A Phase I Study of Targeted, Dose-Escalated Intravenous Busulfan in Combination With Etoposide as Myeloablative Therapy for Autologous Stem Cell Transplantation in Acute Myeloid Leukemia

作者：Mannis Gabriel N; Andreadis Charalambos; Logan Aaron C; Damon Lloyd E; Benet Leslie Z; Ai Weiyun Z; Gaensler Karin M L; Kaplan Lawrence D; Koplowicz Yelena B; Linker Charles A; Olin Rebecca L; Sayre Peter H; Smith Catherine C; Sudhindra Akshay; Venstrom Jeffrey M; Wolf Jeffrey L; Martin Thomas G III^*

来源：Clinical Lymphoma Myeloma & Leukemia, 2015, 15(6): 377-383.

DOI：10.1016/j.clml.2015.02.016

• Acute Myelogenous Leukemia
• Autologous transplant
• High-dose chemotherapy
• Pharmacokinetics
• Phase I Clinical Trial

A phase I study of targeted, dose-escalated busulfan in combination with etoposide as myeloablative therapy, for autologous hematopoietic stem cell transplantation in acute myeloid leukemia identified a busulfan area under the curve (AUC) target of 1400 mu mol/min as the maximum clinically acceptable dose. This busulfan AUG target might be associated with improved relapse-free survival.
Background: Busulfan and etoposide have been used as myeloablative therapy for autologous hematopoietic stem cell transplantation (HSCT) in adults with acute myeloid leukemia (AML) for > 20 years. The use of targeted intravenous (I.V.) busulfan has significantly improved the tolerability and efficacy of this regimen. We designed a dose-escalation study to examine the maximum tolerated dose (MTD) of targeted I.V. busulfan with bolus etoposide as preparative therapy for autologous HSCT in AML. Patients and Methods: In this single-center, phase I study, adult AML patients received I.V. busulfan targeted to either an area under the curve (AUC) of 1250 (cohort 1) or 1400 (cohort 2) mu mol/min over 16 doses. Dose adjustments based on plasma pharmacokinetics occurred before doses 2 and 11. Etoposide 60 mg/kg I.V. was administered 24 hours after the last busulfan dose and 3 days before stem cell infusion. Results: Twelve patients with intermediate-risk AML in first complete remission were treated. All patients in cohort 1 and 5 patients (83%) in cohort 2 were within 10% of the target AUC. The MTD was not reached, although Grade > 3 mucositis occurred in 3 patients (50%) in cohort 1 and in 4 patients (66%) in cohort 2, limiting further dose escalation. Two-year relapse-free survival was 33% in cohort 1 versus 67% in cohort 2 (P=.08). Conclusion: Etoposide and targeted, dose-escalated I.V. busulfan as myeloablative therapy for autologous HSCT in AML is safe, with mucositis being the most significant toxicity. A phase II study is warranted to further evaluate the activity and safety of busulfan targeted to AUC 1400 mu mol/min.

• 出版日期2015-6