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© 2003 American Society for Clinical Oncology Effect of Arsenic Trioxide on QT Interval in Patients With Advanced Malignancies
From the Department of Medicine, Georgetown University, Washington, DC; the Arcus Group, New York, the Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Joan and Sanford I. Weill Medical College of Cornell University, New York, NY. Address reprint requests to Jean T. Barbey, MD, Department of Medicine, Georgetown University, 3900 Reservoir Rd, NW, MedDent Building, C 305, Washington, DC 20007; e-mail: tczjb{at}aol.com.
Purpose: Arsenic trioxide is an effective treatment for patients with acute promyelocytic leukemia (APL) who have relapsed from or are refractory to all-trans-retinoic acid and anthracycline chemotherapy. Since arsenic can prolong the QT interval and lead to torsade de pointes, a life-threatening ventricular arrhythmia, this retrospective analysis was conducted to determine the degree of QT prolongation in patients treated with arsenic trioxide. Patients and Methods: Clinical data and serial ECGs from 99 patients with advanced malignancies who received 170 courses of arsenic trioxide in either a phase I or phase II investigational study were reviewed.
Results: Prolonged QT intervals developed in 38 patients (26 patients had intervals Conclusion: This analysis shows that arsenic trioxide can prolong the QTc interval. However, with appropriate ECG monitoring and management of electrolytes and concomitant medications, arsenic trioxide can be safely administered in patients with relapsed APL.
ACUTE PROMYELOCYTIC leukemia (APL) accounts for approximately 10% to 15% of all cases of adult acute myeloid leukemia.1,2 APL is characterized by a chromosomal translocation, t(15;17), which fuses portions of the retinoic acid receptor alpha gene to the promyelocytic leukemia gene.1 This translocated gene segment encodes a chimeric protein that arrests maturation at the promyelocytic stage of myeloid cell development.3 Since all-trans-retinoic acid (ATRA) has been incorporated into the treatment regimen for APL, disease-free survival has more than doubled.4–6 Despite this advancement, approximately 25% to 30% of these patients relapse.7 Several trials have shown the efficacy of arsenic trioxide in the treatment of patients with relapsed APL.3,8–10 Investigators from China reported rates of complete remission ranging from 85% to 90% with the use of a daily intravenous dose of 10 mg of arsenic trioxide in patients previously treated with ATRA.9,10 In a single-center US study, a new formulation of arsenic trioxide (now distributed commercially as TRISENOX; Cell Therapeutics Inc, Seattle, WA) at a median dose of 0.15 mg/kg/d (range, 0.06 to 0.2 mg/kg/d) induced complete remission in 11 (93%) of 12 patients.3 Subsequently, a US multicenter trial showed achievement of complete remission in 34 (85%) of 40 patients.11 Arsenic trioxide therapy has been relatively well tolerated, even in patients receiving extensive prior therapy.3,11 Well-known effects of outright arsenic poisoning include ECG abnormalities, such as QRS widening, ST depression, T-wave flattening, QT prolongation, and torsade de pointes (TdP), a life-threatening polymorphic ventricular tachycardia.12–15 Early publications by Shen et al10 and Niu et al9 reported only minor asymptomatic ECG abnormalities in some APL patients treated with arsenic trioxide. The present analysis was conducted to assess the degree of QT interval prolongation that occurred in patients with relapsed APL or advanced malignancies who were receiving arsenic trioxide in an investigational study.
Patient Population Four separate clinical studies of arsenic trioxide provided data for this study—two phase I studies in patients with advanced malignancies and two phase II studies in patients with relapsed APL (the US pilot and multicenter studies).11 These studies utilized the formulation of arsenic trioxide currently approved in the United States and Europe. Eligibility criteria for the phase I studies included confirmed diagnosis; relapse from or resistance to standard therapies; serum creatinine and bilirubin levels  2.5X the upper limit of normal; Eastern Cooperative Oncology Group performance status 2; and a negative pregnancy test result in women of childbearing age. Eligibility criteria for patients with solid tumors included histologic diagnosis of cancer; relapse from or resistance to  1 course of standard anticancer therapy; leukocyte count 3,000 mm3; platelet count 100,000/mm3; serum creatinine 2.5X the upper limit of normal; serum bilirubin 2.5X the upper limit of normal; and Eastern Cooperative Oncology Group performance status 3.
