (Bio-Rad) and extracted with the QIAamp® MinElute® Virus Spin Kit (QIAGEN); and cobas® CMV (Roche Diagnostics), using the cobas® 8800 system. VIASURE analysis was performed using the following workflow: the automated extraction method MagDEA® Dx SV with magLEAD® 12gC and CFX96™ Real-Time PCR Detection System (Bio-Rad). Results A total of 273 EDTA-plasma clinical samples were analysed, 120 samples were reported as CMV positive samples and quantified and 153 samples were reported as CMV negative samples. Comparative analysis determined >99% sensitivity and specificity. Regarding quantification, all methods obtained a correlation value of R2 ≥ 0.77. Conclusion With this study it was possible to observe that the VIASURE CMV q Real Time PCR Detection Kit present good clinical sensitivity and specificity compared to reference molecular assays results. No false positive results were observed. However, all variables employed on the workflow contribute to final quantification results and therefore should be taken into account as accumulative error in the calculation.

Cytomegalovirus Disease as a Risk Factor for Invasive Fungal Infections in Liver Transplant Recipients under Targeted Antiviral and Antimycotic Prophylaxis.

We retrospectively analyzed the medical records of 214 adult liver transplant recipients (LTRs). Universal antiviral prophylaxis was utilized in recipients with CMV mismatch; intermediate- and low-risk patients received pre-emptive treatment. Six percent of patients developed CMV disease independent of their serostatus. The occurrence of CMV disease was associated with elevated virus load and increased incidence of leucopenia and IFIs. Furthermore, CMV disease was associated with higher one-year mortality and increased relapse rates within the first year of OLT. CMV disease causes significant morbidity and mortality in LTRs, directly affecting transplant outcomes. Due to the increased risk of IFIs, antifungal prophylaxis for CMV disease may be appropriate. Postoperative CMV monitoring should be considered after massive transfusion, even in low-risk serostatus constellations. In case of biliary complications, biliary CMV monitoring may be appropriate in the case of CMV-DNA blood-negative patients.

1587. Clinical Utility of a Cytomegalovirus (CMV)-specific T Cell Assay in Assessing the Risk of Post-Prophylaxis CMV Infection and Post-Treatment Relapse

Abstract Background Cytomegalovirus (CMV) causes significant morbidity in solid organ transplant recipients (SOTR). As a lack of immunity predisposes to infection, a laboratory test that measures CMV-specific cell-mediated immunity (CMV CMI) may help guide antiviral prophylaxis, predict relapses and correlate with outcomes. We assessed CMV CMI in CMV D+/R- patients during valganciclovir primary prophylaxis and in CMV viremic SOTRs during antiviral treatment, and correlated the results with post-prophylaxis CMV infection and post-treatment relapse, respectively. Methods CMV CMI was assessed in two groups of SOTRs using the QuantiFERON© CMV interferon-gamma release assay (IGRA), with level >0.2 IU/mL suggestive of immunity. The first group included CMV D+/R- SOTRs who underwent monthly CMV CMI testing during 6 months of valganciclovir prophylaxis. These patients were prospectively followed for CMV episodes for 1 year post transplant. The second group included SOTRs with CMV viremia or disease, who underwent CMV CMI testing at time of CMV diagnosis and at various time points during antiviral treatment. These patients were prospectively followed for CMV relapse for 1 year post-primary CMV episode. Standard definitions were used to define CMV infection and disease. Results In the primary prophylaxis cohort, 24 CMV mismatched (D+/R-) SOTRs were enrolled. Only 1 patient (4.2%) demonstrated a CMV CMI >0.2 IU/mL by the end of prophylaxis; this patient did not develop CMV disease. Four (16.6%) patients developed post-prophylaxis CMV infection, none of which had CMV CMI >0.2 IU/ml. In the post-treatment cohort, 20 CMV viremic SOTRs were enrolled, including 12 D+/R- (60%). Eighteen (90%) had CMV CMI levels >0.2 IU/mL by end of treatment and none developed CMV relapse. In contrast, the single patient who relapsed after treatment had a CMV CMI response < 0.2 IU/ml (p=0.05). Conclusion CMV D+/R- SOTRs are unlikely to develop CMV CMI during valganciclovir prophylaxis. Thus, the utility of CMV CMI for risk stratification of post-prophylaxis CMV infection in CMV D+/R- SOTRs is questionable. Conversely, CMV CMI testing may potentially be a useful marker of CMV relapse risk after treatment and guide the role of secondary antiviral prophylaxis. Disclosures Elitza Theel, PhD, D(ABMM), Euroimmun US: Advisor/Consultant|Oxford Immunotech: Advisor/Consultant|Roche Diagnostics: Advisor/Consultant|Serimmune Inc: Advisor/Consultant Raymund R. Razonable, MD, American Society of Transplantation: Board Member|gilead: Grant/Research Support|novartis: DSMB|regeneron: Grant/Research Support|Roche: Grant/Research Support.

