Alkylating Agents

Alkylating agents add alkyl groups to DNA, forming cross-links and strand breaks that block replication and trigger apoptosis. They are active in all phases of the cell cycle and form the backbone of many regimens for lymphoma, myeloma, sarcoma, brain tumour and leukaemia.

Classification. Nitrogen mustards (cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine), alkyl sulphonates (busulfan), nitrosoureas (carmustine, lomustine), triazines (dacarbazine, temozolomide), and procarbazine.

Pharmacokinetics. Cyclophosphamide and ifosfamide are prodrugs activated by CYP2B6 and CYP3A4; their metabolite acrolein damages the bladder. Temozolomide and lomustine cross the blood-brain barrier.

• Cyclophosphamide 500 to 1,000 mg/m2 intravenously every 3 weeks; 50 to 100 mg orally daily for maintenance; 750 mg/m2 in a multi-drug lymphoma regimen.
• Ifosfamide 1.2 to 2 g/m2 daily for 3 to 5 days with mesna at 60 to 100 percent of the ifosfamide dose and hydration.
• Melphalan 8 to 10 mg/m2 orally daily for 4 days (myeloma); 140 to 200 mg/m2 intravenously for autologous transplant.
• Chlorambucil 0.1 to 0.2 mg/kg orally daily.
• Busulfan 0.8 mg/kg intravenously every 6 hours for 4 days in conditioning.
• Bendamustine 70 to 120 mg/m2 on days 1 and 2 every 28 days.
• Temozolomide 75 mg/m2 daily with radiotherapy, then 150 to 200 mg/m2 on days 1 to 5 every 28 days.
• Lomustine 100 to 130 mg/m2 orally every 6 weeks.
• Dacarbazine 250 mg/m2 on days 1 to 5 or 375 mg/m2 on days 1 and 15.

Differences. Cyclophosphamide and ifosfamide need bladder protection. Nitrosoureas cause delayed, cumulative marrow suppression. Busulfan causes seizures at high dose and veno-occlusive disease. Dacarbazine and temozolomide are less myelosuppressive.

• Lymphoma, leukaemia and myeloma: cyclophosphamide, chlorambucil, melphalan and bendamustine.
• Sarcoma and germ cell tumours: ifosfamide.
• Glioma: temozolomide and lomustine.
• Melanoma and Hodgkin lymphoma: dacarbazine.
• Autoimmune disease: low-dose cyclophosphamide is also used by rheumatologists.
• Bladder protection: give 2 to 3 litres of oral or intravenous fluid daily and void often; add mesna with ifosfamide and with cyclophosphamide above 1.5 g/m2.

Selection. Choose by tumour type; avoid prolonged use in young patients who wish to keep fertility; plan sperm or ovarian tissue preservation.

Contraindications. Pregnancy in the first trimester, active cystitis, and severe marrow failure. Ifosfamide in severe kidney impairment.

Adverse effects. Myelosuppression, nausea and vomiting, alopecia, haemorrhagic cystitis, infertility and premature ovarian failure, secondary acute myeloid leukaemia (melphalan, chlorambucil, etoposide combinations), encephalopathy and Fanconi syndrome (ifosfamide), pulmonary fibrosis (busulfan, carmustine), veno-occlusive disease (busulfan, melphalan, dacarbazine).

Interactions. Allopurinol and thiazides increase cyclophosphamide marrow toxicity; phenytoin and rifampicin increase prodrug activation; azole antifungals interact with busulfan; lomustine with alcohol and sedatives.

Special groups.

• Pregnancy: avoid; teratogenic.
• Breastfeeding: avoid.
• Children: ifosfamide and cyclophosphamide are used with weight- and surface-area-based dosing.
• Older adults: reduce chlorambucil and melphalan dose.
• Kidney impairment: reduce cyclophosphamide at creatinine clearance under 30 mL/min, and avoid ifosfamide; reduce melphalan.
• Liver impairment: caution with all.

Monitoring. Full blood count weekly during treatment and at the nadir, urinalysis for blood, creatinine and electrolytes, liver function, pulmonary function for nitrosoureas and busulfan, and lifetime cumulative alkylator dose.

Referral and escalation. Visible haematuria, confusion on ifosfamide, jaundice with weight gain and hepatomegaly, or fever with neutropenia need urgent care.