Once-Daily Intravenous Busulfan Given with Fludarabine as ...

Biology of Blood and Marrow Transplantation 8:468-476 (2002) © 2002 American Society for Blood and Marrow Transplantation

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Once-Daily Intravenous Busulfan Given with Fludarabine as Conditioning for Allogeneic Stem Cell Transplantation: Study of Pharmacokinetics and Early Clinical Outcomes J. A. Russell,1 H. T. Tran,2 D. Quinlan,1 A. Chaudhry,1 P. Duggan,1 C. Brown,1 D. Stewart,1 J. D. Ruether,1 D. Morris,1 S. Glück,1 E. Gyonyor,1 B. S. Andersson2 1

Alberta Bone Marrow Transplant Program and Departments of Medicine and Oncology, Foothills Hospital and Tom Baker Cancer Centre, Calgary, Alberta, Canada; 2University of Texas MD Anderson Cancer Center, Houston, Texas Correspondence and reprint requests: Dr. James A. Russell, Department of Medicine, Tom Baker Cancer Centre, 1331-29th St NW, Calgary, Alberta, Canada T2N 4N2 (e-mail: [email protected]). Received April 19, 2002; accepted May 28, 2002

ABSTRACT The availability of an IV form of busulfan (Bu) has prompted investigation of administration schedules other than the 4-times-daily dosage commonly used with oral Bu. We have studied an allogeneic stem cell transplantation (SCT) preparative regimen comprising fludarabine (FLU) 50 mg/m2 on days –6 to –2 plus IV Bu 3.2 mg/kg daily in a 3-hour infusion on days –5 to –2. The regimen was given to 70 patients aged 15 to 64 years (median, 41 years) with hematologic malignancy. Thirty-six patients (51%) had high-risk malignancy, 28 (40%) had unrelated or genotypically mismatched related donors (alternate donors [AD]) and 29 (41%) received bone marrow rather than blood as stem cell source. Acute GVHD prevention comprised antithymocyte globulin 4.5 mg/kg over 3 days pretransplantation, cyclosporin A, and short-course methotrexate with folinic acid. Hepatic toxicity was transient and there was no clinically diagnosed veno-occlusive disease. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 patients (13%). One patient with subtherapeutic phenytoin levels had a convulsion 8 hours after the third IV Bu dose, but no other neurotoxicity was apparent. Incidence of acute GVHD grades II to IV was 8% and incidence of grade III-IV was 3%, with no deaths from this cause. Actuarial incidence of chronic GVHD at 2 years is 38%. There were 2 cases of graft failure in unrelated donor BMT recipients, 1 of which was reversed by a second transplantation. With a median follow-up of 16 months (range, 6-27 months), transplantation-related mortality at 100 days and 2 years was 2% and 5% for matched related donor (MRD) SCT and 8% and 19% for AD SCT, respectively (P = not significant). Relapse rates were 21% for 34 patients with acute myeloid leukemia (AML) in complete remission or chronic myeloid leukemia in chronic phase (low-risk), 66% for 19 patients with high-risk AML, and 18% for 17 patients with other active malignancy. Projected disease-free and overall survival rates at 2 years were 74% and 88% for low-risk disease, 26% and 37% for advanced AML, and 65% and 71% for other high-risk disease, respectively. Pharmacokinetic studies were done using 11 samples with the first and fourth doses of Bu. Kinetics were linear, and for the first and fourth doses, the half-lives were 2.60 ± 0.44 and 2.57 ± 0.36 hours, respectively. Clearances were 106.77 ± 16.68 and 106.86 ± 21.57 mL/min per m2, peak concentrations (Cmax) were 3.92 ± 0.31 and 3.96 ± 0.28 mcg/mL, and Bu areas under the plasma concentration versus time curve (AUC) were 4866.51 ± 771.42 and 4980 ± 882.80 µM × min, respectively. Bu was completely cleared within 24 hours and the day 4 pharmacokinetic values were very similar to those on day 1 for every patient. The cumulative AUC was comparable to the target range established for PO Bu. This regimen incorporating once-daily IV Bu is convenient to give, is relatively well tolerated, gives predictable blood levels, and deserves further study in circumstances in which cytoreduction as well as immune suppression is needed.

