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

Peter H. O'Donnell, Andrew S. Artz, Samir D. Undevia, Rish K. Pai, Paula Del Cerro, Sarah Horowitz, Lucy A. Godley, John Hart, Federico Innocenti, Richard A. Larson, Olatoyosi M. Odenike, Wendy Stock, Koen Van Besien

Research output: Contribution to journalArticle

22 Scopus citations

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 (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.

Original languageEnglish (US)
Pages (from-to)2240-2249
Number of pages10
JournalLeukemia and Lymphoma
Volume51
Issue number12
DOIs
StatePublished - Dec 1 2010

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Keywords

  • Clinical results
  • pharmacotherapeutics
  • transplant toxicity

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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