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1.
Cmv reactivations in allogeneic hematopoietic stem cell transplant from hla-matched and haploidentical donors with post-transplant cyclophosphamide
Chorão, P., Henriques, M., Villalba, M., Montoro, J., Balaguer-Roselló, A., González, E. M., Gómez, M. D., Gómez, I., Solves, P., Santiago, M., et al
Transplantation and cellular therapy. 2024
Abstract
BACKGROUND Cytomegalovirus (CMV) reactivations cause significant morbidity in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Graft-versus-host disease prophylaxis (GVHD) with post-transplant cyclophosphamide (PTCy) is associated with an increased risk of CMV infections, with limited data on HSCT with PTCy assessing together matched sibling donors (MSD), matched unrelated donors (MUD), and haploidentical donors (HAPLO). OBJECTIVES Characterize CMV reactivation and recurrences, in patients with hematologic malignancies undergoing HSCT from MSD, MUD, and HAPLO using PTCy as GVHD prophylaxis in the pre-letermovir era. Analyze risk factors of CMV reactivations, including GVHD as a time-dependent variable, on the incidence and mortality associated with CMV infections. STUDY DESIGN We analyzed CMV reactivations in patients undergoing HSCT from 160 MSD, 124 MUD and 82 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type. RESULTS Overall, 46% of patients had at least one CMV reactivation. The 1-year cumulative incidence of CMV infection was 39% for MSD, 44% for MUD, and 62% for HAPLO donors (p<0.001), with 96% of reactivations occurring before day +100. Multivariate analysis identified factors associated with the first CMV reactivation, including HAPLO donor, positive recipient CMV serology, older patient age, and grade II-IV acute GVHD. The 1-year cumulative incidence of second reactivation from HSCT was 13%. Recipient CMV seropositivity, older patient age and grade II-IV acute GVHD remained the adverse factors for second CMV reactivation in multivariate analysis, but not type of donor. The 1-year cumulative incidence of third reactivation from HSCT was 4.4%. Ten cases of CMV disease were recorded, with no attributable deaths. Nevertheless, the hazard for NRM was superior for patients who had a CMV reactivation in multivariate time-dependent Cox-model analysis. CONCLUSIONS CMV reactivation is frequent in HSCT with PTCy among patients not receiving letermovir prophylaxis. Identified risk factors include the use of HAPLO donor, recipient CMV seropositivity, and acute grade II-IV GVHD. The prevalence of recurrent CMV reactivations pose a noteworthy issue, especially after acute GVHD, warranting trials for secondary prophylaxis strategies.
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2.
Donor aKIR genes influence the risk of EBV and CMV reactivation after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation
Gao, F., Shi, Z., Shi, J., Luo, Y., Yu, J., Fu, H., Lai, X., Liu, L., Yuan, Z., Zheng, Z., et al
Hla. 2023
Abstract
Hematopoietic stem cell transplantation (HSCT) offers the highest curative potential for patients with hematological malignancies. Complications including infection, graft-versus-host disease (GVHD), and relapse reflect delayed or dysregulated immune reconstitution. After transplantation, NK cells rapidly reconstitute and are crucial for immune surveillance and immune tolerance. NK cell function is tightly regulated by killer immunoglobin-like receptors (KIRs). Previous studies have revealed that donor KIRs, especially some activated KIRs (aKIRs) are closely related to transplant outcomes. Here, we performed a retrospective study, including 323 patients who received haploidentical (haplo) HSCT in our center. In univariate analysis, donor KIR2DS1, KIR2DS3 and KIR3DS1 gene protected patients with lymphoid disease from Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation, while donor KIR2DS1, KIR2DS5 and KIR3DS1 gene conferred a higher risk of CMV reactivation for patients with myeloid disease. Multivariate analysis confirmed that donor telomeric (Tel) B/x and KIR2DS3 gene best protected patients with lymphoid disease from EBV (p = 0.017) and CMV reactivation (p = 0.004). In myeloid disease, grafts lacking Tel B/x and KIR2DS5 gene correlated with the lowest risk of CMV reactivation (p = 0.018). Besides, donor aKIR genes did not influence the rates of GVHD, relapse, non-relapse mortality (NRM) and overall survival (OS) in this study. The reactivation of EBV and CMV was associated with poor prognosis of haplo-HSCT. In conclusion, we found that donor aKIR genes might have a synergistic effect on CMV and EBV reactivation after haplo-HSCT. Whether the influence of donor aKIR genes varies with disease types remained to be studied.
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3.
Evaluating the Impact of Post-Transplant Cyclophosphamide and Anti-Thymocyte Globulin on CMV Reactivation Following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Literature Review
Dybko, J., Giordano, U., Pilch, J., Mizera, J., Borkowski, A., Dereń-Wagemann, I.
