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PubMed1998

Ovarian function after autologous bone marrow transplantation in childhood: high-dose busulfan is a major cause of ovarian failure.

We studied pubertal status and ovarian function in 21 girls aged 11-21 years who had earlier received 1.2-13 years (median 7 years) high-dose chemotherapy and autologous BMT without TBI for malignant tumors. Ten of them were given busulfan (600 mg/m2) and melphalan (140 mg/m2) with or without cyclophosphamide (3.6 g/m2). Eleven others did not receive busulfan. Twelve girls (57%) had clinical and hormonal evidence of ovarian failure. Among nine others who had completed normal puberty, six had normal gonadotropin levels, one had elevated gonadotropin levels and two had gonadotropin levels at the upper limit of normal. The 10 girls who received busulfan all developed severe and persistent ovarian failure. High-dose busulfan is therefore a major cause of ovarian failure even when given in the prepubertal period. These findings emphasize the need for long-term endocrine follow-up of these patients in order to initiate estrogen replacement therapy.

Adolescent↗
PubMed2001

Accidental busulfan overdose: enhanced drug clearance with hemodialysis in a child with Wiskott-Aldrich syndrome.

A 4.6 kg infant with Wiskott-Aldrich syndrome received an accidental overdose of busulfan during preparation for allogeneic stem cell transplantation. Pharmacokinetic analysis of plasma busulfan levels alerted staff to the dosing error. Hemodialysis was immediately performed and resulted in accelerated clearance of busulfan. There were no acute neurologic and hepatic side-effects of the busulfan overdose, and despite 2 months of cough accompanied by rales, the patient is now free of pulmonary symptoms. Stable partial donor chimerism occurred after transplantation. At present, the patient is thriving and infection-free 12 months after transplantation, although his platelet count remains at the lower limit of normal.

Area Under Curve↗
PubMed2001

Evaluation of existing limited sampling models for busulfan kinetics in children with beta thalassaemia major undergoing bone marrow transplantation.

Busulfan pharmacokinetic parameters are useful in predicting the outcome of allogeneic bone marrow transplantation (BMT). Standard pharmacokinetic measurements require multiple blood samples. Various limited sampling models (LSM) have been proposed for reducing the sample number required for these measurements, essentially for patients with malignant disorders undergoing BMT. This study was undertaken to evaluate the existing LSM for busulfan pharmacokinetics to find out the most suitable method for patients with thalassaemia major undergoing BMT. Busulfan levels in plasma samples were analysed by HPLC. The AUC calculated by non-compartmental analysis using the program 'TOPFIT' was compared with previously published LSMs. Our seven sample pharmacokinetic data for AUC calculation was compared with the published LSMs. The three sample models suggested by Chattergoon et al and Schuler et al showed significant agreement with AUC TOPFIT (R(2) = 0.98 and 0.94, respectively) in our clinical context. Other models resulted in significant over or under representation of observed values (Vassal's model R(2) = 0.61; Chattergoon's two sample model R(2) = 0.84; four sample model R(2) = 0.83; Schuler's two sample model R(2) = 0.79). By these data the three sample LSM proposed by Chattergoon et al and Schuler et al are suitable for calculation of the AUC in patients with thalassaemia major undergoing BMT conditioned with oral busulfan.

Adolescent↗
PubMed2003

Intravenous busulfan for allogeneic hematopoietic stem cell transplantation in infants: clinical and pharmacokinetic results.

SUMMARY: High-dose busulfan is an important component of myeloablative regimens. Variable drug exposure may occur following oral administration. Therefore, the use of intravenous busulfan has been advocated. Previous work has suggested a cumulative dosage of 16 mg/kg for haematopoietic transplantation in children less than 3 years of age, but only limited data are available in infants. Pharmacokinetics of intravenous busulfan administered at the suggested dosage were studied in 14 infants (median age 4.7 months). Busulfan plasma concentrations were measured by either GC-MS or HPLC-UV. In seven patients, the dose was decreased to target an area- under- the- curve of 600-1300 micromol min. The median total dose given was 13.8 mg/kg. All patients engrafted. Severe veno-occlusive disease occurred in one patient. Our study demonstrates that a cumulative dosage of 16 mg/kg is associated with higher exposure than expected in infants. We suggest an initial dose of 0.8 mg/kg followed by pharmacokinetically guided dose adjustment.

