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Development and validation of a risk assessment tool for BKPyV Replication in Allogeneic Stem cell Transplant Recipients
Abudayyeh, A., Lin, H., Abdelrahim, M., Rondon, G., Andersson, B. S., Martinez, C. S., Page, V. D., Tarrand, J. J., Kontoyiannis, D. P., Marin, D., et al
Transplant infectious disease : an official journal of the Transplantation Society. 2020;:e13395
Abstract
BACKGROUND BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients. METHODS In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups. RESULTS The total risk score was significantly associated with BKPyV replication (P < .0001). At 30 days after transplantation, the low-risk (score ≤ 0) patients had a 9% chance of developing symptomatic BKPyV replication, while the high-risk (score ≥ 8) of the population had 56% of developing BKPyV replication. We validated the risk score using a separate cohort of 1478 patients. The AUC of the ROC of the risk-score-only model was 0.59. Both the total risk score and 3-level risk variable were significantly associated with BKPyV replication in this cohort (P < 0.0001). CONCLUSIONS This grading system for the risk of symptomatic BKPyV replication may help in early monitoring and intervention to prevent BKPyV-associated morbidity, mortality, and kidney-function decline.
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Clinical and Economic Burden of Pre-emptive Therapy of Cytomegalovirus Infection in Hospitalized Allogeneic Hematopoietic Cell Transplant Recipients
El Haddad, L., Ghantoji, S. S., Park, A. K., Batista, M., Schelfhout, J., Hachem, J., Lobo, Y., Jiang, Y., Rondon, G., Champlin, R., et al
Journal of medical virology. 2019
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Abstract
CMV infection remains a major complication after allogeneic hematopoietic cell transplantation (allo-HCT). We conducted a retrospective study to determine the clinical and economic burden of pre-emptive therapy (PET) for CMV infection in 100 consecutive hospitalized adult CMV positive serostatus allo-HCT recipients and compared their hospitalization cost with allo-HCT recipients hospitalized with graft versus host disease without CMV infection (control group) and across 19 US cancer centers for hospitalized patients with CMV infection between 2012- 2015 (Vizient Database). A total of 192 CMV episodes of PET for CMV infection occurred within 1 year post-HCT. PET consisted of ganciclovir (41% of episodes), foscarnet (40%), and valganciclovir (38%) with the longest average length of stay in foscarnet-treated patients (41 days). The average direct cost per patient admitted for PET was $116,976 (range $7,866-$641,841) compared to $12,496 (range $2,004-$43,069) in the control group (p<0.0001). The total direct cost per encounter was significantly higher in patients treated with foscarnet and had nephrotoxicity ($284,006) compared to those who did not ($112,195). The average cost amongst the 19 US cancer centers, including our institution, was $42,327 with major disparities in cost and clinical outcomes. PET for CMV infection is associated with high economic burden in allo-HCT recipients. This article is protected by copyright. All rights reserved.
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HLA-DP mismatch and CMV reactivation increase risk of aGVHD independently in recipients of allogeneic stem cell transplant
Ghobadi, A., Milton, D. R., Gowda, L., Rondon, G., Chemaly, R. F., Hamdi, A., Alousi, A., Afrough, A., Oran, B., Ciurea, S., et al
Current research in translational medicine. 2019
Abstract
HLA-DP mismatched allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with increased risk of aGVHD and decreased risk of relapse with no effects on overall survival (OS). It has been proposed that CMV-reactivation induces expression of HLA-DP molecules on GVHD target tissues by releasing inflammatory cytokines. We hypothesized that the increased GVHD incidence in HLA-DP mismatched allo-SCTs correlates with recipient CMV serostatus or CMV reactivation. In addition, CMV reactivation is associated with increased risk of GVHD with an unknown mechanism. Here, we analyzed the association between HLA-DPB1 and CMV reactivation on cumulative incidence of aGVHD and relapse as well as OS in 613 patients with AML and MDS who underwent matched related or unrelated allo-HCT at MD Anderson Cancer Center from 2005 to 2011. In multivariable analysis, HLA-DPB1 mismatching was associated with increased risk of aGVHD (hazard ratio (HR): 1.53, P < 0.001) independent of CMV serostatus and CMV reactivation. Additionally, HLA-DPB1 mismatching was associated with decreased risk of relapse and no effect on OS. CMV reactivation increased risks of aGVHD (HR: 5.82, P < 0.001) independent of HLA-DP mismatching with no effect on relapse or OS. In conclusion, our data suggests that HLA-DPB1 mismatching and CMV reactivation increase risk of aGVHD independently.
