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

• Published in: Leukemia & lymphoma Vol. 51; no. 12; pp. 2240 - 2249
• Main Authors: O'Donnell, Peter H., Artz, Andrew S., Undevia, Samir D., Pai, Rish K., Del Cerro, Paula, Horowitz, Sarah, Godley, Lucy A., Hart, John, Innocenti, Federico, Larson, Richard A., Odenike, Olatoyosi M., Stock, Wendy, Van Besien, Koen
• Format: Journal Article
• Language: English
• Published: United States Informa Healthcare 01-12-2010; Taylor & Francis
• Subjects: Alemtuzumab; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - adverse effects; Antibodies, Monoclonal - pharmacokinetics; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm - administration & dosage; Antibodies, Neoplasm - adverse effects; Busulfan - administration & dosage; Busulfan - adverse effects; Busulfan - pharmacokinetics; Clinical results; Dose-Response Relationship, Drug; Down-Regulation; Drug Combinations; Female; Hematologic Neoplasms - epidemiology; Hematologic Neoplasms - metabolism; Hematologic Neoplasms - therapy; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Hepatic Veno-Occlusive Disease - chemically induced; Hepatic Veno-Occlusive Disease - epidemiology; Hepatic Veno-Occlusive Disease - etiology; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Immunosuppressive Agents - pharmacokinetics; Incidence; Male; Metabolic Clearance Rate; Middle Aged; pharmacotherapeutics; transplant toxicity; Transplantation Conditioning - adverse effects; Transplantation Conditioning - methods; Transplantation, Homologous; Vidarabine - administration & dosage; Vidarabine - adverse effects; Vidarabine - analogs & derivatives; Vidarabine - pharmacokinetics
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2010.520773

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.