KEY WORDS Intravenous busulfan

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Fludarabine

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Pharmacokinetics

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Stem cell transplantation

Daily IV Busulfan

Table 1. Patient Characteristics* Number Age, y, median (range) Diagnosis Low risk (n = 34) CML in first chronic phase AML CR1 AML CR2 High risk (n = 36) CML in accelerated phase MDS (RARS) CLL: Refractory CLL (4) /prolymphocytic leukemia (1) /Richter’s (3) Advanced AML (9)† and/or AML arising from MDS Relapsed/refractory HD NHL (2 mantle cell, 1 DLCL, 1 follicular) Hypereosinophilic syndrome Stem cell source Blood Bone marrow Both Donor Genotypically matched related Mismatched related‡ Unrelated (serological match A and B, molecular match DRB1 and DQB1)

70 41 (15-64)

14 17 3 2 1 8 19 1 4 1 40 29 1 43 6 21

*MDS indicates myelodysplastic syndrome; RARS, refractory anemia with ringed sideroblasts; CLL, chronic lymphocytic leukemia; HD, Hodgkin’s disease; NHL, non-Hodgkin’s lymphoma; DLCL, diffuse large cell lymphoma. †Four primary refractory, 5 first relapse (1 refractory, 1 pancytopenic after further chemotherapy). ‡Two phenotypically identical (1 parent, 1 child), 2 A mismatch (1 sibling, 1 parent), 1 B and C mismatched sibling, 1 B and 2 C mismatched sibling.

INTRODUCTION Busulfan (Bu) is a frequent component of cytotoxic preparative regimens for stem cell transplantation (SCT) [1-7]. Until recently, Bu has been available only in an oral form and has been given 4 times daily in the standard BuCy2 (busulfan/cyclophosphamide) protocol. Not only may patients vomit up oral Bu, but the unpredictable bioavailability may lead to overdosing with a higher risk of toxicity or to underdosing with graft failure or suboptimal antitumor activity [6-25]. In addition, gut absorption of Bu may contribute to veno-occlusive disease (VOD) of the liver via a “first pass” effect [26]. An intravenous (IV) preparation (Busulfex; Orphan Medical, Minneapolis, MN) has been recently developed and is currently the only such product commercially available. It is hoped that the IV formulation may avoid the inherent problems of oral administration and improve the accuracy of dosing [27-29]. However, most experience with IV formulations has been with the traditional 4-times-daily dosing [30,31]. If equally effective, daily dosing of Bu would be more convenient, particularly in the outpatient setting. Moreover, if the metabolic handling of Bu is consistent with linear pharmacokinetics (PK) at higher individual doses (>1 mg/kg), one would predict more uniformity in exposure because there would be no accumulation from one dose to the next.

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Limited data indicate that daily oral doses seem to be well tolerated in children [32]. There are also case reports of inadvertent oral administration of single doses from 16 to 36 mg/kg, apparently without serious results apart from seizures [33]. Finally, other IV preparations have been given daily, albeit for only 2 days, and were well tolerated [34,35]. These data encouraged us to study the PK and clinical toxicity profile of IV Bu given once daily in combination with fludarabine in a myeloablative conditioning protocol for allogeneic SCT (FLUdarabine BUsulfan Protocol [FLUBUP]).

PATIENTS AND METHODS Patients Clinical data are presented on 70 consecutive patients, between May 1999 and January 2001, with hematologic malignancy who received daily IV Bu. Some details of diagnoses and stem cell sources are recorded in Table 1. For the purpose of this analysis, low-risk patients were defined as those with acute myeloid leukemia (AML) in first complete remission (CR1) or CR2 and those with chronic myeloid leukemia (CML) in first chronic phase; the remainder were considered high-risk patients. Alternative donor (AD) transplantations included recipients of SCT from unrelated and genotypically mismatched family donors. All patients were undergoing a first SCT. The median follow-up of survivors was 16 months (range, 6-27 months). Treatment Fludarabine 50 mg/m2 was given to all patients on days –6 to –2. Patients received Bu (Busulfex; Orphan Medical) at a dose of 3.2 mg/kg ideal body weight once daily IV as a 3-hour continuous infusion by pump through a right atrial catheter. The infusion time was based on the regimen used for a dimethyl sulfoxide–based Bu preparation by Jencke et al. [34] (G. Ehninger, personal communication, 1999). All patients received loading with oral or IV phenytoin and continued dosing to maintain therapeutic levels of 40 to 80 µmol/L from days –5 through –2. All patients were nursed without protective isolation [36]. All blood products were from cytomegalovirus seronegative donors. Single donor platelets were given to maintain a platelet count >10 × 109/L and red cells to keep the hemoglobin level >80 g/L. Growth factors were not given routinely. Antibacterial and antipneumocystis prophylaxis comprised ciprofloxacin 500 mg twice a day and trimethoprim/sulfamethoxazole twice weekly; no systemic antifungal prophylaxis was used. The acute graft-versus-host disease (GVHD) prophylaxis protocol comprised cyclosporin A orally or intravenously twice daily to maintain blood levels between 150 and 400 µmol/L. Methotrexate was given in doses of 15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11. Folinic acid 5 mg was started 24 hours after each dose of methotrexate and continued every 6 hours until 12 hours before the next dose [37]. Rabbit antithymocyte globulin (ATG) (Thymoglobulin; Sangstat, Fremont, CA) 4.5 mg/kg was given in divided doses of 0.5, 2, and 2 mg/kg on days –2, –1, and 0, respectively. Engraftment Daily blood counts were taken until hospital discharge, with bone marrow aspirations at 3 months for surviving