Allogeneic Peripheral Blood Stem Cell Transplantation for Bone Marrow Failure Syndromes Using CD34+-Selected Progenitor Cells Co-Infused with a Reduced Number of Non-Mobilized T-Cells

Background Severe aplastic anemia (SAA) patients who fail immunosuppressive therapy (IST) may be candidates for curative allogeneic hematopoietic stem cell transplantation (HCT). Patients with SAA are often heavily transfused with underlying immune-mediated disease, which increases their risk for graft rejection when bone marrow (BM) is used as a graft source. Peripheral Blood Stem Cell (PBSC) grafts have been associated with better engraftment but at a cost of a higher incidence of graft-versus-host disease (GVHD). We developed a novel protocol combining high numbers of GCSF-mobilized CD34+ peripheral blood stem cells with a BM transplant-equivalent dose of T-cells (collected from donors before GCSF administration) to improve engraftment and decrease the risk of GVHD associated with a conventional, unmanipulated PBSC HCT. Methods In this phase II trial, eligible patients included those age 4-80 years with a diagnosis of SAA or other bone marrow failure (BMF) syndromes with ≥ 9/10 HLA-matched related (sibling/family) donors (MRD) or 10/10 matched unrelated donors (MUD). All patients received conditioning with cyclophosphamide (day -7 to -6), anti-thymocyte globulin (day -5 to -2), and fludarabine (day -5 to -1). For MUD patients, low dose total body irradiation (200 cGy) was added to the regimen on day -1. GVHD prophylaxis included cyclosporin (day -4 until at least day +30) and methotrexate (5 mg/m2 , day +1, +3 and +6). The primary outcome of the study was chronic GVHD at 1 year. Secondary outcomes included mortality, engraftment and chimerism, acute and chronic GVHD, immune reconstitution, and comparisons of MRD vs. MUD patients. Results Thirty-five patients (27 with MRD and 8 with MUD) were transplanted between February 2011 and December 2021. Patients had a median age of 30 (range 6-70) years, 46% were males and 54% were females, including 31 having SAA, 3 with SAA transformed to myelodysplastic syndrome (MDS), and one with MDS; 11 patients also had PNH clone pre-transplant. The median numbers of transplanted CD34+ and CD3+ T-cells were 8 ´ 106 cells/kg and 2 ´ 107 cells/kg, respectively. After HCT transplants, all patients had neutrophil recovery with a median 14 (10-32) days. Except for 2/35 (6%) patients having late graft failure, all other 33 (94%) patients achieved sustained engraftment. Platelet recovery was reached in 29 (83%) patients at a median 19 (13-321) days. A total of 97% of patients achieved >95% donor myeloid chimerism (median 14 days), and 94% of patients achieved >95% donor T-cell chimerism (median 30 days). Reactivation of CMV occurred in 21/29 (72%) patients at risk with none developing CMV disease. Full immune reconstitution occurred for most patients by 1-year post-transplant. With a median follow-up of 5 years, the estimated 200-day survival and overall survival were 89% and 85%, respectively. The cumulative incidence of acute grade II-IV GVHD was 23%, and 1-year chronic GVHD rate was 11%, which was significantly lower than our hypothesis that this regimen would lower the chronic GVHD rate to 50% (P < .001). The subgroups of patients with MRD and MUD were compared (Table 1): patients with MUD showed a slower time to achieve neutrophil recovery (P = .001) and platelet recovery (P = .03), and a slightly high graft failure incidence (2 cases), but most other outcomes were similar, compared to patients with MRD. Conclusion For patients with SAA and other BMF syndromes, transplanting high doses of mobilized CD34+ selected cells from MRD and MUD donors combined with a bone marrow transplant equivalent of non-mobilized donor T-cells (a partially T-cell depleted PBSC transplant) achieves rapid and durable donor engraftment and excellent survival. The cumulative incidence of both acute and chronic GVHD with this regimen was significantly lower than that historically reported with conventional PBSC transplants. Notably, low acute and chronic GVHD rates were also achieved in SAA patients with disease refractory to conventional IST who received a graft from a 10/10 HLA-matched MUD donor, although hematopoietic recovery was slightly delayed compared to recipients of a partially T-cell depleted graft from a MRD donor. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cytomegalovirus infection and disease in pediatric liver transplantation: Burden of disease under a preemptive therapy approach.

CMV remains a frequent complication after liver transplantation. Few studies exist in children reporting the epidemiology and outcomes of CMV after LT with current prevention strategies. Our goal is to report the incidence of CMV infection and disease in pediatric LT recipients under preemptive therapy, identify risk factors, complications, and adverse reactions to treatment. All pediatric LT recipients from a single center (1998-2018) were included. Antigenemia pp65 (1998-2003) and QNAT or both were used to inform preemptive therapy. Cutoff value for starting treatment was Agpp65 > 10 + cells/200 000 or QNAT >1500 copies/ml or any value in high-risk recipients (D+/R-). One hundred eighteen LT were analyzed. CMV infection was detected in 67% of patients, only 44 (37%) required treatment, and 5 (4%) developed CMV disease. All patients responded well to treatment, and no graft or patients were lost to CMV effects. There were no differences in mortality, CMV indirect effects, or other complications between those who required treatment and those who did not. Thirty-two percent of the patients who received antivirals developed an adverse hematological reaction. Risk factors associated with CMV infection requiring treatment were D+/R- (OR 13.9, p=.01) and fulminant hepatitis (OR 4.8, p=.02). Preemptive therapy for CMV in children is safe and effective, yields low CMV infection rates that require treatment, and minimal rates of CMV disease, without increasing CMV-related complications. Using this strategy, 63% of our patients did not receive treatment. Therefore, drug exposure, adverse reactions, and resistance risk were minimized.

The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Different Donors in Recipients With Mucopolysaccharidosis.

There is limited information regarding hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis (MPS) IV and VI. This study examined the full donor chimerism, specific lysosomal enzyme levels, and the survival of different MPS children after HSCT from various donor sources and compared the prognosis. A total of 42 children with MPS underwent HSCT, 9 cases were type I, 14 were type II, 15 were type IV, and 4 were type VI. A total of 24 patients received peripheral blood stem cells (PBSC) and 18 patients received umbilical cord blood (UCB). Patients who received PBSC were conditioned with intravenous (IV) busulfan every 6 h for a total of 16 doses, IV cyclophosphamide (CY, 200 mg/kg), and antihuman thymocyte globulin (ATG, 10 mg/kg). While conditioning regimen of patients who received UCB was adjusted to ATG (preposed, pre-) + busulfan + fludarabine + Cy, which includes IV ATG (pre-, 6 mg/kg), IV busulfan every 6 h for a total of 16 doses, IV fludarabine (200 mg/m2) and CY (200 mg/kg). Also, 95.2% (40 of 42) of patients achieved full donor chimerism, and all patients’ specific lysosomal enzyme levels reached normal. The estimated overall survival (OS) at 1 year was 92.9%. There was no significant difference in 1-year OS between patients who received PBSC transplantation and those who received UCB grafts (87.5% vs. 100%, p = 0.0247). The incidence of acute and chronic GVHD did not differ between them. The incidences of pneumonia in PBSC recipients and UCB recipients were 45.8 and 33.3%, respectively, but there few patients suffering from respiratory failure (4.2 and 5.6%, respectively) due to pneumonia. The incidence of cytomegaloviremia was also high in both groups, 58.3 and 44.4% respectively, However, no patient developed CMV disease. All deaths (3 of 42) occurred in patients receiving PBSC grafts, and there was no death in patients receiving UCB grafts. There was no death after transplantation in patients with MPS IV and VI. In addition, respiratory and nervous system functions were improved, whereas valvular heart disease was improved in some patients but progressed in more patients after transplantation. In summary, HSCT is a good therapeutic option for MPS, not only for patients with MPS I or II but also for those with MPS IV or VI. The specific lysosomal enzyme levels can be completely restored to normal, which is the basis for patients to resolve a broad range of clinical outcomes. Moreover, UCB with suitable HLA (HLA-match above 7/10 and 4/6) is a suitable donor source for MPS. Patients who underwent UCB transplantation using the conditioning regimen ATG (pre-) + busulfan + fludarabine + Cy can achieve a higher proportion of full donor chimerism and survival with less severe complications. HSCT can improve organs function in patients with MPS, but it is still worth exploring.

Incidence of Cytomegalovirus disease and viral replication kinetics in seropositive liver transplant recipients managed under preemptive therapy in a tertiary-care center in Mexico City: a retrospective cohort study

BackgroundIn the absence of an adequate prevention strategy, up to 20% of CMV IgG+ liver transplant recipients (LTR) will develop CMV disease. Despite improved reporting in CMV-DNAemia, there is no consensus as to what the ideal CMV-DNAemia cutoff for a successful preemptive strategy is. Each transplant centre establishes their own threshold. We aimed to determine the effectiveness of our preventive strategy in CMV IgG+ LTR, and evaluate CMV replication kinetics.MethodsIn this retrospective study we determined the incidence of CMV disease in the first 6 months following transplantation in CMV seropositive LTR in a tertiary-care centre in Mexico. Secondary outcomes were determining the number of patients who required preemptive therapy (treatment cutoff ≥ 4000 UI/ml), adherence to the centre’s prevention protocol and calculation of viral replication kinetics.ResultsOne-hundred and twenty-four patients met inclusion criteria. Four patients (3.2%) developed CMV disease. Ninety-six (85%) had detectable DNAemia and 25 (22%) asymptomatic patients received preemptive therapy, none of them developed CMV disease. The highest viral loads were observed on the second posttransplant month. The number of viral load measurements decreased over time. Patients with DNAemia ≥ 4000 UI/ml had a faster viral load growth rate, shorter viral load duplication time, and higher basic reproductive number. Viral load growth rate and autoimmune hepatitis were associated with development of DNAemia ≥ 4000 UI/ml.ConclusionCytomegalovirus disease occurred in 3.2% of the study subjects. Preemptive therapy using a threshold of CMV ≥ 4000 UI/ml was effective in reducing the incidence of end-organ disease. The viral replication parameters described in this population highlight the importance of frequent monitoring, a challenging feat for transplant programs in low- and middle-income countries.

Associations of high anti-CMV IgG titer with renal function decline and allograft rejection in kidney transplant patients.

