Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease, which is characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia (Ph) chromosome. This translocation results in the fusion of the breakpoint cluster region (BCR) gene and the Abelson murine leukemia (ABL) gene; the product of this fusion gene (BCR-ABL), a protein with deregulated tyrosine kinase activity, is believed to play a central role in the initial development of CML. CML occurs in three difference phases (chronic, accelerated and blast phase) and is usually diagnosed in the chronic phase. CML accounts for 15% of adult leukemias or approximately 5,000 new cases per year in the United States.

Omacetaxine mepesuccinate gained FDA approval based on combined data from two open label single-arm trials enrolling patients with chronic phase CML (CP CML) or in accelerated phase CML (AP CML). The efficacy population included 76 patients with CML-CP and 35 patients with CML-AP who had received two or more prior TKIs, including imatinib. Major cytogenetic response (MCyR) and Major Hematologic Response (MaHR) were the primary endpoints for CML-CP and CML-AP, respectively. MCyR was achieved in 18.4% of patients with CML-CP (median response duration 12.5 months). MaHR was achieved in 14.3% of patients with CML-AP (median response duration 4.7 months).

Omacetaxine mepesuccinate is marketed as Synribo by Teva Oncology in New Wales, Pennsylvania . Synribo was approved by the U.S. Food and Drug Administration (FDA) on October 26, 2012.

In uncontrolled trials with omacetaxine mepesuccinate, patients with chronic phase and accelerated phase CML experienced NCI CTC (version 3.0) Grade 3 or 4 thrombocytopenia (85%, 88%), neutropenia (81%, 71%), and anemia (62%, 80%), respectively. Fatalities related to myelosuppression occurred in 3% of patients in the safety population (N=163). In clinical trials with CP and AP CML patients, a high incidence of Grade 3 and 4 thrombocytopenia (85% and 88%, respectively) was also observed. Fatalities from cerebral hemorrhage occurred in 2% of patients treated with omacetaxine mepesuccinate in the safety population. Severe, non-fatal, gastrointestinal hemorrhages occurred in 2% of patients in the same population.

Omacetaxine mepesuccinate can induce glucose intolerance. Grade 3 or 4 hyperglycemia was reported in 11% of patients in the safety population. Hyperosmolar non-ketotic hyperglycemia occurred in 1 patient in the safety popaultion. Monitor blood glucose levels frequently, especially in patients with diabetes or risk factors for diabetes. Avoid omacetaxine mepesuccinate in patients with poorly controlled diabetes mellitus until good glycemic control has been established.

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

The requirements of the Horizon BCBSNJ Omacetaxine Mepesuccinate (Synribo) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

1. Synribo (omacetaxine mepesuccinate) is considered medically necessary for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia with resistance and/or intolerance to two or more tyrosine kinase inhibitors (such as imatinib, nilotinib, dasatinib, bosutinib, or ponatinib).

• 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

a. Induction dosing: 1.25 mg/m² subcutaneous injection twice daily at approximately 12 hour intervals for 14 consecutive days of a 28-day cycle for the induction phase. Cycles should be repeated every 28 days until patients achieve a hematologic response.
b. Maintenance dosing: 1.25 mg/m² subcutaneous injection twice daily at approximately 12 hour intervals for 7 consecutive days of a 28-day cycle for maintenance.

[INFORMATIONAL NOTES:
Synribo (omacetaxine mepesuccinate) treatment cycles may be delayed and/or the number of days of dosing during the cycle reduced for hematologic toxicities (e.g. neutropenia, thrombocyctopenia). Complete blood counts (CBCs) should be performed weekly during induction and initial maintenance cycles. After initial maintenance cycles, monitor CBCs every two weeks or as clinically indicated. If a patient experiences Grade 4 neutropenia (absolute neutrophil count (ANC) less than 0.5 x 109/L) or Grade 3 thrombocytopenia (platelet counts less than 50 x 109/L) during a cycle, delay starting the next cycle until ANC is greater than or equal to 1.0 x 109/L and platelet count is greater than or equal to 50 x 109/L. Also, for the next cycle, reduce the number of dosing days by 2 days (e.g. to 12 or 5 days).

