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.

Abstract

We explore risk factors and impacts of post-transplant EBV-Reactivation (EBV-R) and PTLD in 270 patients that underwent RIC alloHCT using ATG-PTCy and cyclosporine for GVHD prophylaxis. Twenty-five (12%) patients had probable (n?=?7) or proven (n?=?18) PTLD. Patients were managed with reduction of immunosuppression and 22 with weekly rituximab (375?mg/m(2) IV). ORR was 84%; 8 (32%) recipients died, and one-year OS and NRM of patients with PTLD was 59.7% and 37%, respectively. One hundred seventy-two (63.7%) recipients had EBV-R. One-year OS and RFS of patients with EBV-R were 68.2% and 60.6%, and of EBV-Negative patients were 62.1% and 50.1%, respectively. High incidence but low mortality of EBV-R and PTLD was documented. EBV-R induced a protective effect on RFS in multivariable analysis (HR 0.91, p?=?.011). Therefore, EBV-R may have a protective effect on RFS in this setting. Further research is necessary to evaluate the interplay of EBV-R, immune reconstitution, and post-transplant outcomes.

Abstract

BACKGROUND Human leukocyte antigen (HLA) mismatch and the administration of immunosuppressive agents are considered risks for human herpesvirus 6 (HHV-6) reactivation after stem cell transplantation (SCT). However, the incidence of HHV-6 reactivation in HLA-mismatched related SCT remains unknown. METHODS We monitored plasma HHV-6 DNA loads weekly using real-time quantitative polymerase chain reaction for 5 weeks after SCT and compared serum IL-6 levels in HLA-mismatched SCT groups. RESULTS Compared with detection in all 11 umbilical cord blood transplantation (CBT) patients (100%), plasma HHV-6 DNA was detected in only 3 of 42 haplo-SCT patients (7.1%) despite the use of methylprednisolone and antithymocyte globulin as graft-versus-host disease prophylaxis and a reduced-intensity conditioning regimen, respectively. Correspondingly, serum IL-6 levels in haplo-SCT patients were significantly lower than those in CBT patients. No HHV-6-associated encephalitis developed in either groups. CONCLUSIONS Neither HLA disparity nor the use of methylprednisolone and antithymocyte globulin were risk factors for HHV-6 reactivation in our haplo-SCT patients. Rather than increasing risk, the administration of immunosuppressive agents potentially prevented HHV-6 reactivation after haplo-SCT by suppressing IL-6 production. This article is protected by copyright. All rights reserved.

Abstract

The current study evaluates the clinical effect of sirolimus exposure on the occurrence of CMV DNAemia requiring pre-emptive antiviral therapy. One-hundred and sixty-seven consecutive RIC-allo-HSCT recipients who received sirolimus and tacrolimus-based GvHD prophylaxis and whose CMV-serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with detailed sirolimus consecutive blood levels, describing time to CMV DNAemia-RAT was developed using the NONMEM software version 7.4. Overall, 122 (73%) out of 167 were allografted from an unrelated donor and in 51 (31%) cases the donor CMV-serostatus was negative. Fifty-six (34%) recipients developed CMV DNAemiarequiring pre-emptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia requiring pre-emptive therapy was best described using a Gompertz-function. CMV DNAemia requiring pre-emptive therapy-predicting factors were: ATG-based conditioning regimen (HR=2.2, 95%CI 1.1-4.1, p<0.01) and sirolimus concentration (HR=0.94, 95%CI 0.87-0.99) (p<0.01). The risk of CMV DNAemia-RAT decreased 6% per each 1 ng/mL increase in sirolimus trough concentrations. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia requiring pre-emptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing time to CMV DNAemia requiring pre-emptive antiviral therapy as a function of sirolimus drug concentration.

Abstract

Mycophenolate mofetil (MMF) is an immunosuppressive agent that is widely used in graft-versus-host disease prophylaxis because of its inhibitory function on T cells and B cells. However, the effect of MMF on natural killer cell reconstitution after allogenic hematological transplantation is largely unknown. The present study examined the effects of different MMF administration durations after haploidentical allo-HSCT on NK cell reconstitution. Ninety patients were enrolled in this study and defined into two groups in term of MMF duration. We found that MMF patients in the long-term MMF group were associated with a poor reconstitution of NK cells and a significantly lower cytotoxicity from day 30 to day 180 post-transplantation. Especially, the long-term MMF group inhibits reconstitution of NKp30 NK subsets, which correlated with higher risk of EBV viremia. Multivariate analysis showed that a better reconstitution of NKp30 cells was associated with lower EBV viremia (HR0.957, p=.04). In vitro experiments demonstrated that the active metabolite of MMF, mycophenolic acid (MPA), inhibited the proliferation and cytotoxicity of NK cells from healthy donors or patients at day 30 post-transplantation. In summary, our findings demonstrated that long-term MMF administration delayed the quality and quantity of NK cells, especially NKp30 subpopulations, which was associated with decreased EBV viremia post allogeneic HSCT.

