scholarly journals CMV Serostatus of Donor-Recipient Pairs Influences the Risk of CMV Infection/Reactivation in HSCT Patients

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Emilia Jaskula ◽  
Jolanta Bochenska ◽  
Edyta Kocwin ◽  
Agnieszka Tarnowska ◽  
Andrzej Lange
Keyword(s):  
Multivariate Analysis ◽  
Similar Rate ◽  
Cmv Infection ◽  
Unrelated Donors ◽  
Group Basis ◽  
Cmv Reactivation

CMV donor/recipient serostatus was analyzed in 200 patients allografted in our institution from unrelated (122 patients) donors and 78 sibling donors in the years 2002–2011 in relation to posttransplant complications. On a group basis independently of the CMV serostatus of donor-recipient pairs sibling transplantations and those from unrelated donors that matched 10/10 at allele level had a similar rate of CMV reactivation (17/78 versus 19/71, P=ns). The rate of CMV reactivation/infection was higher in patients grafted from donors accepted at the lower level of matching than 10/10 (18/38 versus 36/149, P=0.008). The incidence of aGvHD followed frequencies of CMV reactivation in the tested groups, being 40/156 and 25/44 in patients grafted from sibling or unrelated donors that 10/10 matched and in those grafted from donors taht HLA mismatched, respectively (P=0.001). Regarding the rate of reactivation in both groups seropositive patients receiving a transplant from seronegative donors had more frequently CMV reactivation as compared to those with another donor-recipient matching CMV serostatus constellation (22/43 versus 32/143, P=0<0.001). Multivariate analysis revealed that seropositivity of recipients with concomitant seronegativity of donors plays an independent role in the CMV reactivation/infection (OR=2.669, P=0.037; OR=5.322, P=0.078; OR=23.034, P=0.023 for optimally matched and mismatched patients and the whole group of patients, resp.).

Donor Toll-Like Receptor 9 Genetic Factors in Susceptibility to Acute Graft-Versus-Host Disease and Cytomegalovirus Infection After Related and Unrelated Hematopoietic Stem Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1938-1938
Author(s):  
Haowen Xiao ◽  
Yi Luo ◽  
Xiaoyu Lai ◽  
Jimin Shi ◽  
Yamin Tan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Unrelated Donor ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Tlr9 Gene ◽  
Variant Genotype ◽  
Unrelated Donors

Abstract Abstract 1938 Background: Toll-like receptors (TLRs) are transmembrane proteins on the surface of immune cells that detect conserved molecular motifs known as “microbe-associated molecular patterns” from a variety of organisms. They interact with several adapter proteins to activate transcription factors, leading to the production of inflammatory cytokines and the activation of adaptive immunity. Current evidence suggests that common polymorphisms in TLR genes have been associated with the susceptibility to autoimmune disease and several infections, their association with outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has yet to be explored. Methods: We unselectively included all patients undergoing allo-HSCT in our Bone Marrow Transplantation Center between January 2001 and March 2009 if donor and patient DNA were available. All the patients and their donors were from a homogeneous genetic background. We analyzed 10 single nucleotide polymorphisms (SNPs) in the TLR1gene (rs4833095 C/T, rs5743565 A/G), TLR2gene (rs11938228 A/C, rs3804099 C/T), TLR3 gene (rs3775291 A/G, rs3775296 G/T), TLR8gene (rs3764880 A/G, rs2159377 C/T) and TLR9 gene (rs352139 G/A, rs352140 C/T) in 2 independent cohorts. The initial cohort consisted of 138 pairs of patients and their unrelated donors (URDs). The second cohort consisted of 102 pairs of patients and their HLA-identical sibling donors. Results: (1) We found that two SNPs in donor side, TLR9 +1174 G/A (rs352139) and TLR9 +1635 C/T (rs352140), influenced the risk of aGVHD. The association was particularly strong in the URD transplantation cohort. Multivariate analysis confirmed that an unrelated donor with the TLR9 +1174 variant allele (A allele) was an independent risk factor for aGVHD (P= 0.009, RR= 3.123). In contrast, an unrelated donor with the TLR9 +1635 variant genotype (TT) was protective (P= 0.067, RR= 3.457). The same effect was observed in the sibling transplantation cohort, although the incidence of clinically significant aGVHD in this cohort was low overall and the association was not statistically significant. (2) Since cytomegalovirus (CMV) reactivation and disease continued to be important complications post-HSCT, and CMV infection is of special concern in the Chinese population. The incidence of asymptomatic infection is high. The episodes of major infection were focused on early CMV infection post-HSCT. Early CMV infection refers to antigenemia or disease with onset by day 100 after transplantation. In the present study cohorts, all patients and almost all donors were CMV seropositive (CMV-specific immune globulin G positive, CMV-IgG(+)) before HSCT and only one donor from the Taiwan Tzu Chi Stem Cells Center was CMV seronegative. All patients received CMV prophylaxis treatment and those experiencing pre-transplantation CMV recurrent infection received preemptive treatment. Of the total of 240 patients, 134 (55.8%) had experienced early CMV infection with a median onset of 27 days (range 2–64) post-HSCT. Patients who received stem cells from donors with the TLR9 +1635 variant genotype (TT) had a reduced incidence of grades II–IV aGVHD, however, they experienced early CMV infection more frequently than those with the wild-type genotype (CT or TT) in both the URD transplantation cohort (TT: 80% vs. CT or CC: 59.3%, Gray's test p =0.02) and the sibling transplantation cohort (TT: 66.7% vs. CT or CC: 41.7%, Gray's test p=0.03), although a higher incidence of early CMV infection was observed in the URD transplantation cohort (63% vs. 46%, Gray's test p = 0.025). Multivariate analysis confirmed unrelated donors (p =0.046, RR = 1.438, 95%CI,1.007–2.053), patients experiencing recurrent CMV infection pre-transplantation (p = 0.004, RR = 0.597, 95%CI, 0.419–0.849) and donors with the TLR9 +1635 TT genotype (p=0.005, RR=0.561, 95%CI, 0.376–0.836) all contributed to the development of early CMV infection. Conclusion: There is increasing evidence for a role for TLR9 in the pathogenesis of aGVHD and viral infection. These result is the first report of donor TLR9 gene polymorphic features with the risk of aGVHD and early CMV infection, which are located within the promoter region and coding polymorphisms and may influence transcriptional regulation and the amino acid exchange of the TLR9 gene. Disclosures: No relevant conflicts of interest to declare.

