Dose modification protocol using intravenous busulfan (Busulfex) and cyclophosphamide followed by autologous or allogeneic peripheral blood stem cell transplantation in patients with hematologic malignancies.
We evaluated the safety and toxicity through a 5-cohort dose-modification model of once-daily administration of IV busulfan (Bu) in combination with high-dose cyclophosphamide (Cy) as preparative therapy for stem cell transplantation. Twenty-one adult patients with hematologic malignancies were evaluated. Eleven patients underwent autologous and 10 patients underwent HLA-matched sibling allogeneic transplantation. Patients were sequentially enrolled into 5 cohorts. Cohort 1 received intravenous (IV) Bu 1.6 mg/kg every 12 hours for 2 doses and then 0.8 mg/kg every 6 hours for 12 doses; cohort 2 received IV Bu 1.6 mg/kg every 12 hours for 4 doses and then 0.8 mg/kg every 6 hours for 8 doses; cohort 3 received IV Bu 3.2 mg/kg for 1 dose and then 1.6 mg/kg every 12 hours for 2 doses and 0.8 mg/kg every 6 hours for 8 doses; cohort 4 received IV Bu 3.2 mg/kg every 24 hours for 2 doses and then 0.8 mg/kg every 6 hours for 8 doses; and cohort 5 received IV Bu 3.2 mg/kg every 24 hours for 4 doses. In all groups, Bu was administered on day -7 through day -4 and was followed at least 6 hours after the last Bu dose by Cy 60 mg/kg daily for 2 doses on days -3 and -2. Blood samples were collected for pharmacokinetic analysis on the first and last day of IV Bu administration. All patients were alive and had engrafted at day 30. Five patients developed grade 3 or 4 toxicities. Four patients developed hepatic abnormalities, and 3 exhibited evidence of veno-occlusive disease. Two of 3 patients in cohort 5 with a Bu area under the curve >6000 micromol/min developed autopsy-confirmed veno-occlusive disease. Interpatient variability in AUCs was observed in patients within and between cohorts, but no statistically significant interpatient differences were observed in Bu half-life, volume of distribution, clearance, or dose-adjusted area under the curve. Further, minimal variability in Bu pharmacokinetics was observed between the 2 evaluations performed in each patient, thus reflecting the stability of Bu disposition within individual patients. On the basis of the dosing guidelines and schedule outlined in this study, our data suggest that administration of IV Bu 3.2 mg/kg IV every 24 hours for 4 doses in combination with Cy may result in excessive toxicity.
Williams
Casey B
CB
Blood and Marrow Transplant Program of the Kansas City Cancer Centers, Cancer Institute at Saint Luke's Hospital, Kansas City, Missouri, USA. casey.williams@usoncology.com
Day
Suzanne D
SD
Reed
Michael D
MD
Copelan
Edward A
EA
Bechtel
Thomas
T
Leather
Helen L
HL
Wingard
John R
JR
Abbott
Brian L
BL
Abhyankar
Sunil
S
McGuirk
Joseph P
JP
D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019540:Area Under Curve; D002066:Busulfan / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*; D019650:Hematopoietic Stem Cell Mobilization; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007275:Injections, Intravenous; D008875:Middle Aged; D018579:Patient Selection; D033581:Stem Cell Transplantation / Q000379:methods*; D019172:Transplantation Conditioning / Q000379:methods*; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D002066:Busulfan