We investigated whether adjusting the oral busulfan (BU) dosage on the basis of early pharmacokinetic data to achieve a targeted drug exposure could reduce transplant-related complications in children with advanced hematologic malignancies. Twenty-five children received a preparative regimen consisting of thiotepa (250 mg/m2 i.v. daily for 3 days), BU (40 mg/m2 per dose p.o. every 6 h for 12 doses), and cyclophosphamide (60 mg/kg i.v. daily for 2 days) and then underwent allogeneic stem cell transplantation. Busulfan clearance and area under concentration time-curve (AUC) were determined after the first dose using a one-compartment pharmacokinetic (PK) model with first-order absorption. The initial PK analysis was successfully completed after the first BU dose in 21 patients (84%). A final AUC of 1000–1500 μm × min/dose was targeted and subsequent doses were modified as necessary to achieve this value. Fourteen of the 25 patients (56%) required dose adjustment. Follow-up PK analysis was completed in 21 patients and 16 of these achieved the targeted BU exposure for the course of therapy. Interpatient variability in BU clearance was high (up to five-fold). The most frequent regimen-related toxicities were cutaneous and gastrointestinal (stomatitis and diarrhea). Only one patient developed hepatic veno-occlusive disease. Our study demonstrates the feasibility of adjusting the oral BU dose in individual pediatric patients. Although toxicity associated with BU seemed to be reduced, this conclusion is tempered by the fact that the overall regimen-related toxicity (RRT) remains substantial and reflected the effects of all agents used in the preparative regimen. Bone Marrow Transplantation (2000) 26, 463–470.
High-dose busulfan is an important component of many myeloablative regimens for patients undergoing hematopoietic stem cell (HSC) transplantation, but BU disposition after oral administration is highly variable, so control of drug exposure is difficult. In children this problem is further complicated by their more rapid, age-dependent clearance of the drug.1234 Initial pediatric transplant regimens using doses equivalent to those administered to adults, on a mg/kg basis, resulted in lower busulfan AUC, less RRT, and higher relapse rates. It has been suggested that BU clearance rates in children are not significantly different from those of adults if the rates are normalized to body surface area (BSA). Thus BU dosages based on BSA, rather than body weight, should lead to a BU exposure more approximate to that observed in adults.567 In subsequent pediatric studies, when fixed doses of BU (600–640 mg/m2) were administered in combination with cyclophosphamide, the incidences of mucositis, VOD, and neurotoxicity approached those seen in the adult population.56789
While dosages based on BSA may result in similar toxicities in both populations, such schemes do not correct for interpatient variability in BU bioavailability and thus therapeutic drug monitoring may prove useful. Steady-state BU plasma concentrations and area under concentration-time curve (AUC) have been correlated to the incidence of hepatic toxicities (especially veno-occlusive disease (VOD)), transplant-related mortality and relapse of the primary disease.10111213 Recent attempts to alter patient outcome by adjusting BU dosages based on pharmacokinetic (PK) data of individual patients have met with various degrees of success.1415 These studies included both autologous and allogeneic transplant recipients who received various preparative regimens.
The combination of thiotepa, BU, and cyclophosphamide is an effective pre-transplant regimen for adult patients with advanced hematologic malignancies.16 In this combination, however, the total dose of BU is reduced from the ‘usual’ 16 mg/kg to 12 mg/kg. This reduction has been questioned as a possible cause of higher graft rejection rates and relapses seen in children vs adults when using the standard combination of BU and cyclophosphamide for transplantation from an alternative donor. To maximize the antineoplastic activities of BU and minimize its toxic effects when used in this combination in children, we designed a prospective study to test the feasibility of adjusting the dose of BU, in individuals, to achieve a target AUC based on first dose pharmacokinetics. We also evaluated the incidence of regimen-related toxicity (RRT) and successful engraftment in allogeneic HSC transplantation for children exposed to a targeted BU level in the presence of multiple alkylating agents.
