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[Busulfan versus busulfan-interferon as maintenance therapy in chronic myeloid leukemia].

We studied 30 patients in order to evaluate the therapeutic efficacy and toxicity of alfa interferon associated with busulfan as maintenance treatment in de novo chronic granulocytic leukemia. Patients received 0.2 mg/kg of busulfan and reached complete hematological remission (CHR). Patients were then randomized in two groups: one to receive busulfan to be administered when the leukocyte count was above 15 x 10(9)/L, and another to receive subcutaneously 5 million IU of alpha-interferon three times per week (plus busulfan if the leukocyte count went above 15 x 10(9)/L). The duration of CHR was longer in the alfa-interferon group: 31 vs 16 months (p = 0.03) but no cytogenetic remissions were observed. Alfa interferon was well tolerated: no patient was excluded from the study due to toxicity.

Adolescent↗
PubMed1999

The determination of methanesulphonic acid content of busulfan drug substance and busulfan (Myleran) tablets by ion chromatography.

A robust ion chromatographic procedure is described for the determination of the methanesulphonic acid content of busulfan drug substance and busulfan (Myleran) 2 mg tablets. The sample was dissolved in aqueous acetonitrile, butanesulphonic acid was added as an internal standard and the solution was injected onto an ion selective column, with ion suppression and conductivity detection. The method has been fully validated and is linear over the concentration range 0.295-14.73 microg of methanesulphonic acid/ml. The method has been demonstrated to be stability indicating.

Alkylating Agents↗
PubMed2000

Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study.

The unpredictable intestinal absorption and erratic bioavailability of oral busulfan (Bu) has limited the drug's use in high-dose pretransplantation conditioning therapy. To standardize drug delivery, we solubilized Bu for parenteral use. This new intravenous (i.v.) Bu formulation was combined with oral Bu and cyclophosphamide (Cy) to evaluate (1) the human acute toxicity of i.v. Bu and its solvent system and (2) the pharmacokinetics of Bu in patients undergoing hematopoietic progenitor cell transplantation (HPCT). One dose of i.v. Bu (escalating from 0.08 to 0.8 mg/kg) was given over 2 hours by pump; 6 hours later, an oral Bu regimen was begun, consisting of 1 mg/kg every 6 hours for 15 doses, followed by Cy, 60 mg/kg daily for 2 days. After 1 day of rest, HPCT was performed. The i.v. Bu dose was well tolerated and did not produce any acute toxicity reaction that could be attributed to the solvent system of dimethylacetamide and polyethylene glycol (PEG)-400. All observed treatment-related toxicity was as would be expected after high-dose oral Bu plus Cy. When the i.v. Bu was used as reference solution, the pharmacokinetic analysis indicated an average bioavailability of oral high-dose Bu of 69%, ranging from <10% to virtually 100%. Further, the 2-hour infusion of i.v. Bu gave a time to maximum plasma concentration following drug administration similar to that of oral Bu (2 hours and 1.8 hours, respectively), and i.v. Bu had a clearance similar to that of oral Bu. Based on the data in this study, we suggest that the optimal (starting) dose of i.v. Bu (in combination with Cy) in our forthcoming phase 2 trial should be on the order of 0.8 mg/kg to target an area under the curve (AUC) of 1100 to 1200 micromol/L per minute. This would secure myeloablation and engraftment but save the vast majority of patients from the increased risk of serious hepatic veno-occlusive disease that has been reported when the AUC level exceeds 1500 micromol/L per minute. Bu administration via the i.v. route will assure complete bioavailability and reliable systemic drug exposure with more predictable blood levels and, therefore, possibly lower the risks for serious/life-threatening toxicity, graft rejection, and recurrent leukemia.

Acetamides↗
PubMed1992

[Measurement of busulfan concentration in plasma and spinal fluid from transplant patients pretreated with busulfan and cyclophosphamide].