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Donor NKG2C Copy Number: An Independent Predictor for CMV Reactivation After Double Cord Blood Transplantation
Cao, K., Marin, D., Sekine, T., Rondon, G., Zhao, W., Smith, N. T., Daher, M., Wang, Q., Li, L., Saliba, R. M., et al
Frontiers in immunology. 2018;9:2444
Abstract
Cytomegalovirus (CMV) remains a major cause of morbidity following allogeneic hematopoietic stem cell transplant. Natural killer cells expressing NKG2C have been shown to play a role in the immune surveillance of human CMV. We studied NKG2C copy number in the donor graft and the risk of CMV reactivation after double umbilical cord blood transplantation (DUCBT) in 100 CMV seropositive DUCBT recipients and their corresponding cord blood (CB) grafts (n = 200). In the setting of DUCBT, the combined graft may contain 0-4 functional copies of NKG2C gene. Sixteen patients received a combined graft with 1 or 2 NKG2C copies and 84 patients were recipients of a combined graft with 3 or 4 NKG2C copies. The 6-month cumulative incidence of CMV reactivation for the two groups was 93.7 and 58.4%, respectively (p = 0.0003). In multivariate analysis, low NKG2C copies in the graft was an independent predictor of CMV reactivation (HR = 2.72, CI = 1.59-4.64; p < 0.0001). Our study points to an important role for donor NKG2C for protection against CMV reactivation after DUCBT. These novel findings may help identify patients at a higher risk of CMV reactivation after DUCBT. Donor NKG2C genotype may be used as a potential criterion in the algorithm for graft selection for DUCBT.
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Pulmonary impairment following respiratory viral infections is associated with high mortality in allogeneic hematopoietic cell transplant recipients
Sheshadri, A., Chemaly, R. F., Alousi, A. M., Shah, P. K., Rondon, G., Bashoura, L., Kmeid, J., Azzi, J., Blanco, D. W., Kaous, M., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Abstract
INTRODUCTION Pulmonary impairment predicts increased mortality in many settings, and respiratory viral infection (RVI) causes considerable morbidity and mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT). We hypothesized that pulmonary impairment following respiratory viral infection, defined as a decline of forced expiratory volume in 1 second values by ≥10%, may identify allo-HCT recipients at high risk for mortality. METHODS We studied all allo-HCT recipients at our institution who had RVI with respiratory syncytial virus, parainfluenza virus, or influenza from 2004-2013 and had pre-RVI and post-RVI pulmonary function tests. We used competing risk regression models to identify risk factors for 2-year non-relapse mortality (NRM) as the primary outcome after RVI and relapse-related mortality as a competing risk. RESULTS From 223 eligible patients, pulmonary impairment following RVI was associated with over a 3-fold increase in 2-year NRM (pulmonary impairment: 25.3%; no impairment: 7.4%, univariate sub-hazard ratio [SHR] 3.9, 95% confidence interval [CI] 1.9-8.1, p<0.001). After adjusting for age and systemic steroid use, pulmonary impairment following RVI was still associated with increased 2-year NRM (SHR, 3.3 [95% CI, 1.6-6.9]; p=0.002). After adjustment for race and GVHD prophylaxis, chronic GVHD at the time of RVI (OR, 2.8 [95% CI, 1.4-5.4]; p=0.003) and lymphopenia (OR, 2.2 [95% CI, 1.1-4.2]; p=0.02) were associated with increased odds of pulmonary impairment, whereas use of non-myeloablative conditioning was associated with reduced odds of pulmonary impairment (OR, 0.4 [95% CI, 0.2-0.8]; p=0.006). CONCLUSION In allo-HCT recipients with RVIs, pulmonary impairment following RVI is associated with high NRM at 2 years.
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Poor immune reconstitution is associated with symptomatic BK polyomavirus viruria in allogeneic stem cell transplant recipients
Abudayyeh, A., Hamdi, A., Abdelrahim, M., Lin, H., Page, V. D., Rondon, G., Andersson, B. S., Afrough, A., Martinez, C. S., Tarrand, J. J., et al
Transplant Infectious Disease. 2017;19(1)
Abstract
BACKGROUND BK polyomavirus (BKPyV) infections are known indicators of immune suppression in hematopoietic stem cell transplant (HSCT) recipients; they can lead to hemorrhagic cystitis, ureteral stenosis, renal dysfunction, and prolonged hospital stays. In this study, we determined transplant-associated variables and immune parameters that can predict for the risk of BKPyV viruria. We hypothesized that BKPyV infection is a marker of poor immune recovery. METHODS We analyzed all engrafted patients undergoing first allogeneic HSCT at MD Anderson Cancer Center in Houston between January 2004 and December 2012. We evaluated their immune parameters and their transplant-associated factors. BKPyV positivity was defined as BKPyV detection in urine by polymerase chain reaction testing. Cox proportional hazards model, as well as competing risk analysis method using subdistribution hazard models with death as competing risk, were applied to assess risk of BKPyV viruria. RESULTS We identified a total of 2477 patients with a median age of 52 years. BKPyV viruria was manifest in 25% (n=629) of the patients. The median time from transplantation to BKPyV viruria development was 42 days among the patients who had BKPyV viruria. On multivariate analysis, tumor type, acute GVHD, chronic GVHD, myeloablative conditioning regimen, cord blood as the graft source, CD3+, CD4+, CD8+, CD56+, NK counts, and low platelet count were shown to be significantly associated with BKPyV infection. These finding were further confirmed when models incorporating the competing risk of death yielded similar findings. CONCLUSION In this study, we report significant associations between BKPyV reactivation following allogeneic HSCT and suppressed immune variables. In addition, this study provides valuable information on the immune status of HSCT recipients as a predictor of BKPyV infections that may in turn help us formulate plans for more effective prevention and treatment of this infection.
