High-dose Oral Busulfan Research Articles

Non‐transferrin‐bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload

Non‐transferrin‐bound iron and oxidative stress during allogeneic hemopoietic stem cell transplantation in patients with or without iron overload

Pharmacokinetic and Pharmacogenetic Analysis of Oral Busulfan in Stem Cell Transplantation: Prediction of Poor Drug Metabolism to Prevent Drug Toxicity

High dose busulfan (BU) has become a mainstay in conditioning regimens for hematopoietic stem cell transplantation (HSCT), despite its unpredictable response, narrow therapeutic index and severe toxicity. The present study provides an integration of pharmacokinetic and genetic data of 63 adults with acute myeloid leukemia (AML) preconditioned for HSCT with high dose oral BU, with the aim of defining biomarkers predictive of poor BU metabolism. BU area under the concentration time curve (AUC) demonstrated that 76% of the patients achieved target AUC; 24% required dose modification. The main findings of this study were: (1) AML patients carrying the GSTP1 rs1695 variant allele were at risk of developing supra-therapeutic BU-AUC due to reduced BU clearance. (2) Combined polymorphisms in GSTM1 and ABCB1 were associated with BU clearance and AUC rates. In conclusion, GST and ABCB1 genotyping may assist care-givers in personalizing BU dosage with less trial-and-error and may enable preemptive identification of patients at risk for BU toxicity.

Treatment of Myelofibrosis Using I.V. Treosulfan and Autologous Peripheral Blood Progenitor Cell Transplantation Is Feasible and Results in Hematologic Responses – Long-Term Follow-up and Final Analysis of a One-Armed Clinical Study and of Individual Cases

Abstract 4514 Introduction:Myelofibrosis with myeloid metaplasia is a chronic myeloproliferative disorder. The only curative therapy to date is myeloablation followed by allogeneic transplantation. Autologous transplantation after myeloablation with high-dose oral busulfan provides a palliative approach which might lead to a long-term relief of symptoms of the disease and is associated with acceptable morbidity and mortality (Anderson et al., Blood, 2001; 98:586–593). However, busulfan pharmacokinetics after oral administration can vary among patients. On the other hand treosulfan, a bi-functional alkylating drug, can be administered safely i.v. with reliable pharmacokinetics and might be suitable for conditioning of patients with myelofibrosis. Methods and Results:In a pilot phase, we treated three patients on an individual basis with an autologous transplantation after myeloablation with treosulfan. Following the encouraging results we initiated a clinical trial. Included were patients with myelofibrosis and a high risk disease according to the 1997 criteria of Cervantes. The study is registered at www.kompetenznetz-leukaemie.de.As of today we have transplanted 11 patients according to the protocol, 9 in Heidelberg, 1 at the Diakoniekrankenhaus Rotenburg and 1 at the University Hospital Rostock. Age at transplantation ranged from 50 to 69 years. For 10 of 11 patients we have been successful in collecting more than 5×106 CD34+ cells/kg body weight (one patient with 4,9 ×106) after mobilization with G-CSF at 16 μg/kg BW s.c. daily for 4 days. The conditioning regimen was treosulfan for three days (total dose 42 g/m2). Hematologic reconstitution was considerably protracted with a median of 26 days (leucocyte count > 1/nl) compared to autologous transplantation for other indications. One patient died on day 34 post transplantation after cerebral hemorrhage. He suffered from severe transfusion refractory thrombocytopenia already before the transplantation.The twelve-month follow-up showed symptomatic relief, mostly as freedom from transfusions in 7 of 11 patients. The two survivors are alive after 9 years, one with allogeneic transplantation 2 years and the other with allogeneic transplantation 8 years after autologous transplantation. The median survival of the other 9 patients was 3.5 years after autologous transplantation (0.1 – 7.5 years). Conclusions:We conclude that myeloablation with treosulfan and autologous PBPCT for patients with myelofibrosis can provide significant palliation. It is associated with an acceptable morbidity and mortality, taking into account the high-risk nature of the disease. The approach is feasible for high-risk patients that cannot or chose not to undergo allogeneic transplantation. Disclosures:Buss:medac GmbH: Research Funding. Off Label Use: Treosulfan, off-label use as an agent for high-dose chemotherapy with subsequent autologous stem cell transplantation. Topaly:medac GmbH: Research Funding. Fruehauf:medac GmbH: Research Funding.

High Dose Oral Busulfan and Intravenous Melphalan as Conditioning Therapy for Autologous Hematopoietic Stem Cell Transplant (HSCT) for the Treatment of Pediatric Solid Tumors

High Dose Oral Busulfan and Intravenous Melphalan as Conditioning Therapy for Autologous Hematopoietic Stem Cell Transplant (HSCT) for the Treatment of Pediatric Solid Tumors

Population Pharmacokinetics of Oral Busulfan in Young Japanese Children Before Hematopoietic Stem Cell Transplantation

The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.