An anti-cytomegalovirus (CMV) immunoglobulin G (IgG) antibody is produced after primary CMV infection and generally persists after the primary infection. However, it is not well-known about the relationship between anti-CMV IgG titer and outcomes in kidney transplant recipients. We, therefore, aimed to explore the role of anti-CMV IgG titer on the risks of CMV disease development, allograft rejection, renal function decline, and mortality. In a hospital-based study, we identified 179 CMV-seropositive kidney transplant recipients between January 2013 and December 2017. These patients were divided into low and high anti-CMV IgG titer groups, respectively. The cutoff level of anti-CMV IgG titer was determined by receiver operating characteristic curve analysis. The outcomes evaluated included CMV disease, decrease of ≥15% in estimated glomerular filtration rate (eGFR), biopsy-proven allograft rejection, and all-cause mortality. The high anti-CMV IgG titer group (≥846.2 AU/mL) exhibited a higher risk of CMV disease (adjusted hazard ratio [aHR], 3.77; 95% CI, 1.47-9.68; p = 0.006), eGFR decline ≥15% (aHR, 2.00; 95% CI, 1.19-3.35; p = 0.009), and renal allograft rejection (aHR, 2.95; 95% CI, 1.11-7.87; p = 0.030) than the low titer group (<846.2 AU/mL). In kidney transplant recipients, a high anti-CMV IgG titer was associated with higher risks for developing CMV disease, undergoing allograft rejection, and eGFR decline.

Time to initiation of pre-emptive therapy for cytomegalovirus impacts overall survival in pediatric hematopoietic stem cell transplant recipients

Background aimsCytomegalovirus (CMV) reactivation is a significant complication following allogeneic hematopoietic stem cell transplant (HSCT) and affects upwards of 40% of pediatric HSCT patients. Pre-emptive therapy remains the only effective treatment strategy available for pediatric patients following CMV reactivation. Little is known about how the timing of induction treatment following CMV reactivation impacts outcomes in pediatric patients, especially following ex vivo T-cell-depleted (TCD) HSCT. MethodsThe authors evaluated how the timing of induction treatment after CMV reactivation impacts overall survival (OS) and CMV disease in pediatric patients undergoing TCD HSCT at a single institution. The authors retrospectively analyzed patients treated on the pediatric service who received an initial ex vivo TCD HSCT at Memorial Sloan Kettering Cancer Center (MSKCC) from January 2010 to June 2018. CMV reactivation was defined as ≥1 CMV polymerase chain reaction >500 copies/mL in whole blood or >137 IU/mL in plasma within the first 180 days after allogeneic HSCT. To analyze the impact of the timing of induction treatment, the authors’ primary study outcome was OS and secondary outcome was CMV disease. ResultsA total of 169 patients who underwent an initial allogeneic TCD HSCT on the pediatric service at MSKCC from January 2010 to June 2018 were included in the analysis. Thirty-seven (22%) patients reactivated CMV during the first 180 days following HSCT. Of those patients who reactivated CMV, CMV donor/recipient (D/R) serostatus was as follows: D+/R+ n = 28 (76%) and D–/R+ n = 9 (24%). There was no CMV reactivation observed among recipients who were CMV-seronegative irrespective of donor serostatus. In those patients who reactivated CMV, the median time from HSCT to CMV reactivation was 24 days (interquartile range, 20–31). Eleven patients ultimately developed CMV disease in addition to CMV viremia, whereas the remaining patients had only CMV viremia. The cumulative incidence of CMV reactivation at 60 days was 45.2% (95% confidence interval [CI], 32.8–57.5) in the D+/R+ subgroup and 31% (95% CI, 14.2–47.9) in the D–/R+ subgroup. For those patients who reactivated CMV, 30 (81%) received induction treatment with ganciclovir or foscarnet. To analyze the impact of the timing of induction treatment on clinical outcomes, the authors restricted the analysis to those patients who reactivated CMV and received induction treatment (n = 30). The timing of induction treatment was significantly associated with OS, with optimal timing of initiation within a week of CMV reactivation (P = 0.02). There was no significant impact on the timing of induction treatment and risk of CMV disease (P = 0.30). ConclusionsIn ex vivo TCD HSCT in pediatric patients, early initiation of induction treatment after CMV reactivation is associated with improved OS.

Letermovir Prophylaxis Versus Pre-Emptive Therapy for Cytomegalovirus after Hematopoietic Stem-Cell Transplantation