Risk Factors and Mortality Associated with CMV Reactivation Post Autologous Stem Cell Transplantation.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4531-4531
Author(s):  
Claudia Bley ◽  
Fabio PS Santos ◽  
Guilherme Fleury Perini ◽  
Ricardo Helman ◽  
Andreza Alice Feitosa Ribeiro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Logistic Regression ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Real Time Pcr ◽  
Cmv Infection ◽  
Cmv Reactivation

Abstract Abstract 4531 Introduction: Cytomegalovirus (CMV) is one of the most common viral pathogens post-allogeneic stem cell transplantation (SCT). However, CMV reactivation and disease are relatively uncommon events after autologous stem cell transplantation (ASCT), with a reported incidence of 2–9%. There are few studies describing risk factors for development of CMV reactivation post-ASCT. Objective: To describe the incidence and risk factors for CMV reactivation post-ASCT in our institution and its impact on survival. Methods: The charts of patients who underwent ASCT at our institution from January 2005 until July 2009 were manually reviewed. CMV reactivation was detected by antigenemia assay and/or real-time PCR. Variables associated with CMV in a univariate analysis with a p<0.15 were included into a multivariable logistic regression model to determine risk factors for developing CMV reactivation. Overall survival (OS) was defined from time of ASCT until death from any cause and was estimated by Kaplan-Meier method. Logrank test was used to compare unadjusted OS between patients with and without CMV reactivation. Results: A total of 115 ASCTs were performed at our institution during that time frame (bone marrow=8; peripheral blood stem cells=107). CMV reactivation was investigated in 50 patients (43.5%) who presented with persistent fever and 14 (12.3%) were found to be positive for CMV by either antigenemia and/or real-time PCR. Diagnosis included multiple myeloma (N=7) non-Hodgkin's lymphoma (N=6) and multiple sclerosis (N=1). Median time to CMV reactivation was 18 days (range 12–41). Seventy-two patients had information on absolute lymphocyte count at day 15. Patients with an ALC < 0.5×109/L at day 15 had a higher incidence of CMV reactivation (28.5% vs. 8%, p=0.02). Variables entered in the logistic regression multivariate analysis were age, sex, years between diagnosis and ASCT and ASCT in the last 12 months. Only age (odds ratio [OR]=1.06; p=0.05) and ASCT in the last year (OR=3.7; p=0.03) were significantly associated with CMV reactivation in the multivariate analysis. When analyzing only the 72 patients that had information on day 15 ALC, the multivariate analysis revealed ASCT in the last 12 months (OR=1.56, p=0.05) and day 15 ALC < 0.5×109/L (OR=4.71, p=0.03) as being associated with CMV reactivation. Patients who had CMV reactivation had a significantly inferior OS (2-years 61% vs. 23.4%, p=0.03). Conclusion: We detected a relatively high incidence of CMV infection post-ASCT and this was associated with a higher mortality. Patients who develop CMV infection post-ASCT may represent a subset that has a higher degree of immunesuppression, as manifested by a lower ALC at day 15 post ASCT. We believe that patients should be monitored post-ASCT for the presence of CMV reactivation, particularly if they present with persistent lymphopenia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cytomegalovirus Reactivation in Hematopoietic Stem Cell Transplant Recipients in High Endemic Population