Area Under Curve↗
PubMed2006

Population pharmacokinetics of intravenous busulfan in patients undergoing hematopoietic stem cell transplantation.

A population pharmacokinetic analysis was performed in 30 patients who received an intravenous busulfan and cyclophosphamide regimen before hematopoietic stem cell transplantation. Each patient received 0.8 mg/kg as a 2 h infusion every 6 h for 16 doses. A total of 690 concentration measurements were analyzed using the nonlinear mixed effect model (NONMEM) program. A one-compartment model with an additive error model as an intraindividual variability including an interoccasion variability (IOV) in clearance (CL) was sufficient to describe the concentration-time profile of busulfan. Actual body weight (ABW) was found to be the determinant for CL and the volume of distribution (V) according to NONMEM analysis. In this limited study, the age (range 7-53 years old; median, 30 years old) had no significant effect on busulfan pharmacokinetics. For a patient weighting 60 kg, the typical CL and V were estimated to be 8.87 l/h and 33.8 l, respectively. The interindividual variability of CL and V were 13.6 and 6.3%, respectively. The IOV (6.6%) in CL was estimated to be less than the intraindividual variability. These results indicate high interpatient and intrapatient consistency of busulfan pharmacokinetics after intravenous administration, which may eliminate the requirement for pharmacokinetic monitoring.

Adolescent↗
PubMed1985

Antifertility effect of busulfan and procarbazine in male and female coyotes.

Antifertility effects of two cytostatic agents, busulfan and procarbazine, were evaluated using 43 captive breeding pairs of adult coyotes. Nineteen pairs served as untreated controls. Only the male or female of remaining pairs was treated. Females received either 8 mg busulfan/kg or 6 mg procarbazine/kg just prior to onset of the breeding season. Males were treated once with either 8 mg busulfan/kg just before onset of breeding or with 4 mg busulfan/kg or 6 mg procarbazine/kg about 1 mo before onset of the breeding season. Uterine implantation sites were counted in females of all breeding pairs postpartum via laparotomy. Busulfan given to males at 4 mg/kg or to either females or males at 8 mg/kg significantly reduced implantation sites compared to untreated controls. Thus, busulfan may be successful in controlling population in coyotes in the field where both the male and female of a breeding pair may ingest the compound. However, multiple doses at a lower rate would be preferred because dosages greater than 10 mg/kg resulted in mortality. Although procarbazine has a mode of action similar to busulfan, doses of 6 mg procarbazine/kg did not reduce implantation sites or disrupt normal spermatogenesis. Increased doses need to be evaluated before effectiveness of procarbazine for coyote population control can be determined.

Animals↗
PubMed1997

Measurement of plasma busulfan concentration by high-performance liquid chromatography with ultraviolet detection.

Busulfan is widely used in bone marrow transplantation. Increased area under the plasma concentration curve has been shown to correlate with venoocclusive disease, which occurs in approximately 20% of these patients. The authors developed a high performance liquid chromatography assay for the determination of plasma busulfan concentration using ultraviolet detection and a single-step derivatization and extraction. The absolute retention times of busulfan and the internal standard were 2.8 and 5.6 min, respectively. The assay possessed linearity up to 200 mumol/l, sensitivity to at least 0.2 mumol/l, average recovery of 101%, and run-to-run precision (n = 34) of < 7%. Furthermore, the assay proved to be free of interference from 59 medications and correlated highly with a validated method employing gas chromatography with electron capture detection (slope = 0.90, intercept = 0.17, r = 0.98, n = 31). The authors conclude that the method described here is ideally suited for the therapeutic monitoring of busulfan.

Busulfan↗
PubMed1985

Pretransplant conditioning with busulfan (Myleran) and cyclophosphamide for nonmalignant diseases. Assessment of engraftment following histocompatible allogeneic bone marrow transplantation.

