Bradycardia during Induction Therapy with All-trans Retinoic Acid in Patients with Acute Promyelocytic Leukemia: Case Report and Literature Review

A 41-year-old man with newly diagnosed acute promyelocytic leukemia (APL) received induction chemotherapy, containing all-trans retinoic acid (ATRA), idarubicin, and arsenic trioxide. On the 11th day of therapy, he experienced complete atrioventricular (AV) block; therefore, ATRA and arsenic trioxide were immediately postponed. His heart rate partially recovered, and ATRA was rechallenged with a half dose. However, complete AV block as well as differentiation syndrome recurred on the next day. ATRA was immediately discontinued, and a temporary pacemaker was inserted. Two days after discontinuing ATRA, AV block gradually improved, and ATRA was uneventfully rechallenged again. The Naranjo adverse drug reaction probability scale was 7 for ATRA, suggesting it was the probable cause of arrhythmia. A literature search identified 6 other cases of bradycardia during ATRA therapy, and all of them occurred during APL induction therapy, with onset ranging from 4 days to 25 days. Therefore, monitoring vital signs and performing electrocardiogram are highly recommended during the first month of induction therapy with ATRA. ATRA should be discontinued if complete AV block occurs. Rechallenging with ATRA can be considered in fully recovered and clinically stable patients.


Introduction
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with distinct morphology, clinical presentation, and cytogenetics. It is characterized by accumulation of abnormal promyelocytes in the bone marrow, potentially fatal coagulopathy, and translocation between chromosomes 15 and 17 [t(15;17)] [1,2].
t (15;17) leads to the promyelocytic leukemia and retinoic receptor-α fusion gene (PML-RARα), which blocks the differentiation of myeloid cells at the promyelocytic stage. All-trans retinoic acid (ATRA or tretinoin) induces a configuration change of PML-RARα or its degradation. As a result of this treatment, abnormal promyelocytes can differentiate into mature myeloid cells, and coagulopathy is significantly reduced [1]. When ATRA combines with anthracycline-based chemotherapy, the complete remission rate is 90%-95%. erefore, this approach is the standard induction therapy for newly diagnosed APL [1][2][3].
Arsenic trioxide (ATO) also promotes differentiation of APL cells by targeting the PML moiety and can be used as a synergistic therapy with ATRA [1,4]. However, rapid differentiation of promyelocytes induced by ATRA or ATO may lead to leukocytosis and differentiation syndrome (DS), especially in patients with an initial white blood cell (WBC) count greater than 10,000/mm 3 . DS is characterized by fever, dyspnea, respiratory distress, pulmonary infiltrates, and pleural or pericardial effusions. is condition is potentially life-threatening; therefore, when DS is suspected, it is crucial to immediately initiate high-dose steroid treatment and temporarily discontinue ATRA and/or ATO in severe DS [2,5,6]. Concurrent use of anthracycline-based chemotherapy can decrease the incidence of DS [1,5,6].
Other common adverse effects of ATRA include headache, dry skin, xerostomia, bone pain, and nausea [7]. Cardiovascular toxicities, such as arrhythmia, have rarely been reported and are often overlooked by clinical practitioners [8]. Here we report the clinical course of a patient with APL suffering from complete atrioventricular (AV) block during induction therapy with an ATRA-based regimen. Moreover, a literature review was conducted to summarize the clinical characteristics of ATRA-associated arrhythmia.
On the 11th day of therapy, WBC and promyelocyte decreased to 6,310/mm 3 and 14%, respectively. ATO infusion at a dose of 0.15 mg/kg was initiated; however, dizziness and chest pain occurred during infusion. ECG showed complete AV block with a heart rate (HR) of 40-50 beats/min (bpm) (Figure 1(b)). e electrolytes and liver function tests were all within normal limits (Na, 138 mmol/L; K, 4.6 mmol/L; Ca, 2.29 mmol/L; Mg, 0.95 mmol/L; T-bil, 0.77 mg/dL; AST, 15 U/L; ALT, 14 U/L). us, ATO and ATRA were immediately discontinued, and aminophylline was administered.
After interruption of ATRA for three doses, complete AV block persisted, but his HR partially recovered to 60 bpm. ATRA was rechallenged with 40 mg once daily on the 13th day of therapy under relatively stable vital signs. On the following morning, his HR decreased to 30 bpm and he required a nonrebreathing mask to maintain oxygen saturation. CXR showed bilateral pulmonary edema, and echocardiogram revealed a large amount of pericardial effusion with signs of cardiac tamponade. In addition, ECG showed complete AV block with QRS widening, and acute renal failure also occurred (Scr, 1.4 mg/dL; blood urea nitrogen (BUN), 45.2 mg/dL; Na, 133 mmol/L; K, 5.2 mmol/L; Ca, 2.22 mmol/L; Mg, 0.93 mmol/L; P, 4.9 mg/dL; T-bil, 1.22 mg/dL; ALT, 17 U/L). erefore, ARTA was immediately postponed, and a temporary pacemaker was inserted. Steroid treatment was switched to dexamethasone (8 mg twice daily) because of suspected DS. Pericardiocentesis and thoracentesis were performed. Two days after stopping ATRA, ECG showed sinus bradycardia with a first-degree AV block and diffuse ST elevation. e Naranjo adverse drug reaction probability scale [9] indicated a score of 7 for ATRA, suggesting it was the probable cause of arrhythmia in this episode. e PML-RARα mutant was still detected using polymerase chain reaction (PCR) of blood sampled on the 19th day of therapy. Consequently, ATRA was resumed the following day with 10 mg twice daily. His HR decreased from 70-90 bpm to 60-70 bpm with stable vital signs. ECG demonstrated sinus rhythm with first-degree AV block. e dose of ATRA was gradually titrated up to 30 mg twice daily on the 24th day. Sinus tachycardia with occasional premature ventricular complexes was noted.
e pacemaker was removed on the 27th day. During follow-up, ECG showed normal sinus rhythm (Figure 1(c)), and echocardiogram revealed minimal pericardial effusion.
Complete molecular remission was documented by bone marrow aspiration done on the 38th day of therapy using flow cytometry and PCR for PML-RARα.
ereafter, the patient received three cycles of consolidation with ATRAbased chemotherapy. No further bradycardia episode was reported. e patient has been free of leukemia for 1.5 years after the diagnosis.

