Pending Policies - Prescription Drugs


Belinostat (Beleodaq)

Number:RX502.037

Effective Date:09-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

When the requested chemotherapeutic agent is being utilized in a regimen in combination with other chemotherapeutic agents, the entire regimen (including dose, frequency, and duration) must be consistent with recommendations in at least one authoritative source, including but not limited to FDA labeling and nationally recognized compendia or clinical Guidelines such as National Comprehensive Cancer Network (NCCN) and CMS coverage policy. HCSC may require a provider to submit documentation from nationally recognized compendia, clinical Guidelines, or active Phase III clinical trials supporting the requested regimen.

Labeled Indication

Belinostat (Beleodaq®) may be considered medically necessary in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

Off-Label Indications

Peripheral T-Cell Lymphomas

Belinostat (Beleodaq®) may be considered medically necessary as a single agent, for the following indications as second-line and subsequent therapy for relapsed/refractory:

Anaplastic large cell lymphoma;

Peripheral T-cell lymphoma not otherwise specified;

Angioimmunoblastic T-cell Lymphoma;

Enteropathy-associated T-cell lymphoma;

Monomorphic epitheliotropic intestinal T-cell lymphoma;

Nodal peripheral T-cell lymphoma with T-follicular helper (TFH) phenotype; or

Follicular T-cell lymphoma.

Mycosis Fungoides (MF)/Sezary Syndrome

Belinostat (Beleodaq®) may be considered medically necessary for patients with mycosis fungoides/Sezary syndrome, as systemic therapy for primary treatment of:

Stage IB-IIA MF with histologic evidence of folliculotropic or large-cell transformed MF, with or without skin-directed therapy for generalized tumor lesions;

Stage IIB MF with generalized tumor lesions, with or without skin-directed therapy;

Stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control.

Belinostat (Beleodaq®) may be considered medically necessary for patients with mycosis fungoides/Sezary syndrome, as systemic therapy for treatment of:

Stage IIB MF with limited tumor lesions refractory to multiple previous therapies or progression, with or without skin directed therapies;

Stage IIB MF with generalized tumor lesions that is relapsed with T3 disease or has persistent T3 disease, with or without skin-directed therapies;

Stage IV non Sezary or visceral disease (solid organ) that is relapsed or persistent, with or without radiation therapy for local control.

Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

Belinostat (Beleodaq®) may be considered medically necessary as a single agent for relapsed/refractory disease for patients with:

Primary cutaneous anaplastic large-cell lymphoma (ALCL) with multifocal lesions, or

Cutaneous ALCL with regional nodes (excludes systemic ALCL)

Adult T-Cell Leukemia/Lymphoma

Belinostat (Beleodaq®) may be considered medically necessary as a

Second-line therapy (with intention to proceed to allogeneic stem cell rescue [ASCR]) or;

Subsequent therapy to ASCR as a single agent for nonresponders to first-line therapy for acute or lymphoma subtypes.

Belinostat (Beleodaq®) is considered experimental, investigational and/or unproven when not meeting the above noted criteria.

NOTE: The safety and effectiveness of Beleodaq in pediatric patients has not been established.

Description:

Non-Hodgkin’s lymphomas (NHL) are a group of diverse lymphoproliferative disorders originating in T-lymphocytes, B-lymphocytes or natural killer (NK) cells. Lymphomas are classified based on the cell of origin (B, T, or NK); further classification subdivides lymphomas into those resulting from precursor lymphocytes and those resulting from mature lymphocytes. Other considerations are based on genetic, clinical features, and immunophenotype.

The National Comprehensive Cancer Network® (NCCN) notes common T-Cell lymphoma subtypes include (8):

Peripheral T-cell lymphomas (PTCL),

Mycosis fungoides (MF) and Sezary syndrome (SS),

Primary cutaneous CD30+ T-cell lymphoproliferative disorders,

T-cell large granular lymphocytic leukemia,

Adult T-cell leukemia/lymphoma (ATLL),

T-cell prolymphocytic leukemia (T-PLL), and

Extranodal NK/T-cell lymphomas, nasal type (ENKL).

Adult T-cell Leukemia/Lymphoma

NCCN notes the “Adult T-cell leukemia/lymphoma (ATLL) is malignancy of peripheral T-lymphocytes caused by the human T-cell lymphotropic virus type 1 (HTLV-1), and is associated with a long period of latency (often manifesting several decades after exposure)” (8) Adult T-cell leukemia/lymphoma have been further classified into four subtypes (smoldering, chronic, acute or lymphoma) from the Lymphoma Study Group of the Japan Clinical Oncology Group as mentioned in the NCCN guidelines for T-cell lymphomas.

