Chlorambucil is an orally administered alkylating agent which is currently used in the therapy of chronic lymphocytic leukemia, Hodgkin and non-Hodgkin lymphomas, and rarely in severe autoimmune conditions including rheumatoid arthritis, uveitis and nephrotic syndrome. Chlorambucil therapy has been associated with low rates of serum enzyme elevations during therapy and to rare instances of acute, clinically apparent injury.
Chlorambucil (klor am' bue sil) is an orally available, alkylating agent similar to mechlorethamine, cyclophosphamide and melphalan (nitrogen mustard-like). The alkylating agents act by causing modification and cross linking of DNA, thus inhibiting DNA, RNA and protein synthesis and causing cell death in rapidly dividing cells. Alkylating agents also have immunosuppressive activity, and chlorambucil has also been used in the therapy of autoimmune diseases and allograft rejection. Chlorambucil was approved for use in the United States in 1957. Current major indications include Hodgkin and non-Hodgkin lymphomas, chronic lymphocytic leukemia and lymphosarcoma. Chlorambucil has also been used for macroglobulinemia, polycythemia vera, rheumatoid arthritis, autoimmune uveitis and minimal change nephrotic syndrome, but its link to development of leukemia and secondary cancers has led to recommendations that its use be restricted to malignant conditions. Chlorambucil is available as Leukeran in tablets of 2 mg, and the usual dose ranges from 2 to 10 mg daily, often being given long term. Chlorambucil is generally well tolerated, and flexible dosing allows for dose adjustment to minimize side effects. Chlorambucil shares common side effects with other alkylating agents such as nausea, vomiting, diarrhea, alopecia, oral ulcers, bone marrow suppression, hypersensitivity reactions and rash. Long term therapy may be associated with an increased rate of acute myelocytic leukemia, interstitial pneumonitis and pulmonary fibrosis. Acute hypersensitivity reactions are rare but can include drug fever, angioedema, erythema multiforme, and Stevens Johnson syndrome.
Chlorambucil therapy is associated with a low rate of serum enzyme elevations, but these are generally mild and self limited, not requiring dose adjustment. Rare instances of clinically apparent acute liver injury attributed to chlorambucil have been reported. The onset of symptoms was within 2 to 6 weeks of starting chlorambucil and the typical enzyme pattern was cholestatic. Some cases have had features of hypersensitivity (rash, fever), and liver injury has recurred upon rechallenge. This form of liver injury is rare and resembles the idiosyncratic acute liver injury due to cyclophosphamide. Chlorambucil has not been linked specifically to sinusoidal obstruction syndrome, but it is not used in high doses in neoplastic disease or in conditioning regimens for hematopoietic cell transplantation, situations in which alkylating agents are commonly associated with this complication. Chlorambucil therapy has also been linked to hypersensitivity reactions and severe cutaneous adverse events such as Stevens Johnson syndrome and toxic epidermal necrolysis, both of which can be accompanied by serum enzyme elevations and hepatitis.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
The idiosyncratic cholestatic liver injury associated with chlorambucil use is probably related to a hypersensitivity reaction to a hepatic metabolite of the drug, which is extensively metabolized by the liver.
Outcome and Management
Liver injury is rare after chlorambucil therapy. The severity of injury in reported cases has been mild-to-moderate and self limited in course. There have been no instances of acute liver failure, chronic hepatitis or vanishing bile duct syndrome definitively linked to chlorambucil therapy. In situations of acute liver injury after chlorambucil use, rechallenge should be avoided and there may be some degree of cross sensitivity to allergic reactions with other nitrogen mustard-like alkylating agents such as cyclophosphamide and melphalan.
Case 1. Cholestatic hepatitis attributed to chlorambucil.
[Modified from: Pichon N, Debette-Gratien M, Cessot F, Paraf F, Labrousse F, Sautereau D, Pillegand B. [Acute cholestatic hepatitis caused by chlorambucil]. Gastroenterol Clin Biol 2001; 25: 202-3. PubMed Citation]
A 77 year old woman with non-Hodgkin lymphoma developed pruritus and jaundice 6 weeks after starting oral chlorambucil (4 mg daily). She had no history of liver disease, alcohol abuse or risk factors for viral hepatitis. Her other medications included sertraline which she had taken for 6 months. On examination, she had splenomegaly which was unchanged from before and new findings of jaundice and excoriations over the forearms. Laboratory testing showed a total serum bilirubin of 13.3 mg/dL (direct 11.8 mg/dL), accompanied by elevations in serum aminotransferase and alkaline phosphatase levels (Table). There was no eosinophilia and the prothrombin time was normal. Tests for hepatitis A, B and C were negative as were autoantibodies. Ultrasound and computerized tomography of the abdomen showed no evidence of biliary obstruction, which was further confirmed by magnetic resonance cholangio-pancreatography. A liver biopsy showed an intrahepatic cholestasis with prominence of eosinophils suggestive of drug induced liver injury. There was also mild congestion of sinusoids and changes of peliosis. There was no bile duct injury or loss. Both chlorambucil and sertraline were stopped and her symptoms and liver test abnormalities gradually improved. Sertaline was restarted and all laboratory results were normal 2 months later.
|Pattern:|| Cholestatic (R=0.4)|
||3+ (jaundice, hospitalization)
|Time After Starting
||Time After Stopping
||Alk P* (U/L)
| Normal Values
* Modified from Table 1.
A typical case of cholestatic hepatitis in which chlorambucil was the likely cause. Sertraline has also been associated with drug induced liver injury, but was unlikely the cause in this instance as shown by the negative rechallenge. The appearance of pruritus at the onset of illness and prolonged jaundice are typical of drug induced cholestatic hepatitis.
REPRESENTATIVE TRADE NAMES
Chlorambucil – Leukeran®
Antineoplastic Agents, Alkylating
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NUMBER
References updated: 05 October 2017
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