title: Maximally tolerated busulfan systemic exposure in combination with fludarabine as conditioning before allogeneic hematopoietic cell transplantation.
abstract: Systemic exposure to high-dose busulfan has been correlated with efficacy and toxicity after hematopoietic cell transplantation for malignancy. We used the area under the concentration-time curve (AUC) to prospectively determine the maximally tolerated systemic exposure to i.v. busulfan when given once daily after fludarabine administered at 40 mg/m(2) for 4 days. Three target AUC levels were planned: 6,000, 7,500, and 9,000 μM-min. Included were patients 16 to 65 years old, with a hematologic malignancy, an HLA A, B, or C, DRB1 8/8 or 7/8 matched donor, Karnofsky performance status ≥70%, and adequate organ function. For level 1 patients, i.v. busulfan doses 1 and 2 were 170 mg/m(2)/day, then doses 3 and 4 were adjusted based on first-dose pharmacokinetic modeling to achieve an average daily AUC of 6,000 μM-min. Doses 1 and 2 for the subsequent cohorts were based on the level 1 data: 180 mg/m(2)/day for AUC 7,500 μM-min (level 2) and 220 mg/m(2)/day for AUC 9,000 μM-min (level 3), with pharmacokinetic targeting for doses 3 and 4. Pharmacokinetic analysis after the last dose showed that 88% of the patients had been exposed to a mean AUC within 10% of the target. Forty patients were treated at level 1, 29 patients at level 2, and three patients at level 3. DLT was veno-occlusive disease of the liver, which occurred in none of 40 patients (0%) at level 1, two of 29 patients (7%) at level 2, and three of three patients (100%) at level 3. Dermatitis (P < .01) and pulmonary toxicity (P = .01) were also increased at higher AUC levels. Level 2 (7,500 μM-min × 4 days) was the maximally tolerated AUC. Within the confines of the trial's small sample size, there was no suggestion that escalating busulfan AUC from 6,000 to 7,500 μM-min × 4 days increased nonrelapse mortality. Assessment of the higher busulfan AUC on relapse prevention requires trials in patients with a homogeneous risk of relapse.
authors.affiliation: Department of Blood and Marrow Transplantation, Moffitt Cancer Center, 12902 USF Magnolia Drive, Tampa, FL 33612, USA. Janelle.perkins@moffitt.org
authors.forename: Janelle B
authors.initials: JB
authors.lastname: Perkins
authors.forename: Jongphil
authors.initials: J
authors.lastname: Kim
authors.forename: Claudio
authors.initials: C
authors.lastname: Anasetti
authors.forename: Hugo F
authors.initials: HF
authors.lastname: Fernandez
authors.forename: Lia E
authors.initials: LE
authors.lastname: Perez
authors.forename: Ernesto
authors.initials: E
authors.lastname: Ayala
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kharfan-Dabaja
authors.forename: Marcie R
authors.initials: MR
authors.lastname: Tomblyn
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Sullivan
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Pidala
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Field
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002066:Busulfan / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D005260:Female; D019337:Hematologic Neoplasms / Q000097:blood / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D012008:Recurrence; D015996:Survival Rate; D019172:Transplantation Conditioning / Q000379:methods*; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D019653:Myeloablative Agonists; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine