Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.69 (BMT)
2,655 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Busulphan (BU) pharmacokinetic (PK) studies in children undergoing bone marrow transplantation suggest that individual BU dosing may be necessary to optimise BU systemic exposure. Optimising BU systemic exposure may improve outcome and decrease toxicity in BMT. Because of practical limitations in obtaining blood from children and for financial reasons, a limited sampling method (LSM) is needed. However, such methods for BU have not been validated in children. In the present study, we individualized oral BU dosing in 10 children to target an area under the curve of BU (BU AUC) of 900-1400 microM/min based on BU AUC(0-infinity) calculated from nine serum BU concentrations performed after a BU test dose of 40 mg/m2. We validated a LSM using 3 BU concentrations to determine AUC. Six of nine patients studied (one patient non-evaluable), required their doses modified (3, lower; 3, higher). The mean percent dose change was 26.2% (range -33.3% to +45.3%). Our three sample LSM BU AUC(0-infinity) (1098 +/- 344, mean +/- 1 s.d.) correlated highly with our nine sample BU AUC(0-infinity) (1132 +/- 389, Pearson r = 0.98, P = 0.0001) and was not significantly different by t-test (P = 0.3). The mean percentage difference between the three sample LSM AUCs and the nine sample AUCs in each of our patients was 7.5%, (range -10.99% to +9.4%). Trough levels correlated extremely well with AUC (r = 0.95, P = 0.0001). Individual BU dosing, based on AUC, is necessary in most children to achieve targeted levels of BU therapy. An LSM of three BU concentrations performed at 0.5 h, 1 h and 6 h post-BU test dose closely predicts the AUC calculated from nine sampling points.
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PMID:An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children. 933 48

The aim of this study was to investigate the importance of busulfan concentrations for short- and long-term survival in autologous (ABMT) and allogeneic (BMT) bone marrow transplant recipients. One hundred and seventy-three patients were included in the study; 87 ABMT and 85 BMT patients. All patients received busulfan 1 mg/kg four times daily for 4 days followed by cyclophosphamide 60 mg/kg/day for 2 days. Busulfan concentrations were measured and the mean concentration calculated for each patient. There was no difference in busulfan concentrations between BMT and ABMT patients. Patients who died before day 100 had significantly higher busulfan concentrations than patients surviving beyond day 100 (719 ng/ml vs 589 ng/ml; P < 0.02). BMT patients who had busulfan concentrations in the highest quartile had significantly worse disease-free survival (DFS) and survival compared to other patients. The transplant-related mortalities (TRM) at 100 days were 29 and 14% in patients in the highest quartile and remaining patients, respectively. There was no difference in relapse incidence. High busulfan concentrations were associated with increased TRM but no difference in either survival or DFS could be found for the ABMT patients. Monitoring of busulfan concentrations is important in reducing the risk for TRM in patients undergoing bone marrow transplantation.
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PMID:High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. 942 68

The pharmacokinetics of busulphan were studied in 23 thalassaemic children undergoing BMT. Patients received busulphan at a dose of either 16 mg/kg with cyclophosphamide and ATG (Group A) or 600 mg/m2 (with cyclophosphamide alone) (Group B) in 16 divided doses every 6 h over 4 days. Busulphan levels were analyzed by a modified GC-MS method. The dose of busulphan/kg for patients in group B was 64% (range 56-71%) higher than that for patients in group A. The mean AUC, Css, Cmax and MRV were significantly higher in group B as compared with group A for both doses 1 and 13. There was no significant difference in Vd/F, T1/2 and Kel between the two groups. A significant decrease in AUC and Css was found between 1st and 13th doses in group B, but not in group A. The Cl/F values in group A were significantly higher than those in group B after dose 1, but not after dose 13. No increase in toxicity due to the higher dose of busulphan was noted. We conclude that busulphan at 600 mg/m2 results in much higher systemic exposure to the drug as compared to 16 mg/kg, without increase in toxicity in children with beta thalassaemia major.
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PMID:Pharmacokinetics of oral busulphan in children with beta thalassaemia major undergoing allogeneic bone marrow transplantation. 1043 27