Four pediatric patients with diseases potentially curable by bone marrow transplantation (BMT)--i.e., common variable immune deficiency, Wiskott-Aldrich Syndrome (WAS), mucopolysaccharidosis type VI, and mucopolysaccharidosis type I received a conditioning regimen consisting of busulfan and cyclophosphamide prior to BMT from HLA-identical, mixed leukocyte culture (MLC)-unreactive siblings. Only one of the four patients achieved full engraftment. Of the remaining three patients, one experienced failure of engraftment, and two had persistent mixed chimerism. Although no serious complications were directly related to the preparative therapy, the doses of busulfan and cyclophosphamide previously described to be adequate for conditioning children with WAS were completely effective in only one of three pediatric patients in this series. Despite a higher dose of busulfan (16 mg/kg), mixed chimerism was observed in a subsequent patient. Of 13 evaluable patients in the literature in whom busulfan and cyclophosphamide had been used as preconditioning regimens for a variety of nonmalignant conditions, eight demonstrated lack of complete and sustained engraftment. On the other hand, clinical improvement has accompanied partial engraftment in some cases. We conclude that additional immunosuppressive and/or myeloablative conditioning is necessary if complete engraftment is attempted in histocompatible allogeneic BMT for many of the nonmalignant disorders.

Adolescent↗
PubMed2003

Fludarabine and once-daily intravenous busulfan for allogeneic bone marrow transplantation for Chediak-Higashi syndrome.

An HLA-identical sibling bone marrow transplant was done for a patient with Chediak-Higashi syndrome. The preparative regimen included intravenous fludarabine (40 mg/m2/dx4) and busulfan (130 mg/m2/dx4). Busulfan was given once daily. Pharmacokinetic studies showed the area under the concentration-time curve of the once-daily intravenous busulfan was similar to that seen with the total daily dose administered with an every-6-hourly regimen. Toxicity was minimal. Myeloid engraftment occurred on day +17 and donor chimerism was complete. Fludarabine and once-daily intravenous busulfan is well tolerated and is adequate for engraftment of sibling transplant in Chediak-Higashi syndrome.

Bone Marrow Transplantation↗
PubMedDate not supplied

Evolution of somatic and germ cell populations after busulfan treatment in utero or neonatal cryptorchidism in the rat.

In order to elucidate the respective effects of depletion of germ cells and of increase in testicular temperature, rats of the same Wistar strain were rendered experimentally bicryptorchid or sterilized by a busulfan injection in utero and compared to control animals. In both models, germ cells were depleted but numeric evolution and functions of somatic cells differed. The aim of that work was to compare the numeric evolutions of testicular somatic and germ cells to their respective functions in each model before puberty and in adult rats of the same strain. Serum concentrations of FSH, LH and testosterone were compared at 20, 40 and 110 days of age. Histological analyses of Sertoli and germ cells in the seminiferous tubules and of Leydig cells in the intertubular tissue were performed before puberty and at adulthood. Testosterone serum concentrations were depleted in both models starting at 40 days of age and more in busulfan-treated rats. Both FSH and LH levels were increased from 20 days onwards in experimental rats. Additional cryptorchidism in busulfan-treated rats depressed the serum testosterone concentration. At 17 days of age, the cryptorchidism do not modify somatic or germ cell populations while busulfan treatment has induced a decrease of both these populations. Conversely, the cross sectional area of the somatic testicular cells was not affected whatever the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed2006

Induction of glutathione synthesis explains pharmacodynamics of high-dose busulfan in mice and highlights putative mechanisms of drug interaction.

Busulfan is an example of a drug eliminated through glutathione S-transferase (GST)-catalyzed conjugation with reduced glutathione (GSH). We studied the pharmacokinetics and toxicity of busulfan in C57BL6 mice in correlation with liver GST activity and GSH synthesis by accurate determination of precursors, namely, gamma-glutamyl-cysteine and cysteine. A significantly lower incidence of acute toxicity was observed in mice receiving busulfan 16.5 mg/kg twice a day compared with animals receiving 33 mg/kg once a day. In both cases, a total dose of 132 mg/kg was administered over 4 days. The difference in toxicity was explained by pharmacokinetics since a strong induction of clearance was observed only in animals treated twice daily. Induction of metabolism was correlated with an increase in liver cysteine content and enhanced glutathione synthesis rate, whereas GST activity was unchanged. To our knowledge, this is the first time that in vivo flux of GSH synthesis has been shown to be closely related to a drug plasma clearance and toxicity. These results allow hypothesizing that GSH liver synthesis may directly influence busulfan clearance in humans with possible implications in the occurrence of hepatic veno-occlusive disease.