Home administration of high-dose oral busulfan in patients undergoing hematopoietic stem cell transplantation

We report our experience with oral busulfan (BU) in 159 consecutive patients to evaluate the safety of home administration. Patients received a myeloablative BU-containing regimen, including oral anticonvulsant and antiemetic prophylaxis, followed by hematopoietic stem cell transplantation. Comprehensive verbal and written education was provided. Pharmacokinetic monitoring was performed and dose adjustments were made to target an area under the plasma concentration-time curve (AUC) of 900-1500 micromol.min/l. Safety was assessed by evaluating therapy-related toxicities, including seizures, venoocclusive disease (VOD) and patient tolerability. The utilization of pharmacokinetic monitoring was reviewed as a secondary end point. Of the 143 patients evaluated for BU-related seizures and VOD, only two (1.4%) experienced a generalized seizure and four patients (3%) were diagnosed with VOD. VOD resolved in three patients and was a contributing cause of death in one patient. Additional BU dosing owing to nausea and/or vomiting occurred in 28 patients (18%) and five patients (3%) were hospitalized. The median measured AUC was 1405 micromol.min/l, 68% of patients required a dose adjustment, and the median total administered BU dose was 13.6 mg/kg. In conclusion, high-dose oral BU can be safely administered on an outpatient basis.

Influence of glutathione S-transferase A1 polymorphism on the pharmacokinetics of busulfan

Background High-dose oral busulfan is used for myeloablative chemotherapy before hematopoietic stem-cell transplantation. Fatal adverse effects or relapse may occur with excess or insufficient busulfan exposure. Glutathione S-transferase (GST) A1, whose genetic polymorphism in its promoter region has been reported, is responsible for busulfan metabolism. We investigated the polymorphism of GSTA1 on busulfan pharmacokinetics. Methods Blood samples (6 or 7 points) were taken from patients receiving high-dose oral busulfan (approximately 1 mg/kg every 6 h) on Doses 1 and 5. Pharmacokinetic parameters were calculated from plasma busulfan concentration. Results Twelve patients were enrolled in this study. Nine patients were genotyped as wildtype (GSTA1 ⁎A/ ⁎A), and 3 as heterozygous variants (GSTA1 ⁎A/ ⁎B). At Dose 5, the heterozygous group had significantly lower elimination constant (0.176 ± 0.038 vs. 0.315 ± 0.021 h-1; P = 0.008) and clearance corrected by bioavailability (0.118 ± 0.013 vs. 0.196 ± 0.011 l/h/kg; P = 0.004), and significantly higher mean plasma busulfan concentration (1344 ± 158 vs. 854 ± 44 ng/ml; P = 0.001) than the wildtype. Conclusions This is the first report on the significant influence of GSTA1 polymorphism on busulfan elimination. This may account for the large inter-individual variance in busulfan pharmacokinetics, and with more information confirming our study, busulfan high-dose therapy may be optimized by GSTA1 genotyping in advance.

Pulmonary Mortality after High-Dose Oral Busulfan and Autologous Stem Cell Transplant (ASCT) in Patients with Non-Hodgkin Lymphoma (NHL).

Many high-dose chemotherapy preparative regimens include agents known to cause pulmonary toxicity such as BCNU. Chemotherapy induced pulmonary toxicity may be fatal. From 1/1/93 to 12/31/04 we treated 533 NHL patients with oral busulfan 14mg/kg, VP-16 60 mg/kg, and cyclophosphamide 120 mg/kg followed by ASCT. Busulfan levels were not measured. We have followed these patients for toxicity, survival, and cause of death (COD). Of these 533 patients, 214 have died, and 53 have died without relapse (15%). Most patients (n=329; 62%) had intermediate grade NHL by the IWF system. The median age was 50 years (range, 16–77) and 43% had a history of smoking. Radiotherapy was delivered to 27% and less than 3 chemotherapy regimens were administered to 75% of patients before ASCT. Sixteen patients (3%) died of non-relapse pulmonary complications. The median time to pulmonary mortality was 5 months (range, 2.5 – 21.4 months). We routinely screen patients with pulmonary function tests including DLCO before ASCT and most patients (n=490; 92%) were screened at a median of 45 days after ASCT (range, 7–90 days). For patients for whom data was available, there was no significant decrease in the median pre-ASCT and the post-ASCT DLCO in the either the whole cohort of patients or the patients dying of pulmonary complications. However, a lower baseline DLCO before ASCT predicted for pulmonary mortality after ASCT in univariable and multivariable analysis. Patients with a baseline DLCO <94% predicted, had an increased risk of pulmonary mortality compared to patients with a baseline DLCO ≥94% predicted (p=0.016). Other significant risk factors included older age, lower baseline FEV1, prior radiotherapy, and longer time from diagnosis to ASCT. A history of smoking and disease status at the time of ASCT did not predict for pulmonary mortality. Because patients died of pulmonary complications at other institutions, we could neither determine treatment, nor confirm chemotherapy induced pulmonary toxicity. However, the early onset of pulmonary mortality after ASCT suggests the possibility of a toxic insult. Busulfan is a known pulmonary toxin, but the dose in this series of patients is relatively low and we have not seen similar pulmonary complications in 95 patients (median age 52 years) with myeloma treated with the combination of busulfan 16 mg/kg and cyclophosphamide 120mg/kg. Nonetheless, caution is warranted for older patients being treated with high-dose oral busulfan.