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patients or as clinically indicated. Granulocyte engraftment was defined as a count of >0.5 × 109/L. The platelet count needed to be above 20 × 109/L without transfusion for 3 days. If neither level had been reached by day 28, in the absence of persistent malignancy in the bone marrow, the patient was deemed to have primary graft failure. The source of engrafted cells in peripheral blood and/or bone marrow was confirmed by comparison of donor and recipient polymerase chain reaction (PCR) amplified and radiolabeled DNA fragments resolved on polyacrylamide gels and detected by autoradiography [38]. Toxicity Evaluation Stomatitis was evaluated according to the Bearman scale with grade I not requiring analgesia and grade II needing continuous systemic analgesics [39]. Hemorrhagic cystitis was defined as macroscopic hematuria accompanied by pain on voiding. Hepatotoxicity was determined according to liver function tests performed before transplantation and twice weekly posttransplantation. The maximum alanine aminotransferase (ALT) and conjugated bilirubin levels before and in each of the first 4 weeks after SCT were recorded, and the median values for each patient group were plotted. VOD was diagnosed according to previously described criteria [40]. PK Studies Twelve patients, 4 in each risk group, had blood sampling for PK studies. Blood samples (5 mL) were taken before Bu infusion and then at target time points of 1, 1.5, 2.9, 3.25, 3.5, 4, 6, 8, 10, 12, 16, and 24 hours after the start of the infusion. Sampling was done with the first and fourth doses only. Samples were taken from a peripheral vein into prechilled heparin tubes with plasma separation within 30 minutes. Plasma was separated by centrifugation at 2500 rpm for 10 minutes at 4°C within 1 hour, placed in cryogenic vials, and stored at –40°C until analyzed by a validated high-pressure chromatography as previously described [30,41-43]. The Bu peak concentrations (Cmax) are observed values. Parameters such as volume of distribution and elimination rate constant were estimated, whereas half-lives and clearance were calculated from the primary parameters. The Bu area under the plasma concentration versus time curve (AUC) per Bu dose was calculated by dividing the drug dose by the Bu plasma clearance estimate. The fourth-dose Bu plasma clearance was determined by modeling Bu plasma concentration versus time data from dose 1 and dose 4. The PK modeling was performed using ADAPT II Software Version 4.0 (BMRS, University of Southern California, Los Angeles, CA) [44]. Informed Consent All recipients of FLUBUP were fully informed about the investigational nature of the regimen, and the purpose of the PK studies was explained to selected patients. The protocol and consent forms were approved by the University of Calgary Conjoint Medical Ethics Committee. All patients gave written consent. Statistical Analysis The distributions of time to events were analyzed using the log-rank test, with patients being censored for relapse

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for estimation of nonrelapse mortality. The distributions of time to events were compared using the log-rank test. P values were reported only if 0.1 or less; those between 0.05 and 0.1 are referred to in the text as trends. Analysis was performed on a Macintosh computer using GraphPad Prism software (GraphPad, San Diego, CA).

