Subject:
Belinostat (Beleodaq)
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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Peripheral T-cell lymphoma (PTCL) consists of a group of rare and aggressive non-Hodgkin's lymphomas that develop from T-cells in various stages of maturity. The World Health Organization has classified peripheral T-cell lymphoma into two main categories: precursor T/natural killer cell neoplasms and peripheral T/natural killer cells neoplasms. PTCLs account for 10-15% of newly diagnosed cases of non-Hodgkin's lymphoma (NHL) in North America. The most common subtypes are PTCL not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL). PTCL-NOS has the worst prognosis: a median overall survival of less than 2 years and a 5-year survival of about 35%.
Standard treatment usually includes initial combination chemotherapy regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). The majority of patients either do not respond or relapse. For relapsed patients, induction of remission with second-line drugs followed by high-dose therapy and autologous or allogeneic stem cell transplant is often tried, but few patients achieve long-term remission.
Belinostat (BeleodaqTM) is a histone deacetylase inhibitor and has an FDA approved indication for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. This indication is approved under accelerated approval based on tumor response rate and duration of response. Belinostat is administered as an intravenous (IV) infusion.
The FDA approval of belinostat (BeleodaqTM) for PTCL was based on an open-label, single-arm, non-randomized international trial conducted at 62 centers in 129 subjects with relapsed or refractory PTCL that were treated with belinostat 1,000 mg/m2 administered over 30 minutes via IV infusion once daily on Days 1-5 of a 21-day cycle. Subjects were treated with repeat cycles every three weeks until disease progression or unacceptable toxicity. The primary efficacy endpoint was response rate (complete response and partial response) as assessed by an independent review committee (IRC) using the International Workshop Criteria (IWC). The key secondary efficacy endpoint was duration of response. Response assessments were evaluated every 6 weeks for the first 12 months and then every 12 weeks until 2 years from the start of study treatment. Duration of response was measured from the first day of documented response to disease progression or death. In all evaluable subjects (N = 120) treated with belinostat, the overall response rate was 25.8% (n = 31), with rates of 23.4% for PTCL, unspecified and 45.5% for Angioimmunoblastic T-cell lymphoma, which were the two largest subtypes enrolled. The median duration of response based on the first date of response to disease progression or death was 8.4 months. Common adverse events included nausea, fatigue, pyrexia, anemia and vomiting.
The package insert has the following warnings and precautions: hematologic toxicity, infections (including pneumonia and sepsis), hepatotoxicity, tumor lysis syndrome, gastrointestinal toxicity, and embryo-fetal toxicity.
Policy:
(Note: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)
The requirements of the Horizon BCBSNJ Belinostat (Beleodaq) 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. Belinostat (BeleodaqTM) is medically necessary for adults 18 years and older for the FDA-approved indication based on the following criteria:
a. Member has a confirmed diagnosis of peripheral T-cell lymphoma (PTCL), including angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or monomorphic epitheliotropic intestinal T-cell lymphoma.
b. Member has relapsed or refractory disease.
c. Member has tried at least one or more systemic treatment (including but not limited to brentuximab vendotin + CHP [cyclophosphamide, doxorubicin, and prednisone], CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone], or dose-adjusted EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin]).
d. Member is at least 100 days away from hematopoietic stem cell transplantation (HSCT).
e. Member has a performance status of 0 to 2
f. Member has adequate hematologic, hepatic, and renal function, including absolute neutrophil count ≥ 1,000/ìuL and platelets ≥ 50,000/ìuL.
g. Member does not have any of the following PTCL subtypes: precursor and adult TCL or leukemia, prolymphocytic leukemia, T-cell large granular lymphocytic leukemia, primary cutaneous anaplastic large cell lymphoma (ALCL), mycosis fungoides, and Sézary syndrome.
h. Member did not receive prior HDAC inhibitor treatment at any time or anticancer therapy within 2 weeks.
i. Member does not have baseline QT prolongation of >450 milliseconds or long QT syndrome.