Longitudinal studies of growth and endocrine function of children with AML transplanted with BUCY are limited. We report a cohort of 23 children with AML transplanted (15 autologous and eight allogeneic) following a single chemotherapy protocol and surviving at least 2 years after BMT. Busulfan was given as a single daily dose. Growth and endocrine function was evaluated yearly from one up to 10 years post transplant (median 4.9 years). The mean height standard deviation score (HtSDS) of the entire group decreased from 0.01 (s.e.m. +/- 0.25) at diagnosis to -0.38 (+/- 0.28) at BMT (P = 0.001). There was no statistically significant difference between HtSDS at BMT and yearly HtSDS from 1 to 5 years post BMT. There was no significant relationship between age at BMT and subsequent change in HtSDS. To date, five of six girls have needed sex steroid replacement. Six of 12 evaluable boys had abnormal gonadotrophins, but none required sex steroid replacement. Children with AML who undergo BMT with BUCY show no significant growth impairment, but gonadal dysfunction is prominent, particularly in girls. Bone Marrow Transplantation (2000).
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PMID:Growth and endocrine function in children with acute myeloid leukaemia after bone marrow transplantation using busulfan/cyclophosphamide. 1082 70

Four hundred and twenty-nine patients received myeloablative chemotherapy for solid and haematological malignancies in a bone marrow transplantation unit. Regimens appropriate to the tumour type were administered and haemopoietic reconstitution was achieved with peripheral blood progenitor cells (PBPC; n = 275), autologous bone marrow (auto-BMT; n = 69) or allogeneic bone marrow (allo-BMT; n = 85). World Health Organization (WHO) oral mucositis scores were collected prospectively from the start of chemotherapy (d 1) until d 28 or discharge. Oral mucositis (OM) was experienced by 425 (99%) patients and in 289 (67.4%) this was grade III or IV. Strong opiate analgesia was prescribed for a median of 6 d to 47% of patients. Univariate analysis suggested that the area under the OM curve (AUC; sum of daily mucositis grades, d 1-28) was associated with the myeloablative regimen, haemopoietic progenitor source (PBPC > allo-BMT > auto-BMT), use of myeloid growth factors and age. Multivariate analysis showed that the only independent risk factor for mucositis was the conditioning regimen (P < 0.00005). The mean OM AUC for high-dose melphalan (HDM) regimens (52 grade-days) exceeded busulphan (41), busulphan-cyclophosphamide (35), cyclophosphamide-total body irradiation (TBI) (34), cyclophosphamide-carmustine (BCNU) (20) and cyclophosphamide-etoposide-carmustine (CVB) (19). HDM regimens resulted in the highest mean peak OM (3.6), followed by busulphan regimens (2.6), cyclophosphamide/TBI (2.3) and cyclophosphamide-carmustine and CVB (1.4). Busulphan produced significantly delayed OM (median 3 d; P < 0.00005). There was a linear association between the area under the OM curve for each treatment group and the time to reach grade 3 OM (P < 0.00005), but no association with the time to reach grade 4 neutropenia (P = 0.24) or thrombocytopenia (P = 0.73), implying that haematological and mucosal toxicity are not associated. The cytotoxic regimen is the most significant determinant of OM. Studies investigating agents to ameliorate mucosal toxicity should be stratified according to cytotoxic regimen.
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PMID:Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. 1097 84

