Chlorambucil
Chlorambucil is an alkylating agent belonging to the nitrogen mustard class and primarily used in chemotherapy for treating various cancers and autoimmune disorders. It works by forming covalent bonds with DNA, leading to DNA damage that is especially lethal to rapidly dividing cells, such as cancer cells. Despite being considered one of the least toxic nitrogen mustard derivatives, chlorambucil is classified as a known human carcinogen since 1981, with significant evidence linking its use to an increased risk of developing acute myeloid leukemia (AML), particularly when combined with other treatments like radiotherapy.
Patients receiving chlorambucil may experience severe side effects, and those at higher risk include individuals undergoing prolonged treatment. The drug is available in sugar-coated tablets and can be administered through various exposure routes, including inhalation and dermal contact. While its use has been prevalent since the 1960s, ongoing discussions between patients and healthcare providers about the risks and benefits of chlorambucil are essential, particularly as new cancer therapies continue to emerge. Awareness of its carcinogenic potential is critical for informed decision-making regarding cancer treatment options.
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Chlorambucil
ROC STATUS: Known human carcinogen since 1981
ALSO KNOWN AS: Leukeran, chloraminophene, Ambochlorin, Ecloril, Linfolysin
RELATED CANCERS: Acute myeloid leukemia (AML), acute nonlymphocytic leukemia (ANLL)
DEFINITION: Chlorambucil is an alkylating agent of the nitrogen mustard class. As with other agents in this class, chlorambucil undergoes chemical activation of the aziridinium ion, which reacts with deoxyribonucleic acid (DNA) to form a covalent bond. This alkylation damages DNA and leaves it more prone to breakage. When taken up by rapidly dividing cells (such as cancer cells), damaged DNA is unable to repair itself quickly, leading to cell death.
Exposure routes: Inhalation, ingestion, dermal contact
Where found: Chemically synthesized; provided as a treatment to people with cancer or autoimmune disorders as sugar-coated two-milligram tablets
At risk: Patients receiving chlorambucil for the treatment of cancer or autoimmune disorder; occupational exposure via skin contact or dust inhalation during pharmaceutical processing
Etiology and symptoms of associated cancers: Acute myeloid (or nonlymphocytic) leukemia is a malignancy of blood in which myeloid precursor cells do not mature. These immature cells proliferate rapidly without normal maturation into granulocytes and monocytes. Early signs and symptoms are similar to those of influenza and include fever, weakness, fatigue, loss of appetite, and pain in the bones and joints. Infections, delayed healing of minor cuts, and unusual bruising or bleeding may occur.
AML may occur at any age, but it typically occurs in adults sixty and over, with an average age of sixty-eight. Prognosis varies by age. Overall, around two-thirds of patients achieve complete remission, with more than 25 percent of them achieving three-year survival. Children and adults older than the age of sixty are less likely to achieve complete remission.
Alkylating agents such as chlorambucil increase the risk of acute myeloid leukemia, as does exposure to radiation and chemicals such as benzene.
History: Chlorambucil has been used in chemotherapy since the 1960s, often for long durations. Although it is considered to be the least toxic nitrogen mustard derivative in use, sufficient evidence for carcinogenicity in animals and humans exists. Anecdotal evidence of carcinogenicity has been reported by the International Agency for Research on Cancer (IARC) since the early 1980s. In most case reports, patients were also receiving radiotherapy or other potential carcinogens. A randomized trial conducted in the 1980s in patients with polycythemia vera showed a thirteenfold increase in the incidence of AML in patients receiving chlorambucil. The risk of developing acute leukemia increased with the dose and length of treatment. Although new cancer treatments are constantly being developed and other options for chemotherapy exist, chlorambucil continued to be used in the mid-2020s as its benefits in treating certain cancers outweighed its potential risks of developing secondary cancers. Further, several chemotherapy drugs in use held long-term risks of developing secondary cancers. It is essential for patients and their medical team to have open discussions to determine what treatment method makes the most sense.
Bibliography
“Chlorambucil (Leukeran) Tablets: Uses & Side Effects.” Cleveland Clinic, clevelandclinic.org/health/drugs/20312-chlorambucil-tablets. Accessed 21 June 2024.
“15th Report on Carcinogens.” National Toxicology Program, 21 Dec. 2021, ntp.niehs.nih.gov/whatwestudy/assessments/cancer/roc. Accessed 21 June 2024.
Selchick, Faith. “Acute Myeloid Leukemia (AML): Survival Rates and Outlook.” Healthline, 23 Jan. 2023, www.healthline.com/health/acute-myeloid-leukemia-survival-rates-outlook. Accessed 21 June 2024.
"Treatment Response Rates for Acute Myeloid Leukemia (AML)." American Cancer Society, 6 June 2024, www.cancer.org/cancer/types/acute-myeloid-leukemia/treating/response-rates.html. Accessed 21 June 2024.
“What Is Acute Myeloid Leukemia (AML)? - What Is AML?” American Cancer Society, 21 Aug. 2018, www.cancer.org/cancer/types/acute-myeloid-leukemia/about/what-is-aml.html. Accessed 21 June 2024.