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Blood, 1 September 2001, Vol. 98, No. 5, pp. 1632-1634
CORRESPONDENCE
To the editor:
Cardiac toxicity of arsenic trioxide
Unnikrishnan et al have reported the occurrence of torsades de
pointes in 3 of 19 patients treated with arsenic
trioxide.1 The propensity for arsenic to cause reversible
Q-T interval prolongation is well known and has previously been
characterized.2 To minimize the risk of long Q-T-related
arrhythmias associated with arsenic therapy, Cell Therapeutics, makers
of the FDA-approved Trisenox (arsenic trioxide), have issued very
specific guidelines regarding electrolyte monitoring and replacement,
as well as avoidance of concomitant Q-T interval prolonging in patients
being treated with their compound.3 Three specific points regarding the cases submitted by
Unnikrishnan et al are worth emphasizing. The rhythm strip submitted for patient 2 clearly demonstrates the "long-short" initiation sequence pathognomonic for torsades de pointes. Presumably, strips from
patients 1 and 3 display similar initiating sequences thus supporting a
diagnosis of acquired long Q-T syndrome rather than that of nonspecific
cardiac arrest, a distinction not always easy to make in such sick
patients. All 3 patients displayed widely fluctuating serum levels of
potassium and magnesium. Hypokalemia, hypomagnesemia, and diuretic use
clearly increase the risk of long Q-T-related arrhythmias, making
aggressive electrolyte replacement mandatory in such a population.
Finally, the Q-Tc intervals reported in Unnikrishnan et al's Table 1 appear surprisingly short for patients experiencing torsades de
pointes. These values are likely machine generated and are probably
incorrect in view of the marked tachycardia and T-wave flattening
observed in these patients. In summary, arsenic trioxide prolongs the Q-T interval in a gradual and
reversible fashion and is liable to cause torsade de pointes unless
stringent precautions are taken. Aggressive electrolyte replacement is
mandatory, and monitoring of the Q-T interval warranted, recognizing
that machine generated values may become unreliable in the presence of
marked tachycardia and T-wave flattening. Finally, if cardiac
arrhythmias occur, distinguishing torsades de pointes (an adverse drug
reaction until proven otherwise) from other arrhythmias has important
therapeutic and public health implications.
Jean T. Barbey
Correspondence: Division of Clinical Pharmacology, Georgetown
University, Washington DC
Acknowledgments
J.T.B. was a paid consultant for Cell Therapeutics but currently
has no financial interest in that company or in any competing company.
References
1.
Unnikrishnan D, Dutcher JP, Varsheneya N, et al.
Torsades de Pointes in 3 patients with leukemia treated with arsenic trioxide.
Blood.
2001;97:1514-1516[Abstract/Free Full Text].
2.
Barbey JT, Soignet SL.
Arsenic trioxide (ATO): analysis of QT prolongation on electrocardiogram (ECG) [abstract].
Blood.
2000;96:319a.
3. Trisenox [package insert]. Seattle, WA: Cell Therapeutics;
2000.