Materials and methods
Children less than 21 years of age with recurrent or high-risk leukemia or lymphoma were eligible. Patients also met the following criteria: left ventricular ejection fraction >50%, serum creatinine and bilirubin no more than twice the upper limit of normal, serum alanine aminotransferase no more than three times the upper limit of normal, no history of microscopic hematuria related to cyclophosphamide, HIV antibody negative and Lansky's performance status >70%. The protocol was approved by the institutional review board of The University of Texas MD Anderson Cancer Center and written informed consent was obtained from parents or guardians for all patients.
The treatment regimen consisted of thiotepa (250 mg/m2 given intravenously over 4 h daily on days −9, −8, and −7), BU (initial dose of 40 mg/m2 given orally every 6 h for 12 doses on days −6, −5, and −4), and cyclophosphamide (60 mg/kg given intravenously over 2 h on days −3, and −2). Mesna given at a dose of 10 mg/kg intravenously every 4 h for a total of 12 doses was used for uroprotection. Doses of BU were rounded to the nearest 2 mg and subsequent dosage was adjusted, as needed, after PK analysis of results from the initial dose, as indicated below. Body surface area (BSA) was calculated using the formula of Haycock et al,17 based on weight and height. The actual body weight (AcBW) was used for calculations, except for patients who were more than 20% above their ideal body weight (IBW). For these patients, the dosage was calculated based on the adjusted body weight (AdBW) according to the following formula: AdBW = (IBW + 0.4(AcBW − IBW)).
BU tablets were placed in gelatin capsules to facilitate swallowing. All patients received the first dose at 8 a.m. Food was withheld for 1 h before and after BU administration. Children under 3 years of age and those unable to swallow medication well received BU as a suspension (2 mg/ml) via a nasogastric tube. If vomiting occurred within 0.5 h of administration, the dose of BU was repeated and any scheduled PK study was cancelled and performed at the same time the next morning. To prevent seizure the first six patients received phenytoin 5 mg/kg per day from 24 h before the first BU dose to 24 h after the last dose of busulfan. With the combination of the additive anti-emetic and anti-seizure potentials of lorazepam, the remaining 19 patients received lorazepam 0.025 mg/kg/dose every 6 h (prior to each busulfan dose) and an additional four doses after the last dose of busulfan. Bone marrow, blood stem cells, or umbilical cord blood from related or unrelated donors was infused for hematopoietic reconstitution on day 0. No T cell depletion was performed. Patients were monitored and received supportive care as per standard procedures in our institution. Filgrastim at a dose of 5 μg/kg/day was given subcutaneously from day +1 until engraftment. Tacrolimus or cyclosporine along with methotrexate was given for the prevention of acute graft-versus-host disease (GVHD) as described elsewhere.18
The regimen-related toxicity (RRT) grading system of Bearman et al19 was used to score pulmonary, cardiac, hepatic, renal, mucosal, bladder and neurologic complications until day 28. The clinical criteria used for the diagnosis of hepatic VOD were presence of two or more of the following occurring within 21 days after transplant (in the absence of other causes of liver disease): bilirubin >2 mg/ml, unexpected weight gain >5% of baseline weight or presence of ascites, and hepatomegaly or right upper quadrant tenderness.20
Engraftment was assessed indirectly by peripheral blood count recovery and marrow examination and confirmed by conventional restriction fragment length polymorphism and cytogenetic analysis as previously described.21 To assess disease response bone marrow aspiration was performed 1, 3, 12 and 24 months after HSCT, and at any time when clinically indicated. Patients who received a transplant during first and second complete remission of acute leukemia or during chronic phase of CML from an HLA-identical donor (related or unrelated) were considered standard risk for disease progression or recurrence of disease; the rest of the patients were regarded as high risk.
All patients were followed to 1 May 1998. Actuarial estimates of treatment-related mortality and survival were calculated according to the method of Kaplan and Meier. Confidence intervals were calculated using the True Epistat Statistical Software (Epistat Services, Houston, TX, USA). Medians were compared using the Mann–Whitney U test, and the signed rank test was used to compare matched samples. All P values were two-tailed, and a P value <0.05 was considered significant.
