Introduction
Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent belonging to the class of antineoplastic drugs. It is a cytidine analog that incorporates into DNA and inhibits DNA methyltransferase, leading to hypomethylation and cellular differentiation or apoptosis. Decitabine is primarily used in the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).
Mechanism of Action
Decitabine is a prodrug that requires phosphorylation by deoxycytidine kinase to become active. The triphosphate form incorporates into DNA during replication, where it forms covalent bonds with DNA methyltransferases (DNMTs), particularly DNMT1. This irreversible binding leads to:
- Depletion of available DNMTs
- Genome-wide DNA hypomethylation
- Reactivation of tumor suppressor genes silenced by hypermethylation
- Induction of cellular differentiation
- Promotion of apoptosis in rapidly dividing cells
The drug is cell cycle-specific, with maximal activity during the S phase of cell division.
Indications
FDA-approved indications:- Treatment of patients with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes
- Treatment of adults with newly diagnosed acute myeloid leukemia (AML) who are ≥65 years old and not candidates for intensive induction chemotherapy
- Chronic myelomonocytic leukemia (CMML)
- Juvenile myelomonocytic leukemia (JMML)
- Sickle cell disease (investigational)
Dosage and Administration
Standard dosing for MDS:- 15 mg/m² by intravenous infusion over 3 hours
- Repeated every 8 hours for 3 consecutive days
- Cycle repeated every 6 weeks
- 20 mg/m² by IV infusion over 1 hour daily for 5 consecutive days
- Cycle repeated every 4 weeks
- Hematologic toxicity: Delay next cycle until absolute neutrophil count (ANC) ≥1,000/μL and platelets ≥50,000/μL
- Renal impairment: No specific dosage adjustment recommended, but use with caution
- Hepatic impairment: No specific dosage adjustment recommended, but use with caution
- Elderly patients: No dosage adjustment required based on age alone
Pharmacokinetics
Absorption: Administered intravenously only; complete bioavailability Distribution: Volume of distribution approximately 75-90 L/m²; crosses blood-brain barrier poorly Metabolism: Undergoes extensive deamination by cytidine deaminase in liver, plasma, and peripheral tissues to inactive metabolite 5-aza-2'-deoxyuridine Elimination: Terminal half-life approximately 30-35 minutes; primarily eliminated renally (50%) Protein binding: <1%Contraindications
- Hypersensitivity to decitabine or any component of the formulation
- Patients with advanced malignant hepatic tumors
Warnings and Precautions
Hematologic toxicity: Severe neutropenia and thrombocytopenia are common; monitor blood counts regularly Fetal harm: Can cause fetal harm; advise women of reproductive potential to use effective contraception Nephrotoxicity: Use with caution in patients with renal impairment Hepatotoxicity: Monitor liver function tests; rare cases of hepatic failure reported Tumor lysis syndrome: May occur, particularly in patients with high tumor burden Pulmonary toxicity: Interstitial lung disease and pulmonary fibrosis reportedDrug Interactions
Cytidine deaminase inhibitors (e.g., tetrahydrouridine): May increase decitabine concentrations Live vaccines: Avoid concomitant use due to immunosuppression Other myelosuppressive agents: Enhanced myelosuppression Drugs affecting hepatic enzymes: Minimal interaction expected due to rapid deaminationAdverse Effects
Very common (>10%):- Neutropenia (90%)
- Thrombocytopenia (89%)
- Anemia (82%)
- Febrile neutropenia (30%)
- Nausea (42%)
- Constipation (39%)
- Pyrexia (35%)
- Fatigue (31%)
- Leukopenia
- Petechiae
- Diarrhea
- Vomiting
- Anorexia
- Headache
- Cough
- Hypokalemia
- Hyperglycemia
- Peripheral edema
- Rash
- Hepatic failure
- Interstitial lung disease
- Sepsis
- Arrhythmias
- Acute renal failure
Monitoring Parameters
Prior to each cycle:- Complete blood count with differential
- Liver function tests
- Renal function tests
- Electrolytes
- Monitor for infusion reactions
- Signs of infection
- Bleeding manifestations
- Hepatic function
- Pulmonary symptoms
- Response assessment per IWG criteria for MDS
- Secondary malignancies (theoretical risk)
Patient Education
- Report signs of infection immediately (fever, chills, sore throat)
- Watch for bleeding or bruising tendencies
- Use effective contraception during treatment and for at least 6 months after
- Avoid live vaccinations during treatment
- Maintain adequate hydration
- Report nausea, vomiting, or diarrhea that persists
- Inform all healthcare providers of decitabine use
- Regular follow-up appointments are essential
- Potential for fatigue; balance activity with rest
References
1. Kantarjian HM, O'Brien S, Cortes J, et al. Results of decitabine (5-aza-2'deoxycytidine) therapy in 130 patients with chronic myelogenous leukemia. Cancer. 2003;98(3):522-528. 2. Wijermans P, Lübbert M, Verhoef G, et al. Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. J Clin Oncol. 2000;18(5):956-962. 3. FDA Prescribing Information: Dacogen (decitabine). 2020. 4. Issa JP, Kantarjian HM. Targeting DNA methylation. Clin Cancer Res. 2009;15(12):3938-3946. 5. Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate- or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy: final results of the randomized phase III study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol. 2011;29(15):1987-1996. 6. National Comprehensive Cancer Network (NCCN) Guidelines: Myelodysplastic Syndromes. Version 2.2023.