Blood Samples to Identify Biomarkers of Busulfan

Optimizing Busulfan: Efficacy, Toxicity, and Pharmacometabolomics

Specific Aim 1: To determine whether endogenous metabolomics-based biomarkers obtained before IV BU administration can predict IV BU clearance.

Specific Aim 2: To characterize IV BU metabolism by metabolomics.

Specific Aim 3: To identify covariates influencing IV BU pharmacokinetics.

Study Overview

• Status: Active, not recruiting
• Conditions: Lymphoma; Leukemia; Multiple Myeloma; Myelodysplastic Syndrome; Immunodeficiency

Detailed Description

The long-range goal of this work is to improve overall survival in hematopoietic stem cell transplant (HCT) recipients by personalizing their conditioning regimen and/or intravenous (IV) busulfan (BU) doses using metabolomics. BU is an essential part of the majority of HCT conditioning regimens, but has a narrow therapeutic index; low BU plasma exposure (caused by rapid clearance) is associated with an increased risk of rejection or relapse, while high BU plasma exposure is associated with an increased risk of hepatotoxicity. Although pharmacokinetic (PK)-based dosing to a target BU exposure is often conducted, relapse and toxicity continue to be problematic. Furthermore, shorter IV BU courses necessitate alternative methods to personalize IV BU. IV BU clearance, however, is not associated with polymorphisms of glutathione S-transferase (GST) A1 and GSTM1, the predominant GSTs in BU conjugation with glutathione. Therefore, investigators seek to test the working hypothesis that metabolomic signature, which provides novel insight into the in vivo cellular response and metabolite identification, is associated with IV BU clearance. Investigators will first determine if endogenous metabolomics-based biomarkers obtained before BU administration can predict IV BU clearance. Researchers will evaluate endogenous biomarkers using a targeted (glutathione pathway) and global analyses via liquid chromatography-mass spectroscopy. In addition, investigators seek to evaluate IV BU metabolism using metabolomics in parallel with gas chromatography-mass selective detection in patients receiving PK-based IV BU. Researchers will evaluate plasma concentrations of eight different metabolites, building upon their experience with tetrahydrothiophene (THT+). To complement this metabolomic work, investigators seek to validate covariates associated with IV BU PK, specifically age and body size, to mitigate a typical challenge for metabolomics research: the lack of understanding of potentially confounding factors. FHCRC has been a reference clinical laboratory for PK-based BU dosing since 1996 and thus, FHCRC researchers have the largest database of IV BU PK. Using population pharmacokinetic (popPK) analysis, investigators will validate covariates for IV BU PK to guide future metabolomic studies. This popPK analysis can immediately improve patient care by using covariates to more accurately estimate an IV BU starting dose (i.e., before PK-based dosing) and by creating a limited sampling schedule to more efficiently use PK-based dosing. These complementary aims, which seek to identify novel metabolomics-based biomarkers, could overcome a critical barrier to HCT conditioning of balancing between response and toxicity. Based on compelling preliminary data, researchers expect to identify an endogenous metabolomic signature that will influence the choice of an IV BU starting dose with the intention of improving overall survival for patients receiving IV BU-containing HCT regimens.

• Study Type: Observational
• Enrollment (Actual): 139

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98105
      • University of Washington

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients receiving targeted IV busulfan as part of conditioning for a hematopoietic stem cell transplant

Description

Inclusion Criteria:

• Scheduled to receive targeted intravenous busulfan (any dose, any number of doses, any dosing frequency) as part of their hematopoietic stem cell transplant conditioning;
• Weight > 21kg.

Exclusion Criteria:

• Unable to read English;
• Female patients who are pregnant or breastfeeding;
• Life expectancy severely limited by diseases other than malignancy.

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Busulfan clearance	24 hours after start of busulfan

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	1 year

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: University of Washington; Seattle Children's Hospital
• Investigators: Principal Investigator: Jeannine S. McCune, PharmD, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2014
• Primary Completion (Actual): April 20, 2019
• Study Completion (Estimated): May 1, 2025

Study Registration Dates

• First Submitted: November 4, 2014
• First Submitted That Met QC Criteria: November 12, 2014
• First Posted (Estimated): November 17, 2014

Study Record Updates

• Last Update Posted (Actual): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 2, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: hematopoietic cell transplant
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Neoplasms, Plasma Cell; Myelodysplastic Syndromes; Multiple Myeloma
• Other Study ID Numbers: 9117; RG1001078 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium)