Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis

Abstract

Background: Intravenous busulfan combined with therapeutic drug monitoring to guide dosing improves outcomes after allogeneic haemopoietic cell transplantation (HCT). The best method to estimate busulfan exposure and optimum exposure in children or young adults remains unclear. We therefore assessed three approaches to estimate intravenous busulfan exposure (expressed as cumulative area under the curve [AUC]) and associated busulfan AUC with clinical outcomes in children or young adults undergoing allogeneic HCT.

Methods: In this retrospective analysis, patients from 15 centres in the Netherlands, USA, Canada, Switzerland, UK, Italy, Germany, and Australia who received a busulfan-based conditioning regimen between March 18, 2001, and Feb 12, 2015, were included. Cumulative AUC was calculated by numerical integration using non-linear mixed effect modelling (AUCNONMEM), non-compartmental analysis (AUC from 0 to infinity [AUC0-∞] and to the next dose [AUC0-τ]), and by individual centres using various approaches (AUCcentre). The main outcome of interest was event-free survival. Other outcomes of interest were graft failure or relapse, or both; transplantation-related mortality; acute toxicity (veno-occlusive disease or acute graft versus-host disease [GvHD]); chronic GvHD; overall survival; and chronic-GvHD-free event-free survival. We used propensity-score-adjusted Cox proportional hazard models, Weibull models, and Fine-Gray competing risk regressions for statistical analyses.

Findings: 790 patients were enrolled, 674 of whom were included: 274 (41%) with malignant and 400 (59%) with non-malignant disease. Median age was 4·5 years (IQR 1·4-10·7). The median busulfan AUCNONMEM was 74·4 mg × h/L (95% CI 31·1-104·6), which correlated with the standardised method AUC0-∞ (r2=0·74), but the latter correlated poorly with AUCcentre (r2=0·35). Estimated 2-year event-free survival was 69·7% (95% CI 66·2-73·0). Event-free survival at 2 years was 77·0% (95% CI 72·1-82·9) in the 257 patients with an optimum intravenous busulfan AUC of 78-101 mg × h/L compared with 66·1% (60·9-71·4) in the 235 patients at the low historical target of 58-86 mg × h/L and 49·5% (29·2-66·0) in the 44 patients with a high (>101 mg × h/L) busulfan AUC (p=0·011). Compared with the low AUC group, graft failure or relapse occurred less frequently in the optimum AUC group (hazard ratio [HR] 0·57, 95% CI 0·39-0·84; p=0·0041). Acute toxicity (HR 1·69, 1·12-2·57; p=0·013) and transplantation-related mortality (2·99, 1·82-4·92; p<0·0001) were significantly higher in the high AUC group (>101 mg × h/L) than in the low AUC group (<78 mg × h/L), independent of indication; no difference was noted between AUC groups for chronic GvHD (<78 mg × h/L vs ≥78 mg × h/L, HR 1·30, 95% CI 0·73-2·33; p=0·37).

Interpretation: Improved clinical outcomes are likely to be achieved by targeting the busulfan AUC to 78-101 mg × h/L using a new validated pharmacokinetic model for all indications.

Funding: Research Allocation Program and the UCSF Helen Friller Family Comprehensive Cancer Center and the Mt Zion Health Fund of the University of California, San Francisco.

Copyright © 2016 Elsevier Ltd. All rights reserved.

Figures

Figure 1

Example plots showing individual concentration observations derived in individuals (black dots), the individual predicted concentrations (blue shaded area) and non-compartmental analysis* to calculate the exposure (AUC-infinity red shaded area and AUC- tau green shaded area)

Figure 2

The polynomial Weibull model of the association between busulfan cumulative AUC and EFS (using uncensored data) is able to reproduce the central tendency in the observed EFS data, shown using Δ 5 mg*h/L AUC groups (dots) in the training (blue solid line) and internal validation dataset (blue dashed line) (A). The busulfan cumulative AUC and EFS model stratified by malignant (red solid line) and non-malignant (blue dashed line) underlying disease shows that the optimum AUC does not depend on indication(B). Shaded areas represent 95% confidence intervals.

Figure 3

Kaplan-Meier plots of event-free survival stratified by busulfan cumulative AUC historic, the new target and the AUC above the new target, defined in the current study. Observed EFS (straight lines) including 95%CI (shaded areas) (Fine & Gray) and modelled events (dotted line, using the final Weibull model) are shown. Two year EFS at AUC of 101 mg*h/L was 49.5%.

Figure 4

The polynomial Weibull model of the association between busulfan cumulative AUC and graft failure/ disease relapse and TRM (using uncensored data) (A) and acute toxicity (at 6 months post-HCT)(B) and cGvHD (C), with toxicities stratified by number of alkylating agents showed that a low cumulative exposure (<78 mg*h/L) increased the probability of graft failure/disease relapse, but an decreased the risk of TRM. A high cum AUC (>101 mg*h/L) and the addition of a second or third alkylator increased the probability of VOD, aGvHD and cGvHD.