To the editor:
Cardiac toxicity of arsenic trioxide
Unnikrishnan et al describe 3 patients out of 19 treated
with arsenic trioxide who developed torsades de pointes (TDP) that proved fatal in 2. The source of the arsenic trioxide given these patients and its characterization and formulation are not stated in the
article. But inasmuch as the article was submitted to Blood prior to FDA approval of Trisenox brand of arsenic trioxide for injection on September 25, 2000, and no Trisenox studies under the Cell
Therapeutics investigational new drug application (IND) were
performed at Our Lady of Mercy Cancer Center, we are sure that the
arsenic trioxide formulation administered in that study was not
manufactured by Cell Therapeutics, the only commercial source of this
agent in the United States. We believe this distinction is important because the safety
experience reported for Trisenox has been very different from that
reported in the Unnikrishnan et al article and that reported with
another research product by Westervelt et al,2 a report cited in Unnikrishnan et al. As director of the Pharmacovigilance Committee at Cell Therapeutics, I would like to review our safety experience to date with Trisenox, particularly with reference to Q-T
prolongation, TDP, and the FDA-approved guidelines for safe and
effective use of Trisenox as described in the product label. Trisenox for injection was approved for marketing in September 2000, for the treatment of relapsed and refractory acute promyelocytic leukemia (APL). In the multicenter pivotal study of Trisenox in relapsed or refractory APL, 70% of the patients achieved a complete remission, with 78% demonstrating a molecular remission. The median survival is greater than 18 months. Our current pharmacovigilance database consists of more than 360 patients treated with Trisenox at doses ranging from 0.15 to 0.35 mg/kg/d. These data include patients treated on clinical investigations
in a variety of malignancies conducted under our company-sponsored IND,
in NCI-sponsored trials under a Cooperative Research and
Development Agreement (CRADA), or on a compassionate-use program for
patients with APL. In addition, postmarketing surveillance adverse-event reports on patients treated since product launch in
October 2000 were evaluated. Q-T prolongation is a well known and
expected effect of arsenic trioxide treatment. To date, only 3 cases of
Q-T prolongation above 500 millisecond (ms) have been reported. No
deaths due to cardiac arrhythmias have been attributed to Trisenox. In a detailed independent review of 1000 electrocardiograms from 99 patients on clinical trials, 26 cases of Q-Tc above 500 ms were
identified, with 3 cases having an absolute Q-T above 500 ms. A single
case of self-limited TDP occurred in a patient undergoing induction
therapy for APL who was also receiving amphotericin B. The TDP resolved
after electrolyte correction, and the patient went on to receive
consolidation therapy uneventfully. Under the management
guidelines included in the label, treatment emergent adverse events
have decreased over time, are less common in consolidation and
maintenance, and usually have not required stopping therapy. The high frequency and severity of complex arrhythmias or deaths
reported by Unnikrishnan et al and Westervelt et al, 2 sites using
investigational arsenic trioxide, appear to be different from the
relatively lower frequency of events that have been reported with
Trisenox. Why these experiences differ so markedly from that reported
by Unnikrishnan et al or Westervelt et al is uncertain. It should be
noted that patients 1 and 2 in the Unnikrishnan et al study received 20 mg of arsenic trioxide per day, potentially a higher than recommended
dose of 0.15 mg/kg/d, although the patient weights were not given. Both
patients had marked hypomagnesemia, hypokalemia, and pulmonary failure
at the time they developed TDP. The "black box" warning in the
Trisenox label recommends that the potassium and magnesium values be
maintained at midnormal levels when administering Trisenox (at least 4 mEq/L for potassium and 1.8 mg/dL for magnesium). The third patient
received 10 mg/d of arsenic trioxide, which was stopped after 7 days
for prolongation of the Q-Tc. TDP developed after the drug had been
discontinued for 5 days and the Q-T interval was normalizing. As this
patient also had respiratory failure and was on a ventilator, factors other than arsenic trioxide may have contributed to his refractory arrhythmia. Based on the available data on more than 360 patients, the safety of
administration of Trisenox can be optimized with appropriate monitoring
and management of electrocardiogram abnormalities as described in the
product label.
Jack W. Singer
Correspondence: Cell Therapeutics, 201 Eliot Ave, West, Suite
400, Seattle, WA 98119
Acknowledgments
J.W.S. is Executive Vice President of Cell Therapeutics and holds
more than $10,000 worth of stock in that company.
References
1.
Unnikrishnan D, Dutcher JP, Varsheneya N, et al.
Torsades de Pointes in 3 patients with leukemia treated with arsenic trioxide.
Blood.
2001;97:1514-1516.
2.
Westervelt P, Brown R, Adkins D, et al.
Sudden deaths among acute promyelocytic leukemia patients treated with arsenic trioxide [abstract].
