Imatinib

證據等級: L5

預測適應症: 10 個

Imatinib: From CML/GIST to Fibroblastic Neoplasm

One-Sentence Summary

Imatinib (Gleevec/Glivec) is a first-in-class tyrosine kinase inhibitor originally developed for Chronic Myeloid Leukemia (CML) and Gastrointestinal Stromal Tumors (GIST), acting through inhibition of BCR-ABL, c-KIT, and PDGFR kinases. The TxGNN model predicts activity across 10 rare oncological and non-oncological conditions, with the strongest mechanistic and clinical evidence supporting Fibroblastic Neoplasm (particularly Dermatofibrosarcoma Protuberans/DFSP), backed by FDA approval since 2006, a 2025 European interdisciplinary guideline, and multiple Phase 2 trials. Imatinib is not currently registered in Singapore, and evidence quality across the 10 predictions varies substantially from L2 (Proceed with Guardrails) to L5 (Hold).

Quick Overview

Item	Content
Original Indication	Chronic Myeloid Leukemia (CML), Gastrointestinal Stromal Tumor (GIST)
Top Predicted Indication (by TxGNN score)	Heart Fibrosarcoma (Rank 1, 99.94%)
Most Actionable Predicted Indication	Fibroblastic Neoplasm / DFSP (Rank 2, 99.94%)
TxGNN Prediction Score (Rank 1)	99.94%
Highest Evidence Level Achieved	L2 (Fibroblastic Neoplasm)
Singapore Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails (Fibroblastic Neoplasm/DFSP)

All 10 Predicted Indications — Summary

Rank	Disease	TxGNN Score	Evidence Level	Recommendation
1	Heart Fibrosarcoma	99.94%	L4	Hold
2	Fibroblastic Neoplasm (DFSP)	99.94%	L2	Proceed with Guardrails
3	Conventional Fibrosarcoma	99.93%	L3	Research Question
4	Kidney Fibrosarcoma	99.93%	L3	Research Question
5	Low Grade Fibromyxoid Sarcoma	99.93%	L5	Hold
6	Liposarcoma	99.88%	L3	Research Question
7	Liver Fibrosarcoma	99.86%	L4	Hold
8	Autosomal Recessive Familial Mediterranean Fever	99.86%	L5	Hold
9	Ovarian Myxoid Liposarcoma	99.85%	L5	Hold
10	Familial Rhabdoid Tumor	99.83%	L5	Hold

Why is This Prediction Reasonable?

Detailed mechanism of action data is not available in the current dataset. Based on well-established pharmacological knowledge, Imatinib is a small-molecule tyrosine kinase inhibitor (TKI) that competitively inhibits three key kinases: BCR-ABL (the oncogenic fusion kinase driving CML), c-KIT (CD117, mutated in GIST and other tumours), and PDGFR-α/β (platelet-derived growth factor receptors). Its clinical success in CML and GIST established the paradigm of molecularly targeted oncology.

For Fibroblastic Neoplasm, particularly Dermatofibrosarcoma Protuberans (DFSP), the mechanistic link is among the strongest in soft tissue oncology. DFSP is defined by a chromosomal translocation t(17;22)(q22;q13) that fuses the COL1A1 gene with PDGFB, creating a fusion protein that drives constitutive PDGFR-β activation. This is a direct, specific molecular target for imatinib. The FDA approved imatinib for unresectable and/or metastatic DFSP in 2006, and the 2025 European interdisciplinary guideline (PMID 39904126) continues to endorse this use.

The high TxGNN scores for rarer fibrosarcoma variants (heart, kidney, liver) and mechanistically unrelated conditions (familial Mediterranean fever, familial rhabdoid tumour) reflect topological similarity in the knowledge graph — these nodes share fibroblastic or sarcoma classification edges — rather than direct molecular driver matching. For FMF (MEFV/pyrin/inflammasome pathway), low grade fibromyxoid sarcoma (FUS-CREB3L2 fusion), and familial rhabdoid tumour (SMARCB1 loss), the known oncogenic drivers have no established connection to imatinib's target kinases.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00085475	Phase 2	Completed	17	Imatinib in locally advanced/metastatic DFSP and Giant Cell Fibroblastoma carrying the t(17;22) COL1A1/PDGF-β translocation; directly validates the fusion-driven PDGFR-β mechanism
NCT00154388	Phase 2	Completed	185	Basket trial of imatinib across rare malignancies associated with imatinib-sensitive tyrosine kinases; potential coverage of kidney fibrosarcoma and other rare subtypes, though subgroup data are limited
NCT00006357	Phase 1/2	Completed	91	STI571 (imatinib) in advanced soft tissue sarcomas including liposarcoma; provides dose-finding, safety and preliminary efficacy data
NCT00031915	Phase 2	Completed	N/A	Gleevec in metastatic/unresectable soft tissue and bone sarcomas; multi-disciplinary North American Sarcoma Study Group trial covering multiple histological subtypes

Literature Evidence (Fibroblastic Neoplasm — Top 10)

