Inhibitory effects of midostaurin and avapritinib on myeloid progenitors derived from patients with KIT D816V positive advanced systemic mastocytosis.
Aged
Alleles
Antineoplastic Agents
/ pharmacology
Biomarkers
Female
Genotype
High-Throughput Nucleotide Sequencing
Humans
Male
Mastocytosis, Systemic
/ diagnosis
Middle Aged
Mutation
Myeloid Progenitor Cells
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins c-kit
/ genetics
Severity of Illness Index
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
05 2019
05 2019
Historique:
received:
09
01
2019
accepted:
08
03
2019
revised:
08
03
2019
pubmed:
27
3
2019
medline:
14
8
2019
entrez:
27
3
2019
Statut:
ppublish
Résumé
Advanced systemic mastocytosis (advSM) is characterized by the presence of an acquired KIT D816V mutation in >90% of patients. In the majority of patients, KIT D816V is not only detected in mast cells but also in other hematopoietic lineages. We sought to investigate the effects of the KIT-inhibitors midostaurin and avapritinib on single-cell-derived myeloid progenitor cells using granulocyte-macrophage colony-forming-units of patients with KIT D816V positive advSM. Colonies obtained prior to treatment were incubated in vitro with midostaurin (n = 10) or avapritinib (n = 11) and showed a marked reduction (≥50%) of KIT D816V positive colonies in 3/10 (30%) and 7/11 (64%) patient samples, respectively. Three of those 7 (43%) avapritinib responders were resistant to midostaurin in both, in vitro and in vivo. Colonies from four patients with high-risk molecular profile and aggressive clinical course were resistant to both drugs. The in vitro activity of midostaurin strongly correlated with clinical and molecular responses, e.g., relative reduction of KIT D816V allele burden and the proportion of KIT D816V positive colonies obtained after six months midostaurin-treatment in vivo. We conclude that the colony inhibition assay provides useful information for prediction of responses on midostaurin and that avapritinib has a superior in vitro activity compared to midostaurin.
Identifiants
pubmed: 30911112
doi: 10.1038/s41375-019-0450-8
pii: 10.1038/s41375-019-0450-8
pmc: PMC6756065
doi:
Substances chimiques
Antineoplastic Agents
0
Biomarkers
0
Protein Kinase Inhibitors
0
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1195-1205Références
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