Low-dose cytosine arabinoside-induced syptomatic bradycardia in a patient with acute myeloid leukemia

Abstract

Cytosine arabinoside (Ara-C) is one of the critical agents for the treatment of acute myeloid leukemia (AML). The toxicity profile of Ara-C is highly dependent on the dose and schedule of administration. Cardiologic complications associated with Ara-C are rare. These side effects were reported with high doses of cytarabine (1–3 g/m², 6–12 doses) in the literature. Herein, we report a patient who developed symptomatic sinus bradycardia while receiving low-dose Ara-C therapy for AML. A 45-year-old female patient diagnosed with AML was treated with standard remission induction chemotherapy protocol that includes 3 days of anthracycline and 7 days of low-dose (100–200 mg/m² 2–1) Ara-C. The same chemotherapy regimen was applied again on the 15th day of admission. During the second chemotherapy cycle, the patient developed symptomatic sinus bradycardia. All causes except Ara-C were excluded after required investigational procedures. Ara-C infusion was discontinued for a while and after her symptoms passed chemotherapy was completed with atropine support. Cardiac toxicity is scarce with Ara-C. We want to remind that clinicians should be aware of this potential toxic manifestation even in low doses of the medication, especially as Ara-C is widely used in the treatment of leukemia.

<Learning objective: Cytosine arabinoside is one of the historic chemotherapeutics in hematology. It was widely used to treat many types of hematological malignancies in high doses and is commonly available in worldwide markets. Symptomatic sinus bradycardia is a rare type of cardiologic side effect, but it should be kept in mind during chemotherapy.>

Introduction

Cytosine arabinoside (Ara-C) is a nucleoside analog in the group of antimetabolite drugs. It represents a mainstay in the induction treatment of acute myeloid leukemia (AML). It is also incorporated into some induction regimens for acute lymphoid leukemia (ALL). Generally, it is used in combination with anthracyclines (7 days of Ara-C 100–200 mg/m² and 3 days of daunorubicin). The major side effects of Ara-C are myelosupression and gastrointestinal toxicity [1].

Cardiopulmonary complications associated with Ara-C are rare. These side effects are supraventricular and ventricular arrhythmias, pericarditis, acute respiratory distress syndrome, and congestive heart failure. They are usually associated with high doses of cytarabine (1–3 g/m², 6–12 doses) [2]. Herein, we report a patient who developed symptomatic sinus bradycardia while receiving low-dose Ara-C as induction therapy (7 + 3) for AML.

Case report

A 45-year-old female patient presented with symptoms of fatigue, high fever, and anorexia. Her skin and conjunctivae were pale on physical examination. A normal cardiac examination with an apex beat of 88/min, blood pressure of 110/70 mmHg, and fever of 38 °C was observed. Normal sinus rhythm was seen on electrocardiography monitoring (ECG) (Fig. 1) and a normal echocardiography evaluation was observed with an ejection fraction of 69%. The laboratory values at presentation were; white blood cell count, 87,000/mm³; hemoglobin, 8.6 g/dl; hematocrit, 26%; platelet count, 14,000/mm³; lactate dehydrogenase, 455 myeloblasts were created ninety percent of leucocytes (Auer body positive) were shown on peripheral blood smear (Fig. 2), U/ml. Other laboratory analyses were all in the normal range. Flow cytometric analysis, which was performed in bone marrow, was compatible with AML-M2 (CD 33, 89%, CD 13, 82%, and MPO, 74% positive). There was a normal karyotype analysis and no cytogenetic anomalies were found. The patient was diagnosed with AML. Standard remission induction therapy was initiated (7 + 3; 200 mg/m²/day of Ara-C for 7 days and 25 mg/m²/day doxorubicin for 3 days). Granisetron was only used as an antiemetic before treatment. The same course of chemotherapy regimen (7 + 3) was applied again because of the presence of 18% myeloblasts on bone marrow aspiration that was performed on the 15th day of therapy. A radial pulse of 42/min and arterial blood pressure of 80/60 mmHg were recorded on the fourth day of therapy. Hence, ECG monitoring was performed, which showed sinus bradycardia (heart rate: 42/min). The corrected QT interval was calculated as 0.44 on the ECG showing bradycardia (Fig. 3). Normal levels of serum potassium 4.1 mmol/l (3.5–5.5 mmol/l), calcium 9.1 mg/dl (9–11 mg/dl), and magnesium, and thyroid hormones were found. All other situations that can cause bradycardia were investigated. The standard dose of Ara-C in the chemotherapy protocol was discontinued in order to treat the bradycardia. Pulse monitoring of the patient was done carefully. The patient's heart rate progressively elevated to 65/min after 3 days as a result of suspension of the therapy. Therapy was restarted with close rhythm monitoring and the support of atropine. After the therapy had been restarted, despite the support of atropine, the pulse varied between 42 and 50/min. Two days after the therapy finished, the patient's heart rate was in the normal range and thereafter the pulse was stabilized above 60/min (Fig. 3).