IntroductionCytomegalovirus (CMV) infection is one of the most common complication after allogeneic hematopoietic stem-cell transplantation (HSCT) still associated with significant morbidity and mortality. Although pre-emptive therapy (PET) are routinely used in treatment of CMV after SCT, their prophylactic use is limited by clinically unacceptable myelosuppression and nephrotoxicity. Letermovir, available since 2019 in Italy, is the first antiviral agent approved by FDA and EMA which is indicated for the prophylaxis of CMV infection in CMV seropositive (R+) patients undergoing SCT. Presently, cost and drug interactions are the main disadvantages of Letermovir use. We performed a single-center observational retrospective study to evaluate the efficacy of primary Letermovir prophylaxis for CMV infection among high-risk patients (R+) receiving HSCT from serological negative donor (D-).MethodsWe evaluated a cohort of R+/D- patients transplanted from January 2017 to December 2020 (86/235 transplanted patients): among those eligible for Letermovir prophylaxis (N=70), 29 patients (transplanted after 2019) received Letermovir until day +100, whereas 41 patients (the historical control group transplanted before 2019) received CMV PET only in case of increased viral load (CMV reactivation). Patients unable to take oral therapy at day +7 from HSCT or assuming drugs for concomitant clinical conditions bringing about major pharmacokinetic interaction were excluded (N=16). We compared day +100 and day +200 cumulative incidence of clinically significant CMV infection (CS-CMVi), defined according to drug registration trial: Letermovir discontinuation before day +100, CMV reactivation (CMV-DNAemia leading to PET), CMV tissue invasive disease, disease relapse and death from any causes. Survival functions between groups were estimated by the Kaplan-Meier method and compared using log-rank test. Moreover, the overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and cumulative incidence of II-IV grade acute graft-versus-host disease (aGVHD) was compared in the two cohorts. Finally, we analyzed the number of accesses in day hospital from initial discharge to day +180, as an indirect cost-effectiveness evaluation of letermovir prophylaxis.ResultsNo severe adverse events related to the therapy were observed in the letermovir group. Letermovir prophylaxis started at a median of 11 days (range, 5-27) after HSCT. The median duration of Letermovir administration was 89 days (range, 40-113). The only early stop was due to patient death, not related to CMV or drug toxicity. CS-CMVi at day +100 occurred in 13.8% vs 61.0% in letermovir and historical group, respectively (p <0.001). Of note, none of the events in letermovir group was related to CMV reactivation whereas 24/25 in the historical group were. A trend toward lower CS-CMVi in the letermovir group was observed also at day +180 (44,8% vs 65,9%, p =0.080), with 6 late reactivations in patients who received prophylaxis. Moreover, at follow-up one patient in the experimental group and 3 in the control group developed CMV disease. Of note, in vivo T-cell depletion was used in 86% of patients in letermovir and 83% in historical group, and most of the CMV reactivations occurred after development of aGVHD: in 83% and 54% of patients, respectively. No differences in OS and DFS were observed between the two cohorts. Finally, a trend toward lower number of day hospital admissions was shown in patients who received letermovir prophylaxis (median 2 admissions, IQR 0-8, vs median 4.5, IQR 0-16), suggesting higher quality of life and costs reduction.ConclusionsOur real-life experience demonstrated the efficacy of Letermovir in reducing the incidence of CMV reactivation. Longer follow-up is needed to clarify advantages in terms of disease-free and overall survival. Further studies are needed to investigate the role of prophylaxis beyond day 100 in high risk patients, such as those who receive a T-depleted transplant or who develop aGVHD. The role of Letermovir prophylaxis on immuno-reconstitution and its cost-effectiveness remains to be evaluated. DisclosuresMarco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Ferrero: EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau.

Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients

AbstractCytomegalovirus (CMV)-seropositive umbilical cord blood transplantation (CBT) recipients have a high incidence of CMV-associated complications. There are limited data regarding the efficacy of letermovir for preventing clinically significant CMV infection (CS-CMVi), and the impact of letermovir prophylaxis on delayed-onset CMV reactivation after letermovir discontinuation, in CBT recipients. We compared the cumulative incidence of CS-CMVi and CMV detection in 21 CMV-seropositive CBT recipients receiving letermovir prophylaxis with a historical cohort of 40 CBT recipients receiving high-dose valacyclovir prophylaxis. Letermovir was administered on day +1 up to day +98. The cumulative incidence of CS-CMVi was significantly lower by day 98 in the letermovir cohort (19% vs 65%). This difference was lost by 1 year due to a higher incidence of delayed-onset CMV reactivation in the letermovir cohort. No patients developed CMV disease in the letermovir cohort within the first 98 days compared with 2 cases (2.4%) in the high-dose valacyclovir cohort; 2 patients developed CMV enteritis after discontinuing letermovir. Median viral loads were similar in both cohorts. Thus, letermovir is effective at preventing CS-CMVi after CBT, but frequent delayed-onset infections after letermovir discontinuation mandate close monitoring and consideration for extended prophylaxis.

Durable Remission of Refractory and Advanced Stage Mycosis Fungoides/Sezary Syndrome (MF/SS) Utilizing an “Outpatient” Alemtuzumab and Fludarabine-Based Reduced Intensity Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT)

