scholarly journals Unpredictability of Intravenous Busulfan Pharmacokinetics in Children Undergoing Hematopoietic Stem Cell Transplantation for Advanced Beta Thalassemia: Limited Toxicity with a Dose-Adjustment Policy

2010 ◽  
Vol 16 (5) ◽  
pp. 622-628 ◽  
Author(s):  
Robert Chiesa ◽  
Barbara Cappelli ◽  
Roberto Crocchiolo ◽  
Ilaria Frugnoli ◽  
Erika Biral ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Beta Thalassemia ◽  
Hematopoietic Stem ◽  
Adjustment Policy

Target Dose Adjustment of Oral Busulfan Using a Test Dose in Japanese Adults Undergoing Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5313-5313
Author(s):  
Yasushi Takamatsu ◽  
Kentaro Ogata ◽  
Noriaki Sasaki ◽  
Shuuji Hara ◽  
Tetsuya Eto ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Prospective Trial ◽  
Conditioning Regimen ◽  
Test Dose ◽  
Hematopoietic Stem

Abstract Oral busulfan (BU) is widely used in patients undergoing hematopoietic stem cell transplantation (HST). Therapeutic effect of BU is related to the area under the plasma concentration-time curve (AUC) or the average plasma concentrations at steady state (Css). It has been shown that BU pharmacokinetics (PK) are highly variable and the dose adjustment according to the BU levels is critical to get the successful results of HST for Caucasians. BU is metabolized mainly in the liver through conjugation with glutathione by glutathione S-transferase (GST). Recent study has shown that the polymorphisms of GST genes are associated with the risk of developing hepatic veno-occlusive disease in patients undergoing HST. Ethnic variation is also demonstrated in relation to a gene deletion polymorphism of GST, suggesting that BU metabolism is influenced by the race. BU PK have been extensively investigated in Caucasians and few studies have focused on Asian people. We therefore underwent a prospective trial of adjusting BU doses depending on the individual BU PK in 36 Japanese patients aged from 16 to 64 years (median; 47 years). All patients received a busulfan-containing conditioning regimen and underwent allogeneic HST. Individual PK were studied following a 0.5 mg/kg test dose of BU administered orally. BU concentrations were measured by a high-performance liquid chromatographic method and individual PK parameters of BU were calculated with a one-compartment model by using Bayesian modeling program. The median clearance (CL/F) was 0.16 L/hr/kg (0.09 to 0.34 L/hr/kg), the median volume of distribution (Vd/F) 0.65 L/kg (range; 0.41 to 0.97 L/kg), the median elimination half-life (t1/2) 2.9 hr (range; 1.9 to 7.0 hr), and the median absorption rate constant (ka) 2.46 /hr (range; 0.53 to 6.03 /hr). BU doses were adjusted to achieve a target BU Css between 800 and 900 ng/mL. Twenty-six (72%) patients were required to reduce BU doses and adjusted BU doses ranged from 0.51 to 1.29 mg/kg/time (median; 0.85 mg/kg/time). After administrating the 6th dose of BU for the conditioning regimen, BU PK were analyzed. Expected Css was significantly correlated with observed Css and predictability of the test dose was 106.4±21.8%. Engraftment was successful in 34 of 36 (94%) patients. Grade 2 to 4 regimen-related toxicity except stomatitis occurred in 4 (11%) patients. These data demonstrate that BU PK vary widely from one patient to another after oral BU in Japanese and individualization of BU doses depending on the BU PK are useful in improving clinical outcome in patients undergoing HST.

