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The importance of a full course of treatment with TRISENOX®

A high rate of molecular remission (MR) with TRISENOX therapy was seen in patients who completed both the induction and consolidation phases1

Of the 40 relapsed/refractory patients in the TRISENOX Phase 2 study, 70% (28/40) achieved complete remission (CR) during the induction phase of therapy.1 Among 22 patients who had relapsed <1 year after treatment with ATRA, 82% (n=18) were complete responders. Of the 18 patients receiving TRISENOX ≥1 year from ATRA treatment, there were 10 complete responders (55%).1

During the consolidation phase of therapy, 79% (22/28) of CR patients went on to achieve MR.1

MR is a treatment goal recommended by the National Comprehensive Cancer Network (NCCN) and the International Working Group (IWG).2,3

Patients who achieve MR—no detection of PML/RAR-α gene by RT-PCR testing—are less likely to relapse again than patients who achieve CR.4 In other words, achieving MR increases the likelihood that patients will not experience a return of the disease.4

Study design

A US multicenter, open-label, single-arm, non-comparative, Phase 2 trial evaluated complete response (CR) rates in 40 patients with APL who had either relapsed after or did not respond to induction chemotherapy using an anthracycline and a retinoid regimen.1

View study data

NCCN Guidelines® recognize arsenic trioxide (ATO) as a recommended treatment option for patients who do not achieve MR at completion of consolidation or who subsequently demonstrate molecular relapse.2

Important Safety Information

WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE MONITORING

APL Differentiation Syndrome: 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. High-dose steroids have been administered 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), immediately initiate high-dose steroids (dexamethasone 10 mg intravenously BID), irrespective of the leukocyte count, and continue 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.

Cardiac Conduction Abnormalities: Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. 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, preexisting 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.

Contraindications: TRISENOX is contraindicated in patients who are hypersensitive to arsenic.

APL Differentiation Syndrome: Nine of 40 patients with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome.

Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, and QT Prolongation: Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned towards baseline by the end of 8 weeks after TRISENOX infusion. Monitor ECG weekly and more frequently for clinically unstable patients. For QTc greater than 500 msec, complete corrective measures and reassess the QTc with serial ECGs prior to initiating TRISENOX. During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Reassess patients who reach an absolute QT interval value > 500 msec and immediately correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. The risk may be increased when TRISENOX is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).

Carcinogenesis: The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Embryo-Fetal Toxicity: TRISENOX can cause fetal harm when administered to a pregnant woman. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with TRISENOX.

Lactation: TRISENOX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, discontinue breastfeeding during treatment with TRISENOX.

Laboratory Tests: Electrolyte and glucose levels, as well as hepatic, renal, hematologic, and coagulation profiles should be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.

Drug Interactions: Avoid the concomitant use of TRISENOX with medications that can prolong the QT/QTc interval or those that can lead to electrolyte abnormalities. Concomitant use of drugs that can prolong the QT/QTc interval with TRISENOX may increase the risk of serious QT/QTc interval prolongation. Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation. Monitor ECGs and electrolytes more frequently in patients who are unable to avoid concomitant use of these medications and TRISENOX.

Pediatric Use: In a pediatric study, the toxicity profile observed in 13 pediatric patients with APL between the ages of 4 and 20 receiving TRISENOX was similar to that observed in adult patients. Additional drug-related toxicities reported included: gastrointestinal disorders, metabolic and nutrition disorders, respiratory disorders, cardiac failure congestive, neuralgia, and enuresis. One case each of pulmonary edema and caecitis were considered serious reactions. No children less than 4 years of age were enrolled in the trial due to the rarity of APL in this age group.

Patients with Renal Impairment: Exposure of arsenic trioxide may be higher in patients with severe renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied.

Patients with Hepatic Impairment: Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.

Most Common Adverse Reactions: Most patients experienced some drug related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.

TO REPORT SIDE EFFECTS:
Contact us at 1-800-896-5855 or USMedInfo@tevapharm.com

References
  1. TRISENOX® (arsenic trioxide) injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals USA, Inc.; 2015.
  2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Acute Myeloid Leukemia V.1.2016. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed March 11, 2016. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.
  3. Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol. 2003;21(24):4642-4649.
  4. Diverio D, Rossi V, Avvisati G, et al; for GIMEMA and AIEOP Cooperative Groups. Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARα fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter “AIDA” trial. Blood. 1998;92(3):784-789.
©2016 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. The information presented on this Web site is intended for US residents only. TRI-40181. June 2016.
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Important Safety Information

WARNING: APL DIFFERENTIATION SYNDROME, CARDIAC CONDUCTION ABNORMALITIES, AND ELECTROLYTE MONITORING

APL Differentiation Syndrome: 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. High-dose steroids have been administered 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), immediately initiate high-dose steroids (dexamethasone 10 mg intravenously BID), irrespective of the leukocyte count, and continue 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.

