Inhibition of calcineurin combined with dasatinib has direct and indirect anti‐leukemia effects against BCR‐ABL1+ leukemia

• Published in: American journal of hematology Vol. 89; no. 9; pp. 896 - 903
• Main Authors: Gardner, Lori A., Klawitter, Jelena, Gregory, Mark A., Zaberezhnyy, Vadym, Baturin, Dmitry, Pollyea, Daniel A., Takebe, Naoko, Christians, Uwe, Gore, Lia, DeGregori, James, Porter, Christopher C.
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2014
• Subjects: Adult; Animals; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Calcineurin Inhibitors; Cell Line, Tumor; Cyclosporine - adverse effects; Cyclosporine - pharmacokinetics; Cyclosporine - therapeutic use; Dasatinib; Drug Synergism; Female; Flow Cytometry; Fusion Proteins, bcr-abl - metabolism; Hematology; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism; Male; Mice; Mice, Inbred C57BL; Middle Aged; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Pyrimidines - therapeutic use; Thiazoles - adverse effects; Thiazoles - pharmacokinetics; Thiazoles - therapeutic use; Treatment Outcome
• ISSN: 0361-8609; 1096-8652; 1096-8652
• DOI: 10.1002/ajh.23776

Treatment of BCR‐ABL1+ leukemia has been revolutionized with the development of tyrosine kinase inhibitors. However, patients with BCR‐ABL1+ acute lymphoblastic leukemia and subsets of patients with chronic myeloid leukemia are at high risk of relapse despite kinase inhibition therapy, necessitating novel treatment strategies. We previously reported synthetic lethality in BCR‐ABL1+ leukemia cells by blocking both calcineurin/NFAT signaling and BCR‐ABL1, independent of drug efflux inhibition by cyclosporine. Here, using RNA‐interference we confirm that calcineurin inhibition sensitizes BCR‐ABL1+ cells to tyrosine kinase inhibition in vitro. However, when we performed pharmacokinetic and pharmacodynamic studies of dasatinib and cyclosporine in mice, we found that co‐administration of cyclosporine increases peak concentrations and the area under the curve of dasatinib, which contributes to the enhanced disease control. We also report the clinical experience of two subjects in whom we observed more hematopoietic toxicity than expected while enrolled in a Phase Ib trial designed to assess the safety and tolerability of adding cyclosporine to dasatinib in humans. Thus, the anti‐leukemia benefit of co‐administration of cyclosporine and dasatinib is mechanistically pleiotropic, but may not be tolerable, at least as administered in this trial. These data highlight some of the challenges associated with combining targeted agents to treat leukemia. Am. J. Hematol. 89:896–903, 2014. © 2014 Wiley Periodicals, Inc.