Busulfan (BU) concentrations in the blood and spinal fluid of 7 patients pretreated with BU for bone marrow transplantation (BMT) were measured using gas chromatography. The data from these periodically obtained samples were used to study the relationship between the BU concentration and complications (e.g. vomiting), indicating that vomiting leads to a lower maximum BU level. The trough level of BU concentration at 6 hours after administration was stable at around 500 ng/ml, not showing little effect of vomiting. The BU concentrations in the spinal fluid were virtually the same as those in plasma collected at the same time and the spinal fluid/plasma ratio of the BU concentration averaged 1.06. No veno-occlusive disease (VOD) was noted. Failure of engraftment occurred in one case of myelofibrosis, however, as the plasma BU concentration in this case was not lower than the others, the graft failure was not considered to be due to the preconditioning regimen including BU.

Adolescent↗
PubMed1996

Busulfan, cyclophosphamide and fractionated total body irradiation for allogeneic marrow transplantation in advanced acute and chronic myelogenous leukemia: phase I dose escalation of busulfan based on targeted plasma levels.

A previous phase I study determined that the maximum tolerated dose (MTD) of busulfan (BU) that could be given with a fixed dose of cyclophosphamide (CY) of 50 mg/kg and total body irradiation (TBI) dose of 12.0 Gy was 7 mg/kg. A phase II study was carried out in patients with advanced myeloid malignancies receiving allogeneic transplants without improvement in outcome as compared to historical controls. In that study, steady-state concentration (Css) of BU in 13 patients receiving a fixed dose of BU varied from 209 to 735 ng/ml. In an attempt to decrease the variability of the Css of BU, a study of targeting specific plasma concentrations was performed. In this study, BU dose was adjusted up or down based on first dose pharmacokinetics. The first dose level evaluated was 7.5 mg/kg with a target BU plasma level of 460 ng/ml. Six patients were entered at this level and the median BU plasma concentration achieved was 410 (range 390-533). One of six patients developed grade 3-4 regimen-related toxicities (RRT). Dose level II was a target of 559 ng/ml with a starting oral dose of BU of 9.6 mg/kg. Twelve patients were entered at this level and median plasma BU level was 548 (range 427-689). Three of 12 (25%) patients developed grade 3-4 RRTs and this was considered to be the MTD. The actuarial probability of grade II-IV acute GVHD was 0.70. Eight of 21 evaluable patients (38%) developed chronic GVHD. Of 18 patients who died, seven died of relapse at a median of 160 days (range 65-353) and 11 (61%) died of causes other than relapse at a median of 152 days (range 18-570). The actuarial probabilities of DFS, relapse and relapse-free mortality at 2 years in all patients were 0.13, 0.50 and 0.75, respectively. This study showed that targeted BU plasma levels within 10% of target can reliably be achieved with a bias of -2.07% and mean absolute error of 7.47%. Overall, targeting made a -31.8% to 100% in plasma BU Css as compared to expected BU Css based on first dose pharmacokinetics if targeting were not performed in this study. Thus targeting avoided much of the variability in BU concentrations seen in other studies. When compared with our previous phase II experience in same group of patients receiving same regimen, dose escalation of BU based on targeted plasma levels did not improve the outcome.

Adolescent↗
PubMed1996

Busulfan, cyclophosphamide and fractionated total body irradiation for autologous or syngeneic marrow transplantation for acute and chronic myelogenous leukemia: phase I dose escalation of busulfan based on targeted plasma levels.