Arsenic Trioxide Treatment In the phase I study conducted in patients with advanced hematologic malignancies, 25 doses of arsenic trioxide, ranging from 0.10 to 0.25 mg/kg/d, were given throughout 4 to 5 weeks. Additional courses were administered beginning 3 to 5 weeks after the preceding course to patients who had no evidence of progressive disease and experienced no significant toxicity. In the other phase I study, conducted in patients with solid tumors, patients received five infusions of arsenic trioxide in doses ranging from 0.15 to 0.35 mg/kg/d. Additional courses were administered at 4-week intervals to patients in whom there was no evidence of progressive disease or severe toxicity.
ECG Evaluation Tracings were first examined in terms of suitability for QT interval analysis according to prospectively defined criteria. Tracings of poor quality (baseline artifact, markedly flattened T waves, marked tachycardia with P on T) or with confounding ECG abnormalities (nonsinus rhythm, bundle branch block, frequent ectopic complexes) were excluded from the analysis. For ECGs found to be suitable, QT and RR intervals were measured manually and subsequently compared with the machine-generated values. If the manually determined QT interval was within 10% of the machine-generated value, the machine-generated value was used for analysis. Otherwise, 40 milliseconds was added to or subtracted from the machine-generated value, depending on whether the machine measurement was significantly shorter or longer than the manually obtained values. All QT measurements were then corrected for heart rate (QTc) using Bazett’s formula (QTc = QT/SQRT [60/heart rate]). ECG data were matched to patient dosing records and individual treatment courses. If multiple ECGs had been obtained on the same day, only the ECG recorded immediately before that day’s infusion was included in the analysis. As stated in the "Points to Consider" document of the Committee for Proprietary Medicinal Products (CPMP), QTc intervals were classified as normal (males, < 430 milliseconds; females, < 450 milliseconds), borderline (males, 431 to 450 milliseconds; females, 451 to 470 milliseconds), or prolonged (males, > 450 milliseconds; females, > 470 milliseconds).16 Similarly, QTc changes relative to baseline were considered as "unlikely to raise concern" if they were less than 30 milliseconds, "likely to represent a drug effect and raise concern" if they were between 30 and 60 milliseconds, and "raising clear concern" if they were more than 60 milliseconds. If an ECG with validated intervals was obtained on the first day of a treatment course, this ECG was used as the baseline study. Otherwise, the ECG with validated intervals closest to, but before the start of treatment was used as the baseline. If no such ECG was available, the first ECG with validated intervals within 48 hours after the beginning of treatment was used as the baseline ECG. Validated ECGs obtained during arsenic trioxide treatment or within 1 day after the end of treatment were used to determine the overall maximal postdose QTc and overall change from baseline. ECGs obtained from 10 days after the start of treatment until 1 day after the end of treatment were used to determine the maximal steady-state QTc and the steady-state changes from baseline.
Statistical Analyses Demographic characteristics were analyzed for individual patients. QTc responses were analyzed for individual treatment courses or individual ECGs, as appropriate. The steady-state change in QTc relative to arsenic trioxide dose (in mg/kg) was evaluated by linear regression using all valid measurements obtained during the steady-state portion of therapy (10 days after the start of therapy until 1 day after the end of therapy). The time-dependent change in QTc (relative to baseline) during the course of treatment was examined graphically, and a first-order (exponential) approach to steady-state value of QTc was postulated. The steady-state prolongation of the QTc and the half-time for first-order approach to steady-state, as well as the 95% confidence limits, were determined by fitting the following function to all valid during-treatment measurements using nonlinear least-squares regression: change in QTc = a * (1.0 to 0.5 [t/b]), where "t" is the time since first infusion for this course of treatment, "a" is the steady-state prolongation, and "b" is the half-time. The time-dependent change in heart rate (relative to baseline) was examined graphically, and a linear model was postulated. The postbaseline, during-treatment values were fitted to the following linear model: heart rate = a + b * (days after initial dose: 20), where "a" is the intercept and "b" is the slope of the heart rate–time curve. In this model, the intercept was shifted to day 20 to be close to the centroid of the treatment times. The effect of multiple courses of therapy was evaluated by comparing the QT and heart rate at baseline, and the QT and heart rate responses before and during the second course of arsenic trioxide with those from the first course.
