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PubMed2006

[Stability of busulfan injection solution (Busilvex, Busulfex) in B/Braun Injekt syringes].

Stability of busulfan injection solution (Busilvex, Busulfex) in B/Braun Injekt syringes Stability of busulfan injection was determined by a modified stability-indicating HPLC method with UV detection. Diethyldithiocarbamate was used as derivatization agent. The stability tests revealed that busulfan injection (Busilvex, Busulfex) stored in B/Braun Injekt syringes at 18-20 degrees C without light protection or refrigerated are stable for up to 28 days. Unused busulfan injection (Busilvex, Busulfex) is not necessarily to be discarded, but can be stored for a prolonged period of time in a rubber free syringe, preferably under refrigeration.

Antineoplastic Agents, Alkylating↗
PubMed1989

Cerebrospinal fluid and plasma concentrations of busulfan during high-dose therapy.

A patient with acute myeloblastic leukemia received high-dose busulfan (1 mg/kg by mouth every 6 h for 4 days) as myelo-ablative therapy for autologous bone marrow transplantation. Rapid entry of busulfan into the cerebrospinal fluid (CSF) was observed. Plasma and CSF concentrations of busulfan were comparable during the 4 days of treatment. The elimination half-lives of busulfan in plasma and CSF were 2.6 h and 2.8 h respectively during the first 12 h after the last dose.

Bone Marrow Transplantation↗
PubMed1977

Busulfan lung.

An uncommon, but lethal, toxic side effect of busulfan (Myleran) therapy for chronic myelogenous leukemia is pulmonary fibrosis. A 16-month-old male infant treated for 11 months with busulfan for chronic myelogenous leukemia is, we believe, the first case of "busulfan lung" in the pediatric age group to be reported. Progressive roentgenographic changes in the lung of a diffuse intra-alveolar and interstitial pattern were noted. The patient died after a four-day episode of cough, fever, and progressive dyspnea. At autopsy, no evidence of infection or leukemic infiltrates were seen in the lungs. Characteristic histologic findings as a result of busulfan therapy were observed in the lung and pancreas.

Busulfan↗
PubMed1987

Clinical and pharmacologic effects of high dose single agent busulfan with autologous bone marrow support in the treatment of solid tumors.

A Phase I-II clinical trial of high dose single agent busulfan (16-20 mg/kg) administered over a 4-day period was undertaken. Pharmacokinetic measurements reveal that steady state total plasma busulfan levels between 2 and 10 microM were achieved by the second day and maintained through the remaining treatment period. Urinary excretion of mutagenic activity monitored by the Salmonella mutagenesis assay persisted for up to 48 h following the last dose of busulfan. The treatment showed specificity for myelocytic precursors as evidenced by selective depression of granulocytes with relative sparing of lymphocytic elements, and by differences in DNA damage as measured by a nucleoid sedimentation assay. Dose limiting toxicity was mucositis, anorexia, and hepatic toxicity. Transient autoimmune disorders were observed in three of the six patients. Partial responses were seen in two of five patients with melanoma, but these lasted for only 2 and 3 months. High dose busulfan represents an alkylating agent with marked myelocytic selectivity and may be useful for inclusion in intensive combination regimens.

Adult↗
PubMed1988

Concurrent activation of granulocytes and osteoclasts in busulfan-suppressed bone marrow in response to transplantation of a mammary carcinoma in mice.

Transplantation of CE mammary adenocarcinoma (CE maca) into normal mice produces both neutrophilia and hypercalcemia due to osteoclastic bone resorption. In order to explore the physiology of osteoclast formation in vivo, the time course of neutrophilia and osteoclast development was examined in mice that had been pretreated with busulfan prior to the CE maca implantation. Busulfan-treated tumor-bearing mice (BUTUM), busulfan-treated control mice (BUCON), tumor-bearing mice with no busulfan (TUM), and normal controls (CON) were sacrificed on days 4, 7, 11, 14, and 17 after tumor implantation. Leukocyte counts, serum calcium levels, marrow cellularity, and marrow colony-forming units (CFU) were determined. Osteoclasts were quantified histologically by the osteoclast: endosteum ratio (OER). BUCON bone marrow was hypoplastic with CFU remaining significantly lower than that of controls over the course of the experiment. In contrast, BUTUM marrow CFU increased dramatically with the growth of the tumor. The most predominant increase was observed in neutrophilic CFU. Development of hypercalcemia closely paralleled neutrophilia in both TUM and BUTUM mice, although these changes were significantly delayed in the BUTUM group. The neutrophil count and serum calcium levels remained within normal control levels for BUCON mice. The OER correlated with serum calcium, and it closely paralleled the neutrophil count in TUM and BUTUM mice. These results clearly indicated the stimulation of bone marrow neutrophilic granulocyte progenitors and osteoclasts by the CE maca, indicating that the bone marrow is the primary target of this tumor. There may be a closely related mechanism in osteoclast and granulocyte stimulation by one or more CE maca factors.