Myeloablative Conditioning in Myelofibrosis using i.v. Treosulfan and Autologous Peripheral Blood Progenitor Cell Transplantation with High Doses of CD34+ Cells Results in Hematologic Responses - Follow-Up of Three Patients.

Myelofibrosis with myeloid metaplasia is a chronic myeloproliferative disorder. The only curative therapy to date is myeloablation followed by allogeneic transplantation. This approach, however, is associated with a high morbidity and mortality. Autologous transplantation after myeloablation with high-dose oral busulfan provides a palliative approach which can lead to a long-term relief of symptoms and is associated with acceptable morbidity and mortality (Anderson JE et al. 2001, Blood 98: 586). However, busulfan pharmacokinetics after oral administration can vary between patients and increased toxicity is encountered in some. On the other hand treosulfan, a bi-functional alkylating drug, can be administered safely i.v. with reliable pharmacokinetics up to the myeloablative dose range. In the study presented here, patients were stimulated with G-CSF 16 μg/kg daily for 4 days and subsequent leukapheresis of a minimum of 5 x 106 CD34+ cells/kg was performed. Myeloablation consisted of treosulfan infusions of 14 g/m2 for three consecutive days (total dose 42 g/m2) and subsequent autologous PBPCT. To date we have transplanted 3 patients, all female. Two patients (#1, #3) had symptomatic splenomegaly and severe anemia. Patient #2 had symptomatic splenomegaly and thrombocytopenia (< 100/nl). The WB nadir after treosulfan therapy was 0.06/nl (#1), 0.28/nl (#2) and 0.09/nl (#3). The time to reconstitution of leucocytes > 1/nl post transplantation was 28 days (#1, #2) and 38 days (#3) and the time for reconstitution of thrombocytes > 50/nl was 36 (#1), 22 (#2) and 33 (#3) days. The prolonged reconstitution period may have been due to the myelofibrosis and has also been observed after busulfan conditioning and PBPCT by others. There were no fever or other severe toxicity. Patients did not require total parenteral nutrition. The patients have been followed-up for 18 months post transplantation, now. The first patient (#1), who required erythrocyte transfusions twice weekly pretransplant received her last erythrocyte transfusion on day 56; her Hb-value is 11.2 g/dl at last follow-up. The second patient (#2) recovered to platelet counts higher than pre-transplantation (58/nl) at 3 months.(143/nl) and had 103/nl at last follow-up. Pat. #3 showed a marked reduction of max. spleen size and a rise in Hb from 9 g/dl to 12 g/dl after 12 months, the Hb value at 18 months is 8.7 g/dl and allogeneic transplantation is considered now. We conclude that myeloablation with treosulfan and autologous PBPCT in these three patients with myelofibrosis was safe and useful. Survival of these patients is promising up to date. The results presented warrant further exploration of this approach in a clinical study which has been initiated by our group. (cf. http://leukaemie.krebsinfo.de/kn_home/Studien/studie_101.html).

Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation.

We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean +/- SD, 1.21 +/- 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4-12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis.

Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies.

We investigated whether adjusting the oral busulfan (BU) dosage on the basis of early pharmacokinetic data to achieve a targeted drug exposure could reduce transplant-related complications in children with advanced hematologic malignancies. Twenty-five children received a preparative regimen consisting of thiotepa (250 mg/m2 i.v. daily for 3 days), BU (40 mg/m2 per dose p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily for 2 days) and then underwent allogeneic stem cell transplantation. Busulfan clearance and area under concentration time-curve (AUC) were determined after the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000-1500 microM x min/dose was targeted and subsequent doses were modified as necessary to achieve this value. Fourteen of the 25 patients (56%) required dose adjustment. Follow-up PK analysis was completed in 21 patients and 16 of these achieved the targeted BU exposure for the course of therapy. Interpatient variability in BU clearance was high (up to five-fold). The most frequent regimen-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea). Only one patient developed hepatic veno-occlusive disease. Our study demonstrates the feasibility of adjusting the oral BU dose in individual pediatric patients. Although toxicity associated with BU seemed to be reduced, this conclusion is tempered by the fact that the overall regimen-related toxicity (RRT) remains substantial and reflected the effects of all agents used in the preparative regimen.