Results were stratified by age (
Patient Population Of the 99 patients evaluated, 71 had hematologic malignancies, and 28 had solid tumors. Table 1  summarizes the sex, age, ethnicity, and tumor type distribution in the study population. Ages ranged from 5 to 75 years, with approximately 61% of patients between the ages of 18 and 59. Most patients were white (81%). Fifty-two percent of patients were diagnosed with APL, 19% with other hematologic malignancies, and 28% with nonhematologic malignancies. All patients with relapsed APL had undergone previous treatment with an anthracycline agent. Among the APL patients, 58% had received at least two regimens before receiving arsenic trioxide therapy. Most of the patients with solid tumors had received three or more previous regimens. Of the 99 patients whose ECGs were included in this analysis, 22 had received at least one concomitant medication known to prolong the QT interval (Table 2). Eight (31%) of these 22 patients had a QTc greater than 500 milliseconds, compared with 18 (23%) of 77 patients among those not receiving a concomitant medication known to prolong QTc (P = .010 using Fisher’s exact test).
Arsenic Trioxide Treatment Among the cases assessed, 170 individual courses of arsenic trioxide therapy were evaluated. The study patients received one course (n = 38), two courses (n = 53), three courses (n = 7), or five courses (n = 1). The arsenic trioxide dose ranged from 0.1 to 0.35 mg/kg/d, with 80% of patients receiving between 0.1 and 0.2 mg/kg/d (Table 3 ). The median cumulative dose of arsenic trioxide was 679.3 mg (range, 11.5 to 1181.2 mg) in patients with relapsed APL, 375.7 mg (range, 19.8 to 1155.0 mg) in patients with advanced hematologic malignancies, and 131.0 mg (range, 31.8 to 630.0 mg) in patients with solid tumors.
ECG Evaluation Before and during arsenic trioxide therapy, 1,189 ECG tracings were obtained. Baseline ECG abnormalities were observed in 36 patients, including marked sinus tachycardia, bundle branch block, ST-T wave changes, atrial fibrillation, and evidence of previous myocardial infarction. Despite these abnormalities, in 949 (80%) of the ECGs, the RR and QT intervals could be determined, and QTc intervals could be calculated. Among the 99 patients for whom ECG tracings were obtained, 10 had no tracings suitable for QT interval analysis. Table 3  lists, by dose group, the number of patients and the number of treatment courses included in each of the analyses presented. Three patients received courses at two dose levels; their data are included in the counts at each dose level in Table 3, but are counted only once in the totals. In all, 89 patients had at least one valid ECG tracing: 86 had a valid baseline tracing, 70 had at least one valid on-therapy tracing, and 56 had valid baseline and steady-state ECG tracings. Among those 56 patients, the median number of evaluable tracings per subject was four (range, one to 10); 36 patients had at least three evaluable tracings; 23 had at least five; 12 had at least eight; and one patient had 10. A total of 143 cycles of therapy are represented in at least one analysis.