Animals↗
PubMed1984

Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation.

The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.

Adolescent↗
PubMed1983

In vitro drug sensitivity studies of CFUc in chronic myelocytic leukemia: I. Suicide indices and busulfan sensitivity determinations during the chronic phase.

Serial clonogenicity studies employing an agar CFUc culture assay are being performed on cells from CML patients to determine if clonal growth, 3HTdR suicide indices (SI) and in vitro busulfan sensitivity are of prognostic significance in predicting blastic transformation. Initial studies performed on specimens obtained from 20 chronic phase patients were directed at determining whether blood and marrow cells differed in growth pattern, SI, and busulfan sensitivity and whether the cells giving rise to clusters differed from those forming colonies. In comparing marrow to blood cells, there was a correlation between the two with respect to the number of colonies produced and the sensitivity of the clonogenic cells to busulfan. By contrast the SI of blood and marrow clonogenic cells were not correlated. In both blood and marrow, colony forming cells had a higher SI and were more sensitive to busulfan than were cluster forming cells.

Adolescent↗
PubMed1994

Phase I study of high-dose busulfan, melphalan and thiotepa with autologous stem cell support in patients with refractory malignancies.

The purpose of this study was to determine the maximal tolerated dose of thiotepa administered with busulfan 12 mg/kg and melphalan 100 mg/m2 followed by autologous stem cell transplantation in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose busulfan 12 mg/kg, melphalan 100 mg/m2 and escalating doses of thiotepa 450-550 mg/m2 followed by infusion of cryopreserved autologous peripheral blood stem cells (n = 26) or marrow (n = 2). The maximum tolerated dose was determined to be busulfan 12 mg/kg, melphalan 100 mg/m2 and thiotepa 500 mg/m2. Two of three patients receiving thiotepa 550 mg/m2 experienced grade 3 colitis. Twenty patients were enrolled at the maximum tolerated dose and the incidence of grade 3-4 regimen-related toxicity and mortality was 10% and 5%, respectively. Ninety-five per cent of patients experienced grade 1-2 mucositis, 50% grade 1-2 gastrointestinal toxicity, 35% grade I hepatic toxicity and 20% experienced grade 1-2 skin toxicity. The median time to achieve a granulocyte count of 0.5 x 10(9)/I was 10 days (range 8-20 days) and platelet transfusion independence was 10 days (range 1-26 days). Five of ten patients with stage 4 refractory breast cancer achieved a complete and two a partial remission with a complete response rate of 50% and a overall response rate of 70%. In conclusion, busulfan, melphalan and thiotepa can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy sensitive malignancies are warranted.

Adolescent↗
PubMed1994

Busulfan bioavailability.

Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in children and is associated with less therapeutic effectiveness, lower toxicities, and higher rates of engraftment failure. We have evaluated the bioavailability of the drug in two groups of patients: eight children between 1.5 and 6 years of age and eight older children and adults between 13 and 60 years. Oral bioavailability showed a large interindividual variation. In children, the bioavailability ranged from 0.22 to 1.20, and for adults, it was within the range 0.47 to 1.03. The elimination half-life after intravenous administration in children (2.46 +/- 0.27 hours; mean +/- SD) did not differ from that obtained for adults (2.61 +/- 0.62 hours). However, busulfan clearance normalized to body weight was significantly higher in children (3.62 +/- 0.78 mL.min-1.kg-1) than that in adults (2.49 +/- 0.52 mL.min-1.kg-1). Also, the distribution volume normalized for body weight was significantly higher in children (0.74 +/- 0.10 L.kg-1) compared with 0.56 +/- 0.10 L. kg-1 in adults. The difference in clearance between children and adults was not statistically significant when normalized to body surface area, which most probably shows that busulfan dosage should be calculated on the basis of surface area rather than body weight. However, to avoid drug-related toxicities, drug monitoring and an individual dose adjustment should be considered because of the variability in busulfan bioavailability.

Administration, Oral↗
PubMed1994

Busulfan pharmacokinetics using a single daily high-dose regimen in children with acute leukemia.

