Search

Voriconazole is a widely used antifungal agent in immunocompromised patients, but its utility is limited by its variable exposure and narrow therapeutic index. Population pharmacokinetic (PK) models have been used to characterize voriconazole PK and derive individualized dosing regimens. However, determinants of temporal within‐patient variability of voriconazole PK were not well established. We aimed to characterize temporal variability of voriconazole PK within individuals and identify predictive clinical factors. This study was conducted as a part of a single‐institution, phase I study of intravenous voriconazole in children undergoing hematopoietic cell transplantation (NCT02227797). We analyzed voriconazole PK study data collected at week 1 and again at week 2 after the start of voriconazole therapy in 59 pediatric patients undergoing HCT (age <21 years). Population PK analysis using nonlinear mixed effect modeling was performed to analyze temporal within‐individual variability of voriconazole PK by incorporating a between‐occasion variability term in the model. A 2‐compartment linear elimination model incorporating body weight and cytochrome P450 2C19 phenotype described the data. The ratio of individual voriconazole clearance between weeks 1 and 2 ranged from 0.11 to 3.3 (−9.1 to +3.3‐fold change). Incorporation of covariate effects by serum C‐reactive protein and albumin levels decreased between‐occasion variability of clearance as compared to the model without them (coefficient of variation, 41.2% and 59.5%, respectively) and improved the model fit (P <.05). As significant covariates on voriconazole PK, C‐reactive protein and albumin concentrations may potentially serve as useful biomarkers as part of therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Summary: For patients with untreated hepatic veno‐occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi‐organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide‐treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post‐HCT benefitted from defibrotide. [ABSTRACT FROM AUTHOR]

To study the contribution of T‐cell receptors (TCR) to resulting T‐cell responses, we studied three different human αβ TCRs, reactive to the same gp100‐derived peptide presented in the context of HLA‐A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen‐induced IFN‐γ responses, which correlated with TCR affinity for peptide–MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL‐17A release. Importantly, in vivo, SILv44‐transgenic T cells mediated superior antitumor responses to 888‐A2 + human melanoma tumor cells upon adoptive transfer into tumor‐challenged mice while maintaining IL‐17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T‐cell receptor in defining host T‐cell physiology than traditionally assumed, while parameters beyond IFN‐γ secretion and TCR affinity ultimately determine the reactivity of tumor‐reactive T cells. [ABSTRACT FROM AUTHOR]

Summary: Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life‐threatening complication of haematopoietic stem cell transplant (HSCT) conditioning and chemotherapy. Defibrotide is approved for treatment of hepatic VOD/SOS with pulmonary or renal dysfunction [i.e., multi‐organ dysfunction (MOD)] after HSCT in the United States and severe VOD/SOS after HSCT in patients aged older than 1 month in the European Union. Defibrotide was available as an investigational drug by an expanded‐access treatment programme (T‐IND; NCT00628498). In the completed T‐IND, the Kaplan–Meier estimated Day +100 survival for 1000 patients with documented defibrotide treatment after HSCT was 58·9% [95% confidence interval (CI), 55·7–61·9%]. Day +100 survival was also analysed by age and MOD status, and post hoc analyses were performed to determine Day +100 survival by transplant type, timing of VOD/SOS onset (≤21 or >21 days) and timing of defibrotide treatment initiation after VOD/SOS diagnosis. Day +100 survival in paediatric patients was 67·9% (95% CI, 63·8–71·6%) and 47·1% (95% CI, 42·3–51·8%) in adults. All patient subgroups without MOD had higher Day +100 survival than those with MOD; earlier defibrotide initiation was also associated with higher Day +100 survival. The safety profile of defibrotide in the completed T‐IND study was similar to previous reports. [ABSTRACT FROM AUTHOR]

Abstract: Background: Pure red cell aplasia (PRCA) is a well‐documented potential side effect of ABO major mismatched allogeneic hematopoietic stem cell transplants. This side effect may be self‐limiting, but is sometimes treated using modalities such as steroids, antithymocyte globulin, donor lymphocyte infusions, rituximab, or plasma exchanges. Another well‐documented cause of pure red cell aplasia is a chronic parvovirus B19 infection, which may be seen in immunocompromised hosts. The treatment of this cause of PRCA includes removal of immunosuppression, intravenous immunoglobulin (IVIg), or rituximab; however, this condition may also be self‐limiting. Case Report: We show a case of a patient with PRCA who had previously received an ABO major mismatched allogeneic hematopoietic stem cell transplant, but also had an identified source of parvovirus B19 in his marrow post‐transplant. Results: He underwent several various treatments for his PRCA, including rituximab, bortezomib, and then plasma exchange. Anti‐A IgM and IgG titers were drawn throughout his treatment course, and fell from 512 (anti‐A IgM) and 1024 (anti‐A IgG) to 2 (anti‐A IgM) and 8 (anti‐A IgG). After his last plasma exchange procedure, the patient's hemoglobin and reticulocyte count rose from 6.6 g/dL and 12.5 × 109/L (respectively) at the onset of the PRCA diagnosis to 9.6 g/dL and 138.1 × 109/L after a series of 14 plasma exchanges. Conclusion: This demonstrates a case of PRCA caused by an ABO major mismatched allogeneic hematopoietic stem cell transplant that was potentially complicated by a parvovirus infection, which was treated with multiple therapeutic interventions including a series of therapeutic plasma exchanges, rituximab, and bortezomib. Successful resolution of the patient's PRCA was achieved. [ABSTRACT FROM AUTHOR]

Pediatric patients requiring kidney transplant after hematopoietic cell transplant receive multiple courses of immunosuppression placing them at risk for infection. To elucidate potential risk factors for infection, we compared the immunosuppressive regimens and infectious complications of pediatric kidney transplant recipients at a single institution who had previously undergone hematopoietic cell transplant from different donors to similar patients reported in the literature. Among the initial four post-hematopoietic cell transplant kidney transplant patients reviewed, viremia episodes were universal, including BK virus, Epstein-Barr virus, and human herpesvirus-6, with one death from presumed BK virus encephalitis. No viremia was reported in five similar cases in the literature. Risk factors for increased infection include use of lymphodepleting serotherapy in HCT conditioning, multiple HCTs, limited immune reconstitution time between transplants, increased pre- KTx viral burden, and use of T-cell-depleting versus -suppressive induction immunosuppression for KTx. These findings suggest that pediatric post- HCT KTx recipients are at increased risk for viral infections, likely benefitting from thorough pre- KTx evaluation of immune reconstitution and preferential use of non-T-cell-depleting induction therapy for KTx. We applied these recommendations to one subsequent post- HCT patient requiring KTx at our institution with excellent outcomes one year post- KTx. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome ( VOD/ SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant ( HSCT). The VOD/ SOS pathophysiological cascade involves endothelial-cell activation and damage, and a prothrombotic-hypofibrinolytic state. Severe VOD/ SOS (typically characterized by multi-organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/ SOS post- HSCT in the European Union, and for hepatic VOD/ SOS with renal or pulmonary dysfunction post- HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded-access treatment protocol for patients with VOD/ SOS. Data from this study were examined post-hoc to determine if the timing of defibrotide initiation post- VOD/ SOS diagnosis affected Day +100 survival post- HSCT. Among 573 patients, defibrotide was started on the day of VOD/ SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post-diagnosis showed superior survival when treatment was initiated closer to VOD/ SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation ( P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/ SOS. [ABSTRACT FROM AUTHOR]

Abstract: We report two patients who underwent cardiac transplantation at a young age and subsequently required a HCT for varied indications. Despite the challenges associated with HCT following cardiac transplant, including need for altered immunosuppression, toxicities related to chemotherapy exposure, and infection risks, both patients are currently alive and well. There is a paucity of such successful cases documented in the literature, and these cases highlight the critical importance of an experienced, multidisciplinary team when caring for this patient population. [ABSTRACT FROM AUTHOR]

Mycophenolate mofetil (MMF) is an immunosuppressant routinely used in allogeneic hematopoietic cell transplantation (alloHCT) to promote stem cell engraftment and prevent acute graft vs host disease. Administered as a prodrug, MMF is converted by esterases to the active moiety, mycophenolic acid (MPA). The impact of clinical covariates on unbound MPA exposure was investigated with a population pharmacokinetic approach. Pharmacokinetic data were obtained from routine area under the curve (AUC) monitoring of unbound MPA drug levels in 36 pediatric (n = 31) and young adult (n = 5) patients undergoing alloHCT for a variety of malignant and nonmalignant disorders. Unbound MPA pharmacokinetics were well described by a 2-compartment model with linear elimination and first-order absorption. The important clinical covariates affecting unbound MPA pharmacokinetics were weight, estimated creatinine clearance, and total bilirubin. Unbound MPA clearance was reduced, and exposure (AUC0-8) increased in individuals with decreased renal function. In individuals with severe hepatic dysfunction (total bilirubin >10 mg/dL) unbound MPA clearance was approximately 3-fold lower compared with patients with normal to mild hepatic impairment. In alloHCT recipients with renal dysfunction or severe hepatic injury, dose reductions may be necessary to prevent toxicity and ensure optimal immunosuppression. [ABSTRACT FROM PUBLISHER]

Umbilical cord blood has rapidly become a valuable alternative stem cell source for allogeneic haematopoietic stem cell transplantation. Extensive research over the last 20 years has established the safety and efficacy of umbilical cord blood transplantation in both children and adults with a variety of malignant and non-malignant diseases. This research has clearly shown that this stem cell source has several unique characteristics resulting in distinct advantages and disadvantages when compared to transplantation with unrelated bone marrow or peripheral blood stem cells. This article reviews the most recent literature comparing the outcomes after umbilical cord blood transplantation with other alternative stem cell sources. [ABSTRACT FROM AUTHOR]