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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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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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3.
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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4.
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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5.
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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6.
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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7.
Impact of CMV reactivation on relapse of acute myeloid leukemia after HCT is dependent on disease stage and ATG
Turki, A. T., Tsachakis-Mück, N., Leserer, S., Crivello, P., Liebregts, T., Betke, L., Alashkar, F., Leimkühler, N. B., Trilling, M., Fleischhauer, K., et al
Blood advances. 2021
Abstract
Cytomegalovirus (CMV) reactivation is a frequent complication after allogeneic hematopoietic cell transplantation (HCT), whose impact on clinical outcome, in particular on leukemic relapse is controversial. We retrospectively analyzed 687 HCT recipients with acute myeloid leukemia (AML) and ciclosporin-based immunosuppression to better understand the differential impact of CMV on transplant outcomes depending on AML disease stage and in-vivo T-cell depletion with anti-thymocyte globulin (ATG). Without ATG, CMV reactivation associated with significantly reduced relapse, yet its effect was more pronounced for advanced disease AML (p=0.0002) than for patients in first complete remission (CR1, p=0.0169). Depending on the disease stage, ATG exposure abrogated relapse protection following CMV reactivation in advanced stages (p=0.796), while it inverted its effect into increased relapse for CR1 patients (p=0.0428). CMV reactivation was associated with significantly increased non-relapse mortality in CR1 patients without ATG (p=0.0187), but not in those with advanced disease and ATG. Following CMV reactivation, only patients with advanced disease had significantly higher event-free survival rates as compared to patients without CMV. Overall, our data suggest that both ATG and disease stage modulate the impact of post-HCT CMV reactivation in opposite directions, revealing a level of complexity that warrants future studies regarding the interplay between anti-virus and anti-tumor immunity.
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8.
Post-Transplant Cyclophosphamide (PTCy) is Associated with Increased Cytomegalovirus Infection: A CIBMTR Analysis
Goldsmith, S. R., Abid, M. B., Auletta, J. J., Bashey, A., Beitinjaneh, A., Castillo, P., Chemaly, R. F., Chen, M., Ciurea, S. O., Dandoy, C. E., et al
Blood. 2021
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Editor's Choice
Abstract
Prior studies suggest increased CMV infection following haploidentical donor transplantation with post-transplant cyclophosphamide (HaploCy). The role of allograft source and PTCy in CMV infection and disease is unclear. We analyzed the effect of graft source and PTCy on incidence of CMV infection as well as transplant outcomes as it relates to CMV serostatus and occurrence of CMV infection by d180. We examined patients reported to CIBMTR between 2012-2017 who had received HaploCy (n = 757), Sib with PTCy (SibCy, n=403), or Sib with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605) for AML/ALL/MDS. Cumulative incidences of CMV infection by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26), respectively [p<0.001]. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3 (14.4 - 175.2); SibCy (n=279): HR 47.7 (13.3 - 171.4); SibCNI (n=1065): HR 24.4 (7.2 - 83.1); p<0.001]. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD (p=0.006). PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy. This study supports aggressive prevention strategies in all patients receiving PTCy.
PICO Summary
Population
Patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or myelodysplastic synrome (n=2765)
Intervention
Haploidentical transplantation with post-transplant cyclophosphamide (HaploCy, n=757),
Comparison
Sibling donor with post-transplant cyclophosphamide (SibCy, n=403), or Sibling donor with calcineurin inhibitor-based prophylaxis (SibCNI, n=1605)
Outcome
Cumulative incidences of CMV infection by day 180 were 42% (HaploCy), 37% (SibCy), and 23% (SibCNI), respectively. CMV end-organ disease was statistically comparable. CMV infection risk was highest for CMV-Seropositive recipients (R+), but significantly higher in PTCy recipients regardless of donor [HaploCy (n=545): HR 50.3; SibCy (n=279): HR 47.7; SibCNI (n=1065): HR 24.4. D+/R- patients also had increased risk for CMV infection. Among seropositive recipients or those developing CMV infection, HaploCy had worse OS and NRM. Relapse was unaffected by CMV infection or serostatus. PTCy was associated with lower chronic GVHD overall, but CMV infection in PTCy recipients was associated with higher cGVHD. PTCy, regardless of donor, is associated with higher incidence of CMV infection, augmenting the risk of seropositivity. Additionally CMV infection may negate the cGVHD protection of PTCy.
