Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients

Abstract

We hypothesized that IV Busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation (allo-HSCT). To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine (Flu) 40 mg/m2 once daily ×4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6,000 µM-min (N=111), stratified for remission-status, and allo-grafting from HLA-matched donors. Toxicity and graft vs. host disease (GvHD) rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease-control, leading to improved overall and progression-free survival, most prominently in MDS-patients and in AML-patients not in remission at allo-HSCT. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu-dosing. This could be considered an alternative to fixed dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

Clarifying busulfan metabolism and drug interactions to support new therapeutic drug monitoring strategies: a comprehensive review

“…improved outcomes, reduced incidence of VOD, development of safer target exposures) across various hematologic malignant sub-types, differing myeloablative conditioning regimens, different HSCT procedures, and diverse patient populations [11,172,173]. One of the earlier clinical studies to document the improved utility of TDM was published in 1993, reporting that adult and pediatric patients receiving fixed Bu doses had a greater incidence of VOD compared to patients receiving PK-based dose adjustments [173].…”

“…For instance, the work of Andersson et al . [11] showed that Flu with PK-guided IV busulfan therapy is superior to fixed-dose delivery, resulting in safer disease control and improved overall survival (OS) and progression free survival (PFS) in patients with active AML and MDS. When compared to patients receiving untargeted oral busulfan doses, patients receiving TDM guided dose adjustments had higher event-free survival (EFS) and OS rates [172].…”

“…Further improvements in Bu therapy are still desirable to overcome these obstacles and improve upon patient safety and treatment outcomes. One major advantage of Bu is the established analytical techniques to monitor its plasma concentrations, which lends itself to PK-based modified therapy with greater improvements in both the toxicity profile and tumor control [11,12]. …”

Test Dose Pharmacokinetics in Pediatric Patients Receiving Once‐Daily IV Busulfan Conditioning for Hematopoietic Stem Cell Transplant: A Reliable Approach?

“…However, changes in clearance within patients varied widely between test and full‐dose conditions. This is in contrast to adult populations in whom the test‐dose strategy has been applied and shown to improve attainment of busulfan target exposures . Mean (range) clearance in adults is ∼2.5 mL/[min·kg] (∼1.5‐4.3 mL/[min·kg]), with low intrasubject variabilities reported .…”

“…Another method has been to perform a test dose before the full conditioning regimen, which involves the administration of IV busulfan at a dose of ∼0.8 mg/kg to assess the patient's pharmacokinetics (PK), with full once‐daily doses adjusted to target exposures assuming dose linearity. This approach has been shown to accurately predict once‐daily dosing requirements and improve outcomes in adult HSCT patients . However, data on the reliability of this approach in children are limited.…”