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Muhammad Farhan ◽  
Qamar Un Nisa Chaudhry ◽  
Syed Kamran Mahmood ◽  
Tariq Ghafoor ◽  
Raheel Iftikhar ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
Viral Load ◽  
High Viral Load ◽  
Transplant Recipients ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Endemic Population ◽  
Cmv Reactivation

Background: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). It causes end-organ disease, multi-organ dysfunction syndrome, graft failure, increased susceptibility to infections and GVHD. According to the published western data greatest risk of CMV infection is the seropositivity of the recipient, however, in a high endemic population where seropositivity is up to 100%, risk factors for CMV reactivation are different and are analyzed in this study. Methods: It is a prospective descriptive study performed at Armed Forces Bone Marrow Transplant Center, Rawalpindi, Pakistan from January 2017 to March 2020. Consecutive patients who underwent allogeneic HSCT during this period were enrolled. All patients were prospectively monitored for CMV reactivation by weekly or two weekly CMV DNA quantitative PCR, from engraftment till day 100 post-transplant. CMV infection was diagnosed on detection of more than 200 copies/ml on PCR. Threshold for starting preemptive antiviral therapy was kept at 2000 copies/ml. Patients with past history of CMV infection, those who expired before day 14 post-transplant or those with less than 70% of required CMV tests were not included in the study. Factors associated with CMV reactivation, outcome of antiviral therapy and effect of CMV on post-transplant survival were studied. Results: Out of 319 transplants during this period, 230 patients fulfilled the inclusion criteria. Of these, 197 were HLA matched sibling, 18 were matched family donor and 15 were haploidentical transplants. There were 163 males and 67 females. Median age at transplant was 9.5 years (0.5-53). Eighty-three transplants were done in thalassemia, 55 in aplastic anemia, 14 in Fanconi anemia, 27 in acute leukemias, 8 in CML, 9 in MDS, 12 in HLH and 22 in other hematological disorders. All the patients and donor were CMV IgG seropositive when tested before transplantation. CMV reactivation was seen in 152 out of 230 patients (66.1%). Of 152, 95 patients had CMV viral load more than 2000 copies/ml and required antiviral treatment. Median time to reactivation since transplant was 35 days (13-90). In multivariate analysis using binary regression, risk factors for high viral load CMV reactivation included steroid administration (p=0.009), recipient age less than 10 years (p=0.003) and haploidentical transplant (p=0.048). No statistically significant association was found with the use of ATG, GVHD, underlying disease, ABO blood group or gender mismatch. Survival analysis using cox regression showed significant impact of high viral load CMV reactivation on post-transplant survival. Event-free survival (EFS) with and without CMV reactivation was 70.5 % and 89.7% respectively (p=0.004) and overall survival (OS) was 80.0 % and 97.4 % with and without CMV reactivation respectively (p=0.002). Valganciclovir was given in 89 patients and 6patients were treated with ganciclovir. Mean time to clear viremia was 19.8±9 days. Myelosuppression was seen in 41% of patients treated with valganciclovir. Renal impairment was seen in 25% of patients treated with valganciclovir. One patient had resistant disease. One patient had CMV pneumonia and she recovered. One patient died of suspected CMV pneumonia Conclusion: CMV reactivation was seen in 66.1% of the transplant recipients, this is higher compared to the western world due to high CMV seropositivity is this region. Steroids administration in post-transplant period significantly increase the risk of CMV reactivation. Preemptive therapy with valganciclovir effectively treats CMV reactivation. Viral threshold for treatment should be decided considering the regional endemicity. CMV adversely effects the transplant outcome in terms of EFS and OS. Disclosures No relevant conflicts of interest to declare.