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Prevention of Cytomegalovirus Reactivation in Haploidentical Stem Cell Transplantation
Hammerstrom, A. E., Lombardi, L. R., Pingali, S. R., Rondon, G., Chen, J., Milton, D. R., Chemaly, R. F., Champlin, R. E., Gulbis, A., Ciurea, S. O.
Biology of Blood & Marrow Transplantation. 2017
Abstract
Cytomegalovirus (CMV) infection can increase the morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Because of a higher degree of immunosuppression, haploidentical transplant recipients may be at an increased risk of viral infections, particularly CMV. We retrospectively analyzed 86 haploidentical HCT recipients at our institution to determine whether a more intensified antiviral strategy would reduce the incidence of CMV reactivation compared with a traditional antiviral prophylaxis regimen. According to practice changes over time in antiviral prophylaxis at our institution, patients were divided into the following 3 groups: hybrid (n=15), traditional (n=26), and intermediate dose (n=45). The hybrid group received valganciclovir from admission to day -2 followed by standard-dose valacyclovir. The traditional group received standard-dose valacyclovir starting on day -1. The intermediate-dose group received ganciclovir from admission through day -2, followed by intermediate-dose valacyclovir. The hybrid and intermediate-dose groups were combined into an intensified group for further analysis. We found the cumulative incidence (CI) of CMV reactivation within 100 days post-HCT was higher for patients receiving the traditional strategy compared with the hybrid and intermediate-dose strategy groups (81% versus 53% versus 71%, respectively; P=.08) and was significantly higher when the traditional group was compared against the intensified group (81% versus 67%, respectively; P=.032). Median time to CMV reactivation was also shorter in the traditional group versus the intensified group (31 versus 41 days, respectively). Moreover, the CI of CMV disease by day 100 was significantly worse for patients receiving the traditional prophylaxis strategy among the 3 groups (8% traditional versus 0% hybrid versus 0% intermediate dose; P=.032). Renal toxicity did not differ between the traditional and intensified group. In conclusion, an intensified approach to prevention of CMV reactivation was associated with lower incidence of CMV reactivation and less CMV disease without increased toxicity. Because the most benefit was observed in the intensified group, further studies are needed to assess which antiviral intervention is the most beneficial on lowering the rates of CMV viremia and disease. Copyright © 2017. Published by Elsevier Inc.
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The impact of pre-transplant valganciclovir on early cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation
Wilhelm, K., Chemaly, R., Saliba, R., Gulbis, A., Saunders, I., Cool, R., Ferguson, J., Westmoreland, M., Rondon, G., Kebriaei, P.
Journal of Oncology Pharmacy Practice. 2014;20(4):257-62
Abstract
Cytomegalovirus reactivation is a common complication of allogeneic hematopoietic stem cell transplant. The use of pre-transplant valganciclovir during the conditioning regimen followed by preemptive therapy has been used in an attempt to reduce the rate of early cytomegalovirus reactivation, but efficacy data are lacking. In this retrospective study, we evaluated the impact of pre-transplant valganciclovir during the conditioning regimen followed by a preemptive approach on the rate of early cytomegalovirus reactivation through day 100. The rate of cytomegalovirus reactivation through day 100 was 41% in the no-valganciclovir group compared to 46% in the valganciclovir group (p=0.4). Interestingly, median time to cytomegalovirus reactivation was earlier in the no-valganciclovir group compared to the valganciclovir group (26 vs. 34 days; p=0.008) and there was a trend toward a higher rate of cytomegalovirus disease through day 100 in the no-valganciclovir group (0.7% valganciclovir vs. 4% no-valganciclovir; p=0.1). Day 100 survival was similar between the groups (90% valganciclovir vs. 91% no-valganciclovir; p=0.8). Although the time to cytomegalovirus reactivation is significantly longer in the valganciclovir group, this did not impact the rate of cytomegalovirus reactivation or survival by day 100 suggesting that other strategies need to be explored. Copyright © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.