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PubMed2004

Continuous infusion idarubicin and oral busulfan as conditioning for patients with acute myeloid leukemia aged over 60 years undergoing autologous stem cell transplantation.

There is growing interest in autologous stem cell transplantation (ASCT) for elderly patients with acute myeloid leukemia (AML). While mortality and toxicity from ASCT have been reduced, relapse rate is still high. In a prospective study, we investigated the feasibility of a new conditioning regimen consisting of high-dose idarubicin plus busulfan in AML patients aged over 60 years undergoing ASCT. A total of 14 patients (median age: 64 years) received 2 days continuous infusion of idarubicin at 20 mg/m2/day, followed by 3 days of oral busulfan (4 mg/kg/day) as conditioning. No case of transplant-related mortality occurred. The median number of days to neutrophil ( > 0.5 x 10(9)/l) and platelet ( > 20 x 10(9)/l) recovery was 11 and 12, respectively. Cardiac toxicity was absent, while 12 patients (86%) had grade 3-4 mucositis. After a median follow-up of 9 months from ASCT, nine of 14 patients are alive in continuous complete remission (CR), four have relapsed at 3, 6, 8 and 9 months, and one died in CR1 from gastric cancer. Our data demonstrate the feasibility of a conditioning regimen based on high-dose idarubicin plus busulfan in elderly AML patients. Results concerning reduction of relapse rate need confirmation in a larger series with longer follow-up.

Acute Disease↗
PubMed2005

CD8+ T-cell-depleted, matched unrelated donor, allogeneic bone marrow transplantation for advanced AML using busulfan-based preparative regimens.

The role of T-cell depletion (TCD) to prevent graft-versus-host disease (GVHD) after matched unrelated donor allogeneic bone marrow transplant (MUD BMT) remains undefined. Most studies employ total body irradiation and pan TCD. Between March 1993 and June 2002, we treated 33 relapsed acute myelogenous leukemia (AML) patients with busulfan-based preparative regimens and selective TCD. The preparative regimen consisted of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and VP-16 50 mg/kg in all but one patient who only received busulfan and cyclophosphamide. Donor marrow was depleted of CD8+ T cells by immunomagnetic bead separation. The patients were also treated with cyclosporine and methylprednisolone or FK-506 and mini-dose methotrexate. Four (15%) of 33 patients developed graft failure or rejection. However, three of these patients were serologically mismatched at HLA-Cw. Although 67% of evaluable patients developed acute GVHD, severe grade III-IV acute GVHD only developed in 19%. The severity of acute GVHD correlated with the degree of CD8+ TCD. Median relapse-free survival was 5 months among 20 patients treated with active AML, and 28 months among 13 patients treated in complete remission. Our results confirm that MUD BMT with CD8+ TCD for AML is a potentially curative treatment option.

Adult↗
PubMed1983

Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide.

Fifty-one patients with acute nonlymphocytic leukemia (16 with end-stage disease, 17 in second or third remission or in early relapse, and 18 in first remission) were given infusions of HLA-identical sibling marrow after cytoreduction with high doses of busulfan and cyclophosphamide. Actuarial two-year survival rates were 0 per cent, 29 per cent, and 44 per cent, respectively. Twelve patients are still alive and in remission after 327 to 1488 days, with 10 surviving beyond two years. Acute graft-versus-host disease and viral pneumonia were the major causes of death. Leukemic cells failed to clear in one patient with end-stage disease, and a relapse with meningeal leukemia occurred in another. Only one other relapse was seen--in a patient given a transplant during a third remission. Survival was favorably affected by younger age and transplantation during first remission. We conclude that high-dose chemotherapy with busulfan and cyclophosphamide, followed by allogeneic-marrow transplantation, can produce long-term remission of acute leukemia. Chemotherapy with high-dose busulfan and cyclophosphamide before transplantation provides an effective alternative to cyclophosphamide and total-body irradiation before transplantation for the treatment of acute nonlymphocytic leukemia.

Acute Disease↗
PubMed1995

Prevention of hemorrhagic cystitis following allogeneic bone marrow transplant preparative regimens with cyclophosphamide and busulfan: role of continuous bladder irrigation.

