Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Histone Deacetylase Inhibitors for Peripheral T-cell Lymphoma (e.g., Istodax®, Beleodaq®)

Policy #:08.00.97h

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

ROMIDEPSIN (ISTODAX®)

MEDICALLY NECESSARY
Romidepsin (Istodax®) is considered medically necessary and, therefore, covered for any of the following indications:

Peripheral T-cell Lymphoma (PTCL)
  • Treatment of PTCL in individuals who have received at least one prior therapy.

Cutaneous T-cell Lymphoma
  • Treatment of cutaneous T-cell lymphoma in individuals who have received at least one prior systemic therapy

Mycosis Fungoides (MF)/Sezary Syndrome (SS)
  • Systemic therapy as primary treatment for:
    • Stage IB-IIA MF with histologic evidence of folliculotropic or large-cell transformed MF:
      • With or without local radiation therapy for limited tumor lesions
      • With or without skin-directed therapy for generalized tumor lesions
    • Stage IIB MF:
      • With limited tumor lesions with or without local radiation therapy
      • With generalized tumor lesions with or without skin-directed therapy
    • Stage III MF with blood B1 involvement, with or without skin-directed therapy
    • Stage IV Sezary syndrome
    • Stage IV non Sezary or visceral disease (solid organ) with or without radiation therapy for local control
  • Systemic therapy as treatment for:
    • Stage IA MF refractory to multiple previous therapies or progression to > stage IA on skin-directed therapies with histologic evidence of folliculotropic or large-cell transformed MF:
      • With or without local radiation for limited tumor lesions
      • With or without skin-directed therapy for generalized tumor lesions
    • Stage IB-IIA MF refractory to multiple previous therapies or progression to > stage IB-IIA
    • Stage IIB MF with limited tumor lesions:
      • That is relapsed with T3 limited extent disease or has persistent T3 limited extent disease with or without local radiation therapy
      • 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 therapy
    • Stage III MF with blood B1 involvement that is relapsed or persistent with or without skin-directed therapy
    • Stage IV Sezary syndrome that is relapsed or persistent
    • 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
  • Single agent therapy for relapsed or refractory:
    • primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions
    • cutaneous ALCL with regional nodes (excludes systemic ALCL)

Other Peripheral T-cell Lymphoma
  • Second-line and subsequent therapy for relapsed or refractory angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, or follicular T-cell lymphoma.

EXPERIMENTAL/INVESTIGATIONAL
All other uses for Romidepsin (Istodax®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

BELINOSTAT (BELEODAQ®)

MEDICALLY NECESSARY
Belinostat (Beleodaq®) is considered medically necessary and, therefore, covered for any of the following indications:

Peripheral T-cell Lymphoma (PTCL)
  • Treatment of individuals with relapsed or refractory PTCL

Adult T-cell Leukemia/Lymphoma
  • Second line therapy (with intention to proceed to high-dose therapy/allogeneic stem cell rescue) or subsequent therapy to HDT/ASCR as a single agent for nonresponders to first-line therapy for acute disease or lymphoma subtypes

Cutaneous T-cell Lymphoma
Mycosis Fungoides (MF)/ Sezary Syndrome (SS)
  • Systemic therapy as primary treatment for
    • 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
  • Systemic therapy as treatment for
    • 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
  • Single agent therapy for relapsed or refractory:
    • primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions
    • cutaneous ALCL with regional nodes (excludes systemic ALCL)

Other Peripheral T-cell Lymphoma
  • Second-line and subsequent therapy for relapsed or refractory angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, nodal peripheral T-cell lymphoma with TFH phenotype, or follicular T-cell lymphoma.

EXPERIMENTAL/INVESTIGATIONAL
All other uses for Belinostat (Beleodaq®) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.
Guidelines

PRIOR SYSTEMIC THERAPIES

For cutaneous T-cell lymphoma (CTCL), prior systemic therapy can include, but is not limited to, retinoids, interferons, extracorporeal photopheresis, denileukin diftitox, methotrexate, liposomal doxorubicin, or gemcitabine.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, histone deacetylase inhibitors for peripheral T-cell lymphoma (e.g., Istodax®, Beleodaq®) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Romidepsin (Istodax®) was approved by the FDA on November 5, 2009, for treatment of individuals with CTCL who have received at least one prior systemic therapy. On June 16, 2011, the FDA issued a supplemental approval for the additional indication of treatment of individuals with peripheral T-cell lymphoma
(PTCL) who have received at least one prior therapy.