In a previous phase I study, it was concluded that tolerable doses of busulfan (BU), cyclophosphamide (CY) and total body irradiation (TBI) were 8 mg/kg, 60 mg/kg and 12.0 Gy, respectively, for autologous marrow transplant recipients. In an attempt to decrease the variability of BU steady-state concentration (Css) following oral dosing, a BU dose escalation study based on targeted plasma levels was performed in patients receiving autologous transplants for AML or syngeneic transplants for CML. In this study, the BU dose was adjusted up or down based on observed plasma concentration. All patients received a fixed dose of CY 60 mg/kg and TBI of 12 Gy. The first dose level evaluated was 8.6 mg/kg with a target BU Css of 511 ng/ml. Eight patients were entered at this level and the median BU Css achieved was 441 (range 253-566). One of eight patients developed grade 3-4 regimen-related toxicities (RRT). The oral dose of BU for dose level II was 10.6 mg/kg with a target Css of 632 ng/ml. Six patients were entered at this level and median BU Css achieved was 642 (range 566-674). One of six patients developed grade 3-4 RRT. The oral dose for dose level III was 12.6 mg/kg with a target BU Css of 754 ng/ml. Five patients with AML were entered at this dose level and the median plasma BU Css was 733 ng/ml (682-900). Two of five (40%) patients at dose level III developed grade 3-4 RRT which was considered excessive making dose level II the MTD. This study showed that targeted BU Css can reliably be achieved with a bias of -5.23% and mean absolute error of 11.3%. Overall, targeting made a -32.5% to 158.3% change in plasma BU Css as compared to expected BU Css based on first dose pharmacokinetics if targeting were not performed in this study. Thus, targeting avoided much of the variability in BU Css seen in other studies and appears to have allowed for an increase in oral dosing from 8 mg/kg to 10.6 mg/kg. Despite achieving higher and more uniform BU Css, there was no apparent effect on relapse or survival, although the number of patients evaluated was small.

Acute Disease↗
PubMed2001

Sensitive and rapid quantification of busulfan in small plasma volumes by liquid chromatography-electrospray mass spectrometry.

BACKGROUND: High-dose busulfan is widely used in conditioning regimens before hematopoietic stem cell transplantation in both adults and children. Large interindividual variability in pharmacokinetics after oral administration has been reported; therefore, therapeutic drug monitoring of busulfan may decrease the incidence of drug-related toxicity (for example, hepatic venoocclusive disease) and may also improve therapeutic efficacy. METHODS: Busulfan concentrations were quantified using 200 microL of plasma and liquid-liquid extraction with diethyl ether after the addition of [2H8]busulfan as the internal standard. Separation and detection of busulfan and [2H8]busulfan were achieved with a LUNA C8 column (5 microm; 150 x 2 mm i.d.) at 30 degrees C, a HP 1100 liquid chromatography system, and a HP 1100 single-quadrupole mass spectrometer. Busulfan and [2H8]busulfan were detected as ammonium adducts in selected-ion monitoring mode at m/z 264.2 and 272.2, respectively. RESULTS: The calibration curve was linear at 5-2000 microg/L busulfan. Intra- and interassay imprecision (CV) and bias were both <11%. The limits of detection and quantification were 2 and 5 microg/L, respectively. Extraction recovery of busulfan was >87%. Analysis of pharmacokinetics in four patients receiving high-dose busulfan indicated that minimum busulfan concentrations before the next dose were 405-603 microg/L, with no interference observed. CONCLUSIONS: The new rapid and sensitive liquid chromatographic-mass spectrometric assay is an appropriate method for quantification of busulfan in human plasma, making therapeutic drug monitoring of busulfan faster and easier in clinical practice.

Adolescent↗
PubMed1990

Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study.