Novel pharmacokinetic behavior of intravenous busulfan in children with thalassemia undergoing hematopoietic stem cell transplantation: a prospective evaluation of pharmacokinetic and pharmacodynamic profile with therapeutic drug monitoring

Blood ◽  
2010 ◽  
Vol 115 (22) ◽  
pp. 4597-4604 ◽  
Author(s):  
Javid Gaziev ◽  
Laurent Nguyen ◽  
Christian Puozzo ◽  
Alessia Francesca Mozzi ◽  
Marialuisa Casella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Dose Adjustment ◽  
Target Range ◽  
Good Survival ◽  
Hematopoietic Stem ◽  
Pharmacodynamic Profile

AbstractWe prospectively studied the pharmacokinetics (PK) and clinical outcomes of intravenous busulfan (Bu) in 71 children with preexisting liver damage who underwent hematopoietic stem cell transplantation for thalassemia. Intravenous Bu was administered every 6 hours as part of a conditioning regimen with PK-based dose adjustment to target a conservative area under the concentration-versus-time curve (AUC) range (900-1350 μMol*min). The first-dose Bu clearance (CL) was significantly higher than the subsequent daily CL that remained unchanged in the ensuing days. One-third of patients required dose escalation based on dose 1 AUC, whereas dose reduction was needed in the subsequent days. At doses 5, 9, and 13, 78%, 81%, and 87% of patients, respectively, achieved the target range of AUC. A population PK analysis confirmed that the first-dose CL was 20% higher and that body weight was the most important covariate to explain PK variability. Patients with variant GSTA1*B had a 10% lower Bu CL than wild-type. These results suggest that the disease-specific behavior of intravenous Bu PK should be considered for PK-guided dose adjustment in patients with thalassemia, and the use of a conservative AUC range resulted in low toxicity, good engraftment, and good survival rate.

scholarly journals What unrelated hematopoietic stem cell transplantation in thalassemia taught us about transplant immunogenetics

2016 ◽  
Vol 8 ◽  
pp. 2016048 ◽  
Author(s):  
Giorgio La Nasa ◽  
Adriana Vacca ◽  
Roberto Littera ◽  
Eugenia Piras ◽  
Sandro Orru ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Malignant Disease ◽  
Human Leukocyte ◽  
Beta Thalassemia ◽  
Hematopoietic Stem ◽  
Free Survival

Abstract Although the past few decades have shown an improvement in the survival and complication-free survival rates in patients with beta-thalassemia major and gene therapy is already at an advanced stage of experimentation, hematopoietic stem cell transplantation (HSCT) continues to be the only effective and realistic approach to the cure of this chronic non-malignant disease. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with HSCT from other sources. Nowadays, the availability of an international network of voluntary stem cell donor registries and cordon blood banks has significantly increased the odds of finding a suitable HLA matched donor. Stringent immunogenetic criteria for donor selection have made it possible to achieve overall survival (OS) and thalassemia-free survival (TFS) rates comparable to those of sibling transplants. However, acute and chronic graft-versus-host disease (GVHD) remains the most important complication in unrelated HSCT in thalassemia, leading to considerable rates of morbidity and mortality for a chronic non-malignant disease. A careful immunogenetic assessment of donors and recipients makes it possible to individuate appropriate strategies for its prevention and management. This review provides an overview on recent insights about immunogenetic factors involved in GVHD, which seem to have a potential role in the outcome of transplantation for thalassemia.

A New IV Busulfan Fixed Dosing as Part of BuMel or BuCy Conditioning Regimens: A Pharmacokinetic/Pharmacodynamic Study in Pediatric Patients Undergoing Autologous or Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5200-5200
Author(s):  
Gilles Vassal ◽  
Hélène Esperou ◽  
Dominique Valteau-Couanet ◽  
Jean Claude Gentet ◽  
François Doz ◽  
...  
Keyword(s):  
Body Weight ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Graft Rejection ◽  
Dose Adjustment ◽  
Fixed Dose ◽  
Hematopoietic Stem