Fig. 1.

Initial normal sinus rhythm of the patient at presentation.

Fig. 2.

Peripheral smear of the patient. Myeloblast was seen which contains Auer body in it (hematoxylin and eosin dye, with 100× magnification field).

Fig. 3.

Sinus bradycardia with 42 beats/min during low-dose cytosine arabinoside therapy.

As a consolidation therapy, high dose Ara-C (HIDAC) (3.5 g/m² totally 6 dose in every 12 h of day, on 1st, 3rd, and 5th days) was administered as three cycles. The patient's pulse was in the normal range during these therapies. Before the fourth consolidation therapy, a relapse was noticed and the patient died due to relapsed-refractory AML.

Discussion

Ara-C is an important antimetabolite agent that is used to treat AML [3]. The concentration of the drug and time of exposure are principal markers of Ara-C toxicity, and the extracellular drug concentration must be maintained between 10 and 15 μmol/l to provide optimum Ara-C cellular pharmacokinetics [4]. Toxicity due to high doses of Ara-C includes myelosupression, gastrointestinal, pulmonary toxicity, and significant but rarely irreversible cerebellar toxicity [1]. Chemotherapeutic agents have some side effects such as hypertension, cardiomyopathy, and long QT on ECG. Agents such as cyclophosphamide (complete heart block), cisplatin (left bundle branch block), paclitaxel (mobitz type 1 and 2 block and complete heart block), and 5-fluorouracil are associated with bradycardia [5].

Congestive heart failure may occur in 20% of patients treated with anthracycline, but so far the literature about sinus arrhythmia is scarce and restricted to taxanes, high dose ifosfamide, and Ara-C, mostly as anecdotal reports [6]. Fifteen cases of patients who developed arrhythmias due to Ara-C are presented in the literature. Of these 15 cases, 1 had wide complex bradycardia, 1 had an idioventricular rhythm, 10 out of the 15 had sinusal bradycardia, 1 had atrioventricular block, and 2 cases had uncharacterized bradycardia. All of these cases were treated with either intermediate- or high-dose Ara-C (1–3 g/m² bid on days 1, 3, and 5) 3, 5, 6, 7, 8. Our case differs from the reported ones in the literature because the patient developed symptomatic sinus bradycardia with low-dose Ara-C.

The 7 + 3 protocol was applied as remission induction therapy, because the diagnosis was AML. There was no bradycardia observed in this patient during the first remission induction therapy. The second remission induction therapy (7 + 3) was applied in order to get remission. The pulse was 42/min on the fourth day of treatment and the heart rate was confirmed as 42/min on ECG. After interruption of the therapy, the heart rate progressively returned to normal. So the, treatment was resumed from the point of interruption. After the first Ara-C infusion, the patient developed symptomatic bradycardia again. It was concluded that the bradycardia was associated with the Ara-C treatment because other probable causes of bradycardia (electrolyte imbalance, ischemic cardiopathy, hypothermia, hypothyroidsm, typhoid fever, identifiable virus infection, cardioactive drug, morphine, etc.) had already been excluded. The calculated Noranjo adverse drug reaction probability scale of the patient's score was 10 and was regarded as definite according to this scale [9]. Therefore, it is reasonable to speculate about a possible relationship between low-dose Ara-C and symptomatic sinus bradycardia observed in our patient.

The real mechanism of bradycardia and cardiac effects due to Ara-C are not known. It is suspected that they are associated with an immune-mediated process or a type of hypersensitivity reaction [2]. All the reactions that cannot be explained by the mechanism of the drug are defined as allergic reactions. Desensitization (immunotherapy) therapy aims to alter the immune response to the drug and results in tolerance to the specific drug and allowing the patient to receive a subsequent course of the medication safely. Bradycardia that was reported in case reports in the literature often developed during high-dose Ara-C therapy; however, in our case it developed with low-dose Ara-C therapy. The hypersensitivity reaction theory is supported because of the development of bradycardia during the second remission induction therapy while it did not develop during the first remission induction therapy and high-dose Ara-C. We attribute the improvement of bradycardia during high-dose Ara-C to the desensitization to the Ara-C.

In conclusion, neither this case nor the others cited above provide conclusive evidence for a direct relationship between bradycardia and Ara-C. Physicians need to take into account the underlying disease and the concomitant medications. We believe that clinicians should be aware of this potential toxic manifestation even in low doses of the medication, especially as Ara-C is widely used in the treatment of leukemia.

Conflict of interest

The authors declare no conflict of interest.