Risk factors associated with early viral reactivation following haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide: a pilot study
Annals of hematology. 2020
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
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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.
High incidence but low mortality of EBV-reactivation and PTLD after alloHCT using ATG and PTCy for GVHD prophylaxis
Leukemia & lymphoma. 2020;:1-11
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.
Characterization of viral infections following antithymocyte globulin-based conditioning in adults undergoing allogeneic hematopoietic stem cell transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
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.
Infectious complications after post-transplantation cyclophosphamide and anti-thymocyte globulin-based haploidentical stem cell transplantation
British journal of haematology. 2019
Tacrolimus blood concentration increase depends on administration route when combined with voriconazole in pediatric stem cell transplant recipients
Pediatric transplantation. 2019;:e13619
BACKGROUND Understanding of TAC pharmacokinetics is required to avoid both overdosing and underdosing. VRCZ is known to increase the TAC blood concentration by inhibiting CYP3A4; however, detailed, practical information on pediatric cases is still scarce. Herein, we investigated the association between the TAC blood concentration and dosage focusing on the administration route and concomitant use of VRCZ in children. METHODS In total, 38 children who received TAC during stem cell transplantation at our hospital between January 2013 and April 2018 were included. The ratio of the TAC blood concentration (ng/mL) to dosage (mg/kg/day) (C/D) was calculated at the last continuous intravenous infusion (C/Div) and after switching to oral administration (C/Dpo). RESULTS Patients with VRCZ (n = 14) showed a higher C/D regardless of administration route (median C/Div: with VRCZ/without VRCZ = 832/643, median C/Dpo: with VRCZ/without VRCZ = 339/45). Additionally, the (C/Div)/(C/Dpo) was about one-fourth in cases with VRCZ; the median (C/Div)/(C/Dpo) was 3.3 for cases with VRCZ and 13.5 for cases without VRCZ. Interestingly, the increase in the TAC blood concentration due to VRCZ was higher when TAC was administered orally, especially in adolescent patients. CONCLUSIONS To obtain an optimal TAC blood concentration, dose adjustment based on multiple factors, such as administration route, concomitant use of VRCZ, and age, is required.
Effect of cyclosporine A and polymorphisms in CYP2C19 and ABCC2 on the concentration of voriconazole in patients undergoing allogeneic hematopoietic stem cell transplantation
Xenobiotica; the fate of foreign compounds in biological systems. 2019;:1-19
1. Voriconazole is known to display highly variable pharmacokinetics affecting treatment efficacy and safety. This study aimed to identify the factors causing the variation of voriconazole concentration in patients with allogeneic hematopoietic stem cell transplantation. 2. The data of patients was collected, including clinical characteristics and voriconazole concentrations. A total of 5 single nucleotide polymorphisms of 3 candidate genes (CYP2C19, ABCC2, ABCG2) related to voriconazole metabolism were genotyped by MassArray method. The correlation between polymorphisms and voriconazole concentration was analyzed. 3. A total of 244 voriconazole concentrations of 43 patients were included in this study. The voriconazole concentration was significantly correlated with patients' total bile acid (P =0.001) and cyclosporin A (P < 0.001). The median concentration of the CYP2C19 normal metabolizers was remarkably lower than poor metabolizers (0.86 vs 2.27 mug/mL). The median concentration of ABCC2 rs2273697 GG genotype carriers was significantly higher than that of GA genotype carriers (P = 0.026). 4. The variability of voriconazole concentration is partially explained by total bile acid, metabolic types of CYP2C19. The voriconazole concentration of CYP2C19 normal metabolizers is likely to be lower than 1.0 mug/mL and thus at risk of infection due to inadequate treatment.