RESULTS Engraftment Of patients alive at day 28, 2 had failed engraftment because of persistent leukemia. For unrelated donor transplants, the median nucleated cell dose was 2.44 × 108/kg (range, 0.29-10.62 × 108/kg) and the median CD34+ cell dose was 2.88 × 106/kg (range, 0.78-18.32 × 108/kg). Two unrelated donor BMT recipients with CML had primary graft failure after nucleated cell doses of 2.4 × 108/kg and 0.83 × 108/kg and CD34+ cell doses of 3.87 × 106/kg and 3.44 × 106/kg, respectively. Both received a second infusion after conditioning with fludarabine 50 mg/m2 for 5 days, total body irradiation (TBI) 200 cGy ×2 fractions, and ATG 4.5 mg/kg over 3 days. One patient had successful engraftment, and the other died of infection before engrafting. Among the remaining patients, neutrophil engraftment occurred at a median of 18 days (range, 12-42 days) and platelet engraftment at 19 days (range, 0-36 days). Regimen-Related Toxicity Neurotoxicity. One patient had a convulsion after the third dose of Bu. The phenytoin level at the time was 16.6 µmol/L (therapeutic range, 40-80 µmol/L). There was no other evidence of neurotoxicity attributable to Bu. Stomatitis and Hemorrhagic Cystitis. Grade II stomatitis occurred in 49 patients (70%) and hemorrhagic cystitis in 9 (13%). The cystitis was invariably self-limiting with no long-term sequelae. Hepatotoxicity. There was some histological evidence of VOD at autopsy in a patient who died suddenly on day 19, but liver function was improving at the time of death and she did not satisfy clinical criteria for VOD. Transient elevation of ALT to above normal levels occurred in 52 patients (74%), with levels usually peaking during the first week (Figure 1A). Conjugated bilirubin levels became elevated in 62 patients (89%), with peak levels tending to occur in the second week after SCT (Figure 1B). Graft-versus-Host Disease. The actuarial incidence rate of acute GVHD grades II to IV was 9% ± 4% and for grades III to IV disease was 3% ± 2%, with no difference between MRD and AD (grades II-IV, 10% ± 5% versus 9% ± 6%; grades III-IV, 3% ± 3% versus 5% ± 4%) (Figure 2A). At 2 years, the projected incidence rate of chronic GVHD was 38% ± 7%, with no difference between MRD and AD at 41% ± 9% and 31% ± 11%, respectively (Figure 2B). No deaths were primarily attributable to either acute or chronic GVHD. Relapse By 2 years, the projected relapse rates were 21% ± 8% in low-risk patients, 66% ± 12% in high-risk AML patients, and 18% ± 9% for other high-risk patients (Figure 2C).

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A

B

Figure 1. A, Pattern of ALT (U/L). Horizontal dotted line shows upper limit of normal range. B, Pattern of conjugated bilirubin (µmol/L). Horizontal dotted line shows upper limit of normal range.

Transplantation-Related Mortality One patient with a prior history of cardiac failure died on day 8 after a myocardial infarction. A second patient, referred to above, died suddenly on day 19; the cause was not apparent at autopsy. The third early death, on day 73, was in the CML patient with graft failure. Three late deaths have occurred, 1 on day 129 from cytomegalovirus, 1 on day 163 from a pulmonary embolus, and the third on day 182 after a second mismatched BCT for late graft failure. Overall actuarial nonrelapse mortality rate at 100 days was 5% ± 3% (MRD, 2% ± 2%; AD, 8% ± 6%, P = not significant) and at 2 years was 10% ± 4% (MRD, 5% ± 4%; AD, 19% ± 9%, P = not significant) (Figure 2D). Disease-Free and Overall Survival With a median follow-up of 16 months (range, 627 months), the projected 2-year relapse-free survival rate

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was 74% ± 8% for low-risk patients, 26% ± 11% for highrisk AML patients, and 65% ± 12% for the other high-risk patients (Figure 3A). Projected overall survival rates at 1 and 2 years for the 3 groups were 88% ± 6%, 37% ± 11%, and 71% ± 11% respectively (Figure 3B). There is no significant difference in these respects between recipients of MRD or AD SCT. PK Studies Details of the PK results in 12 patients are given in Table 2. For each patient, the PK parameters did not change significantly between the first and fourth dose. For the group, the mean dose of IV Bu was 2.91 mg/kg (based on actual body weight), which resulted in an estimated AUC of 4867 µM × min and 4980 µM × min for the first and fourth dose, respectively. With this once-daily dosing of IV Bu, Bu was completely cleared within 24 hours and the day 4 PK

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A

B

C

D

Figure 2. A, Acute GVHD (aGVHD). B, Chronic GVHD (cGVHD). C, Relapse. D, Transplantation-related mortality.

plots were very similar to those on day 1 for every patient analyzed (Figure 4). The only patient dying without relapse was the individual referred to above who died suddenly on day 19, patient 13 in Table 2. Bu AUC was in the middle of the measured range, at about 5000 µM × min.

