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1.
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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2.
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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3.
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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4.
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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5.
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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6.
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.
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7.
Lower dose of ATG combined with basiliximab for haploidentical hematopoietic stem cell transplantation is associated with effective control of GVHD and less CMV viremia
Huang, Z., Yan, H., Teng, Y., Shi, W., Xia, L.
Frontiers in immunology. 2022;13:1017850
Abstract
Currently, the graft-versus-host disease (GVHD) prophylaxis consists of an immunosuppressive therapy mainly based on antithymocyte globulin (ATG) or post-transplant cyclophosphamide (PTCy). GVHD remains a major complication and limitation to successful allogeneic haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We modified the ATG-based GVHD prophylaxis with the addition of basiliximab in the setting of haplo-HSCT and attempted to explore the appropriate dosages. We conducted a retrospective analysis of 239 patients with intermediate- or high-risk hematologic malignancies who received haplo-HSCT with unmanipulated peripheral blood stem cells combined or not with bone marrow. All patients received the same GVHD prophylaxis consisting of the combination of methotrexate, cyclosporine or tacrolimus, mycofenolate-mofetil, and basiliximab with different doses of ATG (5-9mg/kg). With a median time of 11 days (range, 7-40 days), the rate of neutrophil engraftment was 96.65%. The 100-day cumulative incidences (CIs) of grade II-IV and III-IV aGVHD were 15.8 ± 2.5% and 5.0 ± 1.5%, while the 2-year CIs of total cGVHD and extensive cGVHD were 9.8 ± 2.2% and 4.1 ± 1.5%, respectively. The 3-year CIs of treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DFS) were 14.6 ± 2.6%, 28.1 ± 3.4%, 60.9 ± 3.4%, 57.3 ± 3.4%, respectively. Furthermore, the impact of the reduction of the ATG dose to 6 mg/kg or less in combination with basiliximab on GVHD prevention and transplant outcomes among patients was analyzed. Compared to higher dose of ATG(>6mg/kg), lower dose of ATG (≤6mg/kg) was associated with a significant reduced risk of CMV viremia (52.38% vs 79.35%, P<0.001), while the incidences of aGVHD and cGVHD were similar between the two dose levels. No significant effect was found with regard to the risk of relapse, TRM, and OS. ATG combined with basiliximab could prevent GVHD efficiently and safely. The optimal scheme of using this combined regimen of ATG and basiliximab is that administration of lower dose ATG (≤6mg/kg), which seems to be more appropriate for balancing infection control and GVHD prophylaxis.
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8.
Letermovir reduces chronic GVHD risk in calcineurin inhibitor-free GVHD prophylaxis after hematopoietic cell transplantation
Lorentino, F., Xue, E., Mastaglio, S., Giglio, F., Clerici, D., Farina, F., Piemontese, S., Bruno, A., Lazzari, L., Ruggeri, A., et al
Blood advances. 2022
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9.
Evaluation of the pharmacokinetic interaction between letermovir and tacrolimus in allogeneic hematopoietic cell transplant recipients
Marciano, K. A., Seago, K., Dillaman, M., Ross, K. G., Veltri, L., Cumpston, A.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Data describing the magnitude of the pharmacokinetic interaction between letermovir and tacrolimus in allogeneic hematopoietic cell transplant (allo-HCT) recipients are limited, and varying outcomes have been reported. The need for empiric dose adjustment of tacrolimus upon letermovir initiation has not been established; instead, it is suggested to closely monitor tacrolimus trough concentrations and adjust doses as needed. Further understanding of this interaction is imperative to accurately manage the narrow therapeutic window of tacrolimus post-transplant. OBJECTIVES The primary objective of this study was to determine the percent change in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir. Secondary objectives were to describe the frequency of tacrolimus dose adjustments after initiation of letermovir, percent change in daily tacrolimus dose over the 14-day period after initiation of letermovir, and the incidence of both sub- and supratherapeutic tacrolimus trough concentrations. STUDY DESIGN This study was a retrospective chart review that included adult allo-HCT recipients at WVU Medicine who received tacrolimus in combination with oral letermovir and had been taking tacrolimus for at least five days prior to letermovir initiation. Patients receiving strong CYP3A4 inhibitors or intravenous tacrolimus were excluded. RESULTS Thirty-five patients were included in the analysis. The median percent increase in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir was 22% (days 2 to 4), 47% (days 5 to 7), 66% (days 8 to 11), and 81% (days 12 to 14). The mean frequency of tacrolimus dose adjustments was 0.66 (days 2 to 4), 0.69 (days 5 to 7), 1.06 (days 8 to 11), and 0.57 (days 12 to 14). CONCLUSION The pharmacokinetic interaction between tacrolimus and letermovir is substantial based on results from this study and continued to affect tacrolimus concentrations over the 14-day period after letermovir initiation. Close monitoring of tacrolimus trough concentration upon initiation of letermovir should be considered.
PICO Summary
Population
Adults who underwent allogeneic transplant at a single centre in the USA (n=35)
Intervention
Oral letermovir initiated after at least five days of tacrolimus therapy
Comparison
None
Outcome
The median percent increase in tacrolimus concentration-to-dose ratio over the 14-day period after initiation of letermovir was 22% (days 2 to 4), 47% (days 5 to 7), 66% (days 8 to 11), and 81% (days 12 to 14). The mean frequency of tacrolimus dose adjustments was 0.66 (days 2 to 4), 0.69 (days 5 to 7), 1.06 (days 8 to 11), and 0.57 (days 12 to 14).
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10.
Effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease undergoing hematopoietic stem cell transplantation
Chen, X., Wang, D., Lan, J., Wang, G., Zhu, L., Xu, X., Zhai, X., Xu, H., Li, Z.
Annals of translational medicine. 2021;9(18):1477
Abstract
BACKGROUND This study aimed to explore the effects of voriconazole on population pharmacokinetics and optimization of the initial dose of tacrolimus in children with chronic granulomatous disease (CGD) undergoing hematopoietic stem cell transplantation (HSCT). METHODS Thirty-four children with CGD undergoing HSCT were assessed to establish a population pharmacokinetic model (PPM) using the non-linear mixed effect. Tacrolimus concentrations were simulated by the Monte Carlo method in children weighing <25 kg at different doses. RESULTS In the final model, weight and concomitant use of voriconazole were included as covariates. With the same weight, the relative value of tacrolimus clearance was 1:0.388 in children not taking voriconazole: children taking voriconazole. Compared with children not taking voriconazole, the measured tacrolimus concentrations were all higher in children taking voriconazole (P<0.01); however, these were not corrected by dose or body weight for concentration differences. Thus, we simulated the tacrolimus concentrations using different body weights (5-25 kg) and different dose regimens (0.1-0.8 mg/kg/day) for the same body weight and dose. Tacrolimus concentrations in children taking voriconazole were higher than those in children not taking voriconazole (P<0.01). Also, in children with CGD undergoing HSCT who were not taking voriconazole, the initial dose regimen of 0.5 mg/kg/day was recommended for body weights of 5-10 kg, and 0.4 mg/kg/day was recommended for body weights of 10-25 kg. In children with CGD undergoing HSCT who were taking voriconazole, an initial dose regimen of 0.3 mg/kg/day was recommended for body weights of 5-25 kg. CONCLUSIONS We established, for the first time, a PPM of tacrolimus in children with CGD undergoing HSCT in which voriconazole significantly increased tacrolimus concentrations. In addition, the initial dose of tacrolimus in children with CGD undergoing HSCT was recommended.