scholarly journals P276 Reactivation of Epstein–Barr virus and cytomegalovirus behaves differently in pathophysiology of ulcerative colitis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S289-S289
Author(s):  
S Yamada ◽  
S Yamamoto ◽  
Y Honzawa ◽  
Y Hayashi ◽  
H Kitamoto ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Multivariate Analysis ◽  
Epstein Barr Virus ◽  
Colonic Mucosa ◽  
Clinical Severity ◽  
Barr Virus ◽  
Ebv Reactivation ◽  
Endoscopic Score ◽  
Epstein Barr ◽  
Cmv Reactivation

Abstract Background Cytomegalovirus (CMV) and Epstein–Barr virus (EBV) are members of the herpesvirus family. CMV reactivation is often complicated with ulcerative colitis (UC) and is known as one of exacerbation factors. However, the association between EBV reactivation and pathophysiology of UC is still unclear. Methods This study enrolled 116 active UC patients who received colonoscopy between January 2005 and January 2019 in Kyoto University Hospital. 244 biopsy specimens were obtained from inflamed colonic mucosa to assess EVB and CMV reactivation. Viral loads of EBV and CMV in inflamed mucosa were measured by real-time PCR assay. The reactivation of those viruses was defined as DNA quantity more than 10 copies/μg DNA. Clinical severity was assessed by Lichtiger index and defined as follow: 4–8 as mild, 9–12 as moderate, and more than 12 as severe. Endoscopic severity was assessed by Mayo endoscopic score. We examined the correlation between the positivity of each viral reactivation and patients’ characteristics or prognosis of UC. Results (1) Median age, Lichtiger score and Mayo endoscopic score at the time to assess the viral reactivations were 36 years-old, 8, and 3, respectively. (2) EBV and CMV reactivation were observed in 127 samples (52.0%) and 73 samples (29.9%), respectively. There was no correlation between EBV and CMV viral load (correlation coefficient 0.19), although a significant correlation between those viral reactivations was observed in active colonic mucosa of UC patients (p = 0.002). (3) The proportion of EBV reactivation was higher in both clinically and endoscopically severe UC patients compared with those with mild activity. On the other hands, there was no association between CMV reactivation and clinical or endoscopic severity. (4) Multivariate analysis indicated risk factors for EBV reactivation as receiving anti-TNF-α antibodies (odds ratio [OR] 4.2) or calcineurin inhibitors (OR 3.5), and CMV reactivation (OR 2.1), respectively. (5) Multivariate analysis also indicated risks for CMV reactivation as steroid-refractory (OR 4.7) and EBV reactivation (OR 2.0). (6) EBV and CMV reactivation did not affect clinical outcomes including the requirement of colectomy or intensification of immunosuppressive treatments and the incidence of colitis-associated cancer, dysplasia and lymphoproliferative disease. Conclusion Reactivation of EBV or CMV may behave differently in pathophysiology of UC. Further studies are required to clarify the role of EBV reactivation on colonic inflammation in UC patients.

Cytomegalovirus-induced cutaneous ulcer mimicking vasculitis in a patient with systemic lupus erythematous: A case report and review of the literature

Lupus ◽  
2020 ◽  
Vol 30 (1) ◽  
pp. 149-154
Author(s):  
Zahra Hajihashemi ◽  
Farahnaz Bidari-zerehpoosh ◽  
Khatere Zahedi ◽  
Behnaz Eslami ◽  
Nikoo Mozafari
Keyword(s):  
Lupus Erythematosus ◽  
Correct Diagnosis ◽  
Cmv Infection ◽  
Systemic Lupus ◽  
Cytoplasmic Inclusions ◽  
Delay In Diagnosis ◽  
Reactivation Treatment ◽  
Cutaneous Ulcer ◽  
Chronic Autoimmune Disease ◽  
Cmv Reactivation

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which can be complicated with cytomegalovirus (CMV) infection during its course. CMV reactivation can mimic an SLE flare and lead to delay in diagnosis. Here, we reported a previously diagnosed SLE patient who presented with fever, leukopenia, and cutaneous ulcers. Initially, this was diagnosed as an SLE flare and the patient was treated with higher doses of corticosteroids but no improvement was observed. Both nuclear and cytoplasmic inclusions inside the endothelial cells in the skin biopsy as well as positive immunohistochemistry (IHC) staining for CMV antigen were clues to the correct diagnosis of CMV reactivation. Treatment with ganciclovir resulted in clinical resolution. In this report, a very rare clinical form of CMV infection manifesting as cutaneous necrotizing vasculitis on the lower extremity is described and the literature regarding this case is reviewed.

