PGY2 Oncology Pharmacy Resident UW Medicine Temple City, California, United States
Poster Abstract:
Background: Oral tyrosine kinase inhibitors (TKIs) are used as a mainstay in treatment regimens for a variety of cancer types, ranging from hematological malignancies to solid tumors. Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of Philadelphia (Ph) chromosome and chromosomal translocation t(9;22). This fusion of the BCR gene and the ABL1 gene leads to a constitutively active tyrosine kinase thus TKI-based regimens have led to successful patient outcomes. After the approval of imatinib in 2001, several newer generation TKIs have been approved, such as dasatinib, nilotinib, bosutinib, asciminib, and ponatinib. Each TKI has demonstrated not only significant improved clinical outcomes such as overall survival, but also unique adverse event profiles. On average, approximately 50% of patients require TKI dose modification, though this varies based on the agent and patient-specific characteristics. For example, as TKIs are largely protein-bound (imatinib being 95% protein-bound), low serum albumin can lead to increased serum concentrations of TKI due to unbound drug. Previous pharmacokinetic studies have confirmed this association. A retrospective single-center study in patients with solid-tumor malignancies found that hypoalbuminemia was an independent risk factor for TKI discontinuation due to adverse events. Current guidelines do not address hypoalbuminemia as a potential patient-specific risk factor for increased risk of TKI toxicities and thus far, hypoalbuminemia has not been examined in patients with hematological malignancies.
Methods: This study will assess the effects of hypoalbuminemia on TKI safety and efficacy, based on TKI dose reductions or discontinuations. A retrospective chart review will be conducted at the Fred Hutchinson Cancer Center and University of Washington Medical Center, including adult patients who received at least one TKI agent for CML from April 2020 to October 2022, with at least one serum albumin level collected within one month of TKI initiation. Data collection will include baseline demographic information, TKI regimen, incidence of documented adverse events, incidence of TKI dose reductions after treatment initiation, and incidence and time to TKI discontinuations.
Objectives: The primary endpoint of the study will be time to TKI discontinuation in patients with baseline hypoalbuminemia compared to patients with normal serum albumin levels. Secondary endpoints will include incidence of TKI discontinuation due to adverse events and efficacy of TKIs. Lastly, this review may help identify a potential monitoring parameter to inform empiric dose adjustments for CML patients on TKIs.
Results/discussion: Results of this study are pending, with data collection in progress.
References (must also be included in final poster): 1. De Novellis D, Cacace F, Caprioli V, Wierda WG, Mahadeo KM, Tambaro FP. The TKI Era in Chronic Leukemias. Pharmaceutics. 2021;13(12):2201. doi:10.3390/pharmaceutics13122201
2. Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34(4):966-984. doi:10.1038/s41375-020-0776-2
3. Cortes JE, Saglio G, Kantarjian HM, et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34(20):2333-2340. doi:10.1200/JCO.2015.64.8899
4. Wu X, Ge Y, He X, Li J, Zhang J. Changes in imatinib plasma trough level during long-term treatment in patients with intermediate- or high-risk gastrointestinal stromal tumors: Relationship between covariates and imatinib plasma trough level. Front Surg. 2023;10:1115141. doi:10.3389/fsurg.2023.1115141
5. Fu Y, Wang J, Wang Y, Sun H. Investigating the Effect of Tyrosine Kinase Inhibitors on the Interaction between Human Serum Albumin by Atomic Force Microscopy. Biomolecules. 2022;12(6):819. doi:10.3390/biom12060819
6. Jessica Marini, PharmD, BCOP; Bailey Bass Hammond, PharmD; Jacob Rennebaum, PharmD; Erin Weeda, PharmD, BCPS; Jagoda Misniakiewicz, PharmD; Amy Sion, PharmD, BCOP. The Link Between Hypoalbuminemia and Oral Tyrosine Kinase Inhibitor Adverse Events in Adults with Malignant Solid Tumors. Published online August 19, 2022. Accessed April 3, 2023.