Background:Advanced MF/SS carries a poor prognosis with most therapies failing to provide a long-term benefit. Allogeneic hematopoietic cell transplantation may result in durable remissions or clinically meaningful downstaging in a subset of patients. However, the risk of transplant related mortality has substantially curbed enthusiasm in the use of conventional allogeneic transplantation for this disease. In this study, we describe a novel allogeneic transplant approach in which a G-CSF mobilized, unmanipulated PBSC allograft from HLA-matched siblings was infused after conditioning with a regimen customized to maximally cytoreduce the disease and to provide the necessary immunosuppression to achieve sustained donor immune engraftment needed for the generation of a graft-vs-tumor effect (GVT). We theorized that this outpatient based reduced intensity transplant regimen would provide the essential tumor-debulking and a strategy to achieve sufficient degrees of donor T-cell chimerism necessary to result in the generation of curative GVT effects in patients with the most advanced forms of MF/SS.Patients and Methods:Between January 2004 and May 2014, 5 subjects (median age of 57, range 27-59) with refractory, advanced stage (III and IV) MF/SS who had failed a median 3 prior treatment regimens (range 2-7) underwent PBSCT following mostly outpatient conditioning with alemtuzumab (total of 193 mg), and fludarabine (total of 125 mg/m2). On day 0, subjects received a G-CSF mobilized unmanipulated PBSC allograft from an HLA identical sibling. CSA alone was used as GVHD prophylaxis. Donor lymphocyte infusions (DLI) were given to all patients to convert T-cell chimerism from mixed to full donor and when necessary to boost a GVT effect.Results:All 5 subjects initially had mixed lympho-hematopoietic chimerism but eventually converted to full donor chimeras in both myeloid and T-cell lineages; full donor T-cell chimerism was achieved at a median 7 months post-transplant (Figure 1). 3/5 subjects never became neutropenic and the 2 subjects who developed neutropenia had rapid neutrophil recovery occurring after 5 and 7 days. No patients developed severe anemia or thrombocytopenia and none required RBC or platelet transfusion support.No patients developed acute GVHD prior to DLI and only one (20%) developed acute GVHD (GI, grade IV) following DLI (the 2nd DLI for this patient). Three subjects (60%) developed limited cGVHD which resolved with short course of steroids.At a median follow-up of 3 years, 4 subjects achieved a complete remission, documented by labs, skin biopsy, and imaging. Remissions were delayed in onset, occurring at median 8 months post-transplant (Figure 1). 3 subjects remain alive in remission 13, 11, and 3 years after transplant. One subject with a heavy smoking history died in remission 3 years post-transplant from a secondary head and neck squamous cell carcinoma, and one subject died 7 months post-transplant from grade IV GI GVHD which followed a 2nd DLI given to treat progressive disease (Table 1).Among those at risk, 3 of 4 subjects (75%) developed CMV reactivation. None of the subjects developed CMV disease or PTLD.Conclusions:Our custom designed conditioning regimen 1) resulted in cytoreductive effects against advanced MF 2) proved to be immunosuppressive enough to allow sustained donor engraftment serving as a platform for subsequent DLIs which lead to curative GVT effects 3) could be performed in the outpatient setting avoiding severe neutropenia and its associated opportunistic infections and the need for platelet and RBC transfusion support. These data establish that long-term cures of even the most advanced refractory MF/SS can be achieved utilizing this alemtuzumab and fludarabine-based reduced intensity allogeneic hematopoietic cell transplant approach. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Prophylactic pretransplant ganciclovir to reduce cytomegalovirus infection after hematopoietic stem cell transplantation

Objective/BackgroundCytomegalovirus (CMV) reactivation remains a serious complication after allogeneic hematopoietic cell transplantation (HCT) occurring in approximately 60–70% of CMV-seropositive HCT recipients. CMV reactivation leads to adverse outcomes including end-organ damage, graft-versus-host disease, and graft failure. MethodsGanciclovir was administered pretransplant at 5 mg/kg twice daily intravenously from the start of conditioning to Day T-2 to CMV-seropositive patients receiving their first allogeneic HCT. CMV DNA was monitored weekly until at least Day 100 posttransplant. ResultsA total of 109 consecutive patients were treated, median age 57 (range 20–73) years. Of these, 36 (33%) patients had a CMV reactivation within the first 105 days posttransplant with a median time of reactivation of 52.5 (range 36–104) days posttransplant. The cumulative incidence of CMV reactivation at Day 105 posttransplant was 33.1% (95% confidence interval: 24.4–42.0). One patient developed CMV disease. ConclusionThe use of pretransplant ganciclovir was associated with low incidence of CMV reactivation and disease. These data suggest that pretransplant ganciclovir with preemptive therapy for viral reactivation may be a useful strategy to reduce CMV reactivation. Future prospective trials are needed to compare strategies for CMV prophylaxis.

MO225CMV ENCEPHALITIS IN A SLE FLARE

Abstract Background and Aims Cytomegalovirus (CMV) infection is an opportunistic pathogen in immunocompromised patients and its management is well described after solid organ/bone marrow transplant or in HIV patients. Although less common, since Systemic Lupus Erythemathous (SLE) is a chronic auto immune disease often requiring intense immunosuppression to induce remission of disease exacerbation, SLE patients are also prone to it. Besides complicating the course of the disease, it may be a life-threatening infection. Due to the heterogeneity of SLE manifestations, usually is difficult to distinguish between a SLE flare and CMV active infection, making the diagnose challenging. It has also been described in the literature as an exacerbating SLE factor. We report the case of an Asian, 27-year-old woman, with a recent SLE diagnosis that was admitted with a SLE flare while developing a CMV encephalitis. She was previously admitted due to a nephrotic syndrome. Immunological studies revealed an ANA title of 1:640 and a positive anti dsDNA Ab with diminished C3 and C4 levels, nephrotic range proteinuria and a diagnose of SLE was made. Renal biopsy revealed class IV lupus nephritis. She started high dose intravenous methylprednisolone (3 pulses of 500mg) and mycophenolate mofetil (MMF) at a dose of 2g per day. She was discharged taking 60 mg of oral prednisolone and the same dose of MMF. Two weeks after being discharged, she was readmitted due to worsening anaemia (Hb 6.8 g/dL), thrombocytopenia (Pl 27 000/µL) and deteriorating renal function with a sCr of 5.5 mg/dL with de novo haematuria. It was admitted a severe SLE flare and she was given another 3 pulses of 500mg I.V methylprednisolone and cyclophosphamide (CYC) was started (1 pulse of 500mg I.V). At the same time, she started to complain of myalgias and malaise, generalized hypotonia, developed fever, leukopenia with neutropenia and seizures. Serum CMV viremia was 71 000 copies and CMV polymerase chain reaction was positive in cerebrospinal fluid. She was started on I.V Ganciclovir, CYC was suspended and clinical improvement was observed. Conclusion Studies about the risk of different treatment drugs and other risk factors on the development of CMV disease in SLE are lacking. These studies will be useful for establishing guidelines on the institution of prophylaxis or pre-emptive treatment of CMV infection in SLE patients. Protocols for screening and prevention in this population should be implemented to account for this emerging problem. Given the rising prevalence of CMV infection in the past few years, the authors recommend that patients recently diagnosed with SLE while taking high doses of corticosteroids, which appears to be a risk factor for CMV reactivation, should be routinely tested for CMV viremia. There should be a low threshold for suspicion, hence treatment should be started as soon as possible given the high morbidity and mortality in severe cases.