2. When belinostat (BeleodaqTM) is considered medically necessary, initial therapy will be approved for 6 months based on FDA-approved labeling:
a. 1000 mg/m2 intravenous infusion administered over 30 minutes once daily on Days 1-5 of a 21 day cycle, OR
b. For members with reduced UGT1A1 activity (including homozygous for the UGT1A1*28 allele), reduce the starting dose to 750 mg/m2 intravenous infusion administered over 30 minutes once daily on Days 1-5 of a 21 day cycle.
[INFORMATIONAL NOTE: Per the FDA approved package insert, belinostat is primarily metabolized by uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1). UGT1A1 is an enzyme of the glucuronidation pathway for metabolism. The clearance of belinostat could be decreased in patients with reduced UGT1A1 activity (e.g., patients with UGT1A1*28 allele).
Per pre-clinical studies, belinostat glucuronidation was significantly decreased in microsomes homozygous for UGT1A1*28. Based on these preclinical findings only, the drug label of belinostat recommends a dose reduction who are homozygous for UGT1A1*28. Further clinical studies are being done to evaluate the efficacy and safety for patients with UGT1A1*27 allele.]
3. Continued therapy with belinostat (BeleodaqTM) will be approved every 12 months based on the following criteria:
a. The dose does not exceed 1000 mg/m2 on days 1-5 of a 21-day cycle.
b. Member has not experienced unacceptable toxicity while receiving treatment with belinostat (e.g. hematologic toxicity, serious/fatal infection, hepatotoxicity, tumor lysis syndrome, or embryo-fetal toxicity).
c. Tumor response with stabilization of disease or decrease in size of tumor or tumor spread
[INFORMATIONAL NOTE: In O’Connor, et al clinical studies, the median duration of response based on the first date of response to disease progression or death was 8.4 months (95% CI: 4.5 – 29.4). Of the responders, the median time to response was 5.6 weeks (range 4.3 - 50.4 weeks). Nine patients (7.5%) were able to proceed to a stem cell transplant after treatment with Beleodaq.]
4. Belinostat (BeleodaqTM) is considered medically necessary for the following off-label use:
o Adult T-cell leukemia/lymphoma:
§ Second-line or subsequent therapy as a single agent for nonresponders to first-line therapy for acute disease or lymphoma.
§ Second-line and subsequent therapy for relapsed/refractory anaplastic large cell lymphoma, peripheral T-cell lymphoma not otherwise specified (preferred), angioimmunoblastic T-cell lymphoma (preferred), enteropathy-associated T-cell lymphoma (preferred), monomorphic epitheliotropic intestinal T-cell lymphoma (preferred), nodal peripheral T-cell lymphoma with TFH phenotype (preferred), or follicular T-cell lymphoma (preferred), as a single agent
§ Preferred second-line and subsequent therapy as a single agent for refractory disease after 2 primary treatment regimens for hepatosplenic gamma-delta T-cell lymphoma
§ Preferred therapy as a single agent for relapsed, refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used in extranodal NK/T cell lymphoma
o NHL - Mycosis Fungoides (MF)/Sezary Syndrome (SS):
§ Systemic therapy as primary treatment for
o Stage IV non-Sezary or visceral disease, with or without radiation therapy for local control (preferred).
o Large cell transformation (LCT) with generalized cutaenous or extracutaneous lesions, with or without skin-directed therapy (preferred)
§ Systemic therapy as treatment for
· Relapsed or persistent stage IA MF with B1 blood involvement, with or without skin-directed therapy
· Relapsed or persistent stage IB-IIA MF with B1 blood involvement, with or without skin-directed therapy
· Stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapy
· Relapsed or refractory stage IIB MF with generalized tumor lesions, with or without skin-directed therapies
· Stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies or progression
· Relapsed or persistent stage III MF with or without skin-directed therapies or stage III MF that is refractory to multiple previous therapies
· Stage IIIMF that is refractory to multiple previous therapies
· Relapsed or persistent stage IV Sezary syndrome
· Relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
· Large cell transformation with limited cutaneous lesions that is refractory to multiple previous therapies
· Relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions with or wihout skin directed therapy.
o NHL - Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders
§ 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).
