BCBSNJ Medical Policy for - (Drugs) Policy Number

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Horizon BCBSNJ
Uniform Medical Policy Manual	Section:	Drugs
	Policy Number:	177
	Effective Date:	04/10/2020

	Original Policy Date:	03/27/2018
	Last Review Date:	03/10/2020
	Date Published to Web:	11/05/2018

Subject:
Arsenic Trioxide (Trisenox)

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Acute promyelocytic leukemia (APL) is a clinically distinct variant of acute myeloid leukemia. The distinguishing cytogenic indicator for APL is a translocation involving the treinoic acid receptor alpha locus on chromosome 17. APL has a high rate of early mortality, which is often due to hemorrhage due to coagulopathy. APL is responsible for 5 to 20 percent of the cases of AML, with rates around 600 to 800 per year in the United States. APL is very uncommon in the first decade of a person’s life, incidence increase during the second decade and reaches its highest point during early adulthood, then the rates slowly decline to 60 years of age. There is no variation in rates based on gender. There around 600 to 800 new caes of APL each year in the United States.

Trisenox is for the treatment of adults with newly-diagnosed low-risk acute promyelocytic leukemia (APL), whose APL is characterized by the presence of the t(15;17) translocation of the fusion protein promyelocytic leukemia (PML) – retinoic acid receptor (RAR)-alpha gene expression. The medication is also indicated for the 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 of the PML/RAR-alpha gene expression.

The safety and efficacy of Trisenox were evaluated in two clinical trials. The first trial was a multicenter, randomized, open-label trial in patients with newly-diagnosed low-risk APL. Patients were randomized to TRIXENOX and tretinoin for induction and consolidation or chemotherapy and tretinoin for induction, consolidation, and maintenance. The trial enrolled 162 patients with morphologic diagnosis of APL. The median age of patients enrolled was 45 years of age. Inclusion criteria included newly diagnosed classified as low-to-intermediate risk (WBC < 10X10⁹/L at diagnosis), genetic confirmation of t(15;17) translocation or PML/RAR alpha gene expression, and World Health Organization (WHO) performance status score of 2 or lower (0-5 scale, low numbers indicate better performance). Efficacy was based on the rates of event-free survival at 2 years. EFS was defined as the time from randomization to the occurrence of treatment failure, defined as no achievement of complete response (CR) or CRi after induction therapy, no achievement of molecular remission after 3 consolidation courses, molecular relapse, hematologic relapse, or death. The analysis looked at rates of EFS at 2 years between the two groups, and they found that the EFS rate was 94% in the Trisenox group and 82# in the chemotherapy group, a treatment difference of 11% (95% CI: 1,22; P = 0.048). The difference in two year OS data between the two groups was 8%.

The second trial was in patients that were relapsed or refractory APL patients who had previously been treated with at least one course of induction therapy using anthracycline and at least one course of induction or maintenance therapy using a retinoid regimen. Patients received TRIXENOX in this trial. The complete response rate in patients treated was 28 of 40 (70%). Of the 18 patients receiving Trisenox for more than one year from their tretinoin treatment, there were 10 completed responders. Three to six weeks after bone marrow remission, 31 patients received consolidation therapy with Trisenox. At last follow up, 27 of the 40 patients were alive with a median follow-up time of 484 days and 23 of the 40 patients remained in complete response with median follow up of 483 days.

Trisenox carries a black box warning for differentiation syndrome. If symptoms occur, initiate high dose steroids immediately and monitor hemodynamics. The medication can has a black box warning for QT interval prolongation and ventricular arrhythmia. Patients must have their status evaluated prior, including their QT interval, electrolyte status, and possibly discontinuing any drugs known to prolong the QT interval. Do not give to patients with ventricular arrhythmias or prolonged QTcF..

[INFORMATIONAL NOTE: As per the FDA approved package insert, BLACK BOX WARNING: APL DIFFERENTIATION SYNDROME and CARDIAC CONDUCTION ABNORMALITIES, Patients treated with TRISENOX may develop differentiation syndrome, which can be fatal. If symptoms occur, initiate high-dose steroids immediately and monitor hemodynamics. TRISENOX can cause QT interval prolongation and ventricular arrhythmia, which can be fatal. Before administering TRISENOX, assess the QT interval, correct electrolyte abnormalities, and consider discontinuing drugs known to prolong QT interval. Do not administer TRISENOX to patients with ventricular arrhythmia or prolonged QTcF]

Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

I. The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis.

II. Arsenic trioxide (Trisenox) is considered medically necessary based on the following FDA approved indications:

III. When arsenic trioxide (Trisenox) is medically necessary, therapy will be approved at the following FDA-approved doses:

A treatment course of Trisenox consists of 1 induction cycle and 4 consolidation cycles
For the induction cycle, patients are recommended to use 0.15 mg/kg intravenously daily in combination with tretinoin until bone marrow remission. Treatment is not to exceed 60 days
For the consolidation cycles, administer Trisenox 0.15 mg/kg intravenously daily 5 days per week during weeks 1-4 of an 8 week cycle. in combination with tretinoin daily during weeks 1, 2, 5, and 6 of the 8 week cycle.