The most clinically relevant electrocardiographic change noted in patients treated with arsenic trioxide was prolongation of the QT/QTc interval (38 of 56 patients with evaluable baseline ECGs) as defined by the CPMP "Points to Consider." Of these 38 patients, 26 had a total of 126 ECGs with QTc intervals
Sex significantly affected the time-dependent changes in QTc, even after correcting for age, weight, and dose. Although both men and women showed significant prolongation of their QTc interval at steady state (both P < .001), men took longer to reach steady-state (mean ± standard deviation [SD] time: men, half-time = 10 ± 4 days; women, half-time = 3 ± 2 days; P = .118) and had greater steady-state prolongation (men, 62 ± 13 milliseconds; women, 35 ± 5 milliseconds; P = .053). These sex differences approached but did not attain statistical significance. For the combined study population, QTc interval prolonged gradually with each cycle of arsenic trioxide to reach a mean ± SD steady-state prolongation of 47 ± 5 milliseconds (Fig 2 ), with a mean ± SD half-time of 6 ± 2 days. This cumulative effect was observed only during the treatment cycles and was reversible after discontinuation of therapy. Male and female patients had similar heart rate responses to treatment. In both, heart rates were significantly (P < .001) elevated by approximately 10 bpm relative to baseline. However, unlike QTc prolongation, which occurred gradually over many days, the heart rate elevation occurred almost immediately after initiation of treatment, and then persisted unchanged throughout the remainder of the treatment course (Fig 3). Thus, the increase in heart rate does not account for the gradual QTc prolongation that was observed during therapy, despite using Bazett’s correction.
Effect of Treatment Course Twenty-four patients (15 men and nine women) had valid ECG tracings for QTc determination from two or more arsenic trioxide treatment courses. Baseline QTc intervals did not differ significantly before the second course (men, 424.2 milliseconds; women, 436.9 milliseconds) from those obtained before initiation of arsenic trioxide (men, 421.5 milliseconds; women, 426.1 milliseconds), showing that arsenic trioxide does not cause permanent prolongation of the QTc interval. QTc prolongation during the second course was significantly less than during the first course in men (P = .014), but not in women (P = .8) (Fig 4 ), eliminating the borderline (P = .054) greater QTc prolongation seen in men during the first course.
Men had similar heart rates at baseline and during therapy (P = .17), with similar elevations in heart rate during the first and second courses of therapy (P = .88; Fig 5 ). In women, however, the elevation in heart rate was significantly less during the second course of arsenic trioxide therapy (4.1 bpm) than during the first course (19.7 bpm; P = .04), probably resulting, at least in part, from an elevation in baseline heart rate of 8 bpm (P = .08) before the second course.
Clinically Significant Cardiac Arrhythmias Of the 99 patients assessed, two patients developed clinically significant arrhythmias. A 50-year-old African American woman with relapsed APL who was receiving multiple concomitant medications, including amphotericin B, became hypokalemic and developed a prolonged QT interval of 618 milliseconds on day 30 of treatment. She was monitored on telemetry, which showed that she had a brief run of asymptomatic, nonsustained ventricular polymorphic tachycardia. Intravenous potassium and magnesium were given, and therapy with arsenic trioxide was withheld. Her QT interval normalized. Because bone marrow evaluation revealed a remission, the arsenic trioxide was not restarted. On day 60, the patient began consolidation treatment with arsenic trioxide and completed a 25-day course without recurrence of QT prolongation. A 45-year-old man with relapsed APL and neutropenic fever developed acute respiratory distress, hyperkalemia, oliguria with incipient renal failure, atrial fibrillation, and right bundle branch block that ultimately deteriorated into complete atrioventricular block on day 4 of therapy. He was transferred to the intensive care unit, where he was maximally supported with mechanical ventilation and insertion of a temporary pacemaker and was treated symptomatically. Arsenic trioxide was withheld on days 4 and 5. By day 6, his condition had improved markedly, and arsenic trioxide therapy was restarted. By day 7, normal sinus rhythm returned.
In clinical practice, QT interval prolongation is most commonly a result of administration of therapeutic drugs. Arsenic trioxide is one of many noncardiac drugs with this propensity. The aim of this analysis was to assess the degree of QT interval prolongation demonstrated in patients with relapsed APL or advanced malignancies, who receive arsenic trioxide in a clinical trial setting. Similar to previous observations of nontherapeutic exposure to arsenic, arsenic trioxide prolonged the QTc interval of the combined study population. The QT changes observed in this analysis developed gradually during a period of 6 to 24 days, and did not continue to increase with continued exposure; in addition, the changes were predictable and reversible. During the course of treatment, the QTc interval was gradually prolonged by a mean of 47 milliseconds with a half-time of 6 days. This suggests that the QT prolongation observed after 18 to 24 days of therapy closely approximates the maximum expected change. Significant sex differences were detected during the first course of arsenic trioxide therapy; specifically, men had a slower rate of prolongation and a higher steady-state value. This sex difference persisted after adjustments were made for age, weight, and dose. However, during the second course of arsenic trioxide therapy, men had significantly less prolongation than during their first course, eliminating the sex difference in degree of QT prolongation.
