7 research outputs found
Population pharmacokinetic model for once-daily intravenous busulfan in pediatric subjects describing time-associated clearance
This study aimed to characterize the population pharmacokinetics (PK) of busulfan focusing on how busulfan clearance (CL) changes over time during once-daily administration and assess different methods for measuring busulfan exposure and the ability to achieve target cumulative exposure under different dosing adjustment scenarios in pediatric stem cell transplantation recipients. Daily serial blood sampling was performed and concentration-time data were analyzed using a nonlinear mixed-effects approach. The developed PK model was used to assess achievement of target exposure under six dose-adjustment scenarios based on simulations performed in RStudio (RxODE package)Ā®. A total of 2491 busulfan plasma concentrationātime measurements were collected from 95 patients characterizing 379 dosing days. A two-compartment model with time-associated CL best described the data with a typical CL of 14.5Ā L/h for an adult male with 62 kg normal fat mass (NFM; equivalent to 70 kg total body weight), typical volume of distribution central compartment (V1) of 40.6Ā L/59 kg NFM (equivalent to 70 kg total body weight), and typical volume of distribution peripheral compartment of 3.57 L/62 kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model-based exposure estimates with each dose, and either a proportional dose-adjustment calculation or model-based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time-associated reduction in CL during once-daily busulfan treatment was described.</p
Outcomes of jematopoietic stem cell transplantation in primary immunodeficiency: a report from the Australian and New Zealand children's haematology oncology group and the Australasian bone marrow transplant recipient registry
We performed a retrospective analysis on the outcomes of 135 hematopoietic stem cell transplantations (HSCTs) for primary immunodeficiency disorders in Australian and New Zealand Childrenās Haematology Oncology Group transplantation centers between 1992 and 2008. The most common indications for HSCT were severe combined immunodeficiency, Wiskott-Aldrich syndrome, and chronic granulomatous disease. Five-year overall survival (OS) was 72% for the entire cohort. Disease-specific 5-year OS was 70% for severe combined immunodeficiency, 81% for Wiskott-Aldrich syndrome, and 69% for chronic granulomatous disease. Transplantation-related mortality (TRM) was 10% at day +100. TRM and OS were equivalent in recipients of related and unrelated donor transplants. Source of stem cells had no impact on TRM or OS with outcomes following unrelated umbilical cord blood similar to unrelated bone marrow. The presence of interstitial pneumonitis, active cytomegalovirus infection, or veno-occlusive disease were all independent variables that significantly decreased OS. This large series supports the use of HSCT as curative therapy for a range of primary immunodeficiency disorders, demonstrating excellent survival after both related and unrelated donor transplantation
Use of Thiotepa in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: An Australian and New Zealand Children's Haematology/Oncology Group Study
Hematopoietic stem cell transplantation for children with acute myeloid leukemia in second remission: a report from the Australasian Bone Marrow Transplant Recipient Registry and the Australian and New Zealand Children's Haematology Oncology Group
Approximately one-third of children with acute myeloid leukemia (AML) relapse, requiring re-treatment and allogeneic hematopoietic stem cell transplantation (HSCT). Although achieving second complete remission (CR2) prior to HSCT is desirable, once CR2 is attained, it is unclear if there is any benefit from further chemotherapy prior to HSCT. Moreover, although pre-HSCT minimal residual disease (MRD) has prognostic value in acute lymphoblastic leukemia, the benefit of MRD reduction after achieving CR prior to HSCT is less clear for AML.To address these questions, we analyzed data from pediatric transplant centers in Australia and New Zealand concerning relapsed childhood AML cases occurring between 1998 and 2013. Given the retrospective nature of our analysis and assay data available, we analyzed patients on the basis of measurable residual disease (MeRD) by any methodology, rather than MRD in the conventional sense.We observed improved overall survival (OS) in children receiving two chemotherapy cycles, compared to one cycle or three or more cycles pre-HSCT. Improved OS with two cycles remained significant for patients without MeRD after cycle 1.These data suggest that a second chemotherapy cycle pre-HSCT may improve survival by lowering disease burden. Prospective trials assessing strategies to reduce pre-HSCT MRD in relapsed childhood AML are warranted
Results of consecutive trials for children newly diagnosed with acute myeloid leukemia from the Australian and New Zealand Children's Cancer Study Group
Despite improvements in the treatment of acute myeloid leukemia (AML), approximately 50% of children die of the disease. Clinical trials in adult patients with AML indicate that idarubicin may have superior efficacy when compared to daunorubicin in the remission-induction phases of chemotherapy. We conducted consecutive clinical trials in children with newly diagnosed AML in which daunorubicin (group 1, n = 102) or idarubicin (group 2, n = 160) was used during the remission-induction (RI) and the early consolidation phases of chemotherapy. Idarubicin was given at a dose of either 10 mg/m2 (group 2A, n = 106) or 12 mg/m2 (group 2B, n = 53). A high rate of RI was achieved for all groups (95% group 1, 90% group 2A, 94% group 2B). There were no significant differences in 5-year event-free survival (EFS) or in overall survival (OS) when the 3 groups were compared (group 1: EFS 50%, OS 56%; group 2A: EFS 50%, OS 60%; group 2B: EFS 34%, OS 50%). RI deaths resulting from treatment toxicity were low---2% for group 1 and 5% for group 2. More gastrointestinal, pulmonary, and renal toxicity but fewer infections were observed in patients receiving idarubicin (P < .001, P = .04, P = .03, respectively). Following RI chemotherapy, all patients received 3 to 4 more courses of identical chemotherapy and then underwent either autologous (n = 156) or an allogeneic bone marrow transplantation (BMT) (n = 35). OS was higher in allogeneic BMT patients than in autologous BMT patients (79% vs 63%; P = .23). We conclude that daunorubicin is as effective as idarubicin for remission-induction therapy for childhood AML and has reduced toxicity.Tracey A. O'Brien, Susan J. Russell, Marcus R. Vowels, Cecilia M. Oswald, Karin Tiedemann, Peter J. Shaw, Liane Lockwood, Lochie Teague, Michael Rice and Glenn M. Marshal