Animals↗
PubMed1985

The effect of prenatal treatment with busulfan on in vitro androgen production by testes from rats of various ages.

Treatment of rats with busulfan in utero severely depletes the germ cell population of the seminiferous tubules. These studies have examined the in vitro capacity of testicular tissue and Leydig cells from such testes to secrete androgens. Leydig cells were identified by staining for 3 beta-hydroxy steroid dehydrogenase. Rats were studied at several ages to identify any developmental changes in the androgen-secreting capacity of control and treated gonads. At 30 days of age, no effect of treatment on serum androgen was found. At 60 and 90 days of age, treatment caused decreased androgen and increased LH content of the serum. At 12, 30, 60, and 90 days of age, the amount of androgen secreted per milligram of testicular tissue in response to LH was higher in busulfan-treated rats. Leydig cells from 60- and 90-day-old rats which had received busulfan were also hyperresponsive to LH. It was concluded that Leydig cells from testes essentially devoid of germ cells were hyperresponsive to LH. Serum androgen levels were decreased yet androgen production per Leydig cell was increased. A possible explanation of this apparent paradox is that busulfan treatment resulted in decreased numbers of Leydig cells in the gonads.

Aging↗
PubMed1988

[Chemotherapy of chronic myelocytic leukemia. Status of the German Multicenter Study on busulfan versus hydroxyurea versus alpha interferon, October 1897].

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia-positive CML. Additional goals are the examination, whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By November 26, 1987, 321 CML-patients had been randomized, 147 for busulfan, 149 for hydroxyurea and 25 for interferon-alpha. The average age is about 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome-negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

Busulfan↗
PubMed2003

Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells.

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The conditioning regimen consisted of 30 mg/m2 intravenous fludarabine daily from day -9 to day -6, and oral busulfan given at 1 mg/kg 4 times a day every 6 hours from day -5 to day -2, with doses adjusted to target plasma levels of 900 +/- 100 ng/mL at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Enrolled were 42 patients with high-risk CML (n = 4) or MDS (n = 38). The median patient age was 52 years (range, 12-65 years). Mobilized blood stem cells were obtained from HLA-compatible siblings (n = 16) or unrelated donors (n = 26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 months (range, 13-27 months), the probabilities of overall survival, disease-free survival, and nonrelapse mortality were 42.4%, 34.9%, and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard-risk patients.

Adolescent↗
PubMed2004

Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS.

Postulating favorable antileukemic effect with improved safety, we used intravenous busulfan and fludarabine as conditioning therapy for allogeneic hematopoietic stem cell transplantation (HSCT) for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Fludarabine 40 mg/m2 and intravenous busulfan 130 mg/m2 were given once daily for 4 days, with tacrolimus-methotrexate as graft-versus-host disease (GVHD) prophylaxis. We treated 74 patients with AML and 22 patients with MDS; patients had a median age of 45 years (range, 19-66 years). Only 20% of the patients were in first complete remission (CR) at transplantation. Donors were HLA-compatible related (n = 60) or matched unrelated (n = 36). The CR rate for 54 patients with active disease was 85%. At a median follow-up of 12 months, 1-year regimen-related and treatment-related mortalities were 1% and 3%, respectively. Two patients had reversible hepatic veno-occlusive disease. Actuarial 1-year overall survival (OS) and event-free survival (EFS) were 65% and 52% for all patients, and 81% and 75% for patients receiving transplants in CR. Recipient age and donor type did not influence OS or EFS. Median busulfan clearance was 109 mL/min/m2 and median daily area-under-the-plasma-concentration-versus-time-curve was 4871 micromol-min, with negligible interdose variability in pharmacokinetic parameters. The results suggest that intravenous busulfan-fludarabine is an efficacious, reduced-toxicity, myeloablative-conditioning regimen for patients with AML or MDS undergoing HSCT.

Adult↗
PubMed2006

Phase I and pharmacokinetic study of once-daily dosing of intravenously administered busulfan in the setting of a reduced-intensity preparative regimen and allogeneic hematopoietic stem cell transplantation as immunotherapy for renal cell carcinoma.

