Determinants of Interpatient Variability in Treosulfan Pharmacokinetics in AML Patients Undergoing Autologous Stem Cell Transplantation

• Published in: International journal of molecular sciences 2024-08, Vol.25 (15), p.8215
• Main Authors: Ayçiçek, Selin G, Akhoundova, Dilara, Bacher, Ulrike, Hayoz, Michael, Aebi, Yolanda, Largiadèr, Carlo R, Pabst, Thomas
• Format: Article
• Language: English
• Subjects: acute myeloid leukemia (AML); Adult; Adults; Age; Aged; Antimitotic agents; Antineoplastic agents; Antineoplastic Agents, Alkylating - pharmacokinetics; Antineoplastic Agents, Alkylating - therapeutic use; Blood; Busulfan - analogs & derivatives; Busulfan - pharmacokinetics; Busulfan - therapeutic use; Clemastine; Combination therapy; Enzyme inhibitors; exposure; Female; Gender; Hematopoietic Stem Cell Transplantation - methods; high-dose chemotherapy (HDCT); Humans; Induction therapy; interpatient variability; Leukemia; Leukemia, Myeloid, Acute - therapy; Liver; Male; Middle Aged; Patients; Pediatrics; Pharmacokinetics; Physiological aspects; Remission (Medicine); Resveratrol; Retrospective Studies; Stem cell transplantation; Stem cells; Transplantation; Transplantation, Autologous; treosulfan
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25158215

Limited data on treosulfan pharmacokinetics in adults, particularly regarding autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML), is available to date. Furthermore, correlations between treosulfan exposure, toxicity, and clinical outcome remain understudied. In this single-center retrospective study, we analyzed data from 55 AML patients who underwent HDCT with treosulfan (14 g/m ) and melphalan (140 mg/m or 200 mg/m ) (TreoMel) between August 2019 and November 2023 at the University Hospital of Bern. We assessed treosulfan pharmacokinetics and correlations with several physiological parameters with potential impact on its interpatient variability. We further analyzed how treosulfan exposure correlates with toxicity and clinical outcomes. Women above 55 years showed higher area under the curve (AUC) levels (median: 946 mg*h/L, range: 776-1370 mg*h/L), as compared to women under 55 (median: 758 mg*h/L, range: 459-1214 mg*h/L, = 0.0487). Additionally, women above 55 showed higher peak levels (median: 387 mg/L, range: 308-468 mg/L), as compared to men of the same age range (median: 326 mg/L, range: 264-395 mg/L, = 0.0159). Treosulfan levels varied significantly with body temperature, liver enzymes, hemoglobin/hematocrit., and treosulfan exposure correlated with diarrhea severity in women over 55 ( = 0.0076). Our study revealed age- and gender-related variability in treosulfan pharmacokinetics, with higher plasma levels observed in female patients above 55. Moreover, our data suggest that treosulfan plasma levels may vary with several physiological parameters and that higher treosulfan exposure may impact toxicity. Our study underlines the need for further research on treosulfan pharmacokinetics, especially in older patients undergoing HDCT in the ASCT setting.