High incidence of Pneumocystis jirovecii pneumonia in allogeneic hematopoietic cell transplant recipients in the modern era
BACKGROUND International guidelines for Pneumocystis jirovecii pneumonia (PJP) prevention recommend prophylaxis for ≥6 months following allogeneic hematopoietic cell transplantation, and longer in patients with graft-versus-host disease (GVHD) or on immunosuppressive therapy (IST). These recommendations are based on cohorts of patients who did not routinely receive anti-thymocyte globulin (ATG) for GVHD prophylaxis. METHODS We performed a retrospective chart review of 649 patients, all of whom received ATG as part of GVHD prophylaxis. RESULTS The cumulative incidence of definite PJP was 3.52% at both 3 and 5 years (median follow up, 1648 days for survivors). PJP occurred in 13 non-GVHD patients between days 207 and 508, due in part to low CD4 T-cell counts (<200 CD4 T cells/microL). PJP occurred in eight GVHD patients between days 389 and 792, due in part to non-adherence to PJP prophylaxis guidelines (discontinuation of PJP prophylaxis at <3 months after discontinuation of IST). Breakthrough PJP infection was not observed in patients receiving prophylaxis with cotrimoxazole, dapsone or atovaquone, whereas three cases were observed with inhaled pentamidine. DISCUSSION In conclusion, for non-GVHD patients receiving ATG-containing GVHD prophylaxis, 6 months of PJP prophylaxis is inadequate, particularly if the CD4 T-cell count is <200 cells/microL or if there is a high incidence of PJP in the community. For patients with GVHD receiving ATG-containing GVHD prophylaxis, continuing PJP prophylaxis until ≥3 months post-discontinuation of IST is important. Cotrimoxazole, dapsone and atovaquone are preferred over inhaled pentamidine.
The impact of initiating posaconazole on tacrolimus pharmacokinetics in allogeneic stem cell transplantation
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2019;:1078155219833440
BACKGROUND Posaconazole reduces the risk of invasive Aspergillus in transplant patients, but significantly inhibits tacrolimus metabolism. One study demonstrated that a three-fold dose reduction of tacrolimus was required to obtain therapeutic concentrations when used with posaconazole. However, with empiric dose reduction, there is a risk of subtherapeutic tacrolimus levels and subsequent graft failure or graft-versus-host disease. Overall, the existing data on the impact of posaconazole on tacrolimus pharmacokinetics is limited. OBJECTIVE The purpose of this study is to determine whether tacrolimus doses should be decreased upon initiation of posaconazole in patients receiving an allogeneic stem cell transplant. METHODS This is a retrospective chart review at an academic medical center. All allogeneic stem cell transplant adults who received concomitant posaconazole and tacrolimus from February 2016 through December 2017 were included. RESULTS Seventy-nine patients identified using an internal electronic database were analyzed. The median time to therapeutic tacrolimus concentration was significantly longer in patients who did not receive an empiric dose reduction (0% DR, 10d; 1-30% DR, 4d; 31-65% DR, 5d; >65% DR, 4d; p = 0.0395). The rate of supratherapeutic levels was highest amongst patients who did not receive an empiric DR, and was noted to be significant compared to the group that had 31-65% DR ( p < 0.001). CONCLUSION This study validates our current practice of instituting an empiric 50% dose reduction of oral tacrolimus to 0.03 mg/kg/day when used concomitantly with posaconazole to achieve therapeutic levels in allogeneic stem cell transplant patients.
Evaluation of infectious complications after haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide following reduced-intensity and myeloablative conditioning: a study on behalf of the Francophone Society of Stem Cell Transplantation and Cellular Therapy (SFGM-TC)
Bone marrow transplantation. 2019
Several approaches have been developed to overcome historical barriers associated with poor outcomes in the setting of HLA-haploidentical allogeneic transplantation (HaploSCT). Here, we examine the outcome of patients with various hematological disorders undergoing HaploSCT with high-dose, post-transplantation cyclophosphamide. We performed a retrospective study on 381 patients from 30 centers between January 2013 and December 2015. At the last follow-up, a total of 1058 infectious episodes were diagnosed, affecting 90.3% of the cohort. Median time to first infection was 13 days for bacterial, 32 days for viral and 20 days for fungal infections. Around 41% of these infections were of bacterial origin and 35% of viral origin, among which 48.8% of patients presented CMV reactivation. Median of GVHD relapse-free survival, progression-free survival and overall survival were 7.1 months, 19.9 months and 33.5 months, respectively. HSCT procedure was the primary or contributing cause of death (55.6%), followed by relapse of the original disease (34.2%). Infections accounted for 45.7% of the HSCT-related deaths. The present multicenter data on a large cohort of patients receiving HaploSCT with PTCy confirmed the feasibility of the procedure with an acceptable incidence of infectious complications, not different as compared to other haploidentical platforms or HLA-matched transplantation.