Busulfan is known to be neurotoxic in animals and humans, but its acute neurotoxicity remains poorly characterized in children. We report here a retrospective study of 123 children (median age, 6.5 years) receiving high-dose busulfan in combined chemotherapy before bone marrow transplantation for malignant solid tumors, brain tumors excluded. Busulfan was given p.o., every 6 hours for 16 doses over 4 days. Two total doses were consecutively used: 16 mg/kg, then 600 mg/m2. The dose calculation on the basis of body surface area results in higher doses in young children than in older patients (16 to 28 mg/kg). Ninety-six patients were not given anticonvulsive prophylaxis; 7 (7.5%) developed seizures during the 4 days of the busulfan course or within 24 h after the last dosing. When the total busulfan dose was taken into account, there was a significant difference in terms of neurotoxicity incidence among patients under 16 mg/kg (1 of 57, 1.7%) and patients under 600 mg/m2 (6 of 39, 15.4%) (P less than 0.02). Twenty-seven patients were given a 600-mg/m2 busulfan total dose with continuous i.v. infusion of clonazepam; none had any neurological symptoms. Busulfan levels were measured by a gas chromatographic-mass spectrometry assay in the plasma and cerebrospinal fluid of 9 children without central nervous system disease under 600 mg/m2 busulfan with clonazepam:busulfan cerebrospinal fluid:plasma ratio was 1.39. This was significantly different (P less than 0.02) from the cerebrospinal fluid:plasma ratio previously defined in children receiving a 16-mg/kg total dose of busulfan. This study shows that busulfan neurotoxicity is dose-dependent in children and efficiently prevented by clonazepam. A busulfan dose calculated on the basis of body surface area, resulting in higher doses in young children, was followed by increased neurotoxicity, close to neurotoxicity incidence observed in adults. Since plasma pharmacokinetic studies showed a faster busulfan clearance in children than in adults, this new dose may approximate more closely the adult systemic exposure obtained after the usual 16-mg/kg total dose, with potential inferences in terms of anticancer or myeloablative effects. The busulfan dose in children and infants undergoing bone marrow transplantation should be reconsidered on the basis of pharmacokinetic studies.

Adolescent↗
PubMed2000

Plasma concentration monitoring of busulfan: does it improve clinical outcome?

High dosage busulfan (1 mg/kg orally every 6 hours x 16 doses) is frequently used in preparative regimens for haemopoietic stem cell transplantation (HSCT). Busulfan is well absorbed after oral administration, exhibits low protein binding and is metabolised through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of busulfan, typically expressed as area under the plasma concentration-time curve (AUC) or average concentration at steady state (Css). Relative to that in adolescents and adults, patients less than 4 years of age have an increased apparent oral clearance (CL/F) of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. Several investigators have identified relationships between busulfan Css and outcome in patients undergoing HSCT. Busulfan concentration-response relationships are regimen-, age- and disease-dependent. The busulfan/cyclophosphamide (BU/CY) regimen is the only regimen for which substantial concentration-outcome data exist. Generally, the risk of hepatic veno-occlusive disease is increased with busulfan Css > 900 microg/L. The impact of busulfan Css on veno-occlusive disease may be influenced by the age of the patient and the dose of cyclophosphamide. Lower rates of relapse in chronic myelogenous leukaemia occur in patients with a busulfan Css > 917 microg/L without an increased risk of toxicity. Busulfan Css is also related to the engraftment rate in children, and escalating busulfan doses to achieve a target Css > 600 microg/L improves graft retention. Therapeutic drug monitoring of busulfan should be performed to maximise the likelihood of engraftment and minimise the risk of toxicity and relapse in HSCT patients receiving the BU/CY preparative regimen.

Adult↗
PubMed2000

Retrospective appraisal of busulfan dose adjustment in children.

This report describes and critically appraises our experience with busulfan dose adjustment in children undergoing bone marrow transplant between April 1997 and March 1999. All children received an initial busulfan dose of 40 mg/m2 p.o. or by nasogastric tube. Whole blood samples were obtained 1, 1.5 and 6 h later and analyzed for busulfan content by gas chromatography with electron capture detection. The area under the whole blood busulfan concentration vs time curve (AUC) and an individualized dose which would achieve an AUC of 1300 microM/min were calculated. Mean and median busulfan doses were calculated using actual, ideal and effective body weight and stratified according to age. The relationship between the busulfan concentration at hour 6 and AUC was determined using linear regression. Thirty-nine courses of busulfan were evaluated in 38 patients. A change from the initial busulfan dose was required to achieve the target AUC in 34 courses (87%). Most children >1 to 5 years old required dose increments while most children >5 years old required dose reductions. Obesity did not significantly affect busulfan dose requirements. Busulfan concentrations at 6 h only weakly predicted the AUC achieved (r2 = 0.496; P = 0.001). Based on these findings, we recommend that the initial busulfan dose be assigned according to patient age and actual body weight. We also recommend that busulfan AUC be calculated for children using a four-sample (1, 1.5, 4 and 6 h) limited sampling technique.