QT prolongation can lead to TdP, a potentially life-threatening form of polymorphic ventricular tachycardia with a pathognomonic ECG appearance.17 TdP can present as an episode of symptomatic palpitations or even as syncope; it may also be a cause of sudden death. The decision of whether to continue or interrupt therapy with a drug noted to prolong the QT interval is therefore strongly influenced by the benefit derived from such therapy and the extent of QT prolongation. During the course of therapy with arsenic trioxide in this analysis, many patients were also treated with other drugs known to cause QT prolongation, as well as with drugs that affect serum electrolytes, especially potassium. Because the effects of QTc-prolonging agents are additive, it is not surprising that significant QTc prolongation usually occurred in the setting of hypokalemia or when arsenic trioxide was given after or with other QTc-prolonging drugs. The fact that the only patient in this study who was known to develop TdP while receiving arsenic trioxide did so in the setting of hypokalemia supports current US Food and Drug Administration recommendations for the safe administration of arsenic trioxide (Table 4
In contrast to our experience, other groups have reported cardiac complications, including atrioventricular block, monomorphic ventricular tachycardia, polymorphic ventricular tachycardia, and sudden death, during their early experience with arsenic trioxide therapy.20–23 These arrhythmias may have been pre-existing or unrelated to arsenic trioxide–induced QTc prolongation. Previous studies have shown that following cancer therapy, 52% of patients have premature ventricular contractions, and 3% to 5% of patients have ventricular tachycardia detected by a single 24-hour Holter recording.24,25 Thus, the relationship between the QTc prolongation induced by arsenic trioxide and the arrhythmias reported by these studies is uncertain. In patients with relapsed APL, a malignancy with an extremely poor prognosis, the risks and benefits of arsenic trioxide therapy should be considered with respect to the potential for prolongation of the QT interval and the minimal potential for serious consequences such as TdP, as shown in this analysis. Cardiotoxicity is a known complication of many chemotherapeutic agents.26 Anthracyclines produce cardiac arrhythmias and irreversible cardiomyopathy that can lead to severe, sometimes fatal, congestive heart failure.26–29 Despite these risks, anthracyclines constitute one of the most commonly used classes of chemotherapeutic agents, and they represent part of the standard of care for many malignancies. Unlike the cardiotoxic effects of anthracyclines and anthracycline-related agents, which are often irreversible,27,29 QTc changes observed during arsenic trioxide therapy are transient, reversing gradually throughout the weeks following completion of therapy.
All of the patients with APL, and many of those with advanced malignancies in this study, had been exposed to previous anthracycline therapy and possibly had some degree of residual cardiotoxicity, and were prone to cardiac arrhythmia. Of 24 patients who developed a QTc interval Arsenic trioxide is a highly effective treatment for relapsed APL, which is an immediately life-threatening condition. Although QT prolongation was observed in 68% of patients with valid baseline and steady-state ECG tracings, the QT changes observed in this analysis reveal a cumulative but reversible effect. These observations suggest that proper management of patients before and during arsenic trioxide therapy, including recommended ECG and electrolyte monitoring, optimizes safe arsenic trioxide administration. The potential role of arsenic trioxide in other hematologic malignancies, as well as in solid tumors, is currently being explored in several phase II studies.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the past 2 years: Jean T. Barbey, Cell Therapeutics; Steven L Soignet, Cell Therapeutics. Received more than $2,000 a year from a company for either of the past 2 years: Jean T. Barbey, Scherring Plough, Scherring AG Germany, Otsuka Pharmaceuticals, Janssen Pharmaceutica, Bracco Diagnostics, Lundbeck, Takeda Pharmaceuticals, Genesoft.
This study was supported by research funding from Cell Therapeutics Inc, Seattle, WA.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