High dose cyclophosphamide and/or busulfan conditioning treatment of recipients of bone marrow transplants proved to be highly effective but associated with substantial and sometimes life threatening hemorrhagic cystitis. To prevent this complication, a prophylactic continuous bladder irrigation program was instituted in patients receiving cyclophosphamide and/or busulfan in preparation for bone marrow transplantation. Retrospective analysis of 199 patients who underwent allogeneic bone marrow transplantation revealed that continuous bladder irrigation significantly decreased the frequency of hemorrhagic cystitis in patients receiving busulfan and cyclophosphamide (continuous bladder irrigation 23% versus no bladder irrigation 53%, p < 0.004). There was no difference in the frequency of hemorrhagic cystitis between the different preparative regimens in patients who underwent continuous bladder irrigation. There was no relationship between the incidence of hemorrhagic cystitis and the severity of graft-versus-host disease or the time to engraftment. The duration of hemorrhagic cystitis and overall survival rates were similar in both groups, and there was no increase in complications related to catheterization. In general, continuous bladder irrigation was well tolerated, decreased the incidence of hemorrhagic cystitis and may be useful in bone marrow transplant patients.

Adolescent↗
PubMed2001

Monitoring of busulfan area under the curve: estimation by a single measurement.

Because the busulfan area under the concentration-time curve (AUC) has been correlated with the outcome of bone marrow transplantation (BMT) and the occurrence of veno-occlusive disease after BMT, a rapid determination of AUC is needed to ensure its suitable dosage. The present work describes a method based on combining aliquots from the 10 blood samples collected for an AUC busulfan determination and performing a single determination of the resulting mixture. In 42 patients undergoing a preparative regimen for bone marrow transplantation this combined sample AUC was compared with the regular determined AUC obtained from 10 consecutive samples drawn at various time intervals after dosing. It is apparent that the AUCs calculated by pharmacokinetic analysis using a noncompartmental model package and those obtained by analyzing the sample mixture are very similar ( r = 0.961). The proposed method allows rapid adjustment of the busulfan dose, reducing the number of uncorrected dosages during therapy.

Adult↗
PubMed2005

Tandem mass spectrometry method for the quantification of serum busulfan.

Busulfan, an alkylating agent, is most commonly used as a component of bone marrow transplantation preoperative regimens. Significant interpatient and intrapatient variations in pharmacokinetics require individualizing the dosage based on area under the time-versus-concentration curve. Timely result reporting is critical to dose adjustment to reduce morbidity and mortality associated with the regimen. The authors developed a rapid, accurate, and sensitive method for the quantification of serum busulfan using direct inject tandem mass spectrometry. Plasma samples (50 microL) are extracted in 1 mL of methanol containing 1,6-bis-(methanesulfonyloxy)hexane as an internal standard. The supernatant is dried under nitrogen (40 degrees C, 30 minutes) and then dissolved in 200 microL methanol and transferred into a clean glass vial suitable for LC/MS/MS analysis. The sample is delivered using an HPLC pump that delivers 0.2 mL of methanol per minute, and 20 microL of sample is injected into a turbo ion spray-equipped tandem mass spectrometer. Total analysis time is 5 minutes. The Q1/Q3 transition for busulfan (BU) is monitored at 269/55 and 297.1/55.1 for the internal standard. The assay is linear to 10 micromol/L and sensitive to at least 0.5 micromol/L. The interassay reproducibility at 1, 2.2, and 4.4 micromol/L were 4.2%, 5.6%, and 6.3%, respectively. Within-run precision using 3 different control samples was 3.9%, 3.9%, and 6.9%. Mean recovery of 4 different BU concentrations spiked into 10 different BU free plasma samples was 98%. Correlation with an established HPLC-UV method revealed a slope of 0.98, an intercept of 0.1, and r = 0.95 (n = 48). No significant interfering substances or ion suppression was identified. This method is a significant improvement over the existing HPLC-UV method for BU determination. The method is highly accurate, reproducible, and requires less specimen, sample preparation, and analysis time.

Antineoplastic Agents, Alkylating↗
PubMedDate not supplied

Effects of supplementation with impuberal or adult testicular protein extracts on genital tract and testicular histology as well as hormonal levels in adult busulfan treated rats.