Adolescent↗
PubMed2003

Dose-response of RAG2-/-/gammac-/- mice to busulfan in preparation for spermatogonial transplantation.

Practical applications of spermatogonial transplantation require good rates of colonization by the donor cells. Recipient testes are usually depleted of competing endogenous spermatogonia by administration of 32-44 mg busulfan kg(-1) body weight before transplantation. However, it is not clear that this is the optimum dose, especially for immunodeficient mice. In the present study, the response of adult RAG2(-/-)/gamma(c)(-/-) (RAG2) male mice to treatment with 10-50 mg busulfan kg(-1) body weight was determined in terms of mortality rates, testicular masses and histology, and colonization of seminiferous tubules by transplanted spermatogonia. Mortality increased from 0 to 50% at doses between 20 mg busulfan kg(-1) and 40 mg busulfan kg(-1), whereas the maximum effects on testicular mass and histology were observed at 20 mg busulfan kg(-1). Colonization of testes by genetically marked spermatogonia after treatment of mice with 20 mg busulfan kg(-1) was equivalent to rates previously reported in recipients treated with 32-44 mg busulfan kg(-1). Thus, 20 mg busulfan kg(-1) appears to be the optimum dose for preparing RAG2 mice for spermatogonial transplantation. However, because the steepness of the dose-response curves indicates that direct administration of busulfan is not ideal for this purpose, 15 mg busulfan kg(-1) was administered to pregnant females at various times between day 10.5 and day 16.5 of gestation to determine whether this would deplete the number of germ cells in male offspring. Although there were large variations in testicular mass and histology, no mortality was observed and administration of busulfan at day 10.5 or 12.5 after mating delayed initiation of spermatogenesis, indicating that prenatal administration of busulfan combined with neonatal transplantation might be an effective method for further increasing rates of colonization by donor spermatogonia.

Alkylating Agents↗
PubMed1995

A randomized trial comparing interferon-alpha with busulfan for newly diagnosed chronic myelogenous leukemia in chronic phase.

A multicenter randomized study was conducted to compare the effect of interferon-alpha (IFN-alpha) with that of busulfan in newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase. From October 1988 to October 1991, 170 patients were randomized to receive either IFN-alpha or busulfan. Of 159 eligible patients, 31 (38.8%) of 80 patients in the IFN-alpha group and 43 (54.4%) of 79 patients in the busulfan group achieved complete hematologic remission, and 38.8% in the IFN-alpha group and 43.0% in the busulfan group achieved partial hematologic remission. A complete cytogenetic response was induced in seven (8.8%) of 80 patients treated with IFN-alpha and two (2.5%) of 79 patients treated with busulfan, and a partial cytogenetic response was 7.5% (6/80) and 2.5% (2/79), respectively. The difference in major (complete and partial) cytogenetic response between the two groups was significant (P = .046). At a median follow-up of 50 months, the predicted 5-year survival rate was 54% in the IFN-alpha group and 32% in the busulfan group (P = .0290), and the predicted 5-year rate of remaining in chronic phase was 41% in the IFN-alpha group and 29% in the busulfan group (P = .1165). As compared with the patients with no cytogenetic response, the patients with any cytogenetic response (complete, partial or minor) after the IFN-alpha or busulfan treatment were significantly superior in the duration of chronic phase (IFN-alpha group; P = .0017, busulfan group; P = .0010) even after correction for the time to response using the landmark analysis. However, there was no significant difference in survival rate in the IFN-alpha group (P = .1065). There was no significant difference in survival rate (P = .3923) and the duration of chronic phase (P = .6258) between the IFN-alpha and the busulfan group in the patients with a cytogenetic response (complete, partial or minor). These results demonstrate that IFN-alpha treatment produces a significantly superior cytogenetic response and survival rate as compared with the busulfan treatment, and unexpectedly, that busulfan can also eliminate Philadelphia chromosome positive clone in a few patients who showed prolonged survival rate and duration of chronic phase.

