Abstract 732: Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia
Authors: Loera Brenda , Zhang Chunxiao , Cardarelli Pina M. , Caculitan Niña G. , Chien Sylvia , Dai Jin , Oehler Vivian G. , Zhang Jianying , Marcucci Guido , Becker Pamela S. 
Published: March 2024

Introduction: CXCR4 is a chemokine receptor for CXCL12 that plays a critical role in homing of hematopoietic stem cells (HSCs) to the bone marrow microenvironment. The CXCR4 inhibitor plerixafor is used to increase mobilization of peripheral blood stem cells in combination with filgrastim. This pathway has also been investigated for applications in hematologic malignancies such as acute myeloid leukemia (AML), including clinical trials, with the goal of disrupting AML from the protective marrow environment. These have included use of plerixafor with 7+3 or MEC, BL-8040 with cytarabine, and ulocuplumab with MEC. For the ulocuplumab trial, at the study site of the authors, CR/CRi correlated with &gt;10% CXCR4 expression (Becker et al. ASH 2014). The objective of this preclinical study is to identify the AML patient population most likely to respond to CXCR4 inhibition, and the role of combined beta-adrenergic blockade, as the latter has been shown pre-clinically to augment mobilization of HSCs when combined with a CXCR4 inhibitor, GPC-100 (Sukhtankar et al. PLoS One, 2023).

Procedures: AML patient samples (N=124 including 90 blood and 34 bone marrow samples, and 21 with both) were obtained with informed consent on an IRB approved protocol. Multicolor flow cytometry was performed with sequential gating on blasts (by FSC/SSC, CD45/SSC, CD34 or phenotype), and leukemia stem cells (LSCs:CD34+CD38−,CD123+), then analysis for CXCR4 and beta-2 adrenergic receptor (ADRB2) surface expression. Correlations between CXCR4 expression and clinical characteristics including age, gender, new diagnosis vs. relapse, ELN2022 risk, cytogenetics, FLT3/NPM1 mutation status, CR1 duration, and overall survival were performed. GraphPad Prism9 was used for statistical analysis, and Mann Whitney test (two groups) and ordinary one-way ANOVA (&gt;2 groups) were used for comparisons.

Results: The range of CXCR4 expression by AML blasts is 0.05 to 99.7% (median 13.1%; mean 16.2%), and by AML LSCs 0 to 99% (median 2%, mean 15.7%). The expression by blasts and LSCs for each patient exhibited tight correlation, R2=0.88 p=1.23 × 10e-25). There was higher % expression of CXCR4 by both blasts and LSCs for new diagnosis, as compared to relapsed, patient samples (p=0.002). There was no correlation between level of CXCR4 expression and the other clinical features. For a subset of 20 patient samples analyzed for both CXCR4 and ADBR2 expression by AML blasts, ADBR2 expression ranged from 0.4 to 20.1%. For the samples that express ADBR2, there was high level expression of CXCR4, range 35.9 to 98.7% (median 78.4%, mean 76%).

Conclusion: These studies support further investigation of whether simultaneous blockade of CXCR4 and ADBR2 may potentiate chemotherapy response in AML by limiting microenvironment mediated chemotherapy protection and reveal that patients with new diagnosis may be more susceptible to this approach.

Citation Format: Brenda Loera, Chunxiao Zhang, Pina M. Cardarelli, Niña G. Caculitan, Sylvia Chien, Jin Dai, Vivian G. Oehler, Jianying Zhang, Guido Marcucci, Pamela S. Becker. Toward optimizing CXCR4 inhibition with beta adrenergic blockade to enhance chemotherapy response in acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 732.