24 adult Wistar rats received one SC injection of busulfan (10 mg/kg BW) on day 0. They were injected daily from day 1 to day 10 either with BSA (1 and 2 mg/rat, n = 5 respectively), with acetonic extract of adult ram testicular cytosol (2 mg/rat, n = 10) or with acetonic extract of impuberal calf testicular cytosol (2 mg/rat, n = 4). 10 animals served as control. Animals were killed on day 17. Busulfan treatment induced decrease of total volumes of intertubular tissue and of Leydig cells per testis, of accessory glands, and of germ cells from type A spermatogonia to zygotene spermatocytes. Supplementation with adult testicular extract did not modify accessory glands but increased Leydig cell total volume, individual cellular and nuclear areas and Sertoli cell nuclear areas. It decreased further the germ cells from A spermatogonia to zygotene primary spermatocytes. Supplementation with impuberal testicular extract did not modify accessory glands, Leydig cell total volume, individual cellular and nuclear areas or Sertoli cell nuclear area. It increased the germ cells from A spermatogonia to zygotene primary spermatocytes to values intermediate between those of control and busulfan treated rats.

Animals↗
PubMed1985

Cutaneous busulfan effect in patients receiving bone-marrow transplantation.

Epidermal keratinocytes with abnormally large nuclei were found in 12 of 13 patients who received high-dose busulfan and cyclophosphamide prior to receiving bone-marrow transplantation for treatment of hematological malignancies. These cells were similar to those previously described in the lungs, cervix and bladder of patients on long-term busulfan therapy. Marked keratinocyte nuclear abnormalities were not observed in bone-marrow transplant recipients who received a preparatory regimen of cyclophosphamide and total-body irradiation. This histologic cutaneous busulfan effect was transient and was unrelated to the development of graft-versus-host reaction.

Adult↗
PubMed2004

Conditioning regimens including high-dose busulfan cause a high incidence of transplant-related mortality after myeloablative stem cell transplantation.

BACKGROUND: Transplant-related mortality (TRM) significantly decreases the long-term survival of patients with hematopoietic diseases who undergo hematopoietic stem cell transplantation (HSCT). METHODS: We retrospectively evaluated the risk factors for TRM of 58 consecutive patients with hematopoietic disease who underwent allogeneic myeloablative HSCT between April 1994 and June 2002. RESULTS: Thirty-one patients died after HSCT, 16 of whom were diagnosed as TRM. The actuarial incidence of TRM was 57.6 % in patients who received conditioning chemotherapies including high-dose busulfan and 19.4 % in those who did not (p = 0.008). Multivariate Cox model analysis revealed that disease status, graft versus host disease (GVHD) grades III-IV and the use of high-dose busulfan were significant and independent risk factors for TRM. CONCLUSION: These results suggest that high-dose busulfan as a conditioning therapy for allogeneic HSCT should be used cautiously, especially in patients with advanced disease.

Adolescent↗
PubMed1986

Occurrence of premature chromosome condensation in mouse spermatogonia treated with busulfan.

Busulfan induction of premature chromosome condensation (PCC) was examined in mouse spermatogonia. Adult (C3H X SWV) F1 male mice were injected intraperitoneally with busulfan at 10 or 30 mg/kg of body weight and killed 18-72 h later. Polyploid-like mitoses were frequent (ca. 1/4 of all spermatogonial mitoses examined) in both the untreated and treated groups. Most of these were considered to have been derived from normal spermatogonia. In busulfan-treated mice, polyploid-like mitoses with PCC were seen. The frequency of PCC-containing mitoses increased with increasing dose and exposure time. A possible interpretation for PCC induction in mouse spermatogonia is discussed.

Animals↗
PubMed1983

[Comparison of the therapeutic results in treating chronic myelosis with splenic irradiation or busulfan].

In a retrospective study the survival of 111 patients with chronic myeloid leukemia was analyzed. There was a slight superiority of the patients primarily treated with busulfan over those first getting splenic irradiation and busulfan subsequently. This difference was statistically not significant. If spleen size prior to treatment was less than 10 cm below left costal margin, there was also a tendency in favor of primary busulfan therapy. In patients having bigger spleens, neither form of treatment had any advantage.