PMID	Year	Type	Journal	Key Findings
39904126	2025	Clinical Practice Guideline	European Journal of Cancer	2025 EADO/EDF/UEMS/EADV European interdisciplinary guideline update for DFSP; recommends imatinib for unresectable/advanced DFSP based on accumulated evidence
33449152	2021	Review	Cell Mol Life Sci	Comprehensive review of PDGFRA/PDGFRB mutations across diseases; PDGFRB mutations drive myofibroma; directly supports PDGFR-targeted therapy rationale in fibroblastic neoplasms
28795284	2017	Review	Current Treatment Options in Oncology	DFSP management review; outlines role of imatinib in locally advanced or metastatic/unresectable cases where surgical cure is not feasible
31466588	2019	Review	Dermatologic Clinics	DFSP pathology, behaviour and treatment; systemic imatinib therapy for advanced disease described alongside Mohs surgery
26027711	2015	Review	Expert Review of Anticancer Therapy	Current treatment options for DFSP; t(17;22) as critical event creating PDGFB autocrine/paracrine driver; imatinib role in unresectable disease
30297237	2018	Review	Bulletin du Cancer	DFSP management highlighting COL1A1-PDGFB translocation; imatinib recommendation for unresectable/metastatic relapse
35038826	2022	Phase 2 Trial	Cancer Research and Treatment	Phase 2 trial identifying NOTCH2 and HES1 as potential molecular markers of imatinib response in desmoid tumour (aggressive fibromatosis); extends understanding of imatinib activity in fibroblastic conditions
25852058	2015	Translational/Mechanistic	Molecular Cancer Therapeutics	CDKN2A/p16 loss implicates CDK4 as a therapeutic target in imatinib-resistant DFSP; provides insight into acquired resistance mechanisms
36999599	2023	Review	Journal of Surgical Oncology	DFSP surgical management review; NCCN guidelines now prefer Mohs micrographic surgery; imatinib confirmed for advanced/unresectable disease
39580648	2025	Genetics/Case Series	Genetics in Medicine	Novel germline PDGFRB splice variant in infantile myofibromatosis associated with resistance to imatinib; critical for understanding imatinib limitations in PDGFRB-driven conditions

Singapore Market Information

Imatinib is not currently registered with the Health Sciences Authority (HSA) of Singapore. There are no recorded product licences in the current dataset.

Imatinib (Gleevec/Glivec, Novartis) holds regulatory approval in multiple major markets — US (FDA, 2001), EU (EMA), Japan (PMDA), and Taiwan (TFDA). Its absence from the Singapore HSA registry should be verified directly with HSA prior to any clinical consideration. Named patient or compassionate use programmes may represent an access pathway for eligible patients.

Cytotoxicity

Imatinib is an antineoplastic drug used for malignant conditions (CML, GIST, DFSP). It qualifies for cytotoxicity classification as a targeted antineoplastic agent.

Item	Content
Cytotoxicity Classification	Targeted therapy — Tyrosine Kinase Inhibitor (BCR-ABL / c-KIT / PDGFR-α/β inhibitor); not conventional cytotoxic chemotherapy
Myelosuppression Risk	Moderate — neutropenia, thrombocytopenia, and anaemia are commonly reported, particularly in the first months of treatment
Emetogenicity Classification	Low to moderate
Monitoring Items	CBC with differential (neutrophils, platelets), liver function tests (ALT, AST, bilirubin), renal function (creatinine), body weight and signs of fluid retention/oedema
Handling Protection	Follow cytotoxic drug handling regulations for preparation, dispensing, and disposal

Safety Considerations

Please refer to the package insert for safety information.

Safety data (key warnings, contraindications, drug-drug interactions) are not available in the current dataset. A full safety review from the official SmPC (FDA/EMA) or package insert is mandatory before any clinical application. Literature signals of note include: severe hepatotoxicity, clinically significant fluid retention/oedema, cardiac toxicity in patients with pre-existing cardiac disease, and DRESS syndrome (drug reaction with eosinophilia and systemic symptoms; PMID 30096127).

Conclusion and Next Steps

Decision: Proceed with Guardrails (for Fibroblastic Neoplasm / DFSP)

Rationale: Imatinib has FDA approval (2006) for unresectable/metastatic DFSP driven by the COL1A1-PDGFB t(17;22) translocation, supported by Phase 2 clinical trials and endorsed by the 2025 European interdisciplinary guideline. This is one of the most mechanistically validated examples of TKI repurposing in soft tissue oncology. The principal barrier to use in Singapore is the absence of local HSA registration.

To proceed, the following is needed:

Singapore regulatory pathway: Verify HSA registration status or initiate a compassionate use / named patient programme for DFSP indication
Full safety review: Obtain and review the complete imatinib SmPC/package insert (FDA or EMA) for warnings, contraindications, and drug interactions before any clinical application
Molecular pre-screening: Confirm COL1A1-PDGFB t(17;22) translocation by FISH or RT-PCR in all DFSP patients prior to initiating imatinib therapy, as response is translocation-dependent
MOA documentation: Complete DrugBank/literature-based formal documentation of mechanism of action (currently a data gap)
Indications for further research (L3 — Research Question): Conventional fibrosarcoma, kidney fibrosarcoma, and liposarcoma each require dedicated molecular profiling and feasibility assessment before any therapeutic consideration
Hold indications: Low grade fibromyxoid sarcoma (FUS-CREB3L2 driven), familial Mediterranean fever (MEFV/pyrin driven), ovarian myxoid liposarcoma (FUS-DDIT3 driven), and familial rhabdoid tumour (SMARCB1 loss driven) lack mechanistic justification for imatinib use and should not be pursued without substantial new evidence

This report is for research purposes only and does not constitute medical advice. All repurposing candidates require clinical validation before therapeutic application. Data cutoff: 2026-04-04.

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.