5. All other uses of belinostat (BeleodaqTM) is considered investigational, including but not limited to ovarian cancer, bladder cancer, fallopian tube cancer, glioblastoma multifomrme of braine.
Medicare Coverage
There is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for Belinostat (BeleodaqTM ). 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:
Belinostat (Beleodaq)
Beleodaq (Belinostat)
References:
1. BeleodaqTM product information. Spectrum Pharmaceuticals, Inc. Irvine, CA. September 2019.
2. NCCN Drugs and Biologics Compendium™. Beleodaq. 2019. Available at: https://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=410. Accessed November 2019.
3. Gold Standard, Inc. Belinostat. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed February 2018.
4. Micromedex® Healthcare Series. n.d. Thomson Healthcare, Greenwood Village, CO. August 2017. http://www.thomsonhc.com.
5. O’Connor O. Getting the Facts Peripheral T-cell Lymphoma. Lymphoma Research Foundation. [ Available at: http://www.lymphoma.org/atf/cf/%7B0363cdd6-51b5-427b-be48-e6af871acec9%7D/PTCL09.PDF
6. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: T-Cell Lymphomas. Version 3.2018. Available at: https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf. Accessed February 2019.
7. Belinostat (Beleodaq) for Peripheral T-Cell Lymphoma. Med Lett Drugs Ther. 2015 Apr 27;57(1467):e66-67. Accessed August 2017.
8. Campbell P, Thomas CM. Belinostat for the treatment of relapsed or refractory peripheral T-cell lymphoma. J Oncol Pharm Pract. 2017;23(2):143-147.
9. Lee HZ, Kwitkowski VE, Del valle PL, et al. FDA Approval: Belinostat for the Treatment of Patients with Relapsed or Refractory Peripheral T-cell Lymphoma. Clin Cancer Res. 2015;21(12):2666-70.
10. Marchi E, Raufi AG, O'connor OA. Novel Agents in the Treatment of Relapsed or Refractory Peripheral T-Cell Lymphoma. Hematol Oncol Clin North Am. 2017;31(2):359-375.
11. ClinicalTrials.gov. A Multicenter, Open-Label Trial of Belinostat in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma. December 2014. Available at: https://clinicaltrials.gov/ct2/show/NCT00865969?term=belinostat&recrs=e&phase=123&draw=1&rank=1. Accessed August 2017.
12. ClinicalTrials.gov. Phase II Study of PXD101 (NSC-726630) in Relapsed and Refractory Aggressive B-Cell Lymphomas. April 2013. Available at: https://clinicaltrials.gov/ct2/show/NCT00303953?term=belinostat&recrs=e&phase=123&draw=1&rank=9. Accessed August 2017.
13. ClinicalTrials.gov. Belinostat in Treating Patients With Liver Cancer That Cannot Be Removed By Surgery. January 2013. Available at: https://clinicaltrials.gov/show/NCT00321594. Accessed September 2017.
14. ClinicalTrials.gov. An Open-label, Nonrandomized, Phase 1 Study to Evaluate the Safety and Pharmacokinetics of Belinostat in Patients With Relapsed/Refractory Solid Tumors or Hematological Malignancies Who Have Wild-Type, Heterozygous, and Homozygous UGT1A1*28 Genotypes. March 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02680795. Accessed September 2017.
15. ClinicalTrials.gov. Beleodaq. Available at https://clinicaltrials.gov/ct2/results?cond=&term=beleodaq&cntry=&state=&city=&dist. Accessed February 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
* CPT only copyright 2019 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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