Adolescent↗
PubMed2007

Population pharmacokinetic-based dosing of intravenous busulfan in pediatric patients.

The objective of this study was to characterize the pharmacokinetics (PK) of intravenous busulfan in pediatric patients and provide dosing recommendations. Twenty-four pediatric patients were treated with intravenous busulfan, 1.0 or 0.8 mg/kg for ages < or = 4 years or > 4 years, respectively, 4 times a day for 4 days. Dense PK sampling was performed. Body weight, age, gender, and body surface area were explored for effects on PK, and Monte Carlo simulations were performed to assess different dosing regimens. The PK of intravenous busulfan was described by a 1-compartment model with clearance of 4.04 L/h/20 kg and volume of distribution of 12.8 L/20 kg. Simulations indicated that the mg/kg and mg/m2 regimens were similar and achieved the desired target exposure in approximately 60% of patients. This model suggests that patients < or = 12 kg should be dosed at 1.1 mg/kg and those > 12 kg dosed at 0.8 mg/kg. Therapeutic drug monitoring and dose adjustment will further improve therapeutic targeting.

Age Factors↗
PubMed1992

Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

PURPOSE: The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. PATIENTS AND METHODS: We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. RESULTS: Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. CONCLUSION: Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.

Adolescent↗
PubMed1994

Pharmacokinetics of undiluted or diluted high-dose etoposide with or without busulfan administered to patients with hematologic malignancies.

PURPOSE: We used two different methods to administer high-dose etoposide (VP-16) during a myeloablative conditioning chemotherapy regimen before bone marrow transplantation (BMT). VP-16 was administered either diluted (0.5 mg/mL) or undiluted (20 mg/mL), with or without busulfan. PATIENTS AND METHODS: Blood samples were drawn from 17 patients during the infusion (6 hours) and thereafter daily until 2 days after BMT. VP-16 concentrations were measured in all plasma samples by high-performance liquid chromatography (HPLC) and electrochemical detection, and the results were analyzed with a pharmacokinetic data analysis system. RESULTS: All calculated pharmacokinetic parameters in the two patient groups (VP-16 administered diluted or undiluted) were similar. There were no statistically significant differences in half-lives, mean residence time (MRT), volume of distribution, total clearance, or area under the curve (AUC). VP-16 was found in blood samples from eight of 17 patients at the time of BMT. Significant differences in systemic drug exposure and systemic clearance were found when patients were grouped according to treatment with busulfan or with total-body irradiation (TBI). CONCLUSION: The two administration modes for VP-16, either diluted or undiluted, are bioequivalent in pharmacokinetic terms. The terminal half-lives were longer than expected and resulted in significant VP-16 plasma levels at the time of BMT. The biologic significance remains unclear. Busulfan and/or concomitant medication with phenytoin influence plasma clearance (clp) and systemic drug exposure significantly.

Adolescent↗
PubMed2000

Effects of chemotherapy (busulfan-hydroxyurea) and interferon-alfa on bone marrow morphologic features in chronic myelogenous leukemia. Histochemical and morphometric study on sequential trephine biopsy specimens with special emphasis on dynamic features.

We performed a retrospective clinicopathologic study on sequential biopsy specimens from 90 patients with Philadelphia chromosome-positive chronic myelogenous leukemia to study therapy-specific effects of busulfan (28 patients), hydroxyurea (32 patients), and interferon-alfa (IFN-alfa; 30 patients). Bone marrow specimens were evaluated by morphometry after silver impregnation and staining with monoclonal antibodies to identify reticulin fibers, nucleated erythroid precursors, megakaryocytes, and macrophages. To compute dynamics of histopathology implicating corresponding changes in time, relevant indices were calculated. Quantification of megakaryocytopoiesis and its precursor cell population showed a significant increase in the IFN-alfa and busulfan groups compared with the hydroxyurea group. These changes were associated with a development of myelofibrosis during therapy. Although a significant increase in fiber density was detectable in the busulfan group, the progression index proved to be twice as high after IFN-alfa therapy. In contrast, a considerable number of patients displayed a regression of myelofibrosis after hydroxyurea treatment. The general association of the megakaryocyte lineage with myelofibrosis was in line with experimental findings. The mature macrophage population and its activated subfraction revealed a marked proliferation (IFN-alfa group) during treatment. Growth and activation of macrophages may be compatible with their putative function during erythrocytopoietic regeneration and with stimulation of their phagocytic properties.

