Phase 1 study of combinatorial sorafenib, G-CSF, and plerixafor treatment in relapsed/refractory, FLT3-ITD-mutated acute myelogenous leukemia patients.

Abstract

Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.

• Authors: Gautam Borthakur, Zhihong Zeng, Jorge E Cortes, Hsiang-Chun Chen, Xuelin Huang, Marina Konopleva, Farhad Ravandi, Tapan Kadia, Keyur P Patel, Naval Daver, Mary A Kelly, Teresa McQueen, Ru-Yiu Wang, Hagop Kantarjian, Michael Andreeff
• Journal: American journal of hematology (Am J Hematol) Vol. 95 Issue 11 Pg. 1296-1303 (11 2020) ISSN: 1096-8652 [Electronic] United States
• PMID: 32697348 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 Wiley Periodicals LLC.

Chemical References

• Benzylamines
• Cyclams
• Heterocyclic Compounds
• Granulocyte Colony-Stimulating Factor
• Sorafenib
• FLT3 protein, human
• fms-Like Tyrosine Kinase 3
• plerixafor

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects)
• Benzylamines
• Cyclams
• Disease-Free Survival
• Female
• Granulocyte Colony-Stimulating Factor (administration & dosage, adverse effects)
• Heterocyclic Compounds (administration & dosage, adverse effects)
• Humans
• Leukemia, Myeloid, Acute (blood, drug therapy, genetics, mortality)
• Male
• Middle Aged
• Mutation
• Sorafenib (administration & dosage, adverse effects)
• Survival Rate
• fms-Like Tyrosine Kinase 3 (blood, genetics)