Treatment consists of 1 induction cycle and 1 consolidation cycle
For the induction cycle administer Trisenox 0.15 mg/kg intravenously daily until bone marrow remission. Treatment is not to exceed 60 days.
For the consolidation cycle administer 0.15 mg/kg intravenously daily for 25 doses over a period of up to 5 weeks.
The consolidation treatment begins 3 to 6 weeks after induction therapy

investigational

IV. Arsenic trioxide (Trisenox) is medically necessary for the following off-label uses:

Treatment induction in low-risk disease (white blood cell count ≤ 10,000/mcL)
- Daily in combination with tretinoin (ATRA) (preferred regimen)
- On days 1-5 of week 1 and twice weekly in weeks 2-8 in combination with ATRA (preferred regimen)
Treatment induction in high risk disease (WBC > 10,000/mcL) in patients with no cardiac issues either:
· In combination with tretinoin and idarubicin
· Daily in combination with ATRA and gemtuzumab ozogamicin
· On days 1-5 of week 1 and twice weekly in weeks 2-8 in combination with ATRA and gemtuzumab ozogamicin (preferred regimen)
Treatment induction in high risk disease (WBC > 10,000/mcL) in patients with cardiac issues (low ejection fraction or prolonged QTc)
- Daily in combination with tretinoin (ATRA) and gemtuzumab ozogamicin
- On days 1-5 of week 1 and twice weekly in weeks 2-8 in combination with ATRA and gemtuzumab ozogamicin
Consolidation therapy in low-risk disease (white blood cell count ≤ 10,000/mcL)
- 5 days per week for 4 weeks every 8 weeks for a total of 4 cycles, in combination with tretinoin (ATRA) (preferred regimen)
- On days 1-5 of week 1 in consolidation courses 1-4 and twice weekly in weeks 2-4 of consolidation courses 1-4, in combination with ATRA (preferred regimen)
Consolidation therapy in high risk disease (WBC > 10,000/mcL) in patients with no cardiac issues either:
· In combination with tretinoin (ATRA)
· 5 days per week for 4 weeks every 8 weeks for a total of 4 cycles, in combination with ATRA
· On days 1-5 of week 1 in consolidation courses 1-4 and twice weekly in weeks 2-4 of consolidation courses 1-4, in combination with ATRA (preferred regimen)
· In combination with gemtuzumab ozogamicin if ATRA was discontinued due to toxicity
· In combination with ATRA and daunorubicin
Consolidation therapy in high risk disease (WBC > 10,000/mcL) in patients with cardiac issues (low ejection fraction or prolonged QTc) either:
· 5 days per week for 4 weeks every 8 weeks for a total of 4 cycles, in combination with tretinoin
· On days 1-5 of week 1 in consolidation courses 1-4 and twice weekly in weeks 2-4 of consolidation courses 1-4, in combination with ATRA
· In combination with gemtuzumab ozogamicin if ATRA was discontinued due to toxicity
Therapy for first Relapse either:
· In combination with tretinoin (ATRA) and idarubicin, as part of an anthracycline-based regimen in patients with early relapse (<6 months) after ATRA and arsenic trioxide (no anthracycline)
· With or without ATRA, with or without gemtuzumab ozogamicin, in patients with no prior exposure to arsenic trioxide or early relapse (<6 months) after ATRA + anthracycline-containing regimen
· With or without ATRA, with or without anthracycline or gemtuzumab ozogamicin, in patients with late relapse (≥6 months) after arsenic trioxide-containing regimen
Additional therapy as single-agent consolidation in patients that are not transplant candidates and are PCR negative following second remission

V. Arsenic Oxide (Trisenox) is considered investigational for all other indications, including but not limited to:

[INFORMATIONAL NOTE: WHO Performance Status

Grade	Explanation of activity
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2	Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours
3	Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4	Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5	Death}

Medicare Coverage:
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

Medicaid Coverage:
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Arsenic Trioxide (Trisenox)
Trisenox (Arsenic Trioxide)

References:
1. Trisenox^TM Prescribing Information. Teva Oncology. North Wales, PA. June 2019.

2. Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008;19(4):379-90.

3. Dores GM, Devesa SS, Curtis RE, Linet MS, Morton LM. Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007. Blood. 2012;119(1):34-43.

4. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-405.

5. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F. Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008. Cancer. 2012;118(23):5811-8.

6. Larson R., Gurbuxani S. Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults. UpToDate. Last updated April 18, 2017. Accessed March 2018.

7. National Comprehensive Cancer Network: Arsenic trioxide. [Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=414 (accessed 2/234/2020)

8. National Comprehensive Cancer Network: Acute Myeloid Leukemia. Version 1.2018. Available from; https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed 3/7/2018.

9. National Comprehensive Cancer Network: T-Cell Lymphomas Version 3.2018.. Available from; https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed 3/7/2018.

10. Lo-coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013;369(2):111-21.

11. Trisenox. Clinicaltrial.gov. Accessed on 2/234/20. Available at: https://clinicaltrials.gov/ct2/results?cond=&term=trisenox&cntry=&state=&city=&dist=.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

HCPCS

J9017

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy
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