Definition:
Agents that alter gene expression without changing DNA sequence, primarily through effects on:
- DNA methylation
- Histone modification
- Chromatin remodeling
These drugs are particularly important in hematologic malignancies but are increasingly used in solid tumors.
| Class | Drug | Mechanism of Action | Approved Indications | Biomarker Requirement | Key Toxicities | Monitoring | Practical Oncology Pearls |
|---|---|---|---|---|---|---|---|
| DNMT Inhibitor | Azacitidine | Incorporates into DNA/RNA → inhibits DNMT1 → DNA hypomethylation → reactivates tumor suppressor genes | MDS, AMl, CMML | None | Myelosuppression, febrile neutropenia, GI toxicity, injection-site reactions | CBC twice weekly initially, renal function, infection surveillance | Delayed response (≥3 cycles); continue unless progression; backbone of azacitidine + venetoclax in AML |
| Decitabine | MDS, AML (elderly/unfit) | None | Myelosuppression, infection risk | CBC, renal / hepatic function | More profound neutropenia vs azacitidine in some regimens | ||
| Oral DNMT Inhibitor | Inqovi | Oral decitabine + cytidine deaminase inhibitor (cedazuridine) → systemic DNMT inhibition | MDS, CMML | None | Myelosuppression | CBC, adherence monitoring | Oral equivalent exposure to IV decitabine |
| HDAC Inhibitor | Vorinostat | Inhibits histone deacetylase → ↑ histone acetylation → transcription activation → apoptosis | Cutaneous T-Cell Lymphoma | None | Fatigue, thrombocytopenia, diarrhea | CBC, electrolytes | CYP interactions; modest single-agent activity |
| Romidepsin | HDAC inhibition → cell-cycle arrest & apoptosis | Peripheral T-Cell Lymphoma, CTCL | None | QT prolongation, cytopenias | ECG (QTc), K⁺/Mg²⁺, CBC | Correct electrolytes prior to dosing | |
| Belinostat | Pan-HDAC inhibitor | PTCL | None | Myelosuppression, nausea | CBC, LFTs | Dose adjust in hepatic impairment | |
| Panobinostat | Potent pan-HDAC inhibitor | Multiple Myeloma (with bortezomib + dexamethasone) | None | Severe diarrhea, thrombocytopenia, QT prolongation | ECG, CBC, hydration status | Significant GI toxicity; monitor closely early cycles | |
| IDH1 Inhibitor | Ivosidenib | Inhibits mutant IDH1 → ↓ 2-HG → restores differentiation | IDH1-mutated AML | IDH1 mutation required | Differentiation syndrome, QT prolongation | ECG, LFTs, CBC | Continue drug during differentiation syndrome unless severe |
| IDH2 Inhibitor | Enasidenib | Inhibits mutant IDH2 → ↓ 2-HG | IDH2-mutated AML | IDH2 mutation required | Differentiation syndrome, indirect hyperbilirubinemia | LFTs, CBC | Bilirubin elevation often non-hepatotoxic (UGT1A1 inhibition) |
| EZH2 Inhibitor | Tazemetostat | Inhibits EZH2 methyltransferase → ↓ H3K27 trimethylation → gene reactivation | Follicular Lymphoma (EZH2-mut or WT), Epithelioid Sarcoma | Mutation enhances response but not mandatory | Cytopenias (mild), fatigue | CBC | Generally well tolerated; oral targeted option |
| Menin Inhibitor | Revumenib | Blocks menin–KMT2A interaction → restores differentiation | KMT2A-rearranged AML (emerging approvals) | KMT2A rearrangement | Differentiation syndrome, QT prolongation | ECG, CBC | Mechanistically similar differentiation risk as IDH inhibitors |