Phase I study of dose-escalated busulfan with fludarabine and alemtuzumab as conditioning for allogeneic hematopoietic stem cell transplant: reduced clearance at high doses and occurrence of late sinusoidal obstruction syndrome/veno-occlusive disease

Abstract

Disease recurrence after allogeneic hematopoietic cell transplant (alloHCT) remains common, making improvements in conditioning regimens desirable. A dose-response relationship between busulfan exposure and outcome is known. Using individual real-time monitoring of the busulfan area under the curve (AUC), we aimed to determine the maximum-tolerated busulfan AUC in a conditioning regimen with fludarabine/alemtuzumab. Thirty-six patients with advanced hematologic malignancies were treated. Busulfan levels after a test dose and conditioning dose 1 allowed targeting of subsequent AUCs and dose-escalation above the starting AUC of 4800 µmol-min/L. Clearance of busulfan test doses was not always sufficiently predictive of treatment dose AUC and, on average, test dose clearance was faster than treatment dose clearance. When the study was modified to use conditioning dose 1 pharmacokinetics instead, accurately targeted treatment AUCs were achieved, and dose-escalation was possible. Severe, late-occurring sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) was the dose-limiting toxicity seen in 5/8 patients at an AUC level of 6800 µmol-min/L. The risk for SOS/VOD correlated with the highest observed AUC (AUC(max)) rather than with the average cumulative AUC (AUC(avg)). Busulfan dose-escalation to a maximum-tolerated AUC of 5800 µmol-min/L-higher than that achieved by current standard busulfan regimens-was accurate and achievable using real-time pharmacokinetics monitoring of the first conditioning dose. This AUC is now being studied in phase II for patients receiving busulfan/fludarabine/alemtuzumab as alloHCT conditioning.

Trial registration: ClinicalTrials.gov NCT00943319.

Conflict of interest statement

Declaration of interest: This study was supported in part by NCI grant 5 R21 CA115097, by the Pharmacology Core of The University of Chicago Cancer Research Center (NIH P30 CA14599), and by an unrestricted grant from Otsuka Pharmaceutical Group. K.V.B. is supported by 5 K24 CA116471-2.

Figures

Figure 1

Treatment plan. Schema showing the timing of a busulfan test dose prior to conditioning, the administration of busulfan conditioning doses on days −6 through −3, the administration of fludarabine and alemtuzumab on days −7 through −3, and the timepoints of busulfan pharmacokinetics sampling. bu, intravenous busulfan; AUC, area under the curve.

Figure 2

Clearance of a test dose is faster than, and not predictive of, subsequent conditioning doses. For the second cohort, 10 of 15 patients had test dose clearances >10% different from measured treatment dose clearances; in each case test dose clearance overestimated treatment dose clearance. The average disagreement between test dose clearance and measured treatment dose clearance was +15% for the cohort (range: −6.8% to +50.9%).