Journal of clinical medicine. 2023;12(24)
Abstract
Anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) are two frequently utilised strategies in graft-versus-host disease (GvHD) prophylaxis following allogeneic hematopoietic cell transplantation (allo-HCT), currently approved for different recipient-donor settings. In addition, being efficacious in preventing GvHD owing to their T-cell depleting capacity, the employment of these two agents increases the risk of infections, including CMV reactivation, which stands as one of the most common and serious infections following allo-HCT. We performed a systematic literature review of articles published until 1 September 2023, through PubMed, MEDLINE, and Scopus, with the main endpoint being CMV reactivation after PTCy or ATG allo-HCT. The majority of the studies included in the analysis provide supporting evidence for a reduced risk of CMV reactivations following the use of PTCy compared to ATG, although not all findings reached statistical significance. Additionally, it appears that utilising a haploidentical donor leads to a higher incidence of CMV infections and clinically significant CMV infections (CS-CMVis) compared to other donor settings in PTCy allo-HCT. This study aims to compare the risk of CMV infections following allo-HCT in patients who have received either ATG or PTCy as GvHD prophylaxis and discuss other factors that could influence the infectious outcomes of patients who have undergone allo-HCT.
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4.
Dynamics of polyclonal immuno-reconstitution after allogeneic transplant with post-transplant cyclophosphamide and letermovir
Orofino, G., Xue, E., Doglio, M., Noviello, M., Tassi, E., Cristante, M., Acerbis, A., Clerici, D., Farina, F., Campodonico, E., et al
Bone marrow transplantation. 2023
Abstract
Cytomegalovirus (CMV) reactivations are strong stimulators of immune-reconstitution (IR) in hematopoietic stem cell transplantation (HSCT) recipients. Herein, we analyzed 317 CMV-seropositive consecutive patients (n = 109 letermovir, LTV; n = 208 no-LTV), undergoing HSCT with post-transplant cyclophosphamide (PTCy) and calcineurin inhibitor- (CNI) free graft-versus-host-disease (GvHD) prophylaxis. At day+90, median CD19(+)/mm(3) was higher in LTV-cohort: 5.5 [0;439] versus 2 [0;294], p = 0.008; median CD3+/mm(3) counts were lower in LTV-cohort, with no differences in CD4(+), CD8(+) and NK-cells. At day+180 median CD3(+), CD4(+) and CD8(+)/mm(3) values were comparable between groups. Higher CD19(+)/mm(3) counts were observed in LTV-cohort: 62 [0; 2983] versus 42 [0; 863]. Significantly higher median NK/mm(3) values were seen in LTV-cohort: 225.5 [0;763] versus 163.5 [0;1181], p = 0.0003. The impact of LTV on B-cell IR at 3 months and NK-cell levels at 6 months was retained in multivariate analysis (p < 0.01), whereas the effect on T-cells was not confirmed. Moreover, we confirmed a significant reduction of clinically-relevant CMV, and moderate-to- severe chronic GvHD in LTV-cohort. Overall, in our study the use of LTV was associated with a slight improvement of B-cell and NK-cells reconstitution, with only minor impact on T-cell subsets, giving new insights on polyclonal IR for HSCT recipients in the LTV era.
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5.
Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis
Shinogi, Y., Hirai, T., Ishibashi, M., Ino, K., Tawara, I., Iwamoto, T.
Pharmacology research & perspectives. 2023;11(4):e01120
Abstract
Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co-administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2-2721.0] ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co-administered with azole antifungals (n = 30, 1285.5 [662.7-2506.7] ng/mL/mg/kg vs. 547.1 [245.3-1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2-1573.3] ng/mL/mg/kg vs. 616.1 [350.6-979.8] ng/mL/mg/kg, p = .125). For patients co-administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7-2506.7] ng/mL/mg/kg vs. 529.9 [245.3-1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.
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6.
Impact of carbapenem antibiotics on mycophenolate mofetil in hematopoietic stem cell transplant patients with interruption of the enterohepatic recycling: a retrospective study
Tian, J. X., Miao, W. J., Yan, H. H., Wang, X. D., Liao, Y. X., Li, S., Jiang, E. L., Zhang, P.