Co-Transplantation of Haploidentical Stem Cells and a Dose of Unrelated Cord Blood in Pediatric Patients with Thalassemia Major

Allogeneic stem cell transplantation is a cure for patients suffering from thalassemia major (TM). Historically, patients were limited by the selection of donors, while the advancement of haploidentical stem cell transplantation (haplo-SCT) has greatly expanded the donor pool. However, the outcomes of haplo-SCT in TM recipients vary between different programs. In this study, we retrospectively studied 73 pediatric TM patients (median age, 7 years; range, 3 to 14 years) who underwent haplo-cord transplantation. Both the estimated overall survival and transfusion-free survival were 95.26% (CI 95.77% to 96.23%). Neither primary nor secondary graft failures were observed. The median follow-up period was 811 days (range, 370 to 1433 days). Median neutrophil and platelet engraftment times were 22 days (range, 8 to 48 days) and 20 days (range, 8 to 99 days), respectively. Acute graft-versus-host disease (aGVHD) was observed in 52% of patients and of these, 25% developed grade III to IV aGVHD. Cord blood engraftment was associated with delayed immune recovery and increased aGVHD severity. Viral DNAemia occurred in a relatively high proportion of patients but only 7% of patients developed CMV disease, while another 7% of patients had post-transplantation lymphoproliferative disorder. Long-term complication outcomes were good. Only one patient developed extensive chronic GVHD. No surviving patients were reliant on blood transfusion by the time this manuscript was submitted. This is one of the largest studies on the outcomes of pediatric TM patients who received stem cell transplantations from alternative donors. The haplo-cord program is safe and practical for TM patients that do not have matched donors.

EP25 Blau syndrome: a lifetime of sarcoid

Case report - IntroductionHere we explore a case of a 31-year-old female treated with juvenile arthritis rebranded as Blau syndrome. This is characterised by sarcoid involvement principally of her eyes as well as skin, kidneys, and joints. We aim to explore her management challenges and complications.Case report - Case description31 MS of Afro-Caribbean descent was diagnosed with early onset sarcoidosis at the age of 18 months. She was later found to be NOD2 gene positive but has no significant family history. Her health has been further complicated by her diagnoses of growth hormone deficiency and hyperthyroidism secondary to multinodular goitre.Clinically MS has a short stature and profound deafness. A legacy of the ophthalmic morbidity, panuveitis, has led to a visual acuity is 6/15 in her left eye and her right reduced to counting fingers due to developing endophthalmitis in 2019. Her arthritis is stable, but there are flexion deformities primarily involving her proximal interphalangeal joints reducing her grip function. In adulthood she does not have significant cutaneous changes.Investigations have revealed her to be anti-nuclear and anti-neutrophil cytoplasmic antibody negative. Radiologically, hand films show sparing of erosive changes, radiocarpal subluxation, and deformity of carpi in keeping with bilateral Madelung deformity. MRI has never suggested synovial enhancement of sacroiliac joints.Therapeutically she has trialled conventional disease modifying therapy including azathioprine, mycophenolate, and methotrexate. Disease activity continues to be high despite anti-TNF biologic DMARDs (adalimumab, infliximab and golimumab). Use of anti-TNF therapy has been complicated by development of CMV disease and identification of anti-infliximab antibodies following interruption.Ongoing steroid use from 18 months, hyperthyroidism and a chronic inflammatory state has led to osteoporosis. DEXA Z-scores reveal lumbar -2.7, right femoral neck -3.2 and left femoral neck -4.7. Systemic corticosteroid has tried to be offset through dexamethasone intravitreal implants.Consequentially, uncontrolled disease burden has also led to significant input from orthopaedics, including bilateral total knee replacements by age 28.However, with MS, we are hopeful with the commencement of anti-IL6 receptor therapy (Tocilizumab) that this may represent a new line of effective treatment.Case report - DiscussionBlau syndrome is a juvenile sarcoidosis characterised by the triad of granulomatous arthritis, recurrent uveitis, and dermatitis. It is inherited in an autosomal dominant pattern due to a missense mutation in the gene encoding for nucleotide-binding oligomerisation domain containing protein 2 (NOD2/CARD15). It is proposed that NOD2 as intracellular receptors, for antigen such as lipopolysaccharide, may subsequently act like toll-like receptors to cascade NF-kappa B and downstream inflammatory pathways. Its role is also implicated in other inflammatory conditions such as Crohn’s disease.As represented in our case, uveitis presents the highest morbidity, with median age of eye disease presenting at 60 months and remains persistent despite topical or systemic therapy in more than 50% of patients. In comparison to Juvenile idiopathic arthritis, Blau often leads to a pan rather than anterior segment only uveitis and in a greater proportion of cases.In addition to biological factors, much of MS’s treatment decisions have been guided by her and her psychology. In attempting to address the difficulties of her condition, including coordinating several specialities clinics whilst developing as a young woman, she has frequently discontinued therapy which may represent an area that she can exact control given little perceived benefit.TNF-alpha inhibitors have been validated through randomised controlled trials for the use of refractory sarcoidosis. However recent literature has highlighted the use of targeting the IL-6 pathway in multisystem chronic sarcoidosis. It is believed this may represent a key cytokine in promoting Th17 effector cells that have been implicated in sarcoidosis bio-pathology. However ongoing case reports and ideally large-scale studies are needed.Case report - Key learning pointsBlau syndrome as a rare lifelong form of early onset sarcoidosis offers insight into challenging therapeutic decision making where limited clinical trial data is available.