The pharmacokinetics of busulfan, given as a single daily dose (either 4 mg/kg or 150 mg/m2), was determined in 22 children undergoing bone marrow transplantation for acute leukemia. The single daily dose regimen showed similar pharmacokinetics to previously reported regimens of 4 x 1 mg/kg, except for fourfold higher mean peak plasma levels and negligible trough levels. Daily systemic exposure for single dose regimens based on weight (4 mg/kg) or surface area (150 mg/m2), respectively were very similar to regimens of (4 x 1 mg/kg) or (4 x 37.5 mg/m2). Dose (milligrams per kilogram), peak plasma level, and area under the curve (AUC) were all higher in 12 children treated with 150 mg/m2 busulfan than in 9 children treated with 4 mg/kg. AUC was age dependent for the 4 mg/kg dose but not for the 150 mg/m2 dose. The use of a 150 mg/m2 dose allows escalation of the dose above 4 mg/kg, eliminating the tendency for younger children to receive lower systemic exposure. Little toxicity was observed in this study. Clearance and distribution volume correlated negatively with age, and AUC correlated positively with dose (milligram per kilogram). Administration of busulfan as crushed rather than whole tablets reduced the delay time for appearance of busulfan in plasma but had no effect on absorption or other pharmacokinetic parameters.

Administration, Oral↗
PubMed1994

Phase I-II study of busulfan and cyclophosphamide conditioning for transplantation in advanced multiple myeloma.

We evaluated a non-radiation containing preparative regimen for persons with myeloma receiving bone marrow (BM) or blood cell transplants. Twenty-three adults with advanced multiple myeloma (15 responsive to chemotherapy, 8 resistant) received cyclophosphamide 120 mg/kg and busulfan 14-16 mg/kg followed by the infusion of BM or blood progenitor cells. Patients were followed for response by monthly skeletal radiographs, urine and serum monoclonal paraprotein measurement, BM evaluation and beta 2-microglobulin. Three of 18 evaluable patients achieved complete response, 13 patients achieved partial response and two a minimal response. Actuarial 1 year survival post-transplant for all patients is 63% (95% confidence interval, 40-86%). Disease stage and response to chemotherapy pre-transplant correlated with survival post-transplant. Actuarial survival for patients with resistant disease was 38% (4-72%); for patients with chemotherapy-responsive disease, it was 78% (48-100%, p = 0.02). Regimen-related toxicity consisted of five early deaths, three from veno-occlusive disease, one from infection and one from multiorgan failure. Fatal and non-fatal hepatic and renal toxicities were related to busulfan dose with most complications occurring at 16 mg/kg. Our studies suggest that busulfan and cyclophosphamide are an effective conditioning regimen in multiple myeloma. Toxicity precludes increasing the total dose of busulfan beyond 14 mg/kg.

Adult↗
PubMed1978

[Varying course of pancytopenia after busulfan treatment of chronic myelocytic leukemia (CML)].

In 84 patients with chronic myeloid leukaemia receiving a cytostatic monotherapy with busulfan, an aplastic syndrome developed which was confirmed by a biopsy of the pelvis crest and examination of the sternal marrow. The time interval until pancytopenia was detected varied considerably in each case, ranging between 6 and 126 months. There are no correlations to the initial doses of busulfan. 3 patients died of the immediate effects of the bone-marrow damage caused by busulfan. In 4 from 6 of the following pancytopenic patients the leukocyte values lay between 12,800/microliter and 80,400 microliter when busulfan adminstration was interrupted. Thus, it is scarcely possible to give any reliable informations about a leukocyte limit value as a standard for an interruption of therapy in order to prevent bone-marrow aplasia. Taking this into account, the conclusion may be drawn that relatively short control intervals have to be made in this monochemotherapy of CML which often can be used successfully for many years.

Adolescent↗
PubMed1994

Busulfan-containing pre-transplant regimens for the treatment of solid tumors.

This study investigated the toxicity and efficacy of busulfan-containing pre-transplant regimens in patients with solid tumors. The majority of these patients were also treated on protocols involving two transplant courses aiming at further reducing tumor burden. Between October 1984 and November 1993, we treated 44 patients with recurrent breast cancer (n = 28), sarcoma (n = 10) or ovarian cancer (n = 6) with one of two busulfan-containing regimens. All patients except two had measurable disease prior to transplantation. Twenty-one patients had not received chemotherapy for metastatic disease. Of the remaining 23 patients treated with standard-dose chemotherapy, 14 had progressive disease. Busulfan 16 mg/kg was paired with cyclophosphamide 200 mg/kg (BuCY) or with etoposide 60 mg/kg (Bu-Vp). The Bu-Vp combination (32 courses) was used as the second preparative regimen in patients who had received thiotepa, carboplatin and cyclophosphamide for their first transplant. The BuCY regimen was used in 16 courses, either for single or for tandem transplant. Bone marrow cells only were used in 17 transplants and peripheral blood progenitor cells, with or without bone marrow, in 31 courses. Treatments were usually well tolerated. Common toxicities included mucositis, skin rash and veno-occlusive disease of the liver (fatal in two). One patient developed generalized seizures during busulfan therapy. Hematologic recovery was significantly accelerated with peripheral progenitor cells and permitted the administration of closely spaced tandem transplants. Two patients receiving sequential transplants with BuCY experienced severe long-term neurologic and pulmonary toxicity. Objective responses were noted in 26 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

[Alveolar opacities and busulfan pneumonia].

