Order of application and liver toxicity in patients given BU and CY containing conditioning regimens for allogeneic hematopoietic SCT

• Published in: Bone marrow transplantation (Basingstoke) Vol. 46; no. 3; pp. 344 - 349
• Main Authors: Cantoni, N, Gerull, S, Heim, D, Halter, J, Bucher, C, Buser, A, Tsakiris, D A, Passweg, J, Tichelli, A, Stern, M, Gratwohl, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2011; Nature Publishing Group
• Subjects: 631/92/609; 692/699/1503/1607; 692/700/565/251/1574; 692/700/565/545/576/1955; Adolescent; Adult; Aged; Allografts; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Biological and medical sciences; Bone marrow; Bone marrow transplantation; Bone marrow, stem cells transplantation. Graft versus host reaction; Busulfan - administration & dosage; Busulfan - adverse effects; Cell Biology; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - pathology; Cohort Studies; Complications; Complications and side effects; Conditioning; Confidence intervals; Cyclophosphamide - administration & dosage; Cyclophosphamide - adverse effects; Data processing; Drug Administration Schedule; Drug therapy; Female; Graft vs Host Disease - immunology; Graft vs Host Disease - prevention & control; Hematology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic stem cells; Hemopoiesis; Hepatic Veno-Occlusive Disease - chemically induced; Hepatic Veno-Occlusive Disease - immunology; Humans; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - adverse effects; Internal Medicine; Liver; Liver - drug effects; Liver - pathology; Liver diseases; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; original-article; Preoperative care; Public Health; Retrospective Studies; Risk factors; Stem cell transplantation; Stem Cells; Survival; Toxic diseases; Toxicity; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation Conditioning - adverse effects; Transplantation Conditioning - methods; Treatment Outcome; Veno-occlusive disease; Young Adult; Switzerland; hematopoietic SCT; BU; hepatic veno-occlusive disease; conditioning regimen; liver toxicity; CY; Human; Venoocclusive disease; Hematology; Digestive system; Toxicity; Liver; Hepatic disease; Allogeneic hematopoietic stem cell transplantation; Digestive diseases; Conditioning; Hematopoietic stem cell transplantation
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/bmt.2010.137

BU–CY is the established non-TBI-based myeloablative conditioning regimen for allogeneic hematopoietic SCT. However, liver toxicity and hepatic veno-occlusive disease (VOD) are frequent life-threatening complications. Pharmacological considerations suggest that BU can trigger toxicity of subsequent CY. Recent animal data confirmed this hypothesis. Less liver toxicity and better outcomes were observed when mice were treated with the reversed order of CY and BU. We analyzed in this study liver toxicity and outcome in patients receiving BU–CY (16 patients) or CY–BU (59 patients). Liver function differed significantly with higher levels of liver function tests between day +10 and +30, and a higher cumulative incidence of VOD in the BU–CY cohort (2/16 (12.5%) vs 0/59 (0%),
P
=0.006). TRM was significantly higher in patients receiving BU–CY (cumulative incidence BU–CY 45%, CY–BU 17%,
P
=0.02), without yet translating into a significant survival difference (incidence for survival: BU–CY 38%, CY–BU 63%; hazard ratio 1.19 for BU–CY, 95% confidence interval 0.29–4.82,
P
=0.80). Rates of engraftment and relapse were not different. These data support the concepts derived from animal models in favor of CY–BU compared with traditional BU–CY and form the basis for prospective controlled comparisons.