Fatalities from cerebral hemorrhage have occurred. Severe, non-fatal gastrointestinal hemorrhages have also occurred. As per the FDA approved package insert, platelet counthould be monitored as part of the complete blood count (CBC) monitoring as recommended. Anticoagulants, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided when the platelet count is <50,000/ìL as they may increase the risk of bleeding. Manage other clinically significant non-hematologic toxicity symptomatically. Interrupt and/or delay SYNRIBO until toxicity is resolved.

As per the FDA approved package insert, Synribo (omacetaxine mepesuccinate) should be prepared in a healthcare facility and must be reconstituted by a healthcare professional. Before a decision is made to allow Synribo to be administered by someone other than a healthcare professional, ensure that the patient is an appropriate candidate for self-administration or for administration by a caregiver. Provide training on proper handling, storage conditions, administration, disposal, and clean-up of accidental spillage of the product. Ensure that patients receive the necessary supplies for home administration. If a patient or caregiver cannot be trained for any reason, then in such patients, Synribo should be administered by a healthcare professional.]

1) Treatment response (defined by NCCN guidelines on CML) can be indicated by the following:
• Complete hematologic response; AND
  • Complete normalization of peripheral blood counts with leukocyte count <10 X 10⁹/L
  • Platelet count <450 X 10⁹/L
  • No immature cells, such as myelocytes, promyelocytes, or blasts in peripheral blood
  • No signs and symptoms of disease with disappearance of palpable splenomegaly
• Cytogenic response; OR
  • Complete cytogenic response (CCyR) - No Ph-positive metaphases
  • Major cytogenic response (MCyR) - 0%-35% Ph-positive metaphases
  • Partial cytogenic response (PCyR) - 1%-35% Ph-positive metaphases
  • Minor cytogenic response - >35%-65% Ph-positive metaphases
• Molecular response*
  • BCR-ABL1 (IS) transcript levels ≤10% at 3 and 6 months or ≤ 1% at 12 months and beyond
  [INFORMATIONAL NOTE: *Cytogenetic assessment of response may be used if quantitative RT-PCR (QPCR) using International Scale (IS) for BCR-ABL1 is not available]
2) Absence of unacceptable toxicity (i.e. severe neutropenia and/or thrombocytopenia, hemorrhage, uncontrolled hyperglycemia, etc.)

Medicare Coverage

There is no National Coverage Determination (NCD or Local Coverage Determination (LCD) for jurisdiction JL for this service. Therefore, Medicare Advantage will follow the Horizon Policy. See generally: Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/pagebyid?contentId=00024370

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:
Omacetaxine Mepesuccinate (Synribo)
Synribo (Omacetaxine Mepesuccinate)

References:
1. Synribo (omacetaxine mepesuccinate). Prescribing Information. Teva Pharmaceuticals USA, Inc. North Wales, PA. November 2019.

2. Liesveld JL, Lichtman MA. Chapter 90. Chronic Myelogenous Leukemia and Related Disorders. In: Prachal JT, Kaushansky K, Lichtman MA, Kipps TJ, Seligsohn U, eds. Williams Hematology. 8th ed. New York: McGraw-Hill; 2010. http://www.accessmedicine.com/content.aspx?aID=6124901. Accessed October 17, 2012.

3. National Comprehensive Cancer Network: Drugs and Biologics Compendium. Omacetaxine. 2019. Available at:https://www.nccn.org/professionals/drug_compendium/content/. [Accessed 3/21/2019].

4. MICROMEDEX® 2.0 (Healthcare Series). DRUGDEX® Evaluations. Omacetaxine mepesuccinate. Available at: http://www.thomsonhc.com. Accessed April 30, 2016.

5. Cortes J, Kantarjian H, Nicolini F, et al. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up. Cancer [serial online]. January 1, 2015;Available from: Scopus®, Ipswich, MA. Accessed April 13, 2015.

6. National Comprehensive Cancer Network Guidelines Version 1.2019. Chronic Myeloid Leukemia. Criteria for hematologic, cytogenic, and molecular response and relapse. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed 4/5/2019.

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
J9262

* 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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