Mitoxantrone cardiotoxicity

Predisposing factors to mitoxantrone cardiotoxicity include increasing age, prior anthracycline therapy, previous cardiovascular disease, mediastinal radiotherapy, and a cumulative dose of the drug exceeding 120 mg/m. In 801 patients treated with mitoxantrone, prior treatment with doxorubicin and mitoxantrone was significantly associated with risk of cardiotoxicity however, age, sex, and prior mediastinal radiotherapy were not useful predictors (19). 

Cardiotoxicity is a serious, rare adverse effect of mitox-antrone. The incidence of congestive heart failure was 0.15% in patients with normal left ventricular ejection fraction and 2.18% in those who had asymptomatic left ventricular ejection fraction of less than 50% at baseline.46 Therefore, mitoxantrone should not be used in patients with baseline cardiomyopathy, even if asymptomatic. The risk of cardiotoxicity is dose-related. The maximum lifetime dose of mitoxantrone is 140 mg/m2, or about 3 years of MS therapy. The use of cyclooxygenase-2 inhibitors should be avoided in patients receiving mitoxantrone because of a potential for worsening cardiac toxicity.46... 

Dosing and Administration Mitoxantrone is infused intravenously over 30 minutes to reduce the chance of cardiotoxicity.46 Mitoxantrone is administered every 3 months, if cardiac function and laboratory values are normal (Table 26-6). 

Mitoxantrone -anthracycline antitumor antibiotic DNA intercalating agent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) —cardiotoxicity (160 mg/M2) -elevated liver function tests... 

Myocardial toxicity, manifested in its most severe form by potentially fatal CHF, may occur either during therapy with mitoxantrone or months to years after termination of therapy. Mitoxantrone use has been associated with cardiotoxicity this risk increases with cumulative dose. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m. For this reason, monitor patients for evidence of cardiac toxicity and question them about symptoms of heart failure prior to initiation of treatment. Monitor patients with multiple sclerosis (MS) who reach a cumulative dose of 100 mg/m for evidence of cardiac toxicity prior to each subsequent dose. Ordinarily, patients with MS should not receive a cumulative dose greater than 140 mg/m. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with mitoxantrone may occur at lower cumulative doses whether or not cardiac risk factors are present (see Warnings and Administration.and.Dosage). 

Mitoxantrone Blue-green pigmenc in urine blue-grccn sclerae nnusen and vomiting stomatitis fever phlebitis Bone marrow depression cardiotoxicity alopecia white hair skm lesions hepatic damage renal failure extravasation necrosis... 

Abnormalities of left ventricular ejection fraction have been described in 46% of patients n = 14) treated with mitoxantrone (14 mg/m ) and with vincristine and prednisolone (43). A history of cardiac disease or of previous anthracycline exposure was excluded. Only one patient developed clinically overt congestive cardiac failure. Other reports have described less cardiotoxicity compared with the parent compound, doxorubicin (4,44). 

Mather FJ, Simon RM, Clark GM, Von Hoff DD. Cardiotoxicity in patients treated with mitoxantrone Southwest Oncology Group phase 11 studies. Cancer Treat Rep 1987 71(6) 609-13. 

Nausea, vomiting, mucositis, stomatitis, alopecia, bone marrow depression, cardiotoxicity. I I A IV. Rapid, wide distribution, half-life = 6 days. Acute nonlymphocytic leukemia. The usefulness of doxorubicin and daunorubicin is limited by cardiotoxicity. It is hoped that mitoxantrone use will not be limited by cardiotoxicity. 

Mitoxantrone exerts cardiotoxic effects that are similar to those of anthracyclines (Unverferth et al. 1983, Powis 1991, Benjamin 1995). Herman et al. (1997) showed that mitoxantrone and iron(III) form a strong 2 1 complex, in which the drug may be acting as a tridentate ligand. This complex, like the iron(III)-doxorubicin complex, may be capable of redox cycling and produce reactive oxygen intermediates that damage tissue. 

The DNA-binding properties of anthraquinones have been studied intensively over the past 25 years because of their clinical potential as anticancer drugs. The anthraquinone system is often found in anti-tumor drugs such as anthracyclines, mitoxantrone (11a), ametantrone (11b) and derivatives thereof [217-220]. Mitoxantrone (11a) and ametantrone (11b) have attracted much interest because of their lower risks of cardiotoxic effects compared with the naturally occurring anthracyclines doxorubicine (adriamycin) (4b) and daunorubicin [221]. 

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