Results of a Phase I/II-Study on PCR-Based Pre-Emptive Therapy with Valganciclovir or Ganciclovir for Active CMV Infection Following Reduced Intensity Allogeneic Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5011-5011
Author(s):  
ZiYi Lim ◽  
Gordon Cook ◽  
Peter R. Johnson ◽  
Anne Parker ◽  
Mark Zuckerman ◽  
...  
Keyword(s):  
Stem Cell ◽  
Efficacy And Safety ◽  
Cmv Infection ◽  
Reduced Intensity Conditioning ◽  
Intravenous Ganciclovir ◽  
Group A ◽  
Oral Valganciclovir ◽  
Group B ◽  
Cmv Reactivation ◽  
Reduced Intensity

Abstract The advent of reduced intensity conditioning(RIC) protocols for allogeneic haematopoietic stem cell transplantation(HSCT) has reduced the incidence of early transplantation related morbidity largely due to the attenuation of the conditioning intensity. Nevertheless, the incidence of CMV reactivation in these patients remains high. Herein we report the results of a multi-centre randomised prospective study to assess the bioavailability(auc0–12) of ganciclovir in the population of patients undergoing alemtuzumab-based RIC HSCT after oral administration of valganciclovir and secondly, the efficacy and safety of valganciclovir in the treatment of a CMV infection following allogeneic SCT. Recipients of allogeneic bone marrow or peripheral blood stem cell transplants with related or unrelated donors following reduced intensity conditioning, without proven graft versus host disease were eligible for this study. RIC protocols approved for the purposes of this study were FBC(fludarabine, busulphan, alemtuzumab) and FMC(fludarabine, melphalan,alemtuzumab). For inclusion into the study, patients had to have a detectable CMV DNA load in two consecutive blood specimens up to 120 days after transplant. Eligible patients were randomized to 1 of 2 treatment groups: group A received 900 mg oral valganciclovir(2 x 900 mg/d) for 14 days and group B received intravenous ganciclovir 5mg/kg/d twice daily for 14 days. All patients were monitored for 84 days(safety follow-up). pK profiles of ganciclovir were obtained after administration of the study drug in each study arm. pK assessments were scheduled at days 4 and 11. 27 patients were recruited into the study over a 24-month period from Jan 2005 to Dec 2006. The median age was 51 years(range:34–68). The median time to CMV reactivation was 43 days post-HSCT(range:20–114). 18 patients(67%) completed the allocated treatment resulting in CMV DNA load <10 copies/ml at a median of 14 days post-HSCT(range:7–28). In 9 cases, there were changes to the primary treatment regimen. In group A, treatment was modified in 5 cases; 3 due to rising CMV levels, 1 due to drug rash, 1 due to neutropenia. In group B, 4 patients had treatment modification; 3 patients due to rising CMV DNA levels, 1 had neutropenia. None of the patients in the study developed CMV invasive disease. The median value of the systemic clearance of ganciclovir was 11.8 l/h(95%CI: 8–15.6 l/h). The bioavailability of ganciclovir from valganciclovir(expressed as equivalents of ganciclovir) was 73%(95%CI, 34%–112%). The average exposure in the valganciclovir group(36.9 ± 14.9μg.h/ml) was significantly higher than in the ganciclovir cohort(27.9 ±7.5μg.h/ml). As a result, ganciclovir bioavailability in the subjects who received valganciclovir was 79%. In summary, when compared with intravenous ganciclovir, oral valganciclovir had high bioavailability with equivalent efficacy and safety in patients undergoing RIC HSCT. Use of valganciclovir can facilitate the out-patient treatment of patients with CMV reactivation post-HSCT with a potential reduction in hospitalization costs.

The Bidirectional Relationship Between Cytomegalovirus Replication and Graft-Versus-Host Disease - a Retrospective Single Center Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2236-2236
Author(s):  
Nathan Cantoni ◽  
Hans H Hirsch ◽  
Nina Khanna ◽  
Dominik Heim ◽  
Joerg Halter ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Time Dependent ◽  
Cmv Infection ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Cmv Reactivation ◽  
Multiple Episodes

