(133) Impact of Busulfan Pharmacokinetics on Relapse Following Hematopoietic Cell Transplant: A Retrospective Cohort Study

Poster Abstract:

Background: Allogeneic hematopoietic cell transplant (HCT) offers a potential cure for various hematologic diseases, and requires conditioning with high-dose chemotherapy.(1-2) Before allogeneic HCT, myeloablative conditioning regimens are given to completely eliminate the diseased bone marrow and are standard for patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) .(3) Despite continuous improvements with conditioning regimens, disease relapse remains a significant challenge, occurring in an estimated 20-40% of patients following allogeneic HCT.(4)

Busulfan, an alkylating agent with a narrow therapeutic index, is currently incorporated in more than half of myeloablative allogeneic HCT conditioning regimens.(5,6) To ensure optimal busulfan dosing, the area under the concentration-time curve (AUC) is routinely monitored for myeloablative regimens due to wide interpatient variability in its metabolism.(5,7) The benefit of personalized AUC monitoring to enhance busulfan dosing and improve patient outcomes has been acknowledged.(1,5) However, few studies have evaluated the impact of deviations from individualized AUC targets on overall treatment efficacy and outcomes.(5,8)

Objective: The primary objective of this study is to evaluate the impact of an estimated busulfan total AUC exposure ≥ 10% below target using busulfan and fludarabine conditioning regimens on 1-year disease relapse rates following allogeneic HCT in patients with AML and MDS.

Methods: This is a retrospective cohort study of patients admitted to the Huntsman Cancer Institute following allogeneic HCT between 5/1/2014 and 7/31/2023. Patients were identified using The Center for International Blood & Marrow Transplant Research (CIBMTR) registry. Key exclusion criteria were patients who did not achieve complete remission of their primary disease prior to allogeneic HCT and patients without busulfan pharmacokinetic reports. The study was approved by the local Institutional Review Board with exempt status. Descriptive statistics will be used to assess study endpoints with a mean standard deviation and 95% confidence interval calculated for continuous data. A multivariate regression model will be used to assess the influence of age, sex, BMI, donor-type, and disease risk on the study outcomes. Additionally, survival functions for time-to-relapse will be estimated using the Kaplan-Meier method and assessed for statistical significance using the log-rank test based on indication for HCT.

Results: Data analysis is currently in process. A total of 198 patients were identified as receiving a busulfan and fludarabine conditioning regimen prior to allogeneic HCT from the CIBMTR registry between 5/1/2014 and 7/31/2023. Full or partial results will be presented.

Discussion/

Conclusion: To be updated after data analysis is complete.

References (must also be included in final poster): 1. National Comprehensive Cancer Network. Hematopoietic Cell Transplantation (Version 1.2023).https://www.nccn.org/professionals/physician_gls/pdf/hct.pdf. Accessed August 10, 2023.
2. Gyurkocza B, Sandmaier BM. Conditioning regimens for hematopoietic cell transplantation: One size does not fit all. Blood. 2014;124(3). doi:10.1182/blood-2014-02-514778
3. Scott BL, Pasquini MC, Fei M, et al. Myeloablative versus Reduced-Intensity Conditioning for Hematopoietic Cell Transplantation in Acute Myelogenous Leukemia and Myelodysplastic Syndromes—Long-Term Follow-Up of the BMT CTN 0901 Clinical Trial: B. Scott et al. Transplant Cell Ther. 2021;27(6). doi:10.1016/j.jtct.2021.02.031
4. Bolon YT, Atshan R, Allbee-Johnson M, Estrada-Merly N, Lee SJ. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2022.
5. Palmer J, McCune JS, Perales MA, et al. Personalizing Busulfan-Based Conditioning: Considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee. Biology of Blood and Marrow Transplantation. 2016;22(11). doi:10.1016/j.bbmt.2016.07.013
6. McCune JS, Quinones CM, Ritchie J, et al. Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement. Biology of Blood and Marrow Transplantation. 2019;25(9). doi:10.1016/j.bbmt.2019.05.021
7. Smita P, Narayan PA, Kumaravel J, Gaurav P. Therapeutic drug monitoring for cytotoxic anticancer drugs: Principles and evidence-based practices. Front Oncol. 2022;12. doi:10.3389/fonc.2022.1015200
8. Bartelink IH, Lalmohamed A, van Reij EML, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016;3(11). doi:10.1016/S2352-3026(16)30114-4