Leukeran - Drug Monograph

Introduction

Leukeran (chlorambucil) is an oral alkylating agent belonging to the nitrogen mustard family that has been used in clinical practice for over six decades. As a chemotherapy medication, it plays a significant role in the management of various hematologic malignancies. Its oral formulation and generally favorable toxicity profile make it particularly valuable for both induction therapy and maintenance treatment in appropriate patient populations.

Mechanism of Action

Chlorambucil functions as a bifunctional alkylating agent that exerts its cytotoxic effects through covalent bonding with DNA molecules. The drug forms highly reactive ethylenimonium intermediates that cross-link DNA strands, primarily at the N-7 position of guanine residues. This cross-linking interferes with DNA replication and transcription, ultimately leading to apoptosis of rapidly dividing cells, particularly lymphocytes. As a cell cycle non-specific agent, Leukeran is active throughout all phases of the cell cycle but demonstrates greatest efficacy against cells in G1 and S phases.

Indications

FDA-approved indications:

• Chronic lymphocytic leukemia (CLL)
• Hodgkin lymphoma (as secondary therapy)
• Non-Hodgkin lymphomas (particularly follicular lymphoma)

Off-label uses (supported by clinical evidence):

• Waldenström's macroglobulinemia
• Nephrotic syndrome in children (steroid-dependent or frequently relapsing)
• Autoimmune conditions requiring cytotoxic therapy (e.g., rheumatoid arthritis, vasculitis)

Dosage and Administration

• CLL: 0.1 mg/kg/day to 0.2 mg/kg/day (approximately 4-8 mg/day) for 3-6 weeks
• Lymphomas: 0.1 mg/kg/day to 0.2 mg/kg/day continuously or 0.4 mg/kg to 1.4 mg/kg intermittently

• Oral administration, typically as a single daily dose
• Should be taken on an empty stomach (1 hour before or 2 hours after meals)
• Tablets should not be crushed or broken

• Renal impairment: Dose reduction required (25-50% reduction for CrCl <50 mL/min)
• Hepatic impairment: Use with caution; consider dose reduction
• Elderly: Start at lower end of dosing range due to increased susceptibility to myelosuppression
• Pediatrics: Limited data; use only when benefits outweigh risks

Pharmacokinetics

Contraindications

• Hypersensitivity to chlorambucil or other alkylating agents
• Patients who have demonstrated resistance to previous chlorambucil therapy
• Pregnancy (Category D) and breastfeeding
• Severe bone marrow suppression prior to initiation
• Active infection not adequately controlled

Warnings and Precautions

• Myelosuppression: Can cause severe bone marrow suppression, including anemia, leukopenia, thrombocytopenia, and pancytopenia
• Carcinogenicity: Secondary malignancies, including acute leukemias, have been reported
• Infertility: Can cause irreversible infertility in both males and females

• Seizure risk: Higher incidence in patients receiving high doses (>20 mg/day)
• Hepatic toxicity: Monitor liver function regularly
• Pulmonary fibrosis: Rare but potentially fatal complication
• Skin reactions: Severe dermatological reactions including Stevens-Johnson syndrome
• Vaccination: Avoid live vaccines during treatment

Drug Interactions

• Myelosuppressive agents (other chemotherapy, azathioprine): Enhanced bone marrow toxicity
• Live vaccines: Increased risk of vaccine-related infections
• Allopurinol: May increase risk of bone marrow suppression
• Warfarin: Chlorambucil may enhance anticoagulant effect

• CYP450 inducers (phenobarbital, rifampin): May decrease chlorambucil efficacy
• CYP450 inhibitors (fluconazole, cimetidine): May increase chlorambucil toxicity
• Nephrotoxic drugs: May reduce clearance of chlorambucil metabolites

Adverse Effects

• Bone marrow suppression (leukopenia, thrombocytopenia, anemia)
• Nausea/vomiting (mild to moderate)
• Fatigue
• Diarrhea
• Skin rash

• Severe myelosuppression
• Secondary malignancies
• Pulmonary fibrosis
• Seizures (with high doses)
• Hepatotoxicity
• Allergic reactions
• Infertility
• Amenorrhea/azoospermia

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including LFTs, renal function)
• Pregnancy test in women of childbearing potential

• CBC weekly initially, then every 2-4 weeks once stable
• LFTs monthly for first 3 months, then as clinically indicated
• Renal function periodically
• Signs/symptoms of infection
• Pulmonary function tests if respiratory symptoms develop

• Annual screening for secondary malignancies
• Fertility counseling when appropriate
• Periodic assessment of renal and hepatic function

Patient Education

• Take exactly as prescribed; do not adjust dose without medical supervision
• Report signs of infection (fever, chills, sore throat) immediately
• Use effective contraception during and for at least 6 months after treatment
• Avoid contact with people who have recent live vaccinations
• Report unusual bleeding, bruising, or fatigue
• Maintain adequate hydration
• Regular blood tests are essential for safety monitoring
• Do not crush or break tablets
• Store medication properly and keep out of reach of children

• Practice good hygiene to prevent infections
• Consider sperm banking/egg preservation before treatment if future fertility desired
• Avoid alcohol due to increased hepatotoxicity risk
• Use sun protection due to photosensitivity risk

References

1. National Cancer Institute. Chlorambucil - Professional Version. Accessed 2023. 2. Leukemia & Lymphoma Society. Chronic Lymphocytic Leukemia Treatment Guidelines. 2022. 3. Cheson BD, et al. Guidelines for Diagnosis and Treatment of Chronic Lymphocytic Leukemia. Blood. 2018;132(5):439-456. 4. McKeage K, et al. Chlorambucil: A Review of its Use in the Management of Chronic Lymphocytic Leukaemia. Drugs. 2015;75(5):495-511. 5. FDA Prescribing Information: Leukeran (chlorambucil). Revised 2022. 6. Hallek M, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. 7. American Society of Clinical Oncology. Management of CLL Clinical Practice Guideline. JCO. 2018;36(5):492-516.