Drugs of interest to pathologists
Drugs related to surgical pathology
Imatinib mesylate

Topic Completed: 1 November 2011

Minor changes: 11 December 2020

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Imatinib mesylate [title] "loattrfree full text"[sb] review

Him G. Kwee, M.D.
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Cite this page: Kwee HG. Imatinib mesylate. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/drugsgleevec.html. Accessed March 4th, 2021.
Definition / general
  • A specific competitive inhibitor of tyrosine kinase (TK) enzymes
  • Inhibits ATP binding in the tyrosine kinase domains in ABL (Abelson proto-oncogene) in Philadelphia chromosome+ chronic myelogenous leukemia (CML) and c-kit and PDGFRA (platelet derived growth factor receptor alpha) in gastrointestinal stromal tumor / GIST (Med Klin (Munich) 2002;97:28)
Trade name
  • Gleevec®
Approved by U.S. Food and Drug Administration for:
  • GIST (see discussion below)
  • Adults and children with Philadelphia chromosome+ chronic myelogenous leukemia
  • Adults with relapsed or refractory Philadelphia chromosome+ acute lymphoblastic leukemia
  • Adults with myelodysplastic / myeloproliferative diseases with PDGFR gene rearrangements
  • Adults with aggressive systemic mastocytosis without D816V c-kit mutation or with c-kit mutational status unknown
  • Adults with hypereosinophilic syndrome or chronic eosinophilic leukemia
  • Adults with unresectable or recurrent or metastatic dermatofibrosarcoma protuberans (J Clin Aesthet Dermatol 2011;4:17)
  • Cost: $32,000 - $98,000 per year for CML, $64,800 per year for GIST (Wikipedia: Imatinib [Accessed 14 December 2018])
  • KIT and PDGFRA are growth factor receptor tyrosine kinases that catalyze the transfer of phosphate from ATP to cytoplasmic tyrosines, causing activation of signaling pathways that regulate cell proliferation, adhesion, apoptosis and differentaiation
  • Both KIT and PDGFRA are located on the long arm of chromosome 4
  • Imatinib binds to amino acid residues within the ATP binding pocket (TK I) and the activation loop (TK 2), leading to inhibition of phosphorylation, activation and downstream signaling that control cell functions
  • KIT and PDGFRA mutations in GIST cause constitutional activation of the receptor TK pathway in the absence of ligands
  • Most KIT mutations in GIST involve exons 11, 9 and 13 and PDGFRA mutations mostly involve exons 18, 12 and 14
  • KIT and PDGFRA mutations are mutually exclusive (Science 2003;299:708)
Use for pathologists (GIST)
  • Since KIT positivity by IHC has significant therapeutic implications, it is important to titrate each new batch of KIT antibody with appropriate positive and negative controls
  • Mast cells in nonneoplastic tissue can be used as positive internal controls
  • 5% of GISTs are negative for KIT by IHC; they are often of gastric or peritoneal origin and often have epitheliod or mixed phenotype; they tend to be either KIT wild type or have PDGFRA mutations
  • 7% of GISTs have PDGFRA mutations, mostly missense mutations in exon 18; they are often gastric or peritoneal, have epithelioid phenotype and myxoid stroma and have multinucleated and rhabdoid cells
  • PDGFRA mutant GISTs are weakly positive or negative for KIT by IHC
  • 10 - 15% of GISTs do not have KIT or PDGFRA mutations, they are called KIT-PDGFRA wild type GISTs; some have BRAF V600E mutations at exon 15 (Am J Clin Pathol 2010;133:141)
  • There was a significant difference in median overall survival between KIT+ and KIT- GIST treated with imatinib but it is the KIT mutation genotype that appears to drive the therapeutic response to the drug (J Clin Oncol 2003;21:4342); GISTs with exon 11 showed 83.5% response, with exon 9 showed 48% response and the wild type did not respond
  • Increasing the dose of imatinib from 400 mg/day to 800 mg/day improved the progression free survival of GISTs with exon 9 mutation (Eur J Cancer 2006;42:1093)
  • GISTs with the most common PDGFRA mutation, exon 18 D842V, are highly resistant to imatinib (J Clin Oncol 2008;26:5352)

Mutational analysis of GISTs is not routinely recommended at this time but it may be performed in select cases such as:
  • To confirm diagnosis of KIT+ tumors with atypical morphology or clinical features; IHC for DOG 1 and Protein C Kinase- theta may be useful to confirm the diagnosis of GIST
  • To differentiate KIT- GIST from other tumors
  • To identify patients at higher risk of recurrence after imatinib therapy
  • For advanced gastric GIST not responding to imatinib
  • To identify GIST with exon 9 mutation that responds better with a higher dose of imatinib
  • Pediatric GISTs uniformly express KIT by IHC but they rarely have a KIT or PDGFRA mutation
  • It has been suggested that the therapies for pediatric GIST should focus on inhibitors of KIT activation with an emphasis on second generation receptor TK inhibitors such as sunitinib malate (Sutent), a drug that was approved by the FDA in January 2006
  • Following treatment with imatinib, GISTs show hypocellularity, sclerosis, calcifications, myxoid change and necrosis; the spindled phenotype may change to an epitheliod phenotype and the KIT immunoexpression may disappear; mutational analysis shows retention of the same genotype after therapy (Arch Pathol Lab Med 2011;135:1298)
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