DISCUSSION The combination of oral Bu with various doses of cyclophosphamide (Cy) is currently the most widely used myeloablative regimen not incorporating TBI. Randomized comparisons of BuCy2 (16 mg/kg Bu and 120 mg/kg Cy) with Cy and TBI (1200 cGy) have generally indicated comparable efficacy in myeloid leukemias [3-7]. Given our understanding of the difficulty patients have keeping the pills down plus the often erratic and unpredictable absorption, the combination of oral Bu with Cy could be seen as surprisingly successful. Doubtless some of the shortcomings of these regimens can be attributed either to inadequate exposure, with leukemic relapse and/or graft failure, or to toxic levels and consequent organ damage, particularly VOD [8,18-21,23-26,30,31]. An IV preparation has the potential of delivering optimum doses and allowing further evaluation of the therapeutic potential of Bu. The early BuCy regimens required Bu to be given 4 times daily, at least in part because of the difficulty some patients would have with less frequent dosing. The initial studies with IV Bu used the same dosing intervals and have demonstrated predictable and consistent PK profiles with acceptable toxicity [30]. Single daily dosing would be much

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more convenient and would be expected to be equally effective if comparable exposure, reflected in AUC, could be achieved with acceptable toxicity. Our decision to use IV Bu with Flu was based on preliminary studies indicating that the FLUBUP combination using oral Bu was at least as well tolerated as BuCy2 [45]. We have found little difference in toxicity between the oral and IV preparations but have moved exclusively to the IV form because of the more predictable PK [46]. The current study indicates that the combination of Flu with daily IV Bu is very well tolerated. Failure to engraft was seen only in AD transplants, and currently such failures seem no more frequent than with other regimens. This study cannot evaluate speed of engraftment in comparison with other combinations because of the influence of disease stage, donor, and cell source. Stomatitis is the most predictable toxicity but is self-limiting and less frequent with IV Bu than with oral BU in our experience [46]. Cystitis occurs with IV Bu at a similar frequency to that with BuCy2, perhaps partly explaining the lack of success when prophylactic measures are simply directed at Cy [45]. The mechanism by which Bu contributes to cystitis is uncertain, but fortunately this complication is generally brief and selflimiting. Hepatotoxicity seems generally mild and transient; the single case of histologic VOD observed at autopsy was not presenting a clinical problem at the time of death. The pattern of liver function abnormalities resembles that seen after BuCy2 and oral Bu with Flu [45,46]. The similar toxicity profiles of the current regimen, BuCy2, and oral Bu with Flu may indicate that daily IV Bu combined with Cy would be equally tolerable.

Daily IV Busulfan

A

B

Figure 3. A, Disease-free survival. B, Survival.

Both Bu and Flu are known to penetrate the central nervous system and have been responsible for neurotoxicity, usually convulsions in the case of Bu. Neurological side effects have also been attributed to dimethylacetamide, used with PEG-400 in the solvent system for IV Bu [27-29,47]. We observed only 1 neurological event, a generalized seizure in a patient whose phenytoin level was subtherapeutic. Our patients were mostly adults, about half with highrisk disease and one third with donors other than matched siblings. Transplantation-related mortality at 100 days is commonly taken as an indicator of the acute toxicity of the transplantation procedure, and the rates in this study of 8% for AD and 2% for MRD are relatively low. An overall nonrelapse mortality rate of about 10% at this report also indicates that this regimen seems to result in no major delayed effects. There was no predominant cause of death, with none attributable to GVHD. Although the addition of ATG to a methotrexate and cyclosporin regimen may account for the low morbidity and mortality from GVHD, it may also make evaluating the antileukemic potential of the IV Bu difficult. The contribution of a graft-versus-leukemia effect

could be relatively weak in the majority of patients without significant GVHD. The observation by Andersson et al. that GVHD may be affected by the intensity of the conditioning regimen may also be relevant [31]. The more predictable behavior of Bu when given IV could result in less severe GVHD if toxic levels are avoided. The relative contributions of these effects cannot be determined in a study such as ours. Nevertheless, there is no indication from our data of higher-than-expected relapse rates in advanced malignancy. The striking differences in relapse for high-risk AML compared with other diagnoses indicate that it may be inappropriate to consider all high-risk patients as a single group in studies such as this and highlight the need for additional disease-specific evaluation of this regimen. The PK studies indicate that daily IV Bu gives predictable linear kinetics, with less variability than reported with oral dosing. The day 1 and day 4 curves are very similar, and there is no accumulation from one dose to the next. The half-life of about 2.5 hours is somewhat shorter than the median of 3.8 hours reported by Phadungpojna et al. for IV Bu given 4 times daily in a large phase II study [29].