Adult↗
PubMed1996

Busulfan-glutathione conjugation catalyzed by human liver cytosolic glutathione S-transferases.

We have examined the catalytic activity of glutathione S-transferases (GST) in the conjugation of busulfan with glutathione (GSH) in human liver cytosol, purified human liver GST, and cDNA-expressed GST-alpha 1-1. Human liver microsomes and cytosol were incubated with 40 microM busulfan and 1 mM GSH. Cytosol catalyzed the formation of the GSH-busulfan tetrahydrothiophenium ion (THT+) in a concentration-dependent manner, whereas microsomes lacked activity. The total and spontaneous rates of THT+ formation increased with pH (pH range, 6.50-7.75), with the maximum difference at pH 7.4. Due to the limited aqueous solubility of busulfan, a K(m) for busulfan was not determined. The intrinsic clearance (Vmax/K(m)) of busulfan conjugation was 0.167 microliter/min/mg with 50-1200 microM busulfan and 1 mM GSH. GSH Vmax and K(m) for busulfan conjugation were 30.6 pmol/min/mg and 312 microM, respectively. Ethacrynic acid (0.03-15 microM) inhibited cytosolic busulfan-conjugating activity with 40 microM busulfan and 1 mM GSH. Enzyme-mediated THT+ formation was decreased 97% by 15 microM ethacrynic acid with no effect on the spontaneous reaction. In incubations with affinity-purified liver GST and GST-alpha 1-1, the intrinsic clearance for busulfan conjugation was 0.87 and 2.92 microliters/min/mg, respectively. Busulfan is a GST substrate with a high K(m) relative to concentrations achieved clinically (1-8 microM).

Antineoplastic Agents, Alkylating↗
PubMed1996

Busulfan conjugation by glutathione S-transferases alpha, mu, and pi.

Busulfan is eliminated by glutathione S-transferase (GST)-catalyzed conjugation with glutathione (GSH). We have characterized the busulfan-conjugating activity of purified human liver GSTA1-1, GSTA1-2, GSTA2-2, GSTM1-1, and placental GSTP1-1. Isoforms were purified from cytosol by GSH-affinity chromatography and chromatofocusing. In addition, the busulfan-conjugating activity of cDNA-expressed GTH1 and GTH2, corresponding to GSTA1-1 and GSTA2-2, were characterized. The major product of busulfan conjugation, a thiophenium ion (THT+), was assayed by GC/MS after conversion to tetrahydrothiophene (THT). THT+ formation rate increased linearly with busulfan concentration up to its solubility limit for all GST isoforms. Because Vmax and KM could not be determined separately, the slope of the velocity vs. substrate concentration plot, Vmax/KM was used to compare isoform activities. Vmax/KM for GSTA1-1 was 7.95 microliters/min/mg protein, the highest busulfan-conjugating activity of all human liver and placenta isoforms evaluated. GSTM1-1 and GSTP1-1, respectively, had 46% and 18% of the activity of GSTA1-1. Since the polymorphic mu-class GST catalyzed busulfan conjugation, we examined busulfan clearance in 50 patients undergoing high-dose busulfan before bone marrow transplantation. Busulfan clearance was normally distributed, suggesting that GSTM1-1 does not contribute significantly to the elimination of busulfan from the body. We conclude that GSTA1-1 is the major isoform catalyzing busulfan conjugation, whereas GSTM1-1 and GSTP1-1 may be important in the protection of specific cells.

Adolescent↗
PubMed1994

Busulfan.

