Mitoxantrone is an antineoplastic antibiotic that is used in the treatment of acute leukemia, lymphoma, and prostate and breast cancer, but also for late stage, severe multiple sclerosis. Mitoxantrone therapy is often accompanied by mild to moderate elevations in serum aminotransferase levels, but in typical doses it rarely causes clinically apparent, acute liver injury.


Mitoxantrone (mye tox’ an trone) is an antineoplastic antibiotic that is a synthetic derivative of doxorubicin and is considered an anthracenedione. It is believed to act by intercalating into helical double-stranded DNA causing cross links and strand breaks, thus blocking both DNA and RNA synthesis. Mitoxantrone has potent antitumor effects in vitro and has been evaluated in leukemia, lymphoma and several solid tumors in humans. Mitoxantrone also has immunosuppressive activity, inhibiting B cell, T cell and macrophage proliferation and decreasing tumor necrosis factor alpha and interleukin-2 secretion. These actions led to its evaluation in patients with progressive forms of multiple sclerosis where it was shown to have activity in decreasing the rates of relapse and development of new lesions. Mitoxantrone was approved for use in the United States in 1987 and current indications include acute non-lymphocytic leukemia and advanced prostate cancer. Mitoxantrone was subsequently approved for use in secondary progressive forms, progressive-relapsing forms and worsening relapsing-remitting forms of multiple sclerosis. Mitoxantrone is available in several generic formulations as a solution for intravenous injection (usually 2 mg/mL). Mitoxantrone is administered intravenously in doses typically ranging from 12 to 14 mg/m2 at intervals of every 3 months (multiple sclerosis) or in monthly cycles (prostate cancer and leukemia). Side effects of mitoxantrone include bone marrow suppression, nausea, vomiting, abdominal discomfort, diarrhea, alopecia, headache, dizziness and rash. Serious side effects include febrile neutropenia, cardiac toxicity [similar to that caused by doxorubicin] and secondary leukemia [in patients with multiple sclerosis]. Mitoxantrone should be administered by a physician experienced in the use of cytotoxic chemotherapy and must be given intravenously slowly and carefully, as it can cause severe local tissue damage and should not be given subcutaneously, intramuscularly or intrathecally.


Chemotherapy with mitoxantrone alone is associated with serum enzyme elevations in up to 40% of patients, but these elevations are generally mild-to-moderate in severity, transient and not accompanied by symptoms or jaundice. Higher rates of liver enzyme elevations have been reported with combination chemotherapeutic regimens that include mitoxantrone. In high doses, mitoxantrone has been associated with a high rate of jaundice, but the degree of hyperbilirubinemia has been mild, transient and not associated with significant serum enzyme elevations or evidence of hepatitis. Rare instances of acute liver injury have been reported in patients taking mitoxantrone, including a single case of drug-rash with eosinophilia and systemic symptoms (DRESS). The latency to onset was 8 weeks and the pattern of serum enzyme elevations was cholestatic and later mixed. Immunoallergic features were prominent and appeared to respond to corticosteroid therapy. Other drugs were being taken and the association with mitoxantrone was not definite (Case 1). Thus, idiosyncratic and clinically apparent liver injury from mitoxantrone may occur but is quite rare.

Likelihood score: D (possible rare cause of clinically apparent liver injury).

Mechanism of Injury

The transient ALT elevations that can occur during mitoxantrone therapy are likely due to direct toxicity of the drug or its metabolites. Idiosyncratic acute liver injury attributed to mitoxantrone is likely due to a hypersensitivity reaction. Mitoxantrone is at least partially metabolized by the liver, but the specific pathways have not been well defined.

Outcome and Management

The serum aminotransferase and mild serum bilirubin elevations that frequently accompany mitoxantrone therapy are generally self-limited, transient and unaccompanied by symptoms. The product label recommends regular monitoring of serum aminotransferase levels before each monthly or every-three-month infusion of mitoxantrone therapy, but dose modifications or discontinuation are rarely necessary. Patients who develop immunoallergic reactions to mitoxantrone should not be rechallenged with the medication. The possibility of cross reactivity with doxorubicin or other cytotoxic anthracycline antibiotics has not been evaluated, but should be done with caution.

Drug Class: Antineoplastic Agents; Multiple Sclerosis Agents

Other Drugs in the Subclass, Antibiotics, Cytotoxic: Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mitomycin, Plicamycin


Case 1. Drug reaction with eosinophilia and systemic signs (DRESS) attributed to mitoxantrone therapy.(1)

A 44 year old woman with primary, progressive multiple sclerosis developed jaundice 8 weeks after starting mitoxantrone (10 mg every 4 weeks) and piracetam (3 gm daily). She was known to have multiple sclerosis for 3 years and had been treated previously with interferon beta with little clinical improvement. At the time of her third scheduled dose of mitoxantrone, she was found to be jaundiced and had mild fever and facial edema. Laboratory testing showed a total serum bilirubin of 19.3 mg/dL which was primarily direct. Serum ALT was 561 U/L, AST 337 U/L, alkaline phosphatase 705 U/L, GGT 447 U/L. These values had been normal in the past (Table). She took no other medications except for baclofen (75 mg daily), which she had been taking for almost two years. Her medications were stopped and she was admitted for evaluation. Tests for hepatitis A, B and C were negative as were routine autoantibodies. Abdominal ultrasound and magnetic resonance imaging were normal, without evidence of biliary obstruction. However, she failed to improve and after two weeks, her serum bilirubin remained high. A liver biopsy showed canalicular cholestasis with mild portal inflammation suggestive of drug induced liver injury. One week later, she developed a generalized, erythematous, macular rash and laboratory testing demonstrated leukocytosis (15,300/μL) and eosinophilia (>4000/μL). Methylprednisone was stated (20 mg daily) and she improved rapidly. Six months after initial presentation, all liver tests were normal and she underwent drug sensitivity skin testing which showed marked reactions to mitoxantrone, but none to piracetam.

Key Points

Laboratory Values


A woman with multiple sclerosis developed jaundice and fever 8 weeks after starting the combination of mitoxantrone and piracetam. She did not improve immediately after stopping the medications and 3 weeks later developed skin rash and eosinophilia, fully warranting a diagnosis of DRESS syndrome. A liver biopsy demonstrated canalicular cholestasis, which is typical of the intrahepatic cholestasis that is caused by medications. The immunoallergic features of DRESS syndrome improved rapidly with methylprednisolone therapy (the duration of which was unclear), and serum bilirubin began to fall. In follow up 6 months later, she had recovered completely. Skin testing suggested that mitoxantrone rather than piracetam was the cause of the hypersensitivity reaction. Piracetam is a synthetic derivative of GABA, similar in structure to levetiracetam and used as treatment of myoclonus and for cognitive impairment. It is commercially available in Europe and elsewhere, but is not approved for use in the United States. While piracetam has not been specifically linked to hypersensitivity reactions, levetiracetam has been linked to cases of DRESS and Stevens Johnson syndrome. Thus, piracetam may have been the cause of the DRESS syndrome but, without rechallenge (negative or positive), it is impossible to definitively link this outcome to either agent. Certainly, the skin test reactions favor but do not prove the contribution of mitoxantrone.



Mitoxantrone – Generic, Novantrone®


Antineoplastic Agents; Multiple Sclerosis Agents


Product labeling at DailyMed, National Library of Medicine, NIH



Caruso A, Vecchio R, Patti F, Neri S. Drug rash with eosinophilia and systemic signs syndrome in a patient with multiple sclerosis. Clin Ther. 2009;31:580–4. [PubMed: 19393848]


References updated: 19 February 2020

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