Chlorambucil

Chlorambucil is an aromatic derivative of nitrogen mustard and a bifunctional alkylating agent. Its cytotoxic effect is due both to chlorambucil itself and to its main metabolite, phenylacetic acid mustard (PAAM). It is cell-cycle nonspecific.

Mechanism of Action

• Alkylation and cross-linking: chlorambucil attaches alkyl groups to DNA bases and cross-links DNA strands (DrugBank: guanine bases), so the strands cannot separate for replication or transcription. Mispairing of nucleotides can also lead to mutations.
• Apoptosis: besides interfering with DNA replication, it induces apoptosis through accumulation of cytosolic p53 and the subsequent activation of Bax, an apoptosis promoter.
• Active metabolite: PAAM has alkylating activity in animals and contributes to the cytotoxic effect.
• Resistance: resistance to nitrogen mustards has been linked to altered transport of these agents and their metabolites by multidrug-resistance proteins, altered kinetics of DNA cross-link formation, and changes in apoptosis and DNA repair. Chlorambucil is not a substrate of MRP1 (ABCC1), but its glutathione conjugates are substrates of MRP1 (ABCC1) and MRP2 (ABCC2).

Pharmacokinetics

• Absorption: well absorbed by passive diffusion in the gut and measurable within 15–30 minutes. Oral bioavailability is about 70–100% after single doses of 10–200 mg. In 12 patients given 0.2 mg/kg, peak plasma concentration was reached 0.25–2 hours after the dose, and variability between patients was relatively small. Food lowers absorption: in 10 patients it more than doubled the median time to peak, cut the peak concentration by over 50% and lowered the mean AUC by about 27%.
• Distribution: volume of distribution about 0.14–0.24 L/kg. Chlorambucil binds covalently to plasma proteins, mainly albumin (98%), and to red blood cells.
• Metabolism: extensive hepatic metabolism by mono-dichloroethylation and β-oxidation forms PAAM, the main metabolite. Chlorambucil and PAAM degrade in vivo to monohydroxy and dihydroxy derivatives, and chlorambucil reacts with glutathione to form mono- and diglutathionyl conjugates. After about 0.2 mg/kg by mouth, PAAM appeared in the plasma of some patients at 15 minutes and peaked within 1–3 hours.
• Elimination: terminal half-life 1.3–1.5 hours for chlorambucil and about 1.8 hours for PAAM. Renal excretion of unchanged drug is very low: less than 1% of the dose of each is found in urine within 24 hours, and the rest is eliminated mainly as monohydroxy and dihydroxy derivatives.
• Special populations: no formal studies of renal impairment have been done; because urinary excretion is extremely low, the kidney is not an important route of elimination.

The indications follow the Spanish SmPC of Clorambucilo Aspen 2 mg film-coated tablets. Chlorambucil is indicated for the treatment of:

• Hodgkin’s disease.
• Non-Hodgkin lymphoma: certain forms.
• Chronic lymphocytic leukaemia.
• Waldenström’s macroglobulinaemia.

• Use in patients with non-malignant diseases.
• Hypersensitivity to chlorambucil or to any of the excipients.

The SmPC notes that current clinical documentation is lacking to determine exact frequencies, which may vary with the dose and with combination treatment. The frequency groups below follow its table.

Very common (≥1/10): leucopenia, neutropenia, thrombocytopenia, pancytopenia or bone marrow suppression (usually reversible if chlorambucil is stopped in time).

Common (≥1/100 to <1/10): acute secondary haematological malignancies (especially leukaemia and myelodysplastic syndrome), particularly after long-term treatment; anaemia; seizures in children with nephrotic syndrome; gastrointestinal disorders such as nausea, vomiting, diarrhoea and mouth ulceration.

Uncommon (≥1/1,000 to <1/100): rash.

Rare (≥1/10,000 to <1/1,000): hypersensitivity such as urticaria or angioneurotic oedema after the first or later doses; seizures (focal and/or generalised) in children and adults on therapeutic daily doses or high-pulse regimens, to which patients with a history of seizure disorder may be especially susceptible; hepatotoxicity, jaundice; Stevens-Johnson syndrome and toxic epidermal necrolysis (a rash that progresses to severe disease); pyrexia.

Very rare (<1/10,000): irreversible bone marrow failure; movement disorders such as tremor, muscle twitching and myoclonus without convulsions; peripheral neuropathy; interstitial pulmonary fibrosis and interstitial pneumonia; sterile cystitis.

Not known: amenorrhoea, azoospermia.

Severe interstitial pulmonary fibrosis has been reported occasionally in patients with chronic lymphocytic leukaemia on prolonged treatment; it may reverse when chlorambucil is stopped.

• Live vaccines: not recommended in immunosuppressed patients, because immunisation can cause infection.
• Purine nucleoside analogues (fludarabine, pentostatin, cladribine): they increase the cytotoxicity of chlorambucil ex vivo. Combining them with alkylating agents has given high disease response rates in the clinic, but also higher rates of haematological toxicity.
• Phenylbutazone: animal studies indicate that patients taking it may need a lower standard dose of chlorambucil because its toxicity may increase.
• Food: taken on an empty stomach, because food lowers bioavailability. DrugBank advises avoiding echinacea (to be used with caution, if at all, in patients on immunosuppressive therapy) and drinking plenty of fluids.

