chlorambucil

Chlorambucil is an anticancer drug belonging to the class of alkylating agents.

Chlorambucil - Chemical Structure

It is marketed worldwide under the trade name Leukeran ®.

Indications

For what it uses

Chlorambucil is used in the treatment of:

Chronic lymphocytic leukemia;
Hodgkin's disease;
Non-Hodgkin's lymphoma;
Advanced ovarian adenocarcinoma;
Waldenström's macroglobulinemia.

Warnings

Since chlorambucil is a cytotoxic agent, it must be administered under the strict control of a doctor who specializes in the administration of anticancer chemotherapy drugs.

Due to the side effects that chlorambucil can cause, careful monitoring of blood counts is necessary in patients being treated with the drug.

Chlorambucil should not be given to patients recently treated with radiotherapy or who have taken other cytotoxic drugs (toxic to cells).

Patients with a history of seizure disorders should be carefully monitored following the administration of chlorambucil, as the drug increases the risk of seizures.

Prolonged exposure to the sun during chlorambucil treatment is not recommended; in case of exposure it is good to use sunscreen with a high protection index.

Interactions

Vaccination of patients taking chlorambucil with live attenuated virus vaccines is not recommended. Chlorambucil causes a reduction in the production of white blood cells, thus seriously compromising the immune system by preventing the patient from adequately responding to the vaccine. In fact, in immunocompromised patients, the administration of live virus vaccines can cause infections due to an increase in viral replication.

Side effects

The side effects triggered by chlorambucil are many and depend on the amount of drug administered, on the possible administration in association with other anticancer agents and on the patient's condition. Furthermore, there is a great variability in response to individual-to-individual therapy, both as regards the type and the degree of intensity with which the adverse effects occur.

Mutagenesis and carcinogenesis

Chlorambucil treatment has been shown to lead to mutations in the chromosomes.

Chlorambucil is also a leukemogen and can cause the onset of secondary leukemia. It seems that patients treated with alkylating agents - including chlorambucil - are at greater risk of developing acute leukemia than those treated with other classes of anticancer drugs.

In some patients - subjected to long-term treatment with chlorambucil as adjuvant therapy for breast cancer - the occurrence of an acute myelogenous leukemia occurred.

Myelosuppression

Chlorambucil may cause bone marrow suppression ( myelosuppression ). This suppression results in reduced blood cell synthesis ( reduced hematopoiesis ). The decrease in blood cell production can lead to:

Anemia (reduced amount of hemoglobin in the blood);
Leukopenia (reduced number of white blood cells) with consequent increased susceptibility to contraction of infections ;
Plateletopenia (reduced number of platelets) with bruising, abnormal bleeding and an increased risk of bleeding .

Myelosuppression is usually a reversible side effect; provided the therapy is stopped in good time.

Irreversible medullary aplasia

Medullary aplasia (or aplastic anemia ) is a bone marrow disease that causes a reduction in the production of all blood cells ( pancytopenia ). Unlike myelosuppression, this side effect is irreversible, but occurs very rarely.

Allergic reactions

Following the administration of chlorambucile, allergic reactions can occur that occur in the form of hives, skin rash and / or angioedema (rapid swelling of the skin, mucous membranes and subcutaneous tissues).

In rare cases, skin rash progression may occur up to severe conditions such as Stevens-Johnson syndrome (a more severe variant of polymorphous erythema) and toxic epidermal necrolysis (severe skin disease in which the epidermis detaches into laminae) ).

Nervous system disorders

Convulsions may occur in adults and children treated with high doses of chlorambucil and in children with nephrotic syndrome.

Patients with a history of seizure disorders may be particularly susceptible to the onset of this symptom.

Respiratory system disorders

Following treatment with chlorambucil, interstitial pulmonary fibrosis and interstitial pneumonia may occur. These side effects could regress after discontinuation of therapy.

Gastrointestinal disorders

Chlorambucil therapy can cause nausea, vomiting and diarrhea .

Vomiting can be controlled with the use of antivomite drugs, while diarrhea is controlled by anti-diarrheal drugs. However, it is important to drink a lot to replenish lost fluids.

Hepatobiliary disorders

Chlorambucil treatment can lead to hepatitis and jaundice .

Renal disorders

Although rarely, the intake of chlorambucil can lead to the appearance of abnormal cystitis .

Sterility

Chlorambucil can cause suppression of ovarian function and amenorrhea (interruption of the menstrual cycle).

Cases of azoospermia have occurred in some male patients - following chlorambucil therapy.

Other side effects

Another side effect that may arise following the administration of chlorambucile is drug fever ; however, this is a very rare symptom.

Overdose

The symptoms of chlorambucil overdose are pancytopenia and neurological toxicity with the appearance of convulsions and ataxia (loss of muscle coordination). There is no antidote for overdosing; however, blood transfusions may be useful.

Action mechanism

Chlorambucil is an alkylating agent capable of interlayer (i.e. inserting) alkyl groups into the double strand of DNA through the formation of very strong bonds that are difficult to break (covalent bonds). The alteration that chlorambucil induces in DNA prevents the cancer cell from dividing and condemns it to undergo apoptosis (a process of programmed cell death).

Mode of Use - Posology

Chlorambucil is available for oral administration in the form of brown tablets. The tablets should be taken without chewing and generally on an empty stomach (one hour before meals or three hours after meals).

The doses administered vary according to the type of tumor to be treated, the condition of the patient and depending on the administration of the drug in association or not with other anticancer agents.

Hodgkin's disease

Chlorambucil can be used as the only drug in the palliative treatment of advanced Hodgkin's disease. The usual dose in adults is 0.2 mg / kg of body weight per day, for a period of 4-8 weeks.

When used in combination with other anticancer drugs, however, different dosages can be used which are determined by the oncologist.

Doses for the treatment of Hodgkin's disease in children are similar to those used for adults.

Non-Hodgkin's lymphomas

In the treatment of non-Hodgkin's lymphomas the usual dose of chlorambucil - when used alone - is 0.1-0.2 mg / kg of body weight per day, for a period of 4-8 weeks.

The dosage for children is similar to that used for adults.

Chronic lymphocytic leukemia

The starting dose of chlorambucil for the treatment of this disease in adults is usually 0.15 mg / kg of body weight per day. Subsequently, the usual adopted maintenance dose is 0.1 mg / kg of body weight per day.

Waldenström's macroglobulinemia

Chlorambucil is the first choice treatment for this condition. The initial doses used, usually, are 6-12 mg of drug per day, until there is the appearance of leukopenia; after that, the dose is adjusted to 2-8 mg of drug per day.

In patients with renal insufficiency it is not considered necessary to adjust the chlorambucil dosage to be administered.

In patients with liver failure, however, there must be a careful and constant monitoring of liver function. Since chlorambucil is mainly metabolised in the liver, in patients with severe hepatic impairment, the possibility of reducing the dose of the drug administered should be considered.

Pregnancy and breastfeeding

Chlorambucil is believed to be teratogenic, therefore - whenever possible - its use during pregnancy should be avoided, especially during the first trimester.

It is the duty of the oncologist to evaluate - case by case - the risk-benefit ratio that comes from taking the drug, both for the fetus and for the mother.

Mothers treated with chlorambucil should not breast-feed.