Decitabine

Approved Indications:

• Myelodysplastic Syndromes (MDS):
• Including all French-American-British (FAB) subtypes (RA, RARS, RAEB, RAEB-T, CMML) and intermediate-1, intermediate-2, and high-risk groups per International Prognostic Scoring System (IPSS).
• Acute Myeloid Leukemia (AML):
• In adults aged ≥65 years who are not candidates for standard induction chemotherapy.
• Also approved for newly diagnosed de novo or secondary AML.

Clinically Accepted Off-label Uses:

• Chronic Myelomonocytic Leukemia (CMML):
• Used due to overlap with MDS.
• Maintenance Therapy Post-Remission in AML:
• For patients who cannot tolerate intensive consolidation.
• Acute Lymphoblastic Leukemia (ALL):
• Investigational use in combination protocols to induce epigenetic priming.

Route:

• Intravenous infusion only.

Adults – MDS and AML:

• Standard Regimen (5-Day):
• 20 mg/m² IV over 1 hour once daily for 5 consecutive days, repeated every 4 weeks.
• Alternative Regimen (10-Day):
• 20 mg/m² IV daily for 10 consecutive days every 4 weeks (often used in AML with high blast burden).

Treatment Duration:

• A minimum of 4–6 cycles is recommended for response evaluation. Continue as long as benefit is observed without unacceptable toxicity.

Pediatrics:

• Limited data; used in clinical trials and compassionate use settings for MDS/AML. Dosing individualized.

Renal Impairment:

• No formal adjustment guidelines, but use with caution. Monitor for toxicity.

Hepatic Impairment:

• Use with caution; limited data. Monitor liver function.

Elderly:

• No dose adjustment needed; safe and effective in older patients.

Decitabine is a hypomethylating agent that incorporates into DNA and inhibits DNA methyltransferase enzymes. This results in the hypomethylation of DNA, particularly at promoter regions of tumor suppressor genes, leading to their reactivation and subsequent regulation of cell cycle and differentiation. At higher concentrations, it may also exert direct cytotoxic effects via disruption of DNA synthesis, causing DNA damage and apoptosis, especially in rapidly dividing malignant hematopoietic cells.

Absorption:

• Not orally bioavailable due to degradation by cytidine deaminase; administered IV.

Distribution:

• Volume of distribution: ~116 L
• Protein binding: <5%

Metabolism:

• Primarily metabolized by cytidine deaminase (mainly in the liver and blood).

Elimination:

• Half-life: 15–30 minutes (terminal)
• Clearance: ~298 L/hour
• Primarily excreted via urine (~90% as metabolites and unchanged drug)

• Pregnancy:
• FDA Category D. Teratogenic in animal studies. Use only if clearly needed and benefits outweigh risks. Effective contraception required during treatment and for 6 months after (females) or 3 months after (males).
• Lactation:
• Unknown if excreted in breast milk. Breastfeeding is not recommended during treatment and for at least 2 weeks after the final dose.

• Primary Class: Antineoplastic agent
• Subclass: DNA hypomethylating agent (pyrimidine analog)

• Known hypersensitivity to decitabine or any excipients
• Pregnancy (unless absolutely necessary due to teratogenic risk)
• Severe hepatic dysfunction (use caution; limited data)
• Active, uncontrolled infection (postpone therapy until resolved)

• Myelosuppression:
• Neutropenia, thrombocytopenia, and anemia are common. Monitor CBC regularly and delay or reduce dose if necessary.
• Infections:
• High risk due to neutropenia. Monitor for febrile neutropenia; initiate broad-spectrum antibiotics when needed.
• Bleeding Risk:
• Thrombocytopenia may cause bleeding complications; monitor platelet counts.
• Hepatotoxicity:
• Elevated liver enzymes may occur; monitor LFTs.
• Renal Toxicity:
• Use with caution in renal impairment; monitor renal function during treatment.
• Embryo-fetal toxicity:
• Avoid during pregnancy; ensure contraception in men and women of reproductive age.

Hematologic (Very Common):

• Neutropenia
• Thrombocytopenia
• Anemia
• Febrile neutropenia

Gastrointestinal:

• Nausea, vomiting
• Diarrhea
• Constipation
• Mucositis

General/Systemic:

• Fatigue
• Pyrexia
• Edema
• Dyspnea

Infections:

• Pneumonia
• Sepsis
• Urinary tract infection

Hepatic:

• Elevated ALT/AST
• Hyperbilirubinemia

Rare/Serious:

• Hypersensitivity reactions
• Tumor lysis syndrome
• Disseminated intravascular coagulation (DIC)

• Cytidine Deaminase Inhibitors (e.g., tetrahydrouridine):
• May alter metabolism of decitabine; experimental.
• Live Vaccines:
• Avoid due to immunosuppression and risk of infection.
• Other Myelosuppressive Agents:
• Increased risk of additive bone marrow suppression.
• No major CYP450 interactions reported, as decitabine is not metabolized by these enzymes.

• NCCN and ELN 2023–2024:
• Decitabine continues to be a frontline agent for older adults with AML ineligible for intensive chemotherapy, often in combination with venetoclax.
• Also recommended in MDS treatment for higher-risk disease, especially when transplantation is not an option.
• Combination Therapies:
• Increasing use in AML/MDS with BCL-2 inhibitors (e.g., venetoclax) and IDH inhibitors under guideline-directed therapy.
• FDA Update:
• Approval of fixed-dose combination product: Decitabine + Cedazuridine (oral hypomethylating therapy) for MDS and CMML.

• Decitabine for Injection (lyophilized powder):
• Store vials at 2°C to 8°C (36°F to 46°F); protect from light.
• Reconstituted solution (with sterile water):
• Stable for 3 hours at room temperature or up to 24 hours under refrigeration.
• Final diluted solution (in infusion bag):
• Use within 3 hours at room temperature or within 24 hours refrigerated.

Handling Precautions:

• Cytotoxic agent: Use gloves, gown, and protective equipment during preparation and administration.
• Dispose of unused drug and materials as per cytotoxic waste protocol.