Abstract C004: The CXCR4 inhibitor X4-136 enhances the in vivo efficacy of established drugs against preclinical models of aggressive pediatric acute lymphoblastic leukemia

Abstract

Abstract Introduction: While overall survival for pediatric acute lymphoblastic leukemia (ALL) now approaches 90%, new treatment options are urgently required for certain high-risk subtypes including BCR-ABL1 or TCF3-HLF ALL, and relapsed T-cell ALL (T-ALL). CXCR4 (CD184) is the most frequently over-expressed chemokine receptor in hematological malignancies, including ALL. Binding of CXCL12 to its cognate receptor CXCR4 promotes tumor progression, metastasis and cell survival through multiple signaling pathways, including ERK1/2, RAS, p38 MAPK, PLC/MAPK, SAPK/JNK and cancer stem cell regulation. X4-136 (X4 Pharmaceuticals) is a second-generation potent, orally available, allosteric CXCR4 inhibitor under clinical evaluation. Therefore, it was of interest for the Pediatric Preclinical Testing Consortium to evaluate the in vivo activity of X4-136 in combination with established drugs against patient-derived xenograft (PDX) models of aggressive pediatric ALL. Methods: CXCR4 expression was quantified by RNAseq (https://pedcbioportal.org). Specific antibody binding capacity (sABC) was assessed using the CELLQUANT Calibrator. X4-136 was tested in vivo in NSG mice against 3 ALL PDXs (ALL-4, BCR-ABL1; ALL-7, TCF3-HLF; ALL-31, relapsed T-ALL) at 100 mg/kg/day PO for 4 weeks either as a single agent or in combination with an induction-type regimen of vincristine, dexamethasone and L-asparaginase (VXL). Events were defined as the proportion of human CD45+cells in the peripheral blood (%huCD45+) ≥25%. Drug efficacy was assessed by event-free survival (EFS) of treated (T) and control (C) groups by T-C, T/C and stringent objective response criteria (Houghton PJ, et al. Pediatr Blood Cancer, 2007) and leukemia infiltration into the femoral bone marrow on Day 28 post treatment initiation. Results: RNAseq showed significantly higher (P<0.0001) CXCR4 expression in ALL PDXs (n=90) compared with 154 PDXs derived from 9 other pediatric cancer histotypes. Median CXCR4 sABC on 29 ALL PDXs ranged from 0 to 3,796 (median 476). ALL-4 (median sABC 901), ALL-7 (3,796) and ALL-31 (1,483) were selected for in vivo efficacy studies. X4-136 was generally well tolerated, with maximum average animal weight loss of 4.5 to 8.8% for the 3 PDXs. Single-agent X4-136 significantly (P<0.05) delayed the progression of all 3 PDXs (T-C 1.8-16 days, T/C 1.4-2.2) but elicited no objective responses of the disease. In contrast, X4-136 combined with VXL delayed disease progression by 28.4-35.7 days (T/C 3.8-7.9) and elicited objective responses in all 3 PDXs (2 Complete Responses, 1 Maintained Complete Response). Moreover, the X4-136/VXL combination was significantly more effective than X4-136 and VXL alone against ALL-4 (P<0.05) and ALL-31 (P<0.01) but not ALL-7. Finally, the X4-136/VXL combination significantly decreased leukemia bone marrow infiltration compared with X4-136 and VXL alone in ALL-7 and ALL-31 (P<0.0001). Conclusions: The addition of X4-136 to an established anti-leukemia regimen significantly prolongs time to event in preclinical models of aggressive childhood ALL. Our results support further evaluation of X4-136 in combination with established drugs for pediatric ALL. (Supported by NCI Grants CA199000 and CA199922) Citation Format: Richard B Lock, Kathryn Evans, Connor D Jones, Narimanne El-Zein, Stephen W Erickson, Sarah Beaussant-Cohen, E. Lynne Kelley, Beverly A Teicher, Malcolm A Smith. The CXCR4 inhibitor X4-136 enhances the in vivo efficacy of established drugs against preclinical models of aggressive pediatric acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C004. doi:10.1158/1535-7163.TARG-19-C004