The Effect of Iron Overload on the Mobilization of Peripheral Blood Hematopoietic Stem Cells in Pediatric Patients with Thalassemia Major.

INTRODUCTION: The purpose of this study was to examine the effect of iron overload on the mobilization of peripheral blood stem cells (PBSCs) in pediatric patients with ß-thalassemia major (TM). METHODS: We retrospectively reviewed the records of 226 patients with TM from whom PBSCs were collected. Iron overload was based on serum ferritin level, and liver and cardiac iron overload was measured by magnetic resonance imaging (MRI) T2*. RESULTS: The mean age of the TM patients was 7.35 ± 3.41 years. Of the patients, only 171 received MRI. Of the 171 patients, 35 had normal liver iron levels, 39 mild liver iron overload, 90 intermediate liver iron overload, and 7 severe liver iron overload. The intermediate + severe group was associated with significantly higher age and BMI and lower leukapheresis product white blood cell count and CD34+ cell levels (all, p < 0.05). CONCLUSION: Leukapheresis indices were similar between patients with different degrees of iron overload according to the ferritin level and cardiac iron overload, in which the later might be due to the small number of patients with cardiac overload. In patients with TM, the intermediate and severe liver iron overload was associated with poorer mobilization of PBSCs.

A novel conditioning regimen improves outcomes in ß-thalassemia major patients using unrelated donor peripheral blood stem cell transplantation.

We used a novel NF-08-TM transplant protocol based on intravenous busulfan, cyclophosphamide, fludarabine, and thiotepa in 82 consecutive patients with ß-thalassemia major (TM), including 52 with allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors (UDs) with well-matched human leukocyte antigens and 30 with hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSDs). The median age at transplantation was 6.0 years (range, 0.6-15.0 years), and the ratio of male-to-female patients was 56:26. The median follow-up time was 24 months (range, 12-39 months). The estimated 3-year overall survival and TM-free survival were 92.3% and 90.4% in the UD-PBSCT group and 90.0% and 83.3% in the MSD-HSCT group. The cumulative incidences of graft rejection and grades III-IV acute graft-versus-host disease were 1.9% and 9.6%, respectively, in the UD-PBSCT group and 6.9% and 3.6%, respectively, in the MSD-HSCT group. The cumulative incidence of transplant-related mortality was 7.7% in the UD-PBSCT group and 10.0% in the MSD-HSCT group. In conclusion, UD-PBSCTs using the well-tolerated NF-08-TM protocol show similar results to MSD-HSCTs and can be used to treat ß-thalassemia patients in the absence of MSDs.

Avatrombopag for the treatment of thrombocytopenia in children's patients following allogeneic hematopoietic stem-cell transplantation: A pilot study.

Thrombocytopenia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common and life-threatening complication. Thus, new prevention and treatment strategies for post-HSCT thrombocytopenia are urgently required. In recent studies, thrombopoietin receptor agonists (TPO-RA) for treating post-HSCT thrombocytopenia indicated efficiency and safety. The improved effect of post-HSCT thrombocytopenia in adults was found in the administration of avatrombopag which was a new TPO-RA. However, there was no relevant study in the children's cohort. Herein, we retrospectively analyzed the effect of avatrombopag in post-HSCT thrombocytopenia in children. As a result, the overall response rate (ORR) and complete response rate (CRR) were 91% and 78%, respectively. Furthermore, both cumulative ORR and CRR were significantly lower in the poor graft function (PGF)/secondary failure of platelet recovery (SFPR) group compared to the engraftment-promotion group (86.7% vs. 100%, p = 0.002 and 65.0% vs. 100%, p < 0.001, respectively). Achieving OR required a median of 16 days in the PGF/SFPR group while 7 days in the engraftment-promotion group (p = 0.003). Grade III-IV acute graft vs. host disease and inadequate megakaryocytes were identified as risk factors of CRR only in univariate analysis (p = 0.03 and p = 0.01, respectively). No severe adverse events were documented. Conclusively, avatrombopag is an alternatively efficient and safe agent for treating post-HSCT thrombocytopenia in children.

Combined Effect of CYP2C19 Genetic Polymorphisms and C-Reactive Protein on Voriconazole Exposure and Dosing in Immunocompromised Children.

Background: Pediatric patients have significant interindividual variability in voriconazole exposure. The aim of the study was to identify factors associated with voriconazole concentrations and dose requirements to achieve therapeutic concentrations in pediatric patients. Methods: Medical records of pediatric patients were retrospectively reviewed. Covariates associated with voriconazole plasma concentrations and dose requirements were adjusted by using generalized linear mixed-effect models. Results: A total of 682 voriconazole steady-state trough concentrations from 91 Chinese pediatric patients were included. Voriconazole exposure was lower in the CYP2C19 normal metabolizer (NM) group compared with the intermediate metabolizer (IM) group and the poor metabolizer (PM) group (p = 0.0016, p < 0.0001). The median daily dose of voriconazole required to achieve therapeutic range demonstrated a significant phenotypic dose effect: 20.8 mg/kg (range, 16.2-26.8 mg/kg) for the CYP2C19 NM group, 18.2 mg/kg (range, 13.3-21.8 mg/kg) for the CYP2C19 IM group, and 15.2 mg/kg (range, 10.7-19.1 mg/kg) for the CYP2C19 PM group, respectively. The extent of impact of C-reactive protein (CRP) levels on voriconazole trough concentrations and dose requirements varied between CYP2C19 phenotypes. Increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole trough concentration by 22.22, 50, 64.81, and 75% respectively, in the NM group; by 39.26, 94.48, 123.93, and 146.63%, respectively, in the IM group; and by 17.17, 37.34, 46.78, and 53.65%, respectively, in the PM group. Meanwhile, increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole dose requirements by 7.15, 14.23, 17.35, and 19.43%, respectively, in the PM group; with decreases in voriconazole dose requirements by 3.71, 7.38, 8.97, and 10.03%, respectively, in the NM group; and with decreases by 4, 9.10, 11.05, and 12.35%, respectively, in the IM group. In addition, age and presence of immunosuppressants had significant effects on voriconazole exposure. Conclusions: Our study suggests that CYP2C19 phenotypes, CRP concentrations, age, and the presence of immunosuppressants were factors associated with the pharmacokinetic changes in voriconazole. There was heterogeneity in the effect of CRP on voriconazole plasma concentrations across different CYP2C19 genotypes. Combining relevant factors with dose adaptation strategies in therapeutic drug monitoring may help to reduce the incidence of subtherapeutic and supratherapeutic concentrations in clinical practice.