Abstract Abstract 2236 Poster Board II-213 Cytomegalovirus (CMV) infection and graft-versus host disease (GVHD) are important complications after allogeneic HSCT with a clear link. Multiple studies show that GVHD and its treatment put patients at risk for CMV reactivation. Data on CMV infection as a cause of GVHD, in contrast, are controversial. The association of pre-transplant CMV serology with GVHD development and reduced rates of chronic GVHD after preemptive CMV treatment are indicative of such an association. However, analyses of the direct impact of CMV infection on GVHD are rare; a recent small study found no effect of CMV replication on subsequent development of acute GVHD (Wang et al, BMT 2008). We analyzed in a single centre study the association of CMV reactivation with acute GVHD in 517 patients treated between 1993 and 2008. 59% of patients were male, median age was 42 years (range 16 to 70). Diagnoses were AML (31%), ALL (16%), CML (15%), MDS/MPN (13%), lymphoma (21%), and other (4%). Conditioning regimens were Cy/TBI ±/- etoposide (49%), Cy/Bu (17%), fludarabine and TBI (16%), or others (18%). GVHD prophylaxis consisted of CyA/MTX (78%) or CyA/MMF (21%). Donors were HLA-identical siblings (65%), other family members (4%), or unrelated donors (31%). We made use of a standardized CMV policy over the last decades. CMV reactivation was monitored using real-time polymerase chain reaction or pp65 antigenemia assay weekly in patients without infection, twice weekly in patients with CMV replication. CMV was preemptively treated with gancyclovir or foscarnet. To determine the correlation of CMV infection with acute GVHD, we used a stringent Cox regression model, in which CMV replication was modeled as a time-dependent covariate becoming positive on the day of the first detection of CMV and negative on the first negative assay thereafter. Multiple episodes of CMV replication were considered. Acute GVHD was modeled as a time-dependent covariate in models with CMV infection as endpoint. Hazard ratios (HR) were adjusted for patient age, disease, disease stage, donor type, stem cell source, conditioning regimen and GVHD prophylaxis. The analysis was restricted to the time from transplant to day 100. CMV reactivation was detected at least once in 16% (84/517) of patients at a median of 33 (range 1-95) days after HSCT. Median duration of CMV reactivation was 8.5 days (range 2-62). 19 patients showed multiple episodes of CMV replication. Donor and recipient serostatus significantly influenced the day 100 cumulative incidence of CMV infection: D-/R- (N=173) 6%; D±/R- (N=61) 10%; D±/R± (N=128) 25%; and D-/R± (N=99) 37%, p<0.001. The cumulative incidence for any acute GVHD (grade I-IV) was 67% (95% CI 56-78%) with a median onset time at day 14 (range day 5-94); the cumulative incidence for severe acute GVHD (grade II-IV) was 48% (95% CI 40-56%). When both endpoints (CMV, GVHD) were combined, 150 patients (29%) experienced neither GVHD nor CMV reactivation, 281 (54%) GVHD only, 19 (4%) CMV reactivation only, and 67 (13%) both CMV reactivation and GVHD. Of the 67 patients with both GVHD and CMV, 46 (69%) developed GVHD prior to CMV reactivation, 17 (25%) developed GVHD during CMV reactivation, and 4 (6%) developed GVHD after CMV reactivation. Cox modeling revealed that presence of GVHD grade II-IV increased the risk of CMV infection (HR 1.61, 95% CI 1.03-2.52, p=0.04). Similarly, patients were at increased risk of developing acute GVHD during phases of CMV replication (grades I-IV: HR 2.23, 95% CI 1.39-3.81, p=0.001; grades II-IV: HR 2.00, 95% CI 1.08-3.72, p=0.03). GVHD grade was not influenced by concomitant CMV reactivation (median grade II, in patients with or without CMV reactivation). The overall proportion of GVHD that occurred during phases of CMV replication was small (3% versus 64% occurring in CMV non replicating patients). Even if GVHD occurring after resolution of CMV reactivation was additionally taken into account, the majority of GVHD occurred without preceding CMV infection (63% versus 4%). These data describe the complex relationship between CMV infection and GVHD. We confirm previous studies that GVHD (and GVHD therapy) can induce CMV infection. We describe as well that patients with active CMV replication have a significantly higher risk of developing GVHD compared to patients without CMV replication. However, the proportion of GVHD that could be linked to CMV reactivation was small in this population with a low overall incidence of CMV reactivation. Disclosures: No relevant conflicts of interest to declare.

The Use of Bone Marrow Graft for Hematopoietic Stem Cell Transplantation From Matched Unrelated Donors After Reduced Intensity Conditioning Regimen Improves Survival : Analysis of the Societe Française De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 873-873
Author(s):  
Andrea Toma ◽  
Marie-Lorraine Balère-Appert ◽  
Jean-Michel Boiron ◽  
Pierre Bordigoni ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Multivariate Analysis ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Reduced Intensity Conditioning Regimen ◽  
Unrelated Donors ◽  
Grade Ii