Blood samples (3–5 ml) were collected in heparinized tubes just before and at 0.5, 1, 2, 4, and 6 h after the administration of the first, fifth, and ninth doses of oral BU. Samples were analyzed as previously described422 with minor changes. Briefly, samples collected after the first BU dose were processed immediately, and the fifth and ninth dose samples were stored at −40°C for later analysis. Plasma samples were deproteinated with acetonitrile. The supernatant was derivatized with 5% (w/v) diethyldithiocarbamate and 25 mM ammonium acetate to form 1,4 bis-(diethyldithiocarbomoyl) butane. The derivatized BU was extracted using a three-step liquid–liquid extraction procedure with ethyl acetate. Supernatant was slowly dried at 45°C under a gentle flow of nitrogen gas. Dried samples were reconstituted with 100 μl of methanol, and 50 μl of the samples was injected into the HPLC system for analysis.
An autosampler (717-Plus Autosampler, Waters Corp, Milford, MA, USA) was used to inject samples into the HPLC system. Separation was achieved by isocratic elution with a mobile phase consisting of methanol 80% (v/v) and water 20% (v/v) at a flow rate of 1.0 ml/min (616 Pump + 600S Controller, Waters Corp). Isolation of busulfan was accomplished by using a C18 analytical column and pre-column guard filter (Nova-Pak C18, 250 × 4.6 mm, 4 μm particle size). The analytical column was maintained at a temperature of 30°C. Column effluent was monitored using a photodiode array detector over wavelengths of 220 to 320 nm. A derived channel at 254 nm was extracted to create chromatograms for peak analysis. No endogenous human plasma components eluted at the retention time for BU (7.5 min). The BU peak was positively identified using UV absorbance spectral analysis and retention time, and busulfan concentrations were determined by a calibration curve using Millennium Software Version 2.15 (Waters Corp). Linearity was demonstrated to up to 10 μg/ml, with the lower limit of quantification at 0.05 μg/ml. Median recovery of busulfan was greater than 95%. The inter- and intraday coefficients of variation were less than 15%.
All reagents and chemicals used were HPLC grade. Ammonium acetate, chloroform, hydrochloric acid, methanol, and water from were Fisher Chemical (Fair Lawn, NJ, USA); BU powder, diethyldithiocarbamic acid and dimethylsulfoxide were from Sigma Chemical (St Louis, MO, USA); ethyl acetate was from EM Science (Gibbstown, NJ, USA). Millennium Data Station (Waters Corp) was used for data collection and analysis.
Pharmacokinetic analysis and busulfan dose adjustment
Drug clearance and systemic exposure (AUC) were determined by fitting a one-compartment model incorporating Bayesian estimation to the 1- and 4-h BU concentration-time points obtained with the first dose. The population parameter and variance estimates used came from published pediatric data.5710 Based on initial pharmacokinetic data the dosage of BU was changed by dose 2, if necessary. The target busulfan AUC was 1000–1500 μM × min per dose at steady-state. The AUC was estimated and the new dose calculated using the following formulae
Drug clearances and AUC estimates of the intermediate (fifth) and final (ninth) doses were determined by fitting a 1-compartment model to the combined data, ie initial and fifth dose data for intermediate estimates and initial, fifth and ninth dose data for final estimates, using maximum likelihood estimation. These two subsequent estimates were used to predict the performance of the model using only dose 1 data. No BU dose adjustments were made from these revised parameter estimates derived from multiple-dose data. All pharmacokinetic modeling was performed using ADAPT II Software Version 4.0 (BMRS, University of Southern California, Los Angeles, CA, USA).23
Between November 1994 and February 1998, 25 patients met the eligibility criteria and were treated on this adjusted-dose protocol. Their clinical characteristics are described in Table 1. Eleven patients had active disease at the time of pre-transplant conditioning. Eleven patients received HSC from an HLA-identical sibling, four from HLA-mismatched family member, and 10 from unrelated donors. In the latter group, four transplants were performed using HLA-matched marrow and six using umbilical cord blood units mismatched at one HLA locus (three patients) or two HLA loci (three patients).
