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About relapsed/refractory acute promyelocytic leukemia (R/R APL)

What is R/R APL?

Relapsed or refractory APL, or R/R APL, is a quickly progressing form of cancer1

APL facts and statistics:

Classified as an M3 subtype of acute myeloid leukemia (AML)1

WHO classification:

A type of AML with recurrent genetic abnormalities2

A rare disease3

  • Accounts for ≈5% of all AML cases
  • ≈1,500 patients diagnosed annually in the United States

Median age at diagnosis is mid-40s3-5

    R/R APL prevalence:
of patients with APL may relapse6-9
*
Data in this section were derived from studies different from the clinical trial for TRISENOX.
How are “relapsed” and “refractory” defined?10
RELAPSED APL

is the recurrence of APL, after the disease has been in remission

REFRACTORY APL

is the failure to respond to initial treatment, which may lead to progressive disease

Signs and symptoms

Sometimes R/R APL is asymptomatic, but the following symptoms may mean relapse has occurred11:
  • Bruising too easily
  • Unexplained bleeding
  • Bleeding gums
  • Menstrual irregularity

Clinical presentation of R/R APL

  • Characterized by a high incidence of coagulopathy, primarily disseminated intravascular coagulation (DIC)12
  • Moderately severe thrombocytopenia (<50,000/µL)12
  • Dominant cells are promyelocytes comprising 30–100% of the marrow cells12
  • Auer rods and cells with multiple Auer rods11,12

Risk factors for R/R APL

These prognostic factors allow risk of relapse to be assessed in patients with APL:

Genetics and pathology of R/R APL

A specific type of genetic mutation, called a chromosomal translocation, underlies most cases of APL16

The translocation t(15;17) occurs between Chromosome (Chr) 15 and Chr 17, resulting in a chimeric gene, PML/RAR-α16

  • Chr 15 encodes the PML protein, which has shown activity in tumor suppression and apoptosis17
  • Chr 17 encodes the RAR-α protein, which has shown activity in myeloid cell differentiation17

The PML/RAR-α fusion protein18:

  • Inhibits apoptosis
  • Inhibits normal differentiation of promyelocytes
  • Promotes cell proliferation

See the translocation
process in detail

Watch video  

Confirming R/R APL

Several testing methods may be used to confirm R/R APL:
Blood smears19

Detect promyelocytes comprising ≥30% of bone marrow cells and the presence of Auer rods

Karyotyping9,19,20

Analyzes bone marrow samples at the chromosomal level to confirm the presence of pathognomonic translocation t(15;17)

FISH9,20

Employs dual color probes to identify the presence of the PML/RAR-α gene in bone marrow cells

RT-PCR19,20

Analyzes bone marrow cells to confirm the presence and level of PML/RAR-α RNA

Why is monitoring with RT-PCR testing important?

RT-PCR helps reveal if molecular remission (MR), an important treatment goal, has been achieved

Patients who achieve MR are less likely to relapse again than patients who achieve complete remission (CR)21

  • Early identification of R/R APL allows for timely treatment of the disease21
    •   Molecular analysis with RT-PCR can reveal minimal residual disease
    •   Molecular relapse is a predictor of hematologic relapse

Several studies show that positive RT-PCR results help identify refractory patients after consolidation and correlate with APL relapse9,10,22-25

NCCN Clinical Practice Guidelines in Oncology®
(NCCN Guidelines®) recommend it
Expand  

According to NCCN guidelines to detect APL relapse9:

  • RT-PCR should be performed on a marrow sample at completion of consolidation to document molecular remission
  • For low-risk patients, the frequency of patient monitoring by RT-PCR is at the discretion of the physician*
  • For high-risk patients, those >60 years old or who had long interruptions during consolidation, or patients not able to tolerate maintenance, monitoring is recommended every 3 months for 2 years*
  • When confirmed by a second positive test within 2-4 weeks, the patient should be treated for relapsed disease
*NCCN defines high-risk patients as those >60 years of age or who had long interruptions during consolidation, or patients on regimens that use maintenance and are not able to tolerate maintenance and low-risk patients as those who are in molecular remission at completion of consolidation and monitoring may not be necessary outside the setting of a clinical trial.9
Collapse  
The International Working Group (IWG)
AML guidelines recommend it
Expand  

According to the IWG AML26:

  • RT-PCR monitoring for the fusion transcript should be performed every 3 months for the first 2 years of complete remission, then every 3 to 6 months for the following 2 to 3 years
Collapse  
Note: The IWG AML is the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.