Abstract Background: Busulfan (Bu) given in myeloablative doses is frequently included in hematopoietic stem cell transplantation (HSCT) regimens for pediatric (Ped) patients (pts). Following administration of oral Bu, plasma concentrations versus time profiles (AUC) vary considerably. Over-exposure is correlated with higher toxicities while under-exposure is associated with graft rejection. The IV formulation of Bu is demonstrated to provide reliable dosing, reducing inter- and intra-pts pharmacokinetic (PK) variability, and thus avoiding therapeutic drug monitoring (TDM) with dose adjustments. In a previous study, a new body-weight based calculation of IV Bu fixed dose was defined to target AUC (900–1500 μM.min) in children [Nguyen L et al. BMT 2004]. The PK results of a new prospective study in children have been presented earlier [Vassal G. et al, ASCO 2005; # 8535] and we report here the results of the investigated PK vs. pharmacodynamic (PK/PD) relationships. Methods: Children received either IVBu/Melphalan (Mel, 140 mg/m2) or IVBu/Cyclophosphamide (Cy, 200 mg/kg) before autologous (auto-) or allogeneic (allo-) HSCT, respectively. IV Bu was infused over 2 h at a dose of 1.0 mg/kg, 1.2 mg/kg, 1.1 mg/kg, 0.95 mg/kg, and 0.8 mg/kg for pts < 9 kg, 9 to < 16 kg, 16 to 23 kg, >23 to 34 kg, and >34 kg strata of weight, respectively. No dose adjustment was allowed. Bayesian Bu AUCs were calculated at doses 1, 9 and 13. The PK/PD analysis was carried out on engraftment and regimen-related toxicities (RRT). Results: Overall, 55 pts with a median age 6 y [0.3 – 17.2], 20 pts ≤ 4 y, were enrolled: 27 and 28 received IVBuMel and IVBuCy, respectively. Bu clearance was confirmed to be widely variable (CV=50%) however the new dosing enabled homogeneous AUCs whatever the patient’s weight, and AUC inter- pts variability was hugely reduced (CV < 20%). In allo-HSCT, all AUCs were > 900 μΜ.min (threshold value for engraftment), and there was no early and/or late graft rejection. Over-exposure was limited (all AUCs < 2100 μΜ.min) and no correlation was observed with the low incidence of VOD in allo- (2/28, 7%) and auto- (4/27, 15%) pts. Of note, 87 % and 91% of AUCs in allo- and auto- pts were < 1500 μΜ.min. In auto-pts, there was a significantly positive correlation (R2=0.35, p< 0.01) between stomatitis severity and AUC. It was also illustrated that higher AUC tended to increase bilirubin value from baseline, but the correlation was weak. No significant correlations were detected with other RRT and efficacy parameters. Conclusions: Body-weight based calculation of IV Bu fixed doses has successfully targeted a therapeutic AUC in children. The high rate of AUC targeting achieved without any PK monitoring and dose adjustment is likely to favourably contribute to the efficacy and safety in IV Bu-based HSCT regimens.

Hepatocytes of Donor Origin in Recipients Liver, after Hematopoietic Stem Cell Transplantation in BetaThalassemia Major.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4063-4063
Author(s):  
Ardeshir Ghavamzadeh ◽  
Mehrzad Mirzania ◽  
Nahid Sedighi ◽  
Marjan Yaghmaie ◽  
Naser Kamalian ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Beta Thalassemia ◽  
Hematopoietic Stem ◽  
Biopsy Specimens

Abstract Background Bone marrow and circulating stem cells contains stem cells with the potential to differentiate into mature cells of various organs. We determined whether stem cells transformed to hepathcytes. Methods Biopsy specimens from the liver were obtained from 11 patients who had undergone transplantation of hematopoietic stem cells from peripheral blood (8 patients) or bone marrow (3 patients). Four female patients had received transplants from a male donor and seven male patients had received transplants from a female donor.All patients had beta thalassemia major and fibrosis in biopsy specimens from the liver before hematopoietic stem-cell transplantation. Hematopoietic stem-cell engraftment was verified by short tandem repeat analysis. The biopsies were studied for the presence of donor-derived hepatocytes with the use of fluorescence in situ hybridization of interphase nuclei and immunohistochemical staining for CD45 (leukocyte common antigen), and a hepatocyte-specific antigen. Results All 11 recipients of sex-mismatched transplants showed evidence of complete hematopoietic donor chimerism. XY-positive hepatocytes accounted for 4 to 6.7 percent of the cells in histologic sections of the biopsy specimens of female patients. These cells were detected in liver tissue as early as 1 year and as late as 8.5 year after the hematopoietic stem cell transplantation. Conclusions Bone marrow and circulating stem cells can differentiate into mature hepatocytes in beta thalassemia major patients who undergone hematopoietic stem cell transplantation.

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