Busulfan pharmacokinetics (Table 2)
The median initial BU dose was 40 mg/m2 (mean 38.5, range 27–40). Seven patients with a body mass 20% greater than ideal received an initial BU dose calculated using the adjusted BSA formula. The median BU apparent oral clearance (n = 25) was 120 ml/min/m2 (range 50–262) (Table 2). When divided according to age (Table 3), the mean BU apparent oral clearance was as follows: less than 6 years of age: (n = 7) 155 ml/min/m2, between 6 and 8 years: (n = 9) 139 ml/min/m2, between 9 and 18 years: (n = 9) 105 ml/min/m2. The median per dose AUC for the initial BU dose was 1130 μM × min/dose for the entire group. There was marked interpatient variability in BU exposures with an AUC range of 479–3050 μM × min for dose 1. The median initial volume of distribution (Vc) was 21.6 l/m2 (range 13.6–51.3) and the median half-life was 2.41 h (range 1.12–4.40).
Pharmacokinetic analysis was successfully performed after the first BU dose in 21 patients (84%), and after the fourth dose and fifth doses in two patients each; analysis in these latter four patients was delayed because of excessive vomiting. Of the 21 patients with successful first-dose PK analysis, five required dose escalation while six required BU dose reduction. Of the four patients with delayed PK analysis, three required dose reduction. The final PK analysis, which included combined data from doses 1, 5, and 9, demonstrated that 14 of 21 (66.7%) patients achieved the targeted exposure for a course of therapy (Table 2). The largest individual difference in dose 1 vs final apparent oral clearance estimate was 96 ml/min/m2 (Patient No. 5), while the mean difference of initial vs final apparent oral clearance estimate for the group was only 7 ml/min/m2 (120 vs 127 ml/min/m2).
Regimen-related toxicities and hepatic veno-occlusive disease (Table 4)
Sixteen of 25 patients (64%) experienced grade 2 or higher RRT. Stomatitis, esophagitis and diarrhea were the most frequent side-effects. Intertriginous skin hyper-pigmentation and moist desquamation was seen in a third of the patients. There were no cases of neurotoxicity. Seven patients developed hyperbilirubinemia, but only one fulfilled the criteria of hepatic VOD. In this patient, the initial PK analysis was performed at the fifth dose due to excessive vomiting on the first day. An AUC of 1959 μM × min was estimated and the BU dose was reduced to 30 mg/m2 for the remaining seven doses, resulting in a final per dose AUC of 1402 μM × min measured at dose nine. This patient developed VOD on day 17, which was fatal.
Engraftment, relapse and survival
In this group of 25 patients with advanced malignancies, three patients died before hematologic recovery and were not evaluable for engraftment. Twenty-one of the remaining 22 patients achieved complete engraftment. One patient who received a two-antigen mismatched umbilical cord blood transplant from an unrelated donor failed to engraft and had autologous marrow recovery. The BU dose for this patient was increased after a low first-dose AUC, and the AUC subsequently was within the targeted range.
Eight of the 11 patients with active disease at the time of transplant were evaluable for response at day +30. All achieved complete hematologic remission. With a median time of follow-up post transplant of 32 months (range 11–52 months), 11 patients were alive. Of these 10 patients (five high risk and five standard risk) were in continuous complete remission. One patient was in remission after receiving chemotherapy for leukemic relapse. The actuarial 3-year survival was 35% (95% CI, 13–57%). Fourteen patients have died as a result of GVHD (n = 4), infection (n = 2), diffuse alveolar hemorrhage (n = 2), recurrent leukemia (n = 5) and VOD (n = 1). The actuarial day 180 treatment-related mortality was 32% (95% CI, 14–50%).