Abstract

Antithymocyte globulin (ATG) has been shown to reduce the incidence of graft-versus-host-disease (GVHD) following matched related (MRD) and unrelated (MUD) hematopoietic stem cell transplantation (HCT) [1-6]; however, due to increased risks of infection and relapse, use has not translated into a significant improvement in post-transplant survival. The goal of this single-center, retrospective cohort analysis was to quantify the incidence of viral reactivation and viral end organ disease within the first 100 days following MUD HCT with ATG-based conditioning compared to MRD HCT without ATG. Fifty-nine adult patients underwent ATG-based MUD HCT compared to 64 patients receiving MRD HCT without ATG. CMV reactivation was the most frequent event in both groups (65% MUD vs 61% MRD), followed by BKV reactivation (26% vs 24%), and EBV reactivation (20% vs 9%). A higher percentage of MUD patients experienced viral end organ disease (EOD) by day +100 when compared to MRD patients (34% vs 16%, p=0.022). This was most notable for EOD involving BKV (15% vs 6%, p=0.14) and EBV (7% vs 0%, p=0.050). Correspondingly, more patients in the MUD group experienced virus-related complications, including hospitalization (24% vs 3%, p < 0.001), intensive care unit (ICU) admission (10% vs 6%, p=0.19), and mortality (8% vs 4%, p=0.44). There were no significant differences in either RFS (62% vs 78%, p=0.07) or OS (72% vs 86%, p=0.07) at 6 months post-HCT. However, when utilizing the final time point of 21 months in the MUG/ATG group and 23 months in the MRD/No ATG group, MUD patients who received ATG had inferior survival (OS: 27% vs 77%, p=0.009; RFS: 40% vs 59%, p=0.042). Our results add to and further quantify the infectious risks associated with the use of ATG in MUD transplants, as well as promote the implementation of more intensive pre-emptive viral monitoring practices in patients receiving ATG-based MUD transplants.

Abstract

BACKGROUND Human herpesvirus 6 (HHV-6) encephalitis is a known life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, few studies have focused on the occurrence of HHV-6 encephalitis in patients receiving mycophenolate mofetil (MMF) combined with a calcineurin inhibitor as prophylaxis for graft-versus-host disease (GVHD). This study aimed to investigate the impact of MMF administered for GVHD prophylaxis in the occurrence of HHV-6 encephalitis after allo-HSCT and the characteristics of this condition. METHODS AND RESULTS We retrospectively analyzed 73 patients who underwent allo-HSCT (83 transplants) at our hospital between April 2010 and December 2015. MMF (2-3 g/day) was administered along with a calcineurin inhibitor. Seven patients (8.0%) developed encephalitis due to HHV-6. The median period from allo-HSCT to the onset of HHV-6 encephalitis was 23 days (range, 17-98 days). The cumulative incidence of HHV-6 encephalitis on day 100 after treatment was 12% and 6% in patients who underwent cord blood transplantation (CBT) and non-CBT (i.e., bone marrow transplantation and peripheral blood stem cell transplantation), respectively (P = 0.344). Neurological symptoms of encephalitis were more severe in non-CBT cases than those in CBT cases. All patients diagnosed with HHV-6 encephalitis were treated with ganciclovir or foscarnet. None of the enrolled patients died from HHV-6 encephalitis. CONCLUSIONS MMF may have the potential to increase the frequency of severe HHV-6 encephalitis in patients undergoing CBT and non-CBT. Thus, MMF should be administered with caution, and patients should be monitored closely for HHV-6 encephalitis even those who did not undergo CBT. This article is protected by copyright. All rights reserved.

Abstract

Sirolimus appears to protect against CMV in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified three independent covariates which significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure and sirolimus exposure. CMV seropositive recipients with CMV seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia but levels over 8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, p < 0.01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases. This article is protected by copyright. All rights reserved.

Abstract

BACKGROUND Prophylactic immunoglobulin has been used with varying efficacy to reduce complications in hematopoietic stem cell transplant recipients. STUDY DESIGN AND METHODS A systematic review and meta-analysis was conducted of randomized controlled trials that assessed clinical outcomes (overall survival, transplant-related mortality, graft-versus-host disease [GVHD], veno-occlusive disease [VOD], interstitial pneumonitis, disease relapse, cytomegalovirus [CMV] infection and disease, non-CMV infection) of immunoglobulin prophylaxis versus placebo in hematopoietic stem cell transplant recipients. MEDLINE, EMBASE, EBM Reviews, and the Cochrane Central Register of Controlled Trials were searched up to June 2017. Quality of included studies and outcomes were evaluated via Risk of Bias assessment and Grading of Recommendations, Assessment, Development and Evaluation criteria, respectively. RESULTS Of 899 citations screened, 27 studies (n = 3934) were included. Immunoglobulin prophylaxis had no impact on survival (risk ratio [RR], 0.94; 95% confidence interval [CI], 0.88-1.01; 11 studies, n = 1962) but decreased risk of acute GVHD (RR, 0.78; 95% CI, 0.65-0.94; eight studies, n = 1097) and CMV disease (RR, 0.52; 95% CI, 0.28-0.97; two studies, n = 167). Meta-analysis revealed increased risk of VOD (RR, 3.04; 95% CI, 1.10-8.41; three studies, n = 384) and disease relapse (RR, 1.26; 95% CI, 1.07-1.49; seven studies, n = 1647). Other outcomes were small in sample size or nonsignificant. Results should be interpreted cautiously given the low quality of studies and evidence of outcomes. CONCLUSION Immunoglobulin prophylaxis did not have a significant effect on survival. Positive clinical effects were shown for acute GVHD and CMV disease and negative effects against VOD and disease relapse. No studies examined the effect of immunoglobulin treatment in hypogammaglobulinemic patients despite current guidelines, warranting further studies in this population.