Mycosis Fungoides and Sezary Syndrome

Cutaneous T-cell lymphomas (CTCLs) are a group of mature T-cell lymphomas that can progress from the skin to include lymph nodes, blood and visceral organs.

Mycosis Fungoides is the most common subtype of CTCLs and accounts for about half of CTCLs. Sezary syndrome is an erythrodermic, leukemic variant of CTCL that is characterized by significant blood involvement and lymphadenopathy (8)

Peripheral T-Cell Lymphomas

Peripheral T-cell lymphoma account for approximately 10-15% of all NHL cases in the United States. (1) NCCN notes PTCLs as a “heterogeneous group of lymphoproliferative disorder arising from mature T-cells of post-thymic origin.” (6) Subtypes include:

Peripheral T-cell lymphomas not otherwise specified (PTCL-NOS),

Angioimmunoblastic T-cell lymphoma,

ALK-positive anaplastic large cell lymphoma (ALCL),

ALK-negative ALCL, and

Enteropathy-associated T-cell lymphoma.

Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders

NCCN notes that “Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCLPDs) represent a spectrum that includes primary cutaneous anaplastic large cell lymphoma (PC-ALCL), lymphomatoid papulosis (LyP), and “borderline” cases with overlapping clinical and histopathologic features.” (8) Furthermore, NCCN notes that clinical correlation with histopathologic features is essential for establishing the diagnosis of PCLPD they note that the diagnosis cannot be made based on pathology review alone. Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) accounts for about 8% of cutaneous T-cell lymphomas cases.

Beleodaq®

Beleodaq is a histone deacetylase (HDAC) inhibitor. The HDAC enzymes, are responsible for the deacetylation of histone proteins. Belinostat was noted to show preferential cytotoxicity towards tumor cells compared to normal cells. In vitro, belinostat induces cell cycle arrest and/or apoptosis of some transformed cells. (3)

Regulatory Status

Recently Beleodaq® received accelerated approval from the U.S. Food and Drug Administration (FDA) for treatment of patients with relapsed or refractory peripheral T-cell lymphoma. The indication was approved based on tumor response rate and duration of response. Improvement has not been established for survival or disease-related symptoms. (3) This drug product for this indication has an orphan drug designation. The safety and effectiveness of Beleodaq in pediatric patients have not been established. Warnings and precautions listed include hematologic toxicity, infections, hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity and embryo-fetal toxicity.

Rationale:

Clinical Study

Beleodaq® U. S. Food and Drug Administration (FDA)-approval was based on a non-randomized, single-arm international trial performed at 62 centers. One hundred twenty-nine patients with refractory or relapsed peripheral T-cell lymphoma (PTCL) were treated with Beleodaq. Treatment consisted of once daily intravenous infusion on Days 1-5 of a 21-day cycle. Cycles were repeated every three weeks until disease progression or unacceptable toxicity. Primary efficacy endpoint was complete and partial response rate. Duration of response was the secondary efficacy endpoint. Response assessments were conducted up to 2 years from the start of the study treatment. Duration response was evaluated from the first day of recorded response to disease progression or death. The overall response rate was 25.8% (n=31). Median duration of response was 8.4 months (95% confidence interval (CI):4.5 – 29.4). (3) The median time to response was 5.6 weeks (range 4.3 – 50.4 weeks). The median overall survival (OS) was 7.9 months (95% CI:6.1–13.9). The one-year OS (probability of being alive at one year) was 40.9%. (4)

The National Comprehensive Cancer Network (NCCN)

The NCCN Guidelines for Non-Hodkin’s Lymphoma (3.2014 version) indicated an update from the 2.2014 version to include: Belinostat (category 2B) Second-line therapy: for both candidate and non-candidate for transplant for Peripheral T-cell lymphoma patients. (5)

Ongoing Clinical Trials

Multiple trials of belinostat are currently underway for various cancers. There are currently 34 studies listed using the term “belinostat” at ClinicalTrials.gov website.

2016 Update

NCCN Guidelines and Compendium (7) was reviewed through September 19, 2016. The following 2A recommendations for Belinostat/Beleodaq® in the NCCN Compendium are noted below for:

Non-Hodgkin lymphoma (NHL) – Adult T-cell leukemia/lymphoma therapy for nonresponders to first-line therapy for acute disease or lymphoma.