P1765COMBINING THE BEST OF TWO OPTIONS: A SPLIT STRATEGY WITH PROPHYLAXIS OR PRE-EMPTIVE THERAPY TO PREVENT CYTOMEGALOVIRUS AFTER KIDNEY TRANSPLANTATION

Abstract Background and Aims Cytomegalovirus (CMV) remains an important challenge after kidney transplantation. Current Transplantation Society International Consensus Guidelines recommend antiviral prophylaxis or pre-emptive therapy for either high risk CMV-seronegative recipients of a CMV-seropositive donor (D+/R-) and moderate-risk CMV-seropositive recipients (R+). A split strategy according to CMV risk, however, is not specifically mentioned. Method We evaluated a split strategy to prevent cytomegalovirus infection after kidney transplantation. D+/R- patients received valganciclovir (VGC) prophylaxis during 200 days and R+ patients were treated pre-emptively according to CMV DNAemia. Results Between April 2014 and March 2018, 40 D+/R- and 92 R+ patients underwent kidney transplantation. Forty-six % received antithymocyte globuline (ATG) induction and 98 % were treated with calcineurin inhibitors, mycophenolic acid (MPA) and steroids. No D+/R- patient developed CMV disease during prophylaxis (median 200 days), 15 % developed late-onset disease. Fifty-three % developed neutropenia during prophylaxis, including 16/40 (40 %) grade 3 or 4 neutropenia requiring reduction/discontinuation of MPA (30 %) and/or VGC (30 %), and occasional need for granulocyte colony stimulating factors (5 %). In the R+ group, 40 % received antiviral therapy for a median duration of 21 days. Five percent developed CMV disease. Only 5 % developed neutropenia. D+/R+ status (hazard ratio (HR) 2.09, P 0.004) and ATG use (HR 2.81, P &amp;lt; 0.0001) were risk factors for CMV reactivation. Conclusion Prophylaxis leads to acceptable CMV control in high risk patients, but comes with a high risk of neutropenia. Pre-emptive therapy is effective and limits drug exposure in those at lower risk for CMV.

P1775CMV VIREMIA IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING BASILIXIMAB OR LOW DOSE ANTI THYMOCYTE GLOBULIN INDUCTION WITHOUT VALGANCICLOVIR PROPHYLAXIS- SINGLE CENTRE EXPERIENCE IN INDIA

Abstract Background and Aims CMV is a major cause of morbidity in transplant recipients and manifests as tissue invasive disease or CMV viral syndrome. Controversy exists regarding best method for CMV prevention. Therefore, we intended to evaluate incidence of CMV viremia and symptomatic CMV infection in adult KTR with basiliximab or antithymocyte globulin (ATG) induction without the use of valganciclovir prophylaxis. This study will help developing a protocol for management of CMV infection/disease in Indian patients since there is no such data amongst Indians. Method A prospective, open-label, single centre study. Patients were monitored for CMV DNA-PCR twice a week for month 1 post-transplant, once a week in month2, and then every 2 weeks in month 3, and then once a month from month 4 to 6. Results We included 17 patients with low-dose ATG induction (group1) and 20 patients with Basiliximab induction (group2). Mean recipient age was 42.9 and 45.9 yr in group 1 and 2 whereas mean donor age was 50.6 and 51.6 yr respectively. Male recipients were 76.4% (13/17) and 65% (13/20) in group 1 and 2 respectively; male donors were 11.7% (2/17) and 20% (4/20) respectively (not signficant). Average HLA mismatches were 3.4/6 and 3.7/6 (not significant). In group1 average transfusions per patient were 6units (vs 1.7units in group2) and 65% pts in group1 had &amp;gt;3 units transfusion (p&amp;lt;0.05). Mean follow-up was 12.7 and 20.7 months respectively. Incidence of acute rejection was 5.8% (1/17) and 10% (2/20) in group 1 and 2 respectively. (not significant). Incidence of CMV viremia requiring valganciclovir therapy was 11.6% (2/17) and 10% (2/20) in group 1 and 2 respectively. (not significant). No patient developed CMV disease. Mean serum creatinine was 1.1 and 1.09 mg/dL at 1 month and 1.2 and 1.14 mg/dL at 3 months (not significant) Conclusion The incidence of CMV viremia is low and not significantly different in patients receiving basiliximab or low dose ATG induction in living donor kidney transplants on tacrolimus based immunosuppression. In our study patients in ATG group had significantly more transfusions vs basiliximab group and hence were more sensitised. Still the incidence of acute rejection remained low in both these groups (5.8% and 10%). Hence universal prophylaxis with valganciclovir may not be required in all the patients with basiliximab and low dose ATG induction especially in developing countries where cost of therapy is borne by the patients.