Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study.
Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption. An IV Bu formulation was developed to provide dose assurance and complete bioavailability. In a phase I study, the plasma bioequivalence of IV Bu was established at approximately 80% of the oral dose. We now report the findings of the first phase II study, in which 61 adults with hematologic cancers were treated with a Bu-cyclophosphamide (BuCy) regimen consisting of IV Bu (0.8 mg/kg every 6 hours x 16) followed by Cy (60 mg/kg qd x 2) and transplantation of stem cells from an HLA-matched sibling donor. The median age of study participants was 37 years; 75% of patients had active disease; 48% were heavily pretreated, and 13% had undergone a prior transplantation. Median follow-up was 2.3 years; median time to engraftment (absolute neutrophil count, >0.5 x 10(9)/L) was 13 days; 100% of patients with cytogenetic and/or molecular markers had documented chimerism; and there were no engraftment failures. Two-year overall and disease-free survival were 67% and 42%, respectively. There were no unexpected toxic reactions. Fatal veno-occlusive disease occurred in 2 patients, 1 of whom had undergone a prior transplantation. Treatment-related mortality at 100 days was 9.8% (6/61). Bu pharmacokinetics after IV drug administration demonstrated high inter- and intrapatient consistency; 86% of patients maintained an area under the curve between 800 and 1500 microMol-min. In conclusion, the IV Bu in this regimen was very well tolerated and demonstrated excellent antitumor efficacy, most likely because of dose assurance with predictable pharmacokinetics.
Andersson
Borje S
BS
Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, Houston 77005, USA. bandersson@mdanderson.org
Kashyap
Ashwin
A
Gian
Victor
V
Wingard
John R
JR
Fernandez
Hugo
H
Cagnoni
Pablo J
PJ
Jones
Roy B
RB
Tarantolo
Stefano
S
Hu
Wendy W
WW
Blume
Karl G
KG
Forman
Stephen J
SJ
Champlin
Richard E
RE
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000633:toxicity; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003520:Cyclophosphamide / Q000008:administration & dosage*; D005260:Female; D006085:Graft Survival; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000628:therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000633:toxicity; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D033581:Stem Cell Transplantation / Q000379:methods* / Q000401:mortality; D016019:Survival Analysis; D019172:Transplantation Conditioning / Q000379:methods* / Q000401:mortality; D014184:Transplantation, Homologous / Q000379:methods; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D002066:Busulfan