Cardiac Conduction Abnormalities: Before initiating therapy, perform a 12-lead ECG, assess serum electrolytes and creatinine, correct preexisting electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. 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, preexisting 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.

Contraindications: TRISENOX is contraindicated in patients who are hypersensitive to arsenic.

APL Differentiation Syndrome: Nine of 40 patients with APL treated with TRISENOX, at a dose of 0.15 mg/kg, experienced the APL differentiation syndrome.

Cardiac Conduction Abnormalities: Torsade de Pointes, Complete Heart Block, and QT Prolongation: Sixteen of 40 patients (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of the QTc was observed between 1 and 5 weeks after TRISENOX infusion, and then returned towards baseline by the end of 8 weeks after TRISENOX infusion. Monitor ECG weekly and more frequently for clinically unstable patients. For QTc greater than 500 msec, complete corrective measures and reassess the QTc with serial ECGs prior to initiating TRISENOX. During TRISENOX therapy, maintain potassium concentrations above 4 mEq/L and magnesium concentrations above 1.8 mg/dL. Reassess patients who reach an absolute QT interval value > 500 msec and immediately correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending TRISENOX therapy should be considered. The risk may be increased when TRISENOX is coadministered with medications that can lead to electrolyte abnormalities (such as diuretics or amphotericin B).

Carcinogenesis: The active ingredient of TRISENOX, arsenic trioxide, is a human carcinogen. Monitor patients for the development of second primary malignancies.

Embryo-Fetal Toxicity: TRISENOX can cause fetal harm when administered to a pregnant woman. One patient who became pregnant while receiving arsenic trioxide had a miscarriage. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and after treatment with TRISENOX.

Lactation: TRISENOX is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, discontinue breastfeeding during treatment with TRISENOX.

Laboratory Tests: Electrolyte and glucose levels, as well as hepatic, renal, hematologic, and coagulation profiles should be monitored at least twice weekly, and more frequently for clinically unstable patients during the induction phase and at least weekly during the consolidation phase.

Drug Interactions: Avoid the concomitant use of TRISENOX with medications that can prolong the QT/QTc interval or those that can lead to electrolyte abnormalities. Concomitant use of drugs that can prolong the QT/QTc interval with TRISENOX may increase the risk of serious QT/QTc interval prolongation. Electrolyte abnormalities increase the risk of serious QT/QTc interval prolongation. Monitor ECGs and electrolytes more frequently in patients who are unable to avoid concomitant use of these medications and TRISENOX.

Pediatric Use: In a pediatric study, the toxicity profile observed in 13 pediatric patients with APL between the ages of 4 and 20 receiving TRISENOX was similar to that observed in adult patients. Additional drug-related toxicities reported included: gastrointestinal disorders, metabolic and nutrition disorders, respiratory disorders, cardiac failure congestive, neuralgia, and enuresis. One case each of pulmonary edema and caecitis were considered serious reactions. No children less than 4 years of age were enrolled in the trial due to the rarity of APL in this age group.

Patients with Renal Impairment: Exposure of arsenic trioxide may be higher in patients with severe renal impairment. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) should be monitored for toxicity when these patients are treated with TRISENOX, and a dose reduction may be warranted. The use of TRISENOX in patients on dialysis has not been studied.

Patients with Hepatic Impairment: Since limited data are available across all hepatic impairment groups, caution is advised in the use of TRISENOX in patients with hepatic impairment. Monitor patients with severe hepatic impairment (Child-Pugh Class C) who are treated with TRISENOX for toxicity.

Most Common Adverse Reactions: Most patients experienced some drug related toxicity, most commonly leukocytosis, gastrointestinal (nausea, vomiting, diarrhea, and abdominal pain), fatigue, edema, hyperglycemia, dyspnea, cough, rash or itching, headaches, and dizziness. These adverse effects have not been observed to be permanent or irreversible nor do they usually require interruption of therapy.

TO REPORT SIDE EFFECTS:
Contact us at 1-800-896-5855 or USMedInfo@tevapharm.com

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Genetics and Pathology of R/R APL

This informational video summarizes the genetic mutation and pathology that underline relapsed/refractory APL.