Table 2. PK Parameters of Once-Daily IV Bu* Dose 1

Patient ID

IV Bu Dose, mg/M2

IV Bu Dose, mg/kg

Cmax, mcg/mL

T1/2, h

1 2 3 4 9 11 13 15 17 19 20 21 Mean SD

133.33 127.27 131.82 117.35 123.76 132.30 126.37 128.57 123.08 116.82 126.37 113.21 125.02 6.47

2.71 2.96 3.16 3.11 3.11 2.76 2.78 2.57 3.24 2.69 3.00 2.90 2.91 0.21

3.94 3.62 3.92 4.29 3.64 3.80 4.30 4.00 4.20 4.20 3.80 3.30 3.92 0.31

2.58 2.31 2.55 2.67 2.20 3.04 2.48 2.57 3.49 2.96 2.57 1.74 2.60 0.44

Dose 4

Clearance, Clearance, AUC, mL/min/M2 mL/min/kg µM × min 102.70 130.23 113.26 81.88 112.75 105.60 99.85 103.50 80.12 97.00 120.30 134.10 106.77 16.68

2.09 3.03 2.71 2.17 2.83 2.20 2.19 2.07 2.11 2.23 2.86 3.43 2.49 0.46

5277.38 3972.69 4731.07 5825.79 4462.03 5092.63 5144.81 5049.69 6244.48 4895.70 4270.23 3431.68 4866.51 771.42

Cmax, mcg/mL

T1/2, h

4.03 3.97 3.58 4.25 3.60 4.60 4.50 3.75 4.50 3.90 3.80 3.10 3.96 0.28

2.72 2.09 2.55 2.94 2.31 2.75 2.59 2.58 3.29 3.00 2.53 1.74 2.57 0.36

Clearance, Clearance, AUC, mL/min/M2 mL/min/kg µM × min 98.68 124.27 124.42 80.07 107.73 106.40 105.93 114.13 76.03 94.38 115.10 141.10 106.86 21.57

2.01 2.89 2.98 2.12 2.71 2.22 2.33 2.28 2.00 2.17 2.73 3.61 2.50 0.51

5492.36 4163.32 4306.71 5957.48 4669.95 5054.34 4849.51 4579.36 6580.40 5031.61 4463.15 3261.44 4979.97 882.85

*T1/2 indicates half-life.

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A

B

Figure 4. A, Representative PK plot of a patient receiving once-daily IV Bu. B, Comparison of AUC after first and fourth doses of once-daily IV Bu.

The AUCs achieved in our 12 test subjects were scattered around the range deemed optimal from studies with oral Bu. Thus, the target recommended by Phadungpojna et al. for Bu given 4 times a day was 1100 to 1200 µM × min per dose [29]. This amount would be equivalent to 4400 to 4800 µM × min per day, close to our mean level of 4900 to 5000 µM × min and well below the cumulative AUC over 4 days of 6000 µM × min reported to be associated with an increased risk of VOD [20]. The AUC for 1 patient exceeded this limit and in another patient the AUC was

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between 3000 and 4000 µM × min, possibly suboptimal exposure. Given readily available Bu levels, it may now be possible to target precise AUC values after either a test dose or the first therapeutic dose. It remains to be determined whether this ability will demonstrably improve outcomes compared with dosing by weight alone. It is also unclear whether similar targets are desirable for IV compared with oral Bu. IV Bu offers the possibility of ensuring drug exposures that are antileukemic and allow engraftment without undue

Daily IV Busulfan

toxicity. If further studies confirm our initial impressions, we predict a trend toward daily dosing and perhaps even fewer and higher doses. It may then be appropriate to compare conditioning regimens containing Bu administered in a consistent fashion with those incorporating TBI.

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ACKNOWLEDGMENTS We wish to thank the nursing staff of Unit 57 at the Foothills Hospital for their care of these patients.

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