Antineoplastic Agents↗
PubMed1984

Effect of prenatal treatment with busulfan on the hypothalamo-pituitary axis, genital tract and testicular histology of prepubertal male rats.

Female Wistar rats were treated with busulfan or with solvent on Day 20 of pregnancy. Thirty male offspring of each group were killed at 38 days of age. In busulfan-treated rats, compared to controls, hypothalamic LH-RH content was decreased by 52%, whereas pituitary LH and FSH concentrations were increased by 60 and 43% respectively. Plasma LH and FSH were increased by 112 and 275% respectively. Prolactin concentrations were not changed, but plasma testosterone concentration was decreased by 48%. The total number of Leydig cells per testis was decreased by 52%, and LH binding sites per testis were decreased by 70%. The total number of Sertoli cells was decreased by 44%, while FSH binding sites per testis were decreased by 62%. Spermatogenesis was practically absent after prenatal exposure to busulfan. These data demonstrate that on Day 20 of pregnancy all the dividing cells in the fetal testes were depleted by an antimitotic treatment. The stimulation of the hypothalamo-pituitary axis could have been partly induced by the decrease in testosterone production, and by the aplasia of germ cells involving modifications of the remaining Sertoli and Leydig cells.

Animals↗
PubMed1993

The German CML study, comparison of busulfan vs. hydroxyurea vs. interferon alpha and establishment of prognostic score 1.

From July 1983 to January 1991 a total of 622 patients were randomized (585 eligible) to compare the effects of hydroxyurea, interferon alpha (IFN), and busulfan on the duration of chronic phase, and survival. Further goals included the determination of prognostic parameters. 598 CML patients were documented and 575 evaluable. The Ph-status was known for 547 patients. 89.4% of the patients were Ph-positive (+). 11% had additional chromosome aberrations. The median survival of Ph+ patients by now is 4.2 years, that of Ph-patients 1.4 years. Ph-negative patients are older, tend to have lower cell counts and, as a group are more ill at diagnosis. A survival difference of about one year is expected between busulfan and hydroxyurea treated patients. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, number of erythroblasts and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined which was superior to Sokal's score in the study population. 164 patients were randomized to receive IFN. In 54 patients (33%) IFN had to be terminated because of adverse effects, therapy resistance or other reasons. Clinically relevant neutralizing antibodies were detected in 9 cases. Most frequent adverse events were flu-like symptoms in 74%, gastrointestinal symptoms in 52%, and neurologic-psychiatric symptoms in 30% of patients. Reduction of the Ph-chromosome was observed in 13% of evaluable patients (10 of 75). In 4 patients complete cytogenetic remissions were observed, in three of these ongoing. Cytogenetic responders have a survival advantage. Interferon treated Philadelphia-negative CML patients have no survival disadvantage. The study is expected to allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.

Adult↗
PubMed1991

The effects of busulfan on gonadal differentiation and development in Japanese quail (Coturnix coturnix japonica).

To determine the effects on gonadal differentiation and development, two concentrations of busulfan (1,4-butanediol dimethanesulfonate) were injected into the albumen of unincubated Japanese quail eggs, and the eggs were then incubated. Half of the hatchlings were killed at 3 days of age and the rest at 10 wk of age (4 wk past puberty). Hatchability of fertile eggs was lowest in those eggs injected with 420 micrograms of busulfan (19.6%), intermediate in the 210-micrograms group (54.7%), and highest in the sham-injected control group (73.3%). Gonads were examined histologically for germ cells and normal development. All 23 birds evaluated after injection with 210 micrograms of busulfan had histologically normal gonads. In the 420-micrograms group, six out of eight birds were abnormal. Three females and one male in this group had gonads lacking germ cells, and two males had testicles with a combination of normal seminiferous tubules and tubules lacking spermatogonia.

Animals↗