Discussion
e major etiologies of AV block include ischemic heart disease, cardiomyopathy, hyperkalemia, hypothyroidism or hyperthyroidism, and medications. is 41-year-old man did not have any underlying disease, and his baseline CXR, ECG, and echocardiography did not show any abnormalities. e serum potassium level was normal during the first-episode of complete AV block, and it was only mildly elevated and was corrected soon during the second episode of complete AV block. Although idarubicin and ATO have also been reported to cause arrhythmia in the literature, the second arrhythmia episode in this patient recurred only after ATRA rechallenge. Accordingly, ATRA was the most likely culprit drug for this adverse event.
e most common adverse effects of ATRA are headache, dry skin, xerostomia, bone pain, and nausea [7]. Arrhythmia is rarely reported. erefore, we reported a case of this rare adverse reaction of ATRA and reviewed the literature for other cases. We searched literature reports on PubMed by using the following keywords: ("tretinoin" or "all-trans retinoic acid" or "ATRA") and ("bradycardia" or "tachycardia" or "arrhythmia"). Six other cases of bradycardia during ATRA induction therapy were found and summarized, along with the case reported here, in Table 1 [10-15].
Median onset of bradycardia among the seven patients was 9 days (4-25 days). ECG abnormalities consisted of AV block, sinus bradycardia, and junctional bradycardia [10][11][12][13][14][15]. Arrhythmia resolved in two patients without interruption of ATRA [12,14]. Sinus rhythm was restored in another four cases within 3-15 days after discontinuing ATRA [11,13,15]. ree of them required temporary pacemaker support [11,15], and ATRA was rechallenged in two of them [15]. Interestingly, all of the incidents reported in the seven cases occurred during the induction therapy. Among the four cases with available information, three of them also experienced DS [12,13]. e underlying mechanism of ATRA-related bradycardia has not been comprehensively studied. In 1995, Kang and Leaf demonstrated that ATRA significantly lowered the beating rate of cardiomyocytes and reduced the incidence and severity of ventricular tachyarrhythmia induced by isoproterenol in rats [16]. e inhibition of excitability may    Case Reports in Hematology be mediated by the effect of ATRA on membrane ion channels, and this may result in conduction disturbance of the AV node [16]. Further studies are needed to elucidate the effect of ATRA on the AV node. Another possible explanation of ATRA-related arrhythmia was leukemic cell infiltration in the myocardium. Seconddegree AV block and pericardial effusion in a case with AML was reported by Hatake et al. On autopsy, focal leukemic cell infiltration in the His bundle was noted [17]. erefore, eradication of leukemic cell could ameliorate the cardiac symptoms as reported in another case described by Civelek et al., wherein complete AV block spontaneously subsided after chemotherapy [18]. In reviewing the cases of ATRA-related arrhythmia, sinus bradycardia reported by Karakatsanis et al. also spontaneously subsided after chemotherapy without any specific intervention [14]. Moreover, all of the seven cardiac events occurred during induction chemotherapy course but not consolidation ones.
ese observations could possibly provide some evidence that the cardiac toxicity was partially caused by infiltration of leukemic cells in the myocardium.
As described above, APL patients receiving ATRA-based induction therapy may experience DS, which is characterized by fever, dyspnea, respiratory distress, pulmonary infiltrates, and pleural or pericardial effusions [5,6]. e proposed pathophysiology involves tissue infiltration of APL cells. Besides infiltration of leukemic cells, ATRA also stimulates the production of chemokines and further increases lung infiltration of differentiating APL cells. Changes in cytokine production also occur in the liver, spleen, and heart [5]. According to these mechanisms, DS may also interfere with AV node conduction and result in bradyarrhythmia. In reviewing the incidents of ATRA-related bradycardia, three of four cases with available information also experienced DS [12,13]. In Dhar's report, seconddegree AV block simultaneously occurred with DS, and after steroid use, these manifestations resolved at the same time [12]. In our case, the AV block was more severe when DS occurred. Without the presentation of the DS, only mild bradycardia occurred under ATRA use. erefore, DS may further deteriorate ATRA-related AV node conducting dysfunction.
is clinical presentation strengthens the theory that DS may result in cardiac arrhythmia, which needs further study to elucidate the observation.
In conclusion, this case and literature review indicated that ATRA may cause conduction dysfunction-related arrhythmia, and it should be used more cautiously for APL patients during induction chemotherapy, especially those suffering from DS. e onset of bradycardia was usually within 1 month after initiation of ATRA. erefore, closely monitoring vital signs and performing ECG are highly recommended during the first month of ATRA-based induction therapy. ATRA should be promptly discontinued if complete AV block occurs. In severe cases, temporary pacemaker insertion is indicated. After discontinuing ATRA, bradycardia may resolve gradually within 3-15 days. Since ATRA is the cornerstone in APL treatment, rechallenge can be considered in fully recovered and clinically stable patients.

Conflicts of Interest
All the authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.