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Post-Transplant cyclophosphamide is associated with increase in Non-CMV Herpesvirus infections in Acute leukemia and MDS patients
Singh, A., Dandoy, C. E., Chen, M., Kim, S., Mulroney, C. M., Kharfan-Dabaja, M. A., Ganguly, S., Maziarz, R. T., Kanakry, C. G., Kanakry, J. A., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND There is increasing use of post-transplant cyclophosphamide (PTCy) for GVHD prophylaxis for both haploidentical and fully matched transplants. Published studies have reported an increased incidence of CMV infection with the use of PTCy. Limited data exist regarding the incidence and outcomes of infection with non-CMV herpes viruses (NCHV) in this setting. OBJECTIVE The aim of this study was to evaluate the cumulative incidence of NCHV infections and the association of NCHV infections with transplant-specific outcomes in patients receiving haploidentical transplant with PTCy(HaploCy), matched sibling donor transplant with PTCy (SibCy) or matched sibling donor transplant with calcineurin inhibitor based prophylaxis (SibCNI). We hypothesized that, like CMV infection, patients receiving haploidentical transplant with PTCy will have higher risk of NCHV infections. STUDY DESIGN Using the CIBMTR database, we analyzed patients (HaploCy, n=757; SibCNI, n=1605; SibCy, n=403) receiving first hematopoietic stem-cell transplant between 2012 and 2017 for acute myeloid leukemia, acute lymphoblastic leukemia and myelodysplastic syndrome. RESULTS The cumulative incidence of non-CMV herpes virus infection at six months post-transplant in the HaploCy, SibCy and SibCNI were 13.9% (99%CI=10.8-17.3%), 10.7% (99%CI=7.1-15%), and 5.7% (99%CI=4.3-7.3%), p<0.001 respectively. This was primarily due to a higher frequency of HHV-6 viremia reported in patients receiving PTCy. Incidence of Epstein-Barr viremia was low in all groups and no cases of post-transplant lymphoproliferative disorder were seen in PTCy groups. The incidence of non-CMV herpes virus organ disease was low in all three cohorts. Development of NCHV infection was associated with increased treatment-related mortality, particularly in the HaploCy group. There was no association with the development of GVHD, relapse, and disease-free survival. Patients in PTCy cohorts who did not develop non-CMV herpes virus infection had lower rates of cGVHD. CONCLUSIONS This study demonstrates that the use of PTCy is associated with increased risk of NCHV infection. Development of NCHV infection is associated with increased non-relapse mortality, especially in HaploCY group. Prospective trials should consider viral surveillance strategies in conjunction with assessment of immune reconstitution for better understanding of the clinical relevance of viral reactivation in different transplant settings.
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10.
Comparative study of mizoribine and mycophenolate mofetil combined with a calcineurin inhibitor-based immunosuppressive regimen in patients with alternative donor hematopoietic cell transplantation: Mizoribine vs mycophenolate mofetil for hematopoietic cell transplantation
Huang, Y., Han, M., Yang, D., Zhang, R., Ma, Q., Pang, A., Zhai, W., He, Y., Wei, J., Jiang, E., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
BACKGROUND AND OBJECTIVE Cytomegalovirus (CMV) infection and graft versus host disease (GvHD) remain the major causes of nonrelapse mortality (NRM) in patients following alternative donor HCT. Mizoribine (MZR) showed an anti-CMV effect in addition to its immunosuppressive effect in patients with renal transplantation. In this study, we aimed to evaluate the efficacy and safety of MZR combined with CNIs as a method of prophylactic immunosuppression in recipients following alternative donor HCT. METHODS Eighty patients were enrolled in the study and randomized to the MZR (n=40) and MMF (n=40) cohorts before transplant conditioning. Analyses involved a comparison of the outcomes between the two cohorts as well as risk analyses of early NRM and severe CMV infection. RESULTS In contrast to MMF, MZR resulted in a lower but statistically nonsignificant median CMV DNA peak load (p=0.075), significantly fewer episodes of persistent/refractory infection (OR=0.12), and a lower failure rate of CMV treatment (OR=0.82), but the occurrence of hyperuricemia was significantly increased (OR=2.75). The transplant efficacy was comparable between the two cohorts regarding engraftment, the development of secondary poor graft function (sPGF) and GvHD, and the estimated OS and PFS. The 1-y NRM of the MZR cohort was not different from that of the MMF cohort, while the rate of 1-y NRM caused by viral infections was reduced in the MZR cohort and was of borderline statistical significance (p=0.05). In the multivariate analysis, lower doses of CD34+ cells in grafts (HR=3.65) and persistent/refractory CMV infections (vs w/o CMV infection: HR=7.31; vs CMV infection that was not persistent/refractory: HR=4.46) were predictors of increased 1-y NRM. The use of MMF (vs MZR cohort: OR=11.54) and grade to acute GvHD (OR=15.32) were independent risk factors for developing persistent/refractory CMV infections. CONCLUSIONS When combined with CNIs, MZR functioned well in terms of both immunosuppression and the reduction of the severity of CMV infection; however, further studies are warranted to verify whether it could be used as a potential immunosuppressant for alternative donor HCT.