Chlorambucil is an active cytotoxic medicine. It is given only under the supervision of a specialised oncology service with facilities for regular monitoring of the clinical biochemical and haematological effects during and after treatment. The SmPC refers to the relevant literature for the detailed treatment regimens. The tablets are taken by mouth on an empty stomach, at least one hour before or three hours after meals, because a high gastric pH significantly lowers bioavailability.

Hodgkin’s Disease

As a single agent for palliative treatment of advanced disease, the usual dose is 0.1–0.2 mg/kg daily for 4–8 weeks. It is usually used in combination therapy, with various regimens, and has been used as an alternative to nitrogen mustard with lower toxicity but similar results.

Non-Hodgkin Lymphoma

As a single agent, the recommended initial dose is 0.1–0.2 mg/kg daily for 4–8 weeks, followed by maintenance with a lower daily dose or intermittent courses. It is useful in diffuse lymphocytic lymphoma and in patients who relapse after radiotherapy. In advanced lymphocytic non-Hodgkin lymphoma there were no significant differences in overall response rate between single-agent and combination therapy.

Chronic Lymphocytic Leukaemia

• Treatment usually starts once symptoms develop or the blood count shows impaired bone marrow function (but not marrow failure).
• The initial dose is 0.15 mg/kg daily until the total leucocyte count has fallen to 10,000 per µL. Treatment may be resumed four weeks after the end of the first course at 0.1 mg/kg daily.
• In some patients, usually after two years, the leucocyte count returns to normal, enlarged spleen and lymph nodes can no longer be felt and lymphocytes in the bone marrow fall below 20%.
• Patients with bone marrow failure are first treated with prednisolone, and chlorambucil is not started until the marrow shows signs of regeneration.
• High-dose intermittent and daily dosing did not differ significantly in response or in the frequency of side effects.

Waldenström’s Macroglobulinaemia

Chlorambucil is one of the treatments of choice. The recommended starting dose is 6–12 mg daily until leucopenia appears, then 2–8 mg daily indefinitely.

Special Populations

• Renal impairment: no dose adjustment is considered necessary, although formal studies have not been done.
• Hepatic impairment: patients are monitored closely for signs of toxicity. Because chlorambucil is metabolised mainly in the liver, a dose reduction should be considered in severe impairment, but there are not enough data for a specific recommendation.
• Children: chlorambucil may be used for Hodgkin’s disease and non-Hodgkin lymphoma in children, with regimens similar to those in adults.
• Elderly: no specific studies. Renal and hepatic function should be monitored with caution in significant impairment, and treatment usually starts at the low end of the dose range.

Bone Marrow Suppression

Chlorambucil can cause irreversible bone marrow suppression, so blood counts are done frequently. A total dose in the region of 6.5 mg/kg is associated with a risk of irreversible marrow damage. At therapeutic doses it lowers lymphocytes, with less effect on neutrophils, platelets and haemoglobin. The drug need not be stopped at the first fall in neutrophils, but the fall can continue for 10 days or more after the last dose. It should not be given to patients who have recently had radiotherapy or other cytotoxic agents, and is used with caution only in patients with depressed bone marrow function or lymphocytic infiltration of the marrow. With lymphocytic infiltration or hypoplastic marrow, the daily dose should not exceed 0.1 mg/kg.

Vaccines and Stem Cell Transplantation

Live vaccines are not recommended in immunosuppressed patients. Patients who may undergo autologous stem cell transplantation should not receive long-term chlorambucil.

Seizure Risk

Children with nephrotic syndrome, patients on high-pulse regimens and patients with a history of seizure disorders may be at increased risk of seizures and are closely monitored after each dose.

Mutagenicity, Carcinogenicity and Secondary Malignancies

Chlorambucil has damaged chromatids and chromosomes in humans and is carcinogenic in animals. Secondary malignancies, usually acute haematological ones (mainly leukaemia and myelodysplastic syndrome), have been reported, especially after long-term treatment. In ovarian cancer, alkylating agents including chlorambucil significantly raised the incidence of acute leukaemia, and acute myeloid leukaemia has been reported in a small percentage of patients given chlorambucil as long-term adjuvant treatment for breast cancer. The leukaemogenic risk is weighed against the potential therapeutic benefit.

Safe Handling

The SmPC refers to its section 6.6 for the safe handling of this cytotoxic medicine.

Lactose

Each tablet contains 67.65 mg of lactose. Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take it.

Pregnancy, Breastfeeding and Fertility

• Contraception: as with all cytotoxic chemotherapy, adequate contraceptive precautions are recommended when either partner is taking chlorambucil, and the couple should be told that it affects germ cells.
• Pregnancy: avoid during pregnancy, especially the first trimester, unless the physician considers it absolutely essential. Like other cytotoxic agents it is potentially teratogenic.
• Breastfeeding: mothers receiving it must not breastfeed.
• Fertility: ovarian suppression and amenorrhoea have been reported. Azoospermia has been seen, with a total dose of at least 400 mg estimated to be necessary; varying recovery of spermatogenesis was seen in lymphoma patients after total doses of 410–2,600 mg.

Effect on Driving

No information is available on the effect of chlorambucil on the ability to drive and use machines.

Store in a refrigerator at 2–8 °C in the original container. Because the tablets must stay refrigerated, the cold chain applies from dispatch to the patient or clinic. They come in amber glass bottles (type III) with a child-resistant polyethylene closure, holding 25 or 50 tablets; not all pack sizes may be marketed.

3 years.

Prescription only (Rx), for use under the supervision of a specialised oncology service. The tablets are taken at home, so they are supplied to the patient or to the treating clinic on prescription, with cold-chain delivery because they are stored at 2–8 °C.