Successful therapy for relapsed or refractory APL
Clinical studies have demonstrated the important role arsenic trioxide may have
in the treatment of patients with relapsed or refractory acute promyelocytic leukemia
(APL). When initial therapies fail, TRISENOX
® (arsenic trioxide)
injection has shown to be a successful second-line therapy.
Current first-line therapy for APL
In the past, APL was associated with a high risk of early mortality, but with the
introduction of all-trans retinoic acid (ATRA), APL has become the most curable
subtype of acute myeloid leukemia (AML).
1
Multiple studies have established that the combination of ATRA and chemotherapy
in newly diagnosed patients has increased the cure rate to 70% from 35% in patients
treated with chemotherapy alone.
2 Additionally, the incorporation of
ATRA into the treatment regimen has more than doubled the survival rate of newly
diagnosed patients over that achieved with chemotherapy alone.
3,4-7
Given this success, the current first-line standard treatment given to patients
with newly diagnosed APL consists of ATRA and anthracycline-based cytotoxic chemotherapy.
8
Daunorubicin and idarubicin are two commonly used anthracyclines shown to induce
complete remission in 60% to 80% of APL patients.
9-11
Relapse and resistance
Despite improvements in remission and survival rates, 20% to 30% of patients relapse
and are often resistant to further treatment with ATRA.
1,2,8
Approximately 50% of the patients in first relapse presently have the chance to
achieve long-lasting second remissions and probably cure with salvage regimens.
1
Salvage therapy often involves high doses of cytotoxic chemotherapy, followed by
either autologous or allogeneic transplantation. With this approach, these patients
are exposed to, and a certain proportion die from, the toxic effects of chemotherapy,
an important consideration in treating young or elderly patients. TRISENOX may fill
the critical need for therapeutic options in treating relapsed or refractory APL.
3
The role of arsenic trioxide
Studies of arsenic trioxide have demonstrated a high rate of complete remission,
suggesting that TRISENOX is an important treatment option for patients who have
relapsed from, or did not respond to, initial therapy.
3,12 According
to the National Comprehensive Cancer Network (NCCN) guidelines for oncology, arsenic
trioxide is the standard of care for patients who have relapsed from, or did not
respond to, their initial treatment.
13
>> Click here to view the efficacy data
for TRISENOX.
TRISENOX is indicated for induction of remission and consolidation in patients with APL who
are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose
APL is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression.
Serious adverse events, grade 3 or 4, were common. Those events attributable to TRISENOX in the Phase 2
study of 40 patients with refractory or relapsed APL included APL differentiation syndrome (n=3), hyperleukocytosis (n=3), QTc
interval prolongation (n=16), atrial dysrhythmias (n=2), hyperglycemia (n=2), and torsades de pointes (n=1).
In addition to QT interval prolongation, the most common drug-related side effects included leukocytosis, gastrointestinal events (nausea, vomiting, diarrhea, and abdominal pain), fatigue, swelling, hyperglycemia (an abnormal increased content of sugar in the blood), shortness of breath, cough, rash or itching, headache, and dizziness. Have your doctor review side effects with you.
In clinical trials, most patients taking TRISENOX experienced some drug-related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headache, and dizziness. These adverse effects have not been observed to be permanent or irreversible, nor do they usually require interruption of therapy.
To report an adverse event contact Cephalon Medical Services at 1-800-896-5855 or usmedinfo@cephalon.com.
WARNING
Experienced Physician and Institution:
TRISENOX® (arsenic trioxide) injection should be administered under the supervision
of a physician who is experienced in the management of patients with acute leukemia.
APL Differentiation Syndrome:
Some patients with APL treated with TRISENOX have experienced symptoms similar to a syndrome called
the retinoic-acid-acute promyelocytic leukemia (RA-APL) or APL differentiation syndrome, characterized
by fever, dyspnea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or
without leukocytosis. This syndrome can be fatal. The management of the syndrome has not been fully
studied, but high-dose steroids have been used at the first suspicion of the APL differentiation
syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome
(unexplained fever, dyspnea and/or weight gain, abnormal chest auscultatory findings or radiographic
abnormalities), high-dose steroids (dexamethasone 10 mg intravenously BID) should be immediately
initiated, irrespective of the leukocyte count, and continued for at least 3 days or longer until
signs and symptoms have abated. The majority of patients do not require termination of TRISENOX therapy
during treatment of the APL differentiation syndrome.
ECG Abnormalities:
Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can
lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes
is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of
torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of
potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia. One patient
(also receiving amphotericin B) had torsade de pointes during induction therapy for relapsed APL with arsenic
trioxide.
ECG and Electrolyte Monitoring Recommendations:
Prior to initiating therapy with TRISENOX, a 12-lead ECG should be performed and serum electrolytes (potassium,
calcium, and magnesium) and creatinine should be assessed; pre-existing electrolyte abnormalities should be
corrected and, if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc
greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior
to considering using TRISENOX. During therapy with TRISENOX, potassium concentrations should be kept above 4 mEq/L
and magnesium concentrations should be kept above 1.8 mg/dL. Patients who reach an absolute QT interval value > 500
msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while
the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. If syncope, rapid or irregular
heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, TRISENOX
therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities
are corrected, and the syncope and irregular heartbeat cease. There are no data on the effect of TRISENOX on the QTc
interval during the infusion.
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2. Douer D. Advances in the treatment of relapsed acute promyelocytic leukemia.
Acta Haematol. 2002;107:1-17.
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4. Soignet S, Fleishauer A, Polyak T, et al. All-trans retinoic acid significantly
increases 5-year survival in patients with acute promyelocytic leukemia: long-term
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promyelocytic leukemia. N Engl J Med. 1997;337:1021-1028.
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acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of
maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European
APL Group. Blood. 1999;94:1192-1200.
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J Med. 1993;329:177-189.
8. Soignet SL. Clinical experience of arsenic trioxide in relapsed acute promyelocytic
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9. Lowenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic
leukemia. Hematology Am Soc Hematol Educ Program. 2003:82-101.
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treatment by daunorubicin. Blood. 1973;41:489-496.
11. Avvisati G, Mandelli F, Petti MC, et al. Idarubicin (4-demethoxydaunorubicin)
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13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology:
Acute Myeloid Leukemia — v.1.2009.