OBJECTIVE: To review the current published studies evaluating the pharmacokinetics, clinical efficacy, safety, and toxicity of busulfan in pediatric and adult patients. DATA SOURCES: English-language literature published between 1953 and 1993 was analyzed; pertinent literature was reviewed. STUDY SELECTION: Emphasis was placed on pharmacologic studies and clinical trials involving busulfan therapy both in myeloproliferative disorders and in conditioning regimens for autologous or allogeneic bone marrow transplantation. DATA EXTRACTION: Data from both pediatric and adult studies were evaluated; emphasis was placed on the relationship between plasma concentrations of busulfan and its efficacy and toxicity. DATA SYNTHESIS: Busulfan has been used widely at conventional dosages (1-12 mg/d) for the treatment of patients with chronic myelogenous leukemia (CML). Busulfan at high doses (usually 16 mg/kg) given with other cytotoxic drugs (especially cyclophosphamide) is a common preparative regimen in patients undergoing allogeneic or autologous bone marrow transplantation (BMT) for acute or chronic leukemia and other nonmalignant disorders (e.g., hemoglobinopathies, inborn error of immune system, congenital metabolic disorders). Pharmacokinetics of high-dose busulfan are age-dependent. Busulfan systemic exposure and, thus, tissue and tumor exposure are lower in children than with adults. Relationships between toxicity (principally neutropenia, hepatic veno-occlusive disease, incidence of seizures) and drug exposure were found for busulfan. CONCLUSIONS: Busulfan is a useful, sufficiently safe drug in the treatment of patients with CML. At higher dosages, busulfan is a fundamental part of myeloablative therapies for patients undergoing BMT. As the pharmacokinetics and metabolism of busulfan is further understood, there is great potential for improving treatment outcome. An assessment of maximal tolerated exposure determined by therapeutic drug monitoring may decrease the incidence and lethality of regimen-related toxicities.

Age Factors↗
PubMed1994

A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group.

Between October 1988 and December 1992, 167 patients with leukemia receiving marrow transplants from HLA-identical donors and conditioned with cyclophosphamide (120 mg/kg) were randomized to additional treatment with either busulfan (16 mg/kg, n = 88) or total body irradiation (TBI; n = 79). The busulfan-treated patients had an increased cumulative incidence of veno-occlusive disease of the liver, ie, 12% compared with 1% in the TBI group (P = .009). Furthermore, hemorrhagic cystitis occurred in 24% of the busulfan patients versus 8% in the TBI patients (P = .003). In patients with advanced disease beyond first remission or first chronic phase, transplantation-related mortality was 62% among the busulfan-treated patients compared with 12% among the TBI recipients (P = .002). These differences between the two groups were statistically significant in multivariate analysis. Seizures were seen in 6% of the busulfan-treated patients and were absent in the TBI group (P = .03). Grade II-IV of acute graft-versus-host disease (GVHD) was similar in the two groups, but grade III-IV and chronic disease was more common in the busulfan-treated group (P = .04). Death associated with GVHD occurred in 17% of the busulfan-treated group and 2% of the TBI group (P = .003). Patients treated with busulfan had a 3-year actuarial survival of 62%, which was worse than the 76% among those treated with TBI (P < .03). In multivariate analysis, poor survival was associated with advanced disease (P < .0001), no posttransplant septicemia (P = .0006), grade II-IV GVHD (P = .006), and busulfan treatment (P < .02). The incidence of relapse did not differ between the two groups. Relapse-free survival was also similar in the two treatment groups on analysis of data from all patients, children, patients with early disease, and those with acute myeloid leukemia, acute lymphoblastic leukemia, and chronic myeloid leukemia. However, in adults (P = .05) and patients with advanced disease (P = .005), leukemia-free survival was significantly better in those treated with TBI. We conclude that patients treated with busulfan have more early toxicity and an increased transplant-related mortality in patients with advanced disease. TBI is therefore the treatment of choice, especially in adults and patients with advanced disease. However, busulfan is an acceptable alternative for patients with early disease and for those in whom TBI is not feasible.

Adolescent↗