This study represents the first attempt to individualize oral BU dosing in a pediatric population using first dose data. The primary goal was the early control of BU exposure within a defined range to reduce RRT while maximizing the desired drug effect. BU exposure can be projected from the initial-dose AUC, as shown by the fact that values for the median AUC at the time of the fifth and ninth doses were within the targeted range. We confirmed the feasibility of this approach in that 21 of 25 patients had sufficient pharmacokinetic data available to allow for the necessary dosage adjustment from dose 2 onwards. Overall, we had 21/25 (84%) patients with fifth and ninth dose pharmacokinetic data to evaluate our accuracy of initial estimates. Of these 21 patients, two-thirds of them achieved an AUC within our targeted range (Figure 1). The remainder did not with four patients achieving an AUC higher than our targeted range and three patients with lower than targeted exposures. Clinically, all but one evaluable patient had a successful engraftment. No neurotoxicity was observed. Only one patient developed hepatic VOD.
Two other studies have prospectively examined the effectiveness of individualizing BU dosage to achieve a targeted drug exposure in transplant recipients. Grochow14 examined busulfan disposition around the initial dose, making individual dose changes with the fifth dose of busulfan. In this study the incidence of VOD decreased from 75% to 18% when compared to control populations. Dix et al15 reported an association between high initial dose AUC and the occurrence of VOD in adult BMT patients. Patients with a first-dose AUC >1500 μM × min had a 33% incidence of VOD; compared with 3% for patients with an AUC below that level. Ten of 18 patients with high initial AUC had their BU dose reduced by 25%, which was started on or after the 10th dose. This delay in dose adjustment might account for the high (18.2%) incidence of VOD despite drug modification.
In our study, all but two samples obtained were collected in the morning to avoid the reported circadian variation in BU metabolism.24 BU pharmacokinetics are known to be influenced by patient's age, the underlying disease and its status at the time of transplantation.310 While differing in the actual number and doses of alkylating agents administered, our busulfan pharmacokinetic parameters were comparable in value to those previously reported.1112 For instance the median first dose busulfan plasma clearance in our patients was 130 ml/min/m2 or 4.6 ml/min/kg, which is very similar to those reported elsewhere in pediatric populations.124
During the initial investigations of busulfan as part of pediatric transplant preparative regimens, age-dependent busulfan clearance was observed. Doses equivalent to those administered to adults, on a mg/kg basis, resulted in lower busulfan AUCs, less regimen-related toxicities, and higher relapse rates. Several investigators have postulated that doses normalized to body surface area, rather than kg body weight, would result in BU exposure equivalent to that in adults.56 In subsequent studies, when fixed doses of BU were administered in combination with CY, the incidence of mucositis, VOD and neurotoxicities approached those seen in adult populations.56811 While this method increased the dose of busulfan in pediatric patients, and hence the toxicities, it did not reduce the large inter-patient variances in drug exposure associated with toxicity and efficacy. We observed a high (five-fold) amount of inter-patient variation in BU clearance after first dose, in both young children and those over 6 years of age. More than half of our patients required dose adjustment based on initial AUC, a frequency similar to that reported in other studies monitoring BU metabolism.141525 We therefore believe that pharmacokinetic monitoring and dose individualization is necessary for the optimal management of pediatric patients receiving busulfan as part of HSCT preparative regimens.
Complications associated with high-dose BU were very minimal with our approach; there were no cases of neurotoxicity, and hepatic VOD developed in only one patient. The patient in whom VOD developed had his BU dose decreased only after the fifth dose, but his final AUC was within the desired range. It is unclear whether the peak level or the duration of BU exposure is the more important factor for the development of VOD. There was speculation that an early high value for AUC might merely reflect underlying hepatic dysfunction and that even BU dose reduction cannot halt the development of VOD in these patients.15
The use of pharmacokinetic studies around a ‘test dose’ of busulfan prior to the preparative regimen to individualize BU dose has been advocated. Chattergoon et al25 administered a single dose of BU of 40 mg/m2 to nine children to determine drug disposition. The remaining 15 doses were then calculated, based on the ratio of target to test dose AUC, and treatment with the revised doses began 36–48 h later. These authors did not report the results, if any, of follow-up pharmacokinetic evaluations to verify dosing accuracy. No VOD was encountered, but engraftment problems were reported in four patients. One problem with this approach is the possibility of intrapatient changes in BU clearance over time. One report demonstrated a significant decrease in AUC between the first and last dose of a fixed dose of BU in a series of 20 patients.26 Dix noted that after adjustments, AUC values were 1.4- to 2.3-fold lower in follow-up PK studies in patients who received BU dose reduction.15 Similar intrapatient variance was also noted in our population suggesting that our approach may be more successful in achieving target drug exposures. Our data suggest that sequential PK monitoring is feasible and preferable to the use of a single test result to establish the BU dosage for myeloabalative therapy.