Blood.
2000;96:723a.
Response:
Monitoring of cardiac toxicity with arsenic trioxide
We thank you for the opportunity to comment on the letters by
Barbey and by Singer, regarding our brief report on the occurrence of
torsades de pointes in 3 patients with relapsed/refractory acute
myelogenous leukemia treated with arsenic trioxide. First, in response
to Dr Barbey, the arrhythmias observed in all 3 patients were
preceded by the long-short initiation sequence. We did not have room to
present electrocardiograms (ECGs) from all 3 patients. In 2 of the
patients, this rhythm was not symptomatic initially but did recur. It
was not the cause of death in these 2 patients. In discussion of the
electrolytes, "widely fluctuating" is a bit of an overstatement.
Nevertheless, it is clear that the variation in the values presented in
the manuscript are consistent with observations obtained in seriously
ill, hospitalized patients with acute leukemia, who require daily
monitoring of blood values, including electrolytes, and who require
frequent replacement of electrolytes. These patients are not simple to
manage, in that they require multiple antibiotics and blood products,
in addition to daily arsenic, and intravenous intake frequently exceeds
3 liters per day in such patients. Additionally, the fluid retention syndrome noted with the use of arsenic trioxide makes fluid and electrolyte balance even more difficult, and diuretics may be necessary. In contrast, acute promyelocytic leukemia patients, in whom
molecular or cytogenetic relapse can be detected prior to florid
blastic leukemia, may not have such severe problems and may be more
easily managed. But Q-Tc prolongation and ventricular arrhythmias have
been observed even in this population.1 The third point by Dr Barbey is not correct. The Q-Tc values presented
were not machine values, but values calculated independently by 2 cardiologists and then confirmed. We agree that the degree of
prolongation was moderate, but the observation that we made that may be
more important than an isolated Q-Tc interval was our observation of
serial prolongation of Q-Tc, occurring in these patients as treatment
progressed. Thus, the reliability of an isolated prolonged Q-Tc may be
less valuable than serial measurements in predicting the risk of arrhythmia. With respect to the comments by Dr Singer, our initial point in the
brief report was to demonstrate the multiple factors that impact on
seriously ill leukemia patients, in addition to the therapy with
arsenic trioxide. But since torsades de pointes is known to be
associated with arsenic ingestion, as is Q-Tc prolongation, careful and
serial monitoring is required.1-4 We agree with the recommendations provided in the package insert, and we concur that
careful attention to electrolyte replacement is important. Whether that
is sufficient remains to be determined, and further evaluation of the
electrophysiology seems warranted.
Dilip Unnikrishnan, Janice P. Dutcher, Nikita Varshneya, Richard Lucariello, Peter H. Wiernik, and Salvatore Chiaramida
Correspondence: Janice P. Dutcher, Our Lady of Mercy
Cancer Center, 660 E 233rd St, Bronx, NY 10466
References
1.
Ohnishi K, Yoshida H, Shigeno K, et al.
Prolongation of the QT interval and ventricular tachycardia in patients treated with arsenic trioxide for acute promyelocytic leukemia.
Ann Intern Med.
2000;133:881-885[Abstract/Free Full Text].
2.
Goldsmith S, From AH.
Arsenic-induced atypical ventricular tachycardia.
N Engl J Med.
1980;303:1096-1098[Medline]
[Order article via Infotrieve].
3.
Westervelt P, Pollock J, Huag J, Ley TJ, DiPersio JF.
Response and toxicity associated with dose escalation of arsenic trioxide in the treatment of resistant acute promyelocytic leukemia [abstract].
Blood.
1997;90(suppl 1):249b.
4.
Westervelt P, Brown RA, Adkins DR, et al.
Sudden death among patients with acute promyelocytic leukemia treated with arsenic trioxide.
Blood.
2001;98:266-271[Abstract/Free Full Text].
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