Abstract Abstract 873 The use of peripheral blood stem cells (PBSC) for hematopoietic stem cell transplantation (HSCT) is associated with a higher risk of chronic graft versus host disease (GvHD) but its impact on survival is not clear since it may favor a greater graft versus leukemia (GvL) effect. However, in the context of HSCT from unrelated donors (UD), the balance between GvH and GvL may differ from the context of sibling donors and thus the use of PBSC may be deleterious. In this retrospective study, we analyzed 103 patients from the french registry who received a graft from an UD after a reduced intensity conditioning regimen (RIC) to evaluate the role of various parameters including the source of stem cells on the outcome. Seventy-one D/R pairs (69%) were 10/10 HLA match at the allelic level. Mismatches concerned 5, 6, 15, 2 and 7 D/R pairs for HLA-A, -B, -C, -DRB1 and -DQB1, respectively. The median age was 46 years (18-67). All patients had hematologic malignancies: AL (n=35), MM (n=18), CLL (n=5), NHL (n=11), HD (n=9), CML (n=12), MDS (n=9), and MPS (n=4). 39% of the patients were in an advanced phase of the disease at time of HSCT. The conditioning regimen was Fluda/TBI 2Gys for 26 patients, Bu/Fluda/ATG for 24 patients, Fluda/Melph for 16 patients and others for 37 patients. Overall, anti-thymocytes globulins (ATG) were part of the conditioning regimen for 77% of patients. The source of stem cells was PBSC for 65 patients and bone marrow (BM) for 38 patients. The median follow up of the cohort is 61,3 months (1,2-113,7). The results showed that 95% of patients engrafted. Five patients did not engraft (4 in the BM group and 1 in the PBSC group). Acute GvHD grade II to IV and grade III/IV occurred in 47% and 19% of patients, respectively. The risk of developing chronic GvHD was 49% at 2 years. Overall survival (OS) was 36% at five years. The median disease free survival (DFS) was 55 months among the 36 patients alive. We performed univariate and multivariate analysis of factors susceptible to impact on GvHD and survival. The multivariate analysis included the impact of HLA mismatch, disease status, diagnosis, source of stem cells, patient's and donor's ages. This multivariate analysis performed on the global population shows a trend towards an improved OS with the use of BM instead of PBSC. However, when focusing the multivariate analysis on the 71 patients transplanted with a 10/10 match donor, the most potent factor influencing the outcome is the use of BM which is associated with an improved OS (p=0.03) and DFS (p=0.02), less acute GvHD grade II-IV (p=0.05), or grade III/IV (p=0.05) and less chronic GvHD (p=0.05). These results suggest that the use of BM as the source of stem cells should be reconsidered in the context of matched UD after RIC transplantation. Disclosures: No relevant conflicts of interest to declare.

Prevalence and Patterns of Cytomegalovirus (CMV) Reactivation In Adult Acute Lymphoblastic Leukemia Patients on Chemotherapy: Single Center Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2583-2583
Author(s):  
Seema Gulia ◽  
Manju Sengar ◽  
Uma Dangi ◽  
Hari Menon ◽  
Sanjay Biswas ◽  
...  
Keyword(s):  
Viral Load ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clinical Manifestations ◽  
High Dose ◽  
Cell Transplant ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Laboratory Parameters ◽  
Cmv Reactivation

Abstract Abstract 2583 Background: Management of acute lymphoblastic leukemia (ALL) requires use of immunosuppressive agents like high-dose steroids and antimetabolites for prolonged periods which can predispose these patients for CMV reactivation and disease. As opposed to hematopoietic stem cell transplant there has been a real paucity of literature regarding clinical manifestations and management of CMV reactivation in ALL. In countries like India with a background of high CMV seropositivity (>90%), reactivation is a serious concern in ALL patients while receiving chemotherapy. Timely recognition and treatment can avoid the morbidity and mortality as well as help maintaining dose intensity which is the key to achieve cure in ALL patients. Methods: This retrospective case series included adult ALL patients (>14 years) who were being treated with chemotherapy between July 2009 to July 2011 at a tertiary care centre and detected to have CMV viraemia (Real time quantitative PCR with Roche CMV DNA QuantKit). PCR was done in patients with possibility of CMV infection based on clinical suspicion. Case records were analyzed for demography, chemotherapy details, clinical features, laboratory parameters, viral load, antiviral therapy and response. Results: Among 203 adult ALL patients, 23 (males-18, females-5) were detected to have CMV viremia. Median age was 23 years (range, 16–44 years). Occurrence of CMV reactivation was most common during later part of induction or re-induction phase of therapy which includes high dose of steroids (14/23) followed by maintenance therapy with 6-mercaptopurine and methotrexate (5/23) and high dose cytarabine based treatment (4/23). Presenting features were: fever (19/23), fever alone (2/23) respiratory symptoms (9/23), anorexia (10/23), loose stools (8/23), abdominal pain (7/23) and splenomegaly (1/23). Abnormal laboratory parameters were: leukopenia or thrombocytopenia (14/23), deranged liver function tests (12/23). CT thorax was abnormal in 3 patients. Bacterial and fungal co-infection was seen in 5/23 patients. Median CMV viral load was 3.0 ×103 copy numbers (range, 708–1.38×106). Eighteen of these patients were treated with intravenous gancyclovir for a period of 14 days. In remaining 5 patients abnormal clinical and lab parameters improved either with antibiotic therapy or spontaneously. Median time to fever defervescence was 4 days (range, 2–5 days). Blood counts recovered after median period of 5 days (range 3–9 days). Gancyclovir related neutropenia and transaminitis developed in 1 patient. CMV titre became undetectable after a period of 2–4 weeks. Conclusion: Awareness of diverse clinical manifestations of CMV infection and high index of suspicion is important for timely diagnosis. Early diagnosis and treatment with gancyclovir reduces the morbidity, empirical use of other antimicrobials and avoids delays in administration of chemotherapy. Disclosures: No relevant conflicts of interest to declare.