Annals of translational medicine. 2023;11(2):82
Abstract
BACKGROUND Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is widely used in the prophylaxis for graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation (HSCT). MPA undergoes enterohepatic recycling (EHR). Oral antibiotics can affect MPA concentration by reducing intestinal flora-mediated EHR. However, the effect of intravenous antibiotics on MPA concentration is not clear, especially in patients whose EHR is already interrupted. This study was conducted to determine whether intravenous carbapenem antibiotics (CBP) influence the pre-dose plasma concentration (C(0)) of MPA in HSCT patients when the EHR of MPA is interrupted by cyclosporine and gut decontamination. METHODS The HSCT patients who received immunosuppressive therapy with MMF and cyclosporine, as well as treatment with CBP were screened as potential candidates. Patients who lacked MPA C(0) measurements before or during CBP use, had combination therapy of rifampin with MMF, or switched from IV to oral MMF were excluded. The liver/renal function, demographic information, albumin/cyclosporine concentration, MPA C(0) and medication information were collected. The changes in the MPA C(0) before and during CBP use were evaluated, and the influence of related clinical factors was also estimated. RESULTS CBP resulted in a significant reduction in the MPA C(0) from 0.65±0.33 to 0.43±0.30 µg/mL. Linear regression analysis indicated a weak correlation between the dose-normalized C(0) of MPA and the dosage of CBP during CBP use (r(2)=0.129, P=0.009). Univariate and multivariate analysis confirmed that the MPA C(0) had no relevance to rifaximin administration (P=0.249-0.700), demographics (P=0.118-0.599), fluctuation of plasma albumin (ALB, P=0.943 and 0.609) and cyclosporine concentrations (P=0.647 and 0.112), or liver and renal functions (P=0.078-0.887) no matter whether the CBP were used. However, compared with the non-gut decontamination group, larger interindividual variabilities and smaller decreases in MPA C(0) (6.60% vs. 41.73%) during CBP therapy were seen in the gut decontamination group, although it was a nonsignificant trend. CONCLUSIONS CBP decreased the MPA C(0) in Chinese HSCT patients even when MMF is used in combination with cyclosporine and rifaximin. If antibiotics must be used, and CBP in particular, therapeutic drug monitoring should be performed to ensure adequate exposure.
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7.
Patterns of CMV Infection After Letermovir Withdrawal in Recipients of Post-Transplant Cyclophosphamide Based Transplant
Lin, A., Brown, S., Chinapen, S., Lee, Y. J., Seo, S. K., Ponce, D. M., Shahid, Z., Giralt, S. A., Papanicolaou, G. A., Perales, M. A., et al
Blood advances. 2023
Abstract
Reactivation of latent cytomegalovirus (CMV) is increased in CMV seropositive (CMV+) recipients of allogeneic hematopoietic cell transplantation (allo HCT) using post-transplant cyclophosphamide (PT-Cy) based graft versus host disease prophylaxis. Letermovir, a novel DNA terminase complex inhibitor, reduces the incidence of clinically significant CMV infection (csCMVi) in this population; however, parameters that predict csCMVi after letermovir withdrawal are not well described. Here, we examined clinical and immunological parameters in 294 recipients of PT-Cy based allo HCT, including 157 CMV+ patients of whom 80 completed letermovir prophylaxis without csCMVi, and subsequently stopped letermovir. In this population, the median duration of letermovir exposure was 203 days (interquartile range (IQR): 160 - 250 days). After letermovir withdrawal, the 90-day cumulative incidence of csCMVi was 23.0% (14.3 - 32.8). There were no episodes of CMV end-organ disease. Hypo-gammaglobulinemia prior to letermovir discontinuation was predictive of csCMVi (hazard ratio: 0.33, 95% confidence interval: 0.12-0.93, p = 0.03), whereas T-cell and B-cell reconstitution prior to letermovir withdrawal were not predictive of csCMVi. Higher numbers of NK cells were found prior to letermovir withdrawal in patients that experienced csCMVi (median 202 versus 160, p = 0.03). In CMV+ recipients, CD3+CD4-CD8+ T-cell reconstitution was faster in CMV+ patients regardless of letermovir exposure. Taken together, these data suggest that csCMVi after letermovir withdrawal was frequent in patients treated with PT-Cy, despite prolonged exposure. Strategies to boost CMV specific adaptive immunity in patients with persistent hypo-gammaglobulinemia is a logical pathway to reduce csCMVi after letermovir withdrawal.
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8.
Impact of GVHD prophylaxis on CMV reactivation and disease after HLA-matched peripheral blood stem cell transplantation
Ueda Oshima, M., Xie, H., Zamora, D., Flowers, M. E., Hill, G. R., Mielcarek, M., Sandmaier, B. M., Gooley, T. A., Boeckh, M. J.
