Capillary Sampling Enables Venetoclax Concentration Measurement in Acute Myeloid Leukaemia Within Academic Multicentre Trial
Sari Kytölä
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Search for more papers by this authorMika Kurkela
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorJohanna I. Kiiski
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorIda Vänttinen
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Search for more papers by this authorTanja Ruokoranta
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Search for more papers by this authorAnu Partanen
Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Search for more papers by this authorAnnasofia Holopainen
Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Search for more papers by this authorMarja Pyörälä
Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Search for more papers by this authorMilla E. L. Kuusisto
Cancer Center, Oulu University Hospital, Research Unit of Biomedicine and Internal Medicine, Oulu, Finland
Search for more papers by this authorTimo Siitonen
Cancer Center, Oulu University Hospital, Research Unit of Biomedicine and Internal Medicine, Oulu, Finland
Search for more papers by this authorSirpa Koskela
Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
Search for more papers by this authorJohanna Rimpiläinen
Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
Search for more papers by this authorPia Ettala
Department of Clinical Hematology and Stem Cell Transplant Unit, Turku University Hospital, Turku, Finland
Search for more papers by this authorHeikki Kuusanmäki
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Foundation for the Finnish Cancer Institute, Helsinki, Finland
Search for more papers by this authorMikko Niemi
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJanne T. Backman
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCorresponding Author
Mika Kontro
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Foundation for the Finnish Cancer Institute, Helsinki, Finland
Correspondence:
Mika Kontro ([email protected])
Search for more papers by this authorSari Kytölä
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Search for more papers by this authorMika Kurkela
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorJohanna I. Kiiski
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Search for more papers by this authorIda Vänttinen
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Search for more papers by this authorTanja Ruokoranta
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Search for more papers by this authorAnu Partanen
Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Search for more papers by this authorAnnasofia Holopainen
Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Search for more papers by this authorMarja Pyörälä
Department of Medicine, Kuopio University Hospital, Kuopio, Finland
Search for more papers by this authorMilla E. L. Kuusisto
Cancer Center, Oulu University Hospital, Research Unit of Biomedicine and Internal Medicine, Oulu, Finland
Search for more papers by this authorTimo Siitonen
Cancer Center, Oulu University Hospital, Research Unit of Biomedicine and Internal Medicine, Oulu, Finland
Search for more papers by this authorSirpa Koskela
Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
Search for more papers by this authorJohanna Rimpiläinen
Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
Search for more papers by this authorPia Ettala
Department of Clinical Hematology and Stem Cell Transplant Unit, Turku University Hospital, Turku, Finland
Search for more papers by this authorHeikki Kuusanmäki
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Foundation for the Finnish Cancer Institute, Helsinki, Finland
Search for more papers by this authorMikko Niemi
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Search for more papers by this authorJanne T. Backman
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Search for more papers by this authorCorresponding Author
Mika Kontro
Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
Foundation for the Finnish Cancer Institute, Helsinki, Finland
Correspondence:
Mika Kontro ([email protected])
Search for more papers by this authorFunding: This work was supported by Helsinki University: iCAN - Digital Precision Medicine and HiLIFE, FiCAN South, Finnish Medical Foundation, Cancer Foundation Finland, and Helsinki University Hospital Comprehensive Cancer Center.
ABSTRACT
Venetoclax has improved outcomes for acute myeloid leukaemia (AML) patients unfit for intensive chemotherapy. Managing cytopenias and infections remains challenging. Previous pharmacokinetic studies have shown considerable variability in venetoclax concentrations between individuals; however, data regarding whether higher levels increase toxicity or impact efficacy are limited. This study assessed the feasibility of using fingertip capillary blood plasma, collected via microsampling, to measure venetoclax trough concentrations and explored their association with toxicity and treatment outcomes. Concentrations were measured during the first two therapy cycles in 89 patients with newly diagnosed or relapsed or refractory AML receiving azacitidine and venetoclax. Validation with 37 parallel venipuncture and capillary samples showed excellent correlation (R2 of 0.835, p < 0.0001). No significant associations were found between venetoclax concentrations and patient characteristics such as gender, age and weight. While no statistically significant effects on therapy outcomes or adverse events were identified, trends suggested lower concentrations in refractory patients and higher in those with morphologic leukaemia free state or extended cycle length. Additionally, three separate CYP3A4 and CYP3A5 single-nucleotide polymorphisms were analysed in 81 patients for their potential impact on venetoclax concentrations. This study demonstrates that the capillary blood plasma method is viable for measuring venetoclax levels.
Conflicts of Interest
AP reports personal fees (AbbVie, Astra Zeneca, Behring, Janssen-Cilag, Novartis, Sanofi, Takeda); PE reports personal fees (Novartis, Pfizer, Amgen, Sanofi, AbbVie, BeiGene); MP reports personal fees (Pfizer, Novartis, AbbVie, Bristol-Myers Squibb, Servier); JR reports personal fees (Astellas Pharma, AbbVie, Bristol-Myers Squibb, Pfizer, Sanofi) TS reports personal fees (Amgen, AbbVie, Bristol-Myers Squibb, Otsuka Pharma, Janssen-Cilag, GSK); HK reports research funding from (AbbVie, outside the submitted work) and personal fees (Faron Pharmaceuticals); MK reports personal fees (Astellas Pharma, AbbVie, Bristol-Myers Squibb, Faron Pharmaceuticals, Novartis and Pfizer) and research funding (AbbVie, outside the submitted work). All other authors report no competing interests.
Open Research
Data Availability Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
| Filename | Description |
|---|---|
| bcpt70041-sup-0001-Supplementary_appendix.docxWord 2007 document , 415 KB |
Figure S1. Venetoclax Cmin across weight quartiles. Participants were grouped into quartiles based on their screening weight: Q1 (0%–25%): ≤ 70.4 kg (N = 22), Q2 (25%–50%): 70.5–77.4 kg (N = 23), Q3 (50%–75%): 77.5–85.1 kg (N = 22) and Q4 (75%–100%): > 85.1 kg (N = 22). Median Cmin values at A. C1D15 for each quartile were Q1: 760 (116–3480) ng/mL, Q2: 722 (173–4290) ng/mL, Q3: 570 (58–5080) ng/mL and Q4: 823 (187–12 600) ng/mL. B. At C2D15, median Cmin values were Q1: 879 (156–9790) ng/mL, Q2: 847 (186–4330) ng/mL, Q3: 828 (134–2780) ng/mL and Q4: 633 (135–5880) ng/mL. The difference between medians was assessed using the Kruskal–Wallis test. Figure S2. Comparison of median venetoclax capillary trough concentration between age groups (< 75 vs. ≥ 75 years) A. on Day 15 of the first and B. second therapy cycles. The difference between medians was assessed using Mann–Whitney U test. Figure S3. Associations between adverse events and capillary venetoclax trough concentration. The median concentration in patients with A. no reported adverse events, 1–2 adverse events or more than 2 adverse events during Cycle 1 and 2, and B. when stratified by the main type of reported adverse reaction. The difference between medians was assessed using the Kruskal–Wallis test. Figure S4. The median venetoclax capillary trough concentration in patients without concomitant CYP3A4 inhibitors, or with moderate or strong CY3A4 inhibitor, was assessed separately for A. C1D15 and C2D15, and B. on pooled samples on C1D15 or C2D15 with individual measurements marked. The difference between medians was assessed using the Kruskal–Wallis test. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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