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. Lancet JE, Maslak P, Soignet SL. Acute promyelocytic leukemia. In: Greer JP, Arber DA, Glader B, et al. Wintrobe’s Clinical Hematology. 13th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014:1656-1672.
  2. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951.
  3. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2012, National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2012/, based on November 2014 SEER data submission, posted to the SEER web site, April 2015. Accessed June 8, 2016.
  4. Chen Y, Kantarjian H, Wang H, Cortez J, Ravandi F. Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008. Cancer. 2012;118(23):5811-5818.
  5. Lo-Coco F, Cicconi L, Breccia M. Current standard treatment of adult acute promyelocytic leukaemia. Br J Haematol. 2015. doi.10.1111.bjh.13890.
  6. Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J. 2015;5:e304 doi:10.1038/bcj.2015.25.
  7. Tallman MS. Treatment of relapsed or refractory acute promyelocytic leukemia. Best Pract Res Clin Haematol. 2007;20(1):57-65.
  8. Iland H, Bradstock K, Seymour J, et al. Results of the APML3 trial incorporating all-trans-retinoic acid and idarubicin in both induction and consolidation as initial therapy for patients with acute promyelocytic leukemia. Haematologica. 2012; 97(2):227–234.
  9. 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 February 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.
  10. Dorland WAN, ed. Dorland’s Illustrated Medical Dictionary. 29th ed. Philadelphia, PA: Saunders Elsevier; 2012.
  11. Walker DK, Held-Warmkessel J. Acute promyelocytic leukemia: an overview with implications for oncology nurses. Clin J Oncol Nurs. 2010;14(6):747-759.
  12. Parmar S, Tallman MS. Acute promyelocytic leukaemia: a review. Expert Opin Pharmacother. 2003;4(8):1379-1392.
  13. Sanz MA, Martín G, González M, et al; by PETHEMA group. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103(4):1237-1243.
  14. Sanz MA, Lo Coco F, Martín G, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 2000;96(4):1247-1253.
  15. Breccia M, Mazzarella L, Bagnardi V, et al. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols. Blood. 2012;119(1):49-54.
  16. Lo-Coco F, Ammatuna E. The biology of acute promyelocytic leukemia and its impact on diagnosis and treatment. Hematology. 2006:156-161.
  17. Jurcic JG. Monitoring PML-RARα in acute promyelocytic leukemia. Curr Oncol Rep. 2003;5(5):391-398.
  18. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111(5):2505-2515.
  19. Larson RA, Anastasi J. Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate; 2014. http://www.uptodate.com/contents/clinical-manifestations-pathologic-features-and-diagnosis-of-acute-promyelocytic-leukemia-in-adults?source=machineLearning&search=acute+promyelocytic+leukemia&selectedTitle=1%7E67§ionRank=1&anchor=H17#H17. Updated June 16, 2014. Accessed June 8, 2016.
  20. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875-1891.
  21. 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.
  22. Huang W, Sun GL, Li XS, et al. Acute promyelocytic leukemia: clinical relevance of two major PML-RAR alpha isoforms and detection of minimal residual disease by retrotranscriptase/polymerase chain reaction to predict relapse. Blood. 1993;82(4):1264-1269.
  23. Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999;93(12):4131-4143.
  24. Jurcic JG, Nimer SD, Scheinberg DA, DeBlasio T, Warrell RP Jr, Miller WH Jr. Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood. 2001;98(9):2651-2656.
  25. Grimwade D, Lo Coco F. Acute promyelocytic leukemia: a model for the role of molecular diagnosis and residual disease monitoring in directing treatment approach in acute myeloid leukemia. Leukemia. 2002;16(10):1959-1973.
  26. 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.

BMI=body mass index; FISH=fluorescence in situ hydridization; RT-PCR=reverse transcriptase-polymerase chain reaction; WBC=white blood cell.

©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.