Anthracycline-induced cardiotoxicity was well described by Shan and associates [1]. Mitoxantrone is a dihydroxyanthracenedione derivative that seems to be an effective and better-tolerated alternative to the anthracycline component of standard regimens for most hematologic cancer [2]. We report sinus bradycardia in two patients who had acute lymphoblastic leukemia after mitoxantrone treatment. This is, to our knowledge, the second report of mitoxantrone-induced bradycardia [3].

Patient 1 was a 36-year-old, previously healthy man who presented with neutropenic fever; empirical amikacin and ceftazidime therapies were started. Physical examination was remarkable only for a temperature of 39 °C. Blood pressure was normal, and the heart rate was 108 beats/min. Bone marrow was infiltrated with lymphoblasts, which were positive for CD3, HLA-DR, and terminal deoxynucleotidyl transferase. Induction chemotherapy began, comprising mitoxantrone, 10 mg/m² body surface area given as a continuous infusion for 3 days; vincristine, 1.4 mg/m (²) given intravenously on days 1, 8, and 15; and prednisone, 40 mg/m² given orally on days 1 to 21. Electrocardiography done before therapy showed sinus rhythm. On day 2 of mitoxantrone infusion, the pulse rate decreased to 40 beats/min and responded to atropine. Blood pressure was 110/70 mm Hg, and he was asymptomatic. Electrocardiography showed sinus bradycardia. Results of echocardiography and electrophysiology were normal. Bradycardia persisted for 5 days, and the heart rate returned to normal 3 days after mitoxantrone therapy ended. The patient's temperature never decreased despite use of broad-spectrum antibiotics and antifungal agents. Methicillin-resistant Staphylococcus aureus and Pseudomonas maltophilia were isolated from blood cultures. The patient's condition deteriorated, and he died of neutropenic sepsis and disseminated intravascular coagulation 10 days after chemotherapy began.

Patient 2 was a 56-year-old woman admitted with fever, malaise, and abdominal pain in December 1994. Results of physical examination were normal except for fever. Hemoglobin concentration was 8.5 g/dL, platelet count was 23.0 x 10⁹/L, and leukocyte count was 52.8 x 10⁹/L (96% blastocytes). Broad-spectrum antibiotics were started for neutropenic fever. Bone marrow aspiration showed lymphoblasts positive for CD7, HLA-DR, and terminal deoxynucleotidyl transferase. Pre-T-type acute lymphoblastic leukemia was diagnosed, and induction chemotherapy with 3 days of continuous mitoxantrone infusion (10 mg/m²) was started. Results of electrocardiography and echocardiography done before treatment were normal. Two days after mitoxantrone infusion began, the heart rate decreased to 38 beats/min; the patient had no symptoms, and blood pressure was 140/80 mm Hg. Electrocardiography showed sinus bradycardia. Normal heart rate was restored 7 days after mitoxantrone therapy ended. The patient then received intrathecal methotrexate and cranial prophylaxis. She is currently alive, in remission, and receiving maintenance therapy.

Acute or subacute anthracycline-induced cardiotoxicity immediately after treatment is unusual [1]. Sinus tachycardia is the most common rhythm disorder. Bradycardia due to anthracyclines has been reported rarely [3, 4]. Bethell and coworkers [4] described subacute cardiac toxicity in the form of heart blocks, which necessitated pacemaker implantation 4 to 30 days after anthracycline-containing chemotherapy ended. Umemoto and associates [3] recently published the first report of true sinus bradycardia after mitoxantrone therapy in patients previously given anthracyclines. The pathogenesis of anthracycline-induced cardiac toxicity has many causes. Disturbances in myocardial adrenergic function, release of vasoactive amines, and inflammatory cytokines are some probable mechanisms of toxicity [1]. The precise mechanisms are unknown. Patients receiving anthracycline therapy should be monitored for unusual manifestations due to anthracycline cardiotoxicity.