NHL – Mycosis fungoides (MF)/Sezary syndrome (SS) – Single-agent therapy for tumors with aggressive growth rate for:

o Stage IB-IIA MF with histologic evidence of folliculotropic or large cell transformation or stage IIB with generalized extent tumor, transformed, and/or folliculotropic disease with or without skin-directed therapy,

o Stage IV non-Sezary or visceral disease

NHL – Peripheral T-cell lymphoma preferred second-line or subsequent therapy for relapsed or refractory angioimmunoblastic T-cell lymphoma peripheral T-cell lymphoma not otherwise specified anaplastic large cell lymphoma, or enteropathy-associated T-cell lymphoma

NHL – Primary cutaneous CD30+T-cell lymphoproliferative disorders as single-agent therapy for relapsed or refractory

o Primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions

o Cutaneous ALCL with regional nodes (excludes systemic ALCL)

2018 Update

This policy was updated with searches of scientific literature through February 2018. The following is a summary of the key literature to date.

National Comprehensive Cancer Network (NCCN)

National Comprehensive Cancer Network (NCCN) Guidelines and Compendium changes and additions in 2A recommendations for Belinostat/Beleodaq® were noted for the following T-cell lymphoma subtypes (10):

Peripheral T-Cell Lymphomas,

Mycosis Fungoides/Sezary Syndrome,

Adult T-Cell Leukemia/Lymphoma.

Ongoing Clinical Trials

Multiple trials of belinostat are currently underway for various cancers. As of February 28, 2018, there were 42 studies listed using the term “belinostat” at ClinicalTrials.gov website.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

J9032

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. Peripheral T-Cell Lymphoma (PTCL). Lymphoma Research Foundation. Available at: <http://www.lymphoma.org> (accessed 2018 February 28).

2. Belinostat (Beleodaq) TEC Specialty Pharmacy Report #12-2014. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (2014 Aug):1-23.

3. Beleodaq® Highlights of Prescribing Information. United States Food and Drug administration. Available at: <http://www.accessdata.fda.gov> (accessed 2018 February 28).

4. Beleodaq Summary Review. United States Food and Drug Administration. Available at: <http://www.accessdata.fda.gov> (accessed 2018 February 28).

5. NCCN – Non-Hodgkin’s Lymphomas 5.2014 (2014 November 21). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Available at: <http://www.nccn.org> (accessed on 2014 November 21).

6. NCCN – Non-Hodgkin’s Lymphomas Version 3.2016 (2016 May 3). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines ™). Available at: <http://www.nccn.org> (accessed on 2016 November).

7. NCCN –Belinostat (2016). National Comprehensive Cancer Network Drugs & Biologics Compendium. Available at <http://www.nccn.org> (accessed on 2016 September).

8. NCCN – T-cell Lymphomas Version 3.2018 (February 22, 2018). National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines ™). Available at: <http://www.nccn.org> (accessed 2018 February 27).

9. NCCN – B-cell Lymphomas Version 2.2018 (February 26, 2018) National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines ™). Available at: <http://www.nccn.org> (accessed 2018 February 28).

10. NCCN –Belinostat (2018). National Comprehensive Cancer Network Drugs & Biologics Compendium. Available at <http://www.nccn.org> (accessed 2018 February 28).

Policy History:

Date Reason
9/15/2018 Document updated with literature review. The following changes were made to Coverage under the Off-Label Indications section: 1) Added “as a single agent” and additional types of lymphomas to the peripheral T-cell lymphoma medically necessary statement. 2) Split medically necessary statement on mycosis fungoides/Sezary syndrome into two statements with one specific to primary treatment, and added additional medically necessary indications. 3) Modified conditional indications for Adult T-Cell Leukemia/Lymphoma. References 8-10 added.
4/15/2017 Document updated with literature review. The following conditional coverage was added for: Adult T-Cell Leukemia/Lymphoma, Mycosis Fungoides (MF)/ Sezary Syndrome (SS), Peripheral T-cell lymphoma and Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders. The following statement was changed from: Belinostat (Beleodaq®) is considered experimental, investigational and/or unproven when used in the treatment of any other conditions to: Belinostat (Beleodaq®) is considered experimental, investigational and/or unproven when not meeting the above noted criteria.
1/1/2015 New medical document. Belinostat (Beleodaq®) may be considered medically necessary in the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Belinostat (Beleodaq®) is considered experimental, investigational and/or unproven when used in the treatment of any other conditions.

Archived Document(s):

Title:Effective Date:End Date:
Belinostat (Beleodaq)04-15-201709-14-2018
Belinostat (Beleodaq)01-01-201504-14-2017
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