In order to control busulfan pharmacokinetic variability and toxicity, a specific monitoring protocol was instituted in our bone marrow transplant BMT paediatric patients including a test dose, daily Bayesian forecasting of busulfan plasma levels, and Bayesian individualization of busulfan dosage regimens. Twenty-nine children received BMT after a busulfan-based conditioning regimen. Individual pharmacokinetic parameters were obtained following a 0.5 mg*kg test dose and were used for daily individualization of dosage regimens during the subsequent 4-day course of treatment. Doses were adjusted to reach a target mean AUC per 6 h between 4 and 6 microg.h.ml(+1). Plasma busulfan assays were performed by liquid chromatography. Pharmacokinetic analysis used the USC*PACK software. The performance of the test dose to predict AUC during the busulfan regimen was evaluated. Incidence of toxicity, chimerism and relapse, overall Kaplan-Meier survival, and VOD-free survival were compared after matching our patients (group A) with patients conditioned by using standard doses of busulfan (group B). Busulfan doses were decreased in 69% of patients compared to conventional doses. Expected AUC was significantly correlated with observed AUC and predictability of the test dose was 101.9 +/- 17.9%. Incidence of VOD in group A was 3.4% vs 24.1% in group B, while the incidence of stomatitis was similar. Engraftment was successful in all patients in group A. The rate of full engraftment at 3 months post-BMT was higher in group A (P = 0.012). Long-term overall survival did not differ between the two groups, in contrast to the 90-day survival. VOD-free survival was higher in group A (P = 0.026). Pharmacokinetic monitoring and individualization of busulfan dosage regimen are useful in improving clinical outcome and reducing early mortality in paediatric bone marrow transplant recipients.
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PMID:Improved clinical outcome of paediatric bone marrow recipients using a test dose and Bayesian pharmacokinetic individualization of busulfan dosage regimens. 1178 25

Allogeneic SCT remains the only potential cure for patients with thalassemia. However, most BMT candidates lack a suitable family donor and require an unrelated donor (UD). We evaluated whether BMT using UDs in high-risk adult thalassemia patients can offer a probability of cure comparable to that reported employing an HLA-compatible sibling as donor. A total of 27 adult thalassemia patients (15 males and 12 females, median age 22 years) underwent BMT from a UD selected by high-resolution HLA molecular typing. The conditioning regimen consisted of Busulphan (BU, 14 mg/kg) plus Cyclophosphamide (CY, 120 or 160 mg/kg) in 12 cases and BU (14 mg/kg), Thiotepa (10 mg/kg) and CY (120-160 mg/kg) in the remaining 15 cases. Cyclosporine-A and short-term Methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. In all, 19 patients (70%) are alive and transfusion-independent after a median follow-up of 43 months (range 16-137). A total of 10 patients (37%) developed grade II-IV acute GVHD and six (27%) chronic GVHD. Eight patients (30%) died from transplant-related causes. UD-BMT can cure more than two-thirds of adult thalassemia patients, and is a particularly attractive option for patients who are not compliant with conventional treatment.
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PMID:Unrelated donor stem cell transplantation in adult patients with thalassemia. 1620 30

To investigate the efficacy and feasibility of parent non-T cell depleted haploidentical bone marrow transplants (haploidentical BMT) for children with leukemia, the efficacy of haploidentical BMT was evaluated in 8 leukemia children (1.9-9 years) received hematopoietic stem cell transplantation, donors were their parents with HLA-mismatched for two or three loci. Five children were pre-conditioned with a myeloablative regimen consisting of high-dose cytarabine (Ara-C), cyclophosphamide (CY) and total body irradiation. Busulfan (BU), Ara-C and CY were used for preconditioning regimen in other three children. The donors were given G-CSF prior to marrow harvest and the non-T-cell depleted grafts were used. A combination of CsA, MTX, ATG, mycophenolate mofetil (MMF) and CD25 monoclonal antibody were used for GVHD prophylaxis. The results showed that rapid engraftment was observed in all cases after transplantation by cytogenetic evidence. The mean time of neutrophil count exceeded 0.5 x 10(9)/L and the mean time of platelet count exceeded 20 x 10(9)/L were 16 and 17 days after transplantation respectively. Incidence of lethal aGVHD was lower, II-III acute aGVHD was found only in one out of eight patients. Chronic GVHD was observed in five patients, 4 from which showed local cGVHD, one developed extensive cGVHD. During the follow-up of 33 months (range 7-56 months), two patients died from relapsed leukemia, including one relapsed as donor-origin leukemia. Disease-free survival was achieved in the remaining six patients. No death occurred during the follow-up of 6 months. It is concluded that above-mentioned preconditioning regimen and GVHD prophylaxis procedure in non-T-cell depleted bone marrow transplantation from HLA-mismatched parents are effective approaches and safe strategy for the treatment of children leukemia.
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PMID:[Clinical investigation on treatment of children leukemia with non-T-cell depleted haploidentical bone marrow transplantation]. 1831 10


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