We performed a Phase I and pharmacokinetic study of once-daily, intravenously administered busulfan in the setting of a reduced-intensity preparative regimen and matched sibling donor allogeneic stem cell transplantation for treatment of metastatic renal cell carcinoma. Seven male patients with metastatic renal cell carcinoma received intravenously administered busulfan at 3.2 mg/kg once daily on day -10 and day -9, fludarabine at 30 mg/m2 on day -7 through day -2, and equine antithymocyte globulin at 15 mg/kg per day on day -5 through day -2. The mean area under the plasma concentration-time curve (AUC) and the half-life of the first dose of intravenously administered busulfan were 6,253 microM x minute (range, 5,036-7,482 microM x minute) and 3.37 hours (range, 2.54-4.00 hours), respectively. The AUC was higher than predicted from extrapolation of AUC data for the same total dose of intravenously administered busulfan divided into four doses daily. Patients experienced greater than expected regimen-related toxicity for a reduced-intensity preparative regimen, and the study was stopped. In conclusion, this preparative regimen was associated with unacceptable regimen-related toxicity among patients with metastatic renal cell carcinoma.

Aged↗
PubMed1992

[Second marrow transplantation following high dose busulfan, etoposide, and Ara-C after testicular relapse in a patient with AML].

Prognosis of second marrow transplantation after leukemia relapse is usually gloomy. We report a patient with AML who was successfully treated by the second marrow transplant following high dose busulfan, etoposide, and Ara-C for the testicular relapse after the first marrow transplantation. A 24-year-old man was diagnosed as having acute myeloid leukemia (AML) in September, 1988. In December of 1989 when he was in early relapse after his 2nd remission, he received the first allogeneic BMT from his HLA identical brother after high dose busulfan and cyclophosphamide conditioning. His posttransplant course was uneventful and graft versus host disease was not observed. Three months after BMT, he noticed swelling on right testicle. Leukemic cell infiltration was confirmed by aspiration cytology. The testicular relapse was followed by marrow relapse. After successful remission induction chemotherapy, he received 17.5 Gy testicular irradiation and second marrow transplantation using high dose busulfan, etoposide, and Ara-C conditioning. Although his posttransplant period was complicated by severe mucositis, high fever and bronchopneumonia, hematologic recovery was obtained by 3 weeks after the second transplant. He is now continuing in complete remission 18 months after the second BMT. This case report suggests that the combination of high dose busulfan, etoposide, and Ara-C could be a choice as a conditioning regimen for resistant AML relapsing after BMT.

Adult↗
PubMed2005

Successful engraftment following allogeneic stem cell transplantation in very high-risk patients with busulfan as a single agent.

BACKGROUND AND OBJECTIVES: Busulfan is the most commonly used myeloablative alkylating agent, but is considered a poor anti-lymphocyte agent. Since engraftment of allogeneic stem cells depends not only on adequate immunosuppression but also on successful hematopoietic competition, and considering the fact that residual lymphocytes of host origin may play a beneficial role in preventing graft-versus-host disease (GVHD), we used low doses of oral busulfan as a single agent for conditioning prior to stem cell transplantation (SCT) in recipients of transplants from a variety of donors. DESIGN AND METHODS: Fifteen heavily pretreated high-risk patients (age 25-66, median 42 years) with hematologic malignancies were conditioned with busulfan alone, 4mg/kg/day for 2, 3, or 4 consecutive days. No additional pre- or post-transplant immunosuppressive agents were used in order to exploit the capacity of donor lymphocytes to induce graft-versus-malignancy (GVM) effects. RESULTS: Conditioning was well tolerated, trilineage engraftment was documented in all patients and none exhibited immune-mediated rejection. Time to recovery of absolute neutrophil count >0.5x10(9)/L and 1.0x10(9)/L was 12 - 38 (median 15) days and 12 - 41 (median 15) days, respectively. The time to platelet recovery >or=20 and >or=50x10(9)/L ranged from 0 to 26 (median 11) days, and from 0 to 83 (median 14) days, respectively. Acute GVHD (<or=grade I) occurred in 13/15 patients. Three patients benefited from long-term survival. INTERPRETATION AND CONCLUSIONS: We suggest that using busulfan alone for the preparation of patients for SCT may be sufficient for engraftment, in very high-risk heavily pre-treated patients.

Adult↗