Blood advances. 2023
Abstract
The kinetics of early and late CMV reactivation after hematopoietic cell transplantation using various methods of graft-versus-host-disease (GVHD) prophylaxis are poorly defined. We retrospectively compared CMV reactivation and disease among 780 seropositive patients given HLA-matched peripheral blood stem cell (PBSC) grafts and calcineurin-inhibitor plus post-transplantation cyclophosphamide (PTCy; n=44), mycophenolate mofetil (MMF; n=414) or methotrexate (MTX; n=322). Transplantation occurred between 2007-2018; CMV-monitoring/management followed uniform standard practice. Hazards of CMV reactivation at various thresholds were compared. Spline curves were fit over average daily viral load, and areas under the curve (AUC) within one-year were calculated. PTCy and MMF were associated with an increased risk of early (day 100) CMV reactivation ≥250 IU/mL after multivariable adjustment (PTCy vs. MTX: HR=1.64; 95% CI: 1.03-2.61; p=0.039; MMF vs. MTX: HR=1.50; 95% CI: 0.97-2.32; p=0.067). The viral load AUC at one-year was highest with MMF (mean difference 0.125 units vs. MTX; 95% CI 0.061-0.189; p<.001) and similar between PTCy vs. MTX (mean difference 0.016 units vs. MTX group; 95% CI, -0.126-0.158, p=0.827). CMV disease risk was similar across groups. There was no interaction between GVHD prophylaxis and CMV reactivation on chronic GVHD risk. Despite PTCy-associated increased risk of early CMV reactivation, the CMV disease risk by 1 year was low in HLA-matched PBSC transplant recipients. In contrast, MMF was associated with higher overall CMV viral burden in the 1-year posttransplant. While different mechanisms of immunosuppressive agents may impact CMV reactivation risk, effective prevention of GVHD may reduce corticosteroid exposure and mitigate infection risk over time.
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9.
Post-transplantation cyclophosphamide is associated with increased bacterial infections
Ustun, C., Chen, M., Kim, S., Auletta, J. J., Batista, M. V., Battiwalla, M., Cerny, J., Gowda, L., Hill, J. A., Liu, H., et al
Bone marrow transplantation. 2023
Abstract
Post-transplant cyclophosphamide (PTCy) is increasingly used to reduce graft-versus-host disease after hematopoietic cell transplantation (HCT); however, it might be associated with more infections. All patients who were ≥2 years old, receiving haploidentical or matched sibling donor (Sib) HCT for acute leukemias or myelodysplastic syndrome, and either calcineurin inhibitor (CNI)- or PTCy-based GVHD prophylaxis [Haploidentical HCT with PTCy (HaploCy), 757; Sibling with PTCy (SibCy), 403; Sibling with CNI-based (SibCNI), 1605] were included. Most bacterial infections occurred within the first 100 days; 953 patients (34.5%) had at least 1 infection and 352 patients (13%) had ≥2 infections. Patients receiving PTCy had a greater incidence of bacterial infections by day 180 [HaploCy 46%; SibCy 48%; SibCNI 35%; p < 0.001]. Compared with the SibCNI without infection cohort, 1.99-fold, 3.33-fold, 2.78-fold, and 2.53-fold increased TRM was seen for the HaploCy cohort without infection and HaploCy, SibCy, and SibCNI cohorts with infection, respectively. Bacterial infections increased mortality [HaploCy (HR1.84, 99% CI: 1.45-2.33, p < 0.0001), SibCy cohort (HR,1.68, 99% CI: 1.30-2.19, p < 0.0001), and SibCNI cohort (HR,1.76, 99% CI: 1.43-2.16, p < 0.0001). PTCy was associated with increased bacterial infections regardless of donor, and bacterial infections were associated with increased mortality irrespective of GVHD prophylaxis. Patients receiving PTCy should be monitored carefully for bacterial infections following PTCy.
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10.
Bacterial Bloodstream Infections in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide
Salas, M. Q., Charry, P., Alcalde, P. P., Cibrian, N. M., Solano, M. T., Serrahima, A., Nomdedeu, M., Cid, J., Lozano, M., Chumbinta, M., et al
Transplantation and cellular therapy. 2022
Abstract
This study investigates the incidence and predictors for bacterial bloodstream infection (BSI) in 330 adults undergoing allo-HCT, and explores the effect of PTCY on the probability of presenting this complication. All patients received levofloxacin during the aplastic phase. Only the first episode of BSI was accounted as an event. Patients were classified into two groups: PTCY-based (n=200) vs. other prophylaxis (n=130). 124 patients were diagnosed with a first episode of BSI, most of them during the first 30 days (70.2%). Proportions of BSIs caused by Gram-positive bacteria were comparable to those caused by Gram-negative bacteria (48.3% vs. 45.9%). The cumulative incidence of BSI was higher in patients receiving PTCY than in those receiving other prophylaxis (Day +30 and +100: 35.0% and 37.0% vs. 13.1% and 18.5%, P<0.001). At day +30, the likelihood of BSI was 2.41 (P=0.012) times higher in the PTCY's than in the non-PTCY's group. The day 30 mortality rate in all patients with BSI was 8.0%, lower (P=0.002) in the PTCY's group (2.3%) than in the non-PTCY's one (21.6%). Finally, the overall survival of patients receiving PTCY and diagnosed with BSI was similar to that of patients without presenting this complication.