Belinostat (Beleodaq®) was approved by the FDA on July 3, 2014, for the treatment of individuals with relapsed or refractory PTCL.

Description

Non-Hodgkin's lymphoma (NHL) is a cancer that originates in the lymphocytes, a type of white blood cell that is part of the body's immune system. There are two main types of lymphocytes: B lymphocytes (B-cells) and T lymphocytes (T-cells). T-cell lymphomas comprise less than 15 percent of NHL cases in the United States. Peripheral T-cell lymphoma (PTCL), a T-cell NHL, accounts for about 5 percent of all lymphomas and reflects a biologically diverse and uncommon group of blood cancers. Currently, there is no standardized treatment for PTCL, and, because of the relative rareness of the disease, no randomized controlled trials (RCTs) exist that compare chemotherapeutic treatments for PTCL alone.

According to classification by the Revised European-American Lymphoma (REAL) and the World Health Organization (WHO), PTCL is classified into four groups: cutaneous, extranodal, nodal, and leukemic.

Types of Peripheral T-cell Lymphomas
Cutaneous Mycosis Fungoides
Sezary syndrome
Primary cutaneous CD30+ T-cell lymphoproliferative disorders
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Nodal Peripheral T-cell lymphoma, unspecified
Anaplastic large cell lymphoma
Angioimmunoblastic T-cell lymphoma
Leukemic Adult T-cell leukemia/lymphoma
T-cell prolymphocytic leukemia
T-cell large granular lymphocytic leukemia
Aggressive NK cell leukemia
Uncertain lineage and usage Blastic NK cell lymphoma

Histone deacetylase inhibitor (HDAC) is used to treat individuals with PTCL. HDACs catalyze the removal of acetyl groups from the lysine residues of histones and some non-histone proteins causing an accumulation of acetylated histones and other proteins, inducing cell cycle arrest and/or apoptosis of some transformed cells. There are two FDA-approved HDACs for PTCL, romidepsin (Istodax®) and belinostat (Beleodaq®).

ROMIDEPSIN (ISTODAX®)

On November 5, 2009, romidepsin (Istodax®) was approved by the US Food and Drug Administration (FDA) for treatment of individuals with cutaneous T-cell lymphoma (CTCL) who received at least 1 prior systemic therapy based on two multicenter single-arm clinical studies. Study 1 evaluated romidepsin (Istodax®) in 96 individuals with confirmed CTCL who failed at least 1 prior systemic therapy. Study 2 evaluated efficacy of romidepsin (Istodax®) in 71 individuals with a primary diagnosis of CTCL who received at least 2 prior skin-directed therapies or at least 1 systemic therapy. In both studies the individuals were treated with romidepsin (Istodax®) at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15, every 28 days. The number of cycles differed between the two studies. The overall objective disease response rate (ORR) was 34 percent for study 1, and 35 percent for study 2. The confirmed complete response (CR) was 6 percent for both studies.

On June 16, 2011, the FDA issued an approval for romidepsin (Istodax®) for an additional indication, treatment of individuals with PTCL who have received at least 1 prior therapy. One of the studies that led to this approval is a multicenter, single-arm international clinical study of 131 individuals with PTCL who failed at least 1 prior systemic therapy. The individuals were treated with romidepsin (Istodax®) at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15, every 28 days. The ORR was 25.4 percent, with a CR of 14.6 percent.

According to the June 2013 FDA-approved labeling information for romidepsin (Istodax®), treatment with romidepsin (Istodax®) has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematologic parameters should be monitored during treatment with romidepsin (Istodax®). (See FDA label for inclusive list of warnings and precautions.) Prolongation of the QT interval has also been observed with romidepsin (Istodax®). Accordingly, the FDA label warns that serum potassium and magnesium levels should be checked before starting romidepsin (Istodax®) to ensure that they are within normal ranges. The safety and effectiveness of romidepsin (Istodax®) in pediatric individuals has not been established.

BELINOSTAT (BELEODAQ®)

On July 3, 2014, belinostat (Beleodaq®) was approved by the FDA for treatment of individuals with relapsed or refractory PTCL. An open-label, single-arm, non-randomized international clinical study evaluated the efficacy of belinostat (Beleodaq®) among 120 individuals with histologically confirmed relapsed or refractory PTCL. The ORR was 25.8 percent with a CR of 10.8 percent.

According to the FDA-approved labeling information, treatment with belinostat (Beleodaq®) has been associated with thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; therefore, these hematologic parameters should be monitored weekly during treatment with belinostat (Beleodaq®). Fatal hepatotoxicity and liver function test abnormalities have been observed with belinostat (Beleodaq®). The FDA label advises the liver function tests should be monitored before treatment and before the start of each cycle.

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


Belinostat (Beleodaq®). American Hospital Formulary Service (AHFS). AHFS Drug Information [Lexi-Drug Web site]. 09/13/2017. Available at: http://online.lexi.com/lco/action/home#.. [via subscription only]. Accessed November 20, 2017.

Coiffer B, Pro B, Miles Prince H, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol.2012; 30:631-636.

Elsevier Gold's Standard Clinical Pharmacology Compendium. Belinostat. [Clinical Key Web site. 06/19/2017. Available at https://www.clinicalkey.com/. [via subscription only]. Accessed November 20, 2017.

Elsevier Gold's Standard Clinical Pharmacology Compendium. Romidepsin. [Clinical Key Web site. 11/01/2017. Available at: https://www.clinicalkey.com/. [via subscription only]. Accessed November 20, 2017.

Leukemia & Lymphoma Society (LLS). Cutaneous T-Cell Lymphoma Facts. [LLS web site]. 06/2014. Available at:http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/cutaneoustcelllymphoma.pdf. Accessed November 20, 2017.

Leukemia & Lymphoma Society (LLS). Peripheral T-Cell Lymphoma Facts. [LLS web site]. 07/2014. Available at:http://www.lls.org/sites/default/files/file_assets/FS25%20Peripheral%20T-Cell%20Lymphoma%20Facts.pdf. Accessed November 20, 2017.

Lexi-Drugs Compendium. Belinostat. [Lexicomp Online Web site]. 11/16/2017. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2017.

Lexi-Drugs Compendium. Romidepsin. [Lexicomp Online Web site]. 11/15/2017. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed November 20, 2017.

Lymphoma Research Foundation. T-cell Lymphomas. http://www.lymphoma.org/site/pp.asp?c=bkLTKaOQLmK8E&b=6300161. Accessed November 20, 2017.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - T-cell Lymphoma. V1.2018. [NCCN Web site]. 02/17/2016. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf [via subscription only]. Accessed November 20, 2017.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium™. Romidepsin. [NCCN Web site]. 2017. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=352 [via subscription only]. Accessed November 16, 2017.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium™. Belinostat. [NCCN Web site]. 2017. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=410 [via subscription only]. Accessed November 16, 2017.

Rodriguez J, Gutierrez A, Martinez- Delgado B. Current and future aggressive peripheral T-cell lymphoma treatment paradigms, biological features and therapeutic molecular targets. Crit Rev Oncol/Hematol. 2009;71:181-198.

Romidepsin (Istodax®). American Hospital Formulary Service (AHFS). AHFS Drug Information [Lexi-Drug Web site]. 03/08/2017. Available at: http://online.lexi.com/lco/action/home#.. [via subscription only]. Accessed November 20, 2017.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Belinostat (Beleodaq®). 04/19/2017. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2017.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Romidepsin (Istodax®). 11/06/2017. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed November 20, 2017.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Prescribing Information. Belinostat (Beleodaq®). [FDA Web site]. 04/12/2017. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206256lbl.pdf. Accessed November 16, 2017.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Prescribing Information. Romidepsin (Istodax®). [FDA Web site]. 07/27/2016. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022393s013lbl.pdf. Accessed November 16, 2017.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

See Attachment A for ICD-10 codes.


HCPCS Level II Code Number(s)



J9032 Injection, belinostat, 10 mg

J9315 Injection, Romidepsin, 1 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References

Attachment A: Histone Deacetylase Inhibitors for Peripheral T-cell Lymphoma (e.g., Istodax®, Beleodaq®)
Description: ICD-10 CODES AND NARRATIVES




Policy History

08.00.97h
10/10/2018This policy has been reissued in accordance with the Company's annual review process.
12/27/2017This policy has undergone a routine review and the medical necessity criteria have been revised to reflect the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 12/27/2017
Version Issued Date: 12/27/2017
Version Reissued Date: 10/11/2018

Connect with Us        


© 2017 Independence Blue Cross.
Independence Blue Cross is an independent licensee of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.