Expression of SOCS1 and SOCS3 Genes with Human Cytomegalovirus Infection After Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3038-3038
Author(s):  
Tae Hyang Lee ◽  
Ji Yoon Lee ◽  
Sohye Park ◽  
Jae-Ho Yoon ◽  
Seung Hwan Shin ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Myelogenous Leukemia ◽  
Cmv Infection ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Acute Myelogenous ◽  
Cmv Reactivation

Abstract Abstract 3038 Background: After allogeneic hematopoietic stem cell transplantation (HSCT), cytomegalovirus (CMV) infection is highly prevalent in recipients. Although the suppressor of cytokine signaling (SOCS) genes are mainly regarded as pivotal negative feedback regulators for signaling of cytokines, the expression pattern of SOCS genes in CMV infections remains largely unexplored. To understand the molecular mechanism of cytokine cascades associated with CMV infection, we investigated the expression of SOCS genes from various types of hematologic malignancies after allogeneic HSCT. Methods: In the present study, we investigated SOCS1 and SOCS3 gene expressions, in order to examine the feasibility of SOCS genes as a promising therapeutic target as well as a prognostic predictor in CMV infection. A total of 99 recipients with acute myelogenous leukemia (AML; n=64), acute lymphoblastic leukemia (ALL; n=23), myelodysplastic syndrome (MDS; n=12), who received allogeneic HSCT and 55 normal donors were included. Real-time quantitative polymerase chain reaction (RQ-PCR) was used and all sample analyses were performed in triplicate. Results: The expression levels of the SOCS3 gene were clearly decreased in recipients compared to normal donors, including in the Pre-HSCT, Post-HSCT No CMV, and Post-HSCT CMV subgroups (P=0.0007, P=0.0009, and P=0.0014, respectively). Meanwhile, expressions of SOCS1 gene were significantly decreased in the Pre-HSCT, Post-HSCT No CMV, and normal donors, when compared to Post-HSCT CMV subgroup (P=0.026, P=0.0129, and P<0.0001, respectively), suggesting a correlation between expression of SOCS genes and CMV reactivation. In addition, expression of SOCS1 gene was remarkably increased in patients who received allogeneic HSCT with myeloablative conditioning (MAC), compared to reduced-intensity conditioning transplantation (RIST) and normal donors (P=0.0119, P=0.0002, respectively), while, both regimen with MAC and RIST showed a decreasing pattern with statistical significance compared to normal donors (P=0.0037, P=0.0024, respectively). Notably, SOCS1 gene expression in acute lymphoblastic leukemia and myelodysplastic syndrome recipients were higher than acute myelogenous leukemia, when compare to normal donors (P=0.0239). Furthermore, high expression of SOCS1 gene unarguably showed high mortality (P=0.0068). In AML patients, decreased SOCS3 gene was detected (P=0.0007) and overall high expression of SOCS3 gene was displayed high mortality, but there is no statistical significance. Conclusions: We firstly report that the SOCS genes are differently expressed in human CMV infection after allogeneic HSCT, suggesting a correlation between cytokines by modulation of SOCS genes associated with CMV reactivation. This result provides a new platform for studying CMV immunobiology and these genes may be a potential of diagnostic and therapeutic targets in post-allogeneic HSCT associated with CMV infection. Disclosures: No relevant conflicts of interest to declare.

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