Leukemia recurrence and graft failure have been associated with low BU exposure.13 In our study six patients relapsed with leukemia with one evaluable patient who experienced final per dose AUC values <1000 μM × min due to dose reductions. On the other hand, there was only one engraftment failure despite a high percentage of unrelated and mismatched donors used. Our success with engraftment was probably the result of the immunosuppressive effect contributed by the addition of thiotepa in the conditioning regimen.1627
Children often have difficulty ingesting a large quantity of oral BU, and vomiting is more frequent when a large dose is ingested over a short period of time. In our patients, exposure to high-dose thiotepa prior to BU administration may have increase the likelihood of emesis. When vomiting leads to incomplete dose administration estimation of pharmacokinetic parameters becomes unreliable making individualization of drug dose impossible. We now routinely administer BU through a nasogastric tube in children who have a history of emesis with medication. This measure has helped reduce the vomiting associated with the administration of oral busulfan. Since busulfan absorption is erratic, and emesis often accompanies oral administration, the use of intravenous busulfan may be the only way to achieve consistent drug exposure in these patients. Preliminary results from studies at our center indicate that an intravenous formulation of busulfan is well tolerated and provides consistent drug plasma concentrations.27
In this study we were able to individualize and maintain BU exposure within a desired range in most patients. This approach allowed successful engraftment with minimal ‘BU-specific’ toxicities. However the incidence of RRT remained high because of the advanced disease status and the use of alternative donors for many of our patients. The inclusion of thiotepa may have also resulted in added toxic effects independent of the BU level. We feel that further studies are required to determine the optimal busulfan AUC in a variety of disease states and patient groups. For instance, a higher steady-state BU level was advocated for partially-matched or unrelated donor transplants.11 Additionally, Vassal et al9 observed a higher incidence of VOD related not to an altered BU disposition but rather to the additional alkylating agents in their regimen. Demirer et al28 combined cyclophosphamide, total body irradiation, and BU (dose adjusted) for transplantation of advanced myeloid leukemia. Despite a high degree of targeting accuracy and relatively low busulfan AUC in this study, the incidence of RRT remained high and outcome was not improved. However, patients with CML treated in another study were able to tolerate a higher exposure of BU, suggested to be a consequence of less intensive prior therapy.13
Individualized BU dosing can help in the management of transplant patients, but optimal BU exposure for a patient should be defined in the context of the combination treatment with other myeloablative agents used, condition of the patient, prior therapy and the type of donor used for the transplant procedure. What is clear is that PK monitoring to individualize drug dose for an orally administered agent with a relatively high emetogenic potential can be difficult. These models are best applied to situations that do not have oral absorption or drug loss through emesis as confounding variables. This is why we must be very careful in evaluating data derived from the use of oral busulfan. Recent study with an intravenous formulation of busulfan at our hospital shows promising results.29 We are currently applying this strategy to the use of a parenteral form of busulfan in our adult and pediatric stem cell transplant programs.
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We gratefully acknowledge the wonderful care given to our patients by our pediatric nursing staff at UT MD Anderson Cancer Center. Dr Tran would like to dedicate this work in memory of Heather Clark. This study was supported in part by the Cancer Center Support Grant (No. 16672).
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Tran, H., Madden, T., Petropoulos, D. et al. Individualizing high-dose oral busulfan: prospective dose adjustment in a pediatric population undergoing allogeneic stem cell transplantation for advanced hematologic malignancies. Bone Marrow Transplant 26, 463–470 (2000). https://doi.org/10.1038/sj.bmt.1702561
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