A case of toxic pneumonia due to busulfan is reported in a man aged 65 treated for three years with busulfan for chronic myeloid leukaemia. He was admitted to hospital for dyspnoea, cough, fever and presented with crepitations, dense alveolar opacities, and a restrictive ventilatory defect. Trans-bronchial biopsy showed a filling of the alveoli by fibroblastic tissue, as well as voluminous dystrophic pneumocytes. Four months later in spite of steroid therapy the clinical state and respiratory function were worse. The alveolar opacities have regressed but some diffuse interstitial opacities had appeared. This new case is a reminder that the appearance of alveolar opacities in a patient treated with busulfan should raise the possibility of a toxic pneumonitis to busulfan in the differential diagnosis. This observation also underlines the role of the initial endo-alveolar fibrosis in the ultimate development of interstitial fibrosis.

Aged↗
PubMed1976

Erythroleukemia-like syndrome due to busulfan toxicity in polycythemia vera.

Over a 19-year period, a patient with polycythemia vera who had undergone a splenectomy received six courses of busulfan for recurrent thrombocytosis. The total dose of busulfan given for the sixth course was greater than that used for the previous ones. Severe pancytopenia followed, which persisted for 4 months. During this period there was marked erythroid hyperplasia in the bone marrow with striking dyserythropoiesis; PAS-positive red cell precursors, as well as moderate numbers of circulating normoblasts and evidence of chronic and acute hemolysis, were present. All of these findings reverted to normal without therapy, and the polycythemic state eventually recurred. These events are interpreted as an unusual marrow reaction following busulfan overdosage rather than a transient erythroleukemia.

Adult↗
PubMed1982

Busulfan versus hydroxyurea in long-term therapy of chronic myelogenous leukemia.

Survival of patients with chronic myeloid leukemia seen in the University of Colorado Leukemia Clinic were reviewed with respect to therapy. A total of 55 patients seen consecutively through mid 1980 were included in this study. Of these patients 30 were treated with busulfan, 14 were treated with hydroxyurea and 11 received under modalities. Busulfan treated patients who are now deceased, have had a median survival of 35 months (range, 13-108) and actuarial analysis shows the total busulfan treated population to have an expected median survival of 48 months. Hydroxyurea treated patients who are still alive have been followed for a median period of 69 months (range, 25-136 months) and a projected median survival for periods of 56 and 90 months, respectively. These data suggest that hydroxyurea may be an important treatment modality in the treatment of chronic myelogeous leukemia.

Adolescent↗
PubMed1987

A comparative study of dibromomannitol and busulfan in the treatment of chronic myeloid leukemia. A study of cancer and leukemia group B.

In a prospective, randomized trial the effectiveness of dibromomannitol (DBM), a brominated sugar alcohol derivative, was compared to busulfan in previously untreated patients. One hundred thirty-one patients were evaluated for response and survival. The effective dose of DBM was 4 mg/kg. The persistence of sensitivity to either DBM or busulfan was shown in a quantified fashion. Despite initial reports of the alleged unique effectiveness of DBM in treating chronic myeloid leukemia (CML), this study did not disclose any advantage of DBM over busulfan. Multivariate analysis investigating the importance of prognostic factors in CML indicated that age, sex, splenomegaly, and initial platelet count were important for predicting survival. Determination of such factors in CML are valuable in deciding those patients who could benefit from alternative forms of therapy. It also insures that study results are related to treatment rather than selection of patients with favorable or unfavorable prognostic factors.

Adolescent↗
PubMed1979

Cytogenetic effects of busulfan in vivo on bone marrow cells and oocytes of adult mice and liver cells of transplacentally exposed embryos.

Adult female mice were twice treated orally with 15, 30, or 60 mg busulfan per kg of body weight. In bone marrow, a dose-dependent linear increase in the frequency of chromosome aberrations was observed. Similar to the effects of other alkylating agents, busulfan induced all types of aberrations, including exchanges. In metaphase II oocytes, only a few chromosome aberrations were observed. An intervening round of DNA-replication seems to be necessary to translate busulfan-induced lesions in oocytes into chromosome aberrations. In embryonic liver cells of transplacentally exposed mice, chromosome aberrations were induced.

Animals↗