Phase 1 study of combinatorial sorafenib, G-CSF, and plerixafor treatment in relapsed/refractory, FLT3-ITD-mutated acute myelogenous leukemia patients.
Adolescent
Adult
Aged
Aged, 80 and over
Antineoplastic Combined Chemotherapy Protocols
/ administration & dosage
Benzylamines
Cyclams
Disease-Free Survival
Female
Granulocyte Colony-Stimulating Factor
/ administration & dosage
Heterocyclic Compounds
/ administration & dosage
Humans
Leukemia, Myeloid, Acute
/ blood
Male
Middle Aged
Mutation
Sorafenib
/ administration & dosage
Survival Rate
fms-Like Tyrosine Kinase 3
/ blood
Journal
American journal of hematology
ISSN: 1096-8652
Titre abrégé: Am J Hematol
Pays: United States
ID NLM: 7610369
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
12
05
2020
revised:
14
07
2020
accepted:
20
07
2020
pubmed:
23
7
2020
medline:
30
12
2020
entrez:
23
7
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Benzylamines
0
Cyclams
0
Heterocyclic Compounds
0
Granulocyte Colony-Stimulating Factor
143011-72-7
Sorafenib
9ZOQ3TZI87
FLT3 protein, human
EC 2.7.10.1
fms-Like Tyrosine Kinase 3
EC 2.7.10.1
plerixafor
S915P5499N
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1296-1303Subventions
Organisme : Foundation for the National Institutes of Health
ID : R01FD003733
Pays : International
Organisme : Foundation for the National Institutes of Health
ID : R21CA143805
Pays : International
Organisme : Foundation for the National Institutes of Health
ID : CA055164
Pays : International
Organisme : Foundation for the National Institutes of Health
ID : CA016672
Pays : International
Informations de copyright
© 2020 Wiley Periodicals LLC.
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