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985 Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic Analysis of the Cerebrospinal Fluid in Pediatric Leukemia Patients

Program: Oral and Poster Abstracts
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
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Ahmed Hamed Salem, PhD, FCP1, Mohamed A Badawi, PhD1*, Andrew E. Place, MD, PhD2, Tammy L. Palenski, PhD1, Richard Arrendale, PhD1*, Su Young Kim1*, Sara Federico, MD3*, Todd M. Cooper, DO4 and Rajeev Menon, PhD1*

1AbbVie Inc., North Chicago, IL
2Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
3St. Jude Children's Research Hospital, Memphis, TN
4Division of Hematology and Oncology, Seattle Children's Hospital, Seattle, WA

Introduction: Venetoclax is a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults and is currently being evaluated in several hematologic and solid malignancies. While plasma pharmacokinetics (PK) of venetoclax is well documented, data regarding the accumulation of venetoclax into the central nervous system (CNS) are limited. Venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the blood brain barrier (BBB). Moreover, venetoclax is a substrate of the P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS. In this analysis we characterized the passage of venetoclax into the CNS using PK samples collected during a phase 1 study (NCT03236857) of pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy.

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.

References:

  1. 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
  2. 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.

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