SINGLE CELL SIGNALING PHARMACODYNAMICS IN A PHASE 1B CLINICAL TRIAL OF THE AXL INHIBITOR BEMCENTINIB IN ACUTE MYELOID LEUKEMIA AND MYELODYSPLASTIC SYNDROME
Author(s): ,
Monica Hellesøy
Affiliations:
Haukeland University Hospital,Bergen,Norway
,
Oda Helen Eck Fagerholt
Affiliations:
University of Bergen,Bergen,Norway
,
Benedicte Sjo Tislevoll
Affiliations:
Department of Internal Medicine,University of Bergen,Bergen,Norway
,
Stein Erik Gullaksen
Affiliations:
Department of Internal Medicine,University of Bergen,Bergen,Norway
,
Rakel Brendsdal Forthun
Affiliations:
Haukeland University Hospital,Bergen,Norway
,
Randi Hovland
Affiliations:
Haukeland University Hospital,Bergen,Norway
,
Håkon Reikvam
Affiliations:
Haukeland University Hospital,Bergen,Norway
,
Astrid Olsnes Kittang
Affiliations:
Haukeland University Hospital,Bergen,Norway
,
Jorge Cortes
Affiliations:
MD Anderson Cancer Center,Houston,United States
,
David Micklem
Affiliations:
BerGenBio ASA,Bergen,Norway
,
Robert J Holt
Affiliations:
BerGenBio ASA,Bergen,Norway
,
Sonja Loges
Affiliations:
University Medical Center Hamburg-Eppendorf,Hamburg,Germany
Bjørn Tore Gjertsen
Affiliations:
Department of Internal Medicine,University of Bergen,Bergen,Norway;Haukeland University Hospital,Bergen,Norway
EHA Library. Helen Eck O. Jun 15, 2019; 267300; PS999
Oda Helen Eck
Oda Helen Eck
Contributions
×
Abstract

Abstract: PS999

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Axl is a type III receptor tyrosine kinase shown to have a strong oncogenic potential in many cancer types. Overexpression of Axl has been established as a poor prognostic marker, linked to acquired resistance to chemotherapy and other anticancer therapies in many malignancies, including AML.

BGB324 (Bemcentinib) is an orally available highly specific small molecule inhibitor of Axl, which is currently being investigated in a phase II clinical trial in patients with refractory/relapsed AML and MDS (BGBC003, ClinicalTrials.gov Identifier: NCT02488408).

Aims
We aimed to investigate the effect of bemcentinib on the Axl signaling pathway in treated patients using flow- and mass cytometry.

Methods
25 patients (21 relapsed/refractory AML and 4 MDS) were treated in a classical 3+3 dose escalation design (loading dose/continuation dose): 400/100mg, 600/200mg and 900/300mg. PB sampled at frequent intervals was fixed immediately and analyzed by flow- and mass cytometry to investigate the effects of BGB324 treatment in signaling proteins known to be downstream of Axl. Sequential BM samples were also analyzed by mass cytometry for extensive single cell immune profiling using a 35 marker panel, and mutational profiling of patients was performed by TruSight myeloid panel (Illumina) sequencing of pre-treatment BM samples.

Results
PhosphoFlow and CyTOF analyses of PB from 11 patients showed altered signaling in circulating leukemic blasts relative to pre-treatment in several proteins downstream of Axl, including pPLCγ1, pErk and pAkt. Changes in signaling relative to pre-treatment were seen within 4-24 hours of treatment start in all patients. The time point of signaling response correlated to measurable plasma drug concentrations (figure A). Signaling responses were heterogeneous in the cohort examined, and we did not find a signaling profile correlating to clinical response. The divergence of signaling responses is probably due to a heterogeneous patient population with composite mutational profiles (figure B).

Deep single cell immune profiling of BM samples from 7 patients by mass cytometry revealed the presence of blast populations with composite immune phenotypes in all patients, with moderate drift during treatment. Blast immune phenotypic composition was more complex than what was reflected by the clonal composition. The mutational profiles will be validated with using exome sequencing.

Conclusion
BGB324 has unique pharmacodynamic properties, and signaling responses to exposure can be observed in peripheral blood leukemic blasts by phospho-flow and mass cytometry within hours of ingestion of the first treatment dose, corresponding to measurable drug exposure in plasma. Further studies may establish whether single cell signal profiling can discriminate responders from non-responders and provide information about dose-response in a clinically meaningful way. 

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): AML, Clinical trial, MDS

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies