Session: 613. Acute Myeloid Leukemia: Clinical Studies: Poster I
Hematology Disease Topics & Pathways:
Leukemia, ALL, AML, Diseases, Non-Biological, Therapies, chemotherapy, Pediatric, Young Adult, Lymphoid Malignancies, Study Population, Myeloid Malignancies, Clinically relevant
Methods: PK samples from cerebrospinal fluid (CSF) were collected at screening and if a lumbar puncture was performed as standard of care during treatment. Plasma PK samples were collected throughout the study. CSF and plasma concentrations of venetoclax were determined using liquid-liquid extraction followed by liquid chromatography (LC) with tandem mass spectrometric detection (MS/MS). The lower limit of quantitation for venetoclax was 2.14 ng/mL in plasma and 0.1ng/mL in CSF.
Results: There was a total of 66 samples from 33 patients with relapsed or refractory AML or ALL. The venetoclax concentration in CSF ranged between <0.1 and 13 ng/mL with a mean concentration of 3 ng/mL. Of the 66 CSF samples collected, 17 CSF samples (from 9 patients) had a plasma PK sample collected on the same day. The venetoclax CSF concentrations in this subgroup were consistent with the overall group and ranged between <0.1 and 11 ng/mL with a mean concentration of 2.8 ng/mL. Venetoclax plasma concentrations ranged from <2 ng/mL to 4.3 ug/mL. The mean plasma-to-CSF ratio was 300 with a range of 67-1003. This mean is more than 4-fold higher than the blood-to-brain ratio observed preclinically in mice. The plasma-to-CSF ratios did not show a trend over the dosing interval.
Conclusion: To our knowledge this is the first study reporting venetoclax CSF pharmacokinetics in the AML and ALL setting. The lower disposition observed in humans is contrary to our expectation, given the significantly higher expression of P-gp in mice BBB compared to humans and suggests that other factors are involved in venetoclax disposition to the CSF. The ability of venetoclax to cross the blood brain barrier may explain the reported activity of venetoclax in treatment of hematologic malignancies with CNS involvement1,2.
- Reda G, Cassin R, Dovrtelova G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104(5):e222-e223. doi:10.3324/haematol.2018.213157
- Beziat G, Gauthier M, Protin C, et al. Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep. 2020;8(2):269-273. Published 2020 Jan 10. doi:10.1002/ccr3.2580
Disclosures: Salem: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Badawi: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Palenski: AbbVie: Current Employment, Other: may hold stock or other options. Arrendale: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Kim: AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019). Menon: AbbVie Inc.: Current Employment, Other: may hold stock or other options.
See more of: Oral and Poster Abstracts