100 Studying the Optimal Intravenous Busulfan Exposure in Pediatric Allogeneic Hematopoietic Cell Transplantation (alloHCT) to Improve Clinical Outcomes: A Multicenter Study

Track: Pediatric BMT Program
Thursday, February 12, 2015, 5:45 PM-7:15 PM
Grand Hall AB (Manchester Grand Hyatt)
Arief Lalmohamed, PharmD, PhD , Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, Netherlands
Imke Bartelink, PharmD, PhD , University of San Francisco, San Francisco, CA
Liesbeth van Reij, PharmD , Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, Netherlands
Christopher C. Dvorak, MD , University of San Francisco, San Francisco, CA
Rada Savic, PhD , University of San Francisco, San Francisco, CA
Juliëtte Zwaveling, PharmD, PhD , Leiden University Medical Center, Leiden, Netherlands
Robbert Bredius, MD, PhD , Leiden University Medical Center, Leiden, Netherlands
Antoine Egberts, PharmD, PhD , Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, Netherlands
Marc Bierings, MD, PhD , Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands
Morris Kletzel, MD, FAAP, MBA , Northwestern University Feinberg School of Medicine, Chicago, IL
Peter John Shaw, MD , BMT, Children's Hospital at Westmead, Sydney, Australia
Christa Nath, PhD , Children’s Hospital at Westmead, Sydney, Australia
Georg Hempel, PhD , Universitätsklinikum at Münster, Muenster, Germany
Marc Ansari, MD , Hôpital des enfants (HUG) Genève, Geneve, Switzerland
Maja Krajinovic, MD, PhD , Hôpital des enfants (HUG) Genève, Geneve, Switzerland
Tayfun Gungor, MD , University Childrens Hospital Zurich, Zurich, Switzerland
Robert F. Wynn, MD , Royal Manchester Children's Hospital, Manchester, United Kingdom
Paul Veys, MBBS , Great Ormond Street Hospital for Children, London, United Kingdom
Geoff Cuvelier, MD , CancerCare Manitoba, Winnipeg, MB, Canada
Robert Chiesa, MD, PhD , Great Ormond Street Hospital for Children, London, United Kingdom
Mary Slatter, MD , Great North Children's Hospital, Newcastle, United Kingdom
Janel Long-Boyle, PharmD, PhD , University of San Francisco, San Francisco, CA
Jaap-Jan Boelens, MD, PhD , Pediatric Blood and Marrow Transplantation Program, University Medical Center Utrecht, Utrecht, Netherlands
Audio File Recorded Presentation

Background: In children, the therapeutic drug monitoring (TDM) of intravenous (IV) busulfan (BU) in alloHCT can contribute to better clinical outcomes. Current therapeutic targets for exposure are however primarily based on adult studies. Therefore, this study aimed to define the optimal therapeutic target of BU in children and identify other patient-specific variables to optimize outcomes following alloHCT.

Methods: This retrospective study utilized exposure-response data available from routine pharmacokinetic analysis with or without TDM of BU levels in children and young adults treated with HCT between the years of 2000-2013 from 13 different centers. Primary endpoints were event-free survival (EFS) and overall survival (OS). Secondary endpoints included treatment-related mortality (TRM), veno-occlusive disease (VOD), acute graft-versus-host disease (aGVHD) grade II–IV and cGVHD. A predictor analysis using Cox regression and multivariate Weibull models was performed.

Results: A total of 685 subjects (range 11-116 per center) treated for a variety of malignant (n=318) and non-malignant disorders (n=367), with a median age of 5.0 years (range 0.1 - 28.7) were included in the analysis. The median cumulative BU area-under-the-concentration-curve (AUC) was 77mg*hr/L (range 21-160). In all patients, three-year probability of EFS, OS and graft failure was 72%, 79%, and 5.4% respectively. BU AUC below 75 or above 100mg*hr/L (p = 0.03), “ex-vivo T-cell depletion” (p = 0.02) & “in vivo T-cell depletion using serotherapy” (ATG or alemtuzumab: p = 0.02) were negative predictors of EFS. A U-shaped relationship between BU AUC & EFS was observed (Figure 1). In patients with malignant disease optimal BU AUC was lower compared to non-malignant disorders (83-95mg*hr/L vs 99-111 mg*h/L, p= 0.04, Figure 2). Below the optimal BU target, the incidence of graft failure and relapse (malignant only) was higher (p=0.01), while above the target TRM increased (p=0.04). BU AUC above the median and addition of melphalan were both independently associated with the risk of aGvHD (p=0.01, p=0.04), and melphalan use further increased the risk of VOD (p<0.01). No association was found with cGvHD.

Conclusion: BU AUC targeted to a narrow therapeutic range, which is indication dependent, (83-95 mg*h/L for malignant and 99-111 mg*h/L for non-malignant diseases) was found to increase EFS and OS in children. Lower BU AUC was associated with graft-failure and relapse and higher BU AUC with TRM. Our findings suggest that personalizing BU AUC by patient-specific factors may improve efficacy and reduce toxicity.

Figure 1. Weibull model visualizing the relationship between busulfan exposure and the probability of EFS (highest EFS rates at 75-100mg*h/L, HR = 0.37, 95% CI 0.15-0.92 compared to <50mg*h/L).

Figure 2. Weibull models visualizing the relationship between busulfan exposure and EFS, by underlying disease.

Disclosures:
P. Veys, Astellas, none: Honoraria
Gilead, none: Advisory Board
Pfizer, none: Honoraria
EUSA, none: Advisory Board

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