Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Humans Busulfan Cyclophosphamide Drug Monitoring Hematologic Neoplasms / drug therapy Hematopoietic Stem Cell Transplantation Neoplasm Recurrence, Local / drug therapy Transplantation Conditioning Vidarabine

Allogeneic hematopoietic stem cell transplantation Busulfan Pretransplant conditioning Therapeutic drug monitoring

Journal

Annals of hematology

ISSN: 1432-0584

Titre abrégé: Ann Hematol

Pays: Germany

ID NLM: 9107334

Informations de publication

Date de publication:
Oct 2023

Historique:

received: 11 11 2022

accepted: 01 04 2023

medline: 11 9 2023

pubmed: 14 4 2023

entrez: 13 4 2023

Statut: ppublish

Résumé

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Identifiants

DOI: 10.1007/s00277-023-05209-2 PMID: 37052663

pubmed: 37052663

doi: 10.1007/s00277-023-05209-2

pii: 10.1007/s00277-023-05209-2

doi:

Substances chimiques

Busulfan G1LN9045DK

Cyclophosphamide 8N3DW7272P

Vidarabine FA2DM6879K

Types de publication

Clinical Trial, Phase II Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

2909-2922

Subventions

Organisme : Ministry of Education, Culture, Sports, Science and Technology

ID : 021515

Informations de copyright

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