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 (AUCmax) rather than with the average cumulative AUC (AUCavg). 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.

Association Between Busulfan Exposure and Outcome in Children Receiving Intravenous Busulfan Before Hematopoietic Stem Cell Transplantation

“…In adults, many authors have shown an association between higher Bu exposure and toxicity/NRM. 4,7,16,25,40,41 However, a relationship between Bu exposure and toxicity remains to be defined in pediatric patients, with most authors showing absence of such a correlation. 2,21,37,42 Our results are consistent with results reported by Baker et al that showed a significantly higher NRM in patients with a Bu Css .578 ng/mL.…”

Clinicopathologic features of late-onset veno-occlusive disease/sinusoidal obstruction syndrome after high dose intravenous busulfan and hematopoietic cell transplant

“…While sharing these clinical features, our cases of VOD/SOS (7 biopsy-confirmed) in contrast all occurred beyond the usual immediate time frame: median time to diagnosis in our series was 52 days (range: 33–77 days). All 8 patients were treated on a 36-patient protocol using dose-escalated intravenous busulfan along with fludarabine/alemtuzumab as conditioning [22], for a VOD/SOS incidence of 22% (all late-onset).…”

“…All patients provided written informed consent to participate in a previously-described 36-patient phase I study of dose-escalated intravenous busulfan along with fludarabine/alemtuzumab as conditioning chemotherapy prior to HCT [22]. The eight cases observed within this study were retrieved from the surgical and autopsy pathology files at the University of Chicago.…”

Increasing the dose intensity of the conditioning regimen prior to allogeneic hematopoietic stem cell transplant: the role of pharmacokinetic monitoring

“…The next step is to build on this less toxic platform and to increase the busulfan dose above the standard myeloablative dose, trying to reduce the relapse rate. In this issue of Leukemia and Lymphoma, O'Donnell et al report a phase I study of dose-escalated busulfan with fludarabine and determine the dose-limiting toxicity of busulfan in this setting [5].…”

“…O'Donnell et al aimed at increasing daily the AUC up to 6800 mmol-min using two approaches [5]. The initial one was calculating PK parameters after a small test-dose given within 8 days of conditioning.…”