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. Romidepsin (Istodax®)

A. Romidepsin (Istodax®) is medically necessary for adult patients 18 years or older for:
1. the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. (Prior systemic therapy can include, but is not limited to the following: retinoids, interferons, extracorporeal photophoresis, denileukin diftitox, methotrexate, liposomal doxorubicin or gemcitabine).
2. the treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. (Prior systemic therapy can include, but is not limited to the following: retinoids, interferons, extracorporeal photophoresis, denileukin diftitox, methotrexate, liposomal doxorubicin or gemcitabine).

[INFORMATIONAL NOTE: In clinical studies for romidepsin, patients were eligible for inclusion if they had relapsed, refractory, or advanced CTCL, either as mycosis fungoides or Sezary syndrome. In Piekarz, et al, 25% of patients in cohort 1 (93%) and 62 (87%) in cohort II had advanced disease (stages IIB to IVB). The median number of prior therapies was 3 and 4 in cohorts I and II, respectively.]

B. The initial therapy with romidepsin (Istodax®), when medically necessary, will be covered for 6 months at the FDA-recommended dose of 14 mg/m² administered intravenously on days 1, 8 and 15 of a 28-day cycle.

[INFORMATIONAL NOTE: As per the FDA approved package insert, dose modification for toxicities is as follows:
A. Nonhematologic toxicities except alopecia
• Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 or baseline, then therapy may be restarted at 14 mg/m2 . If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 or baseline and the dose should be permanently reduced to 10 mg/m2 .
• Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to Grade 0-1 or baseline, then the dose should be permanently reduced to 10 mg/m2 .
• Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction.
B. Hematologic toxicities
• Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC greater than or equal to 1.5×109 /L and platelet count greater than or equal to 75×109 /L or baseline, then therapy may be restarted at 14 mg/m2 .
• Grade 4 febrile (greater than or equal to 38.5ºC) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to less than or equal to Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2.
Dosage in patients with hepatic impairment: for patients with moderate or severe hepatic impairment, reduce the starting dose of Istodax as shown in the below table and monitor for toxicities more frequently. Dose adjustment is not required for patients with mild hepatic impairment.]



Hepatic impairment	Bilirubin levels	Istodax dose
Moderate	> 1.5 x ULN to ≤ 3 x ULN	7 mg/m2
Severe	> 3 x ULN	5 mg/m2

C. Continuing therapy with Romidepsin (Istodax®) is considered medically necessary for renewal every 6 months if ALL of the following criteria are met:
• Individual continues to meet initial approval criteria
• Response to treatment is indicated by stabilization of disease or decrease in size of tumor or tumor spread
• Absence of unacceptable toxicity the drug (e.g., neutropenia, anemia, leucopenia, thrombocytopenia, severe infections, severe tumor lysis syndrome, ECG T-wave changes, etc.)
D. Romidepsin (Istodax®) is medically necessary for the following off-label uses:
• NHL - Mycosis fungoides (MF)/Sezary syndrome (SS)
  • Preferred systemic therapy as primary treatment for
    • stage IA mycosis fungoides (MF) with B1 blood involvement, with or without skin-directed therapy
    • stage IB-IIA MF with a higher disease burden (eg, predominantly plaque disease), with or without skin-directed therapy
    • stage IIB MF with limited tumor lesions, with or without local radiation therapy
    • stage IIB MF with generalized tumor lesions, with or without skin-directed therapy
    • stage III MF, with or without skin-directed therapy
    • stage IV Sezary syndrome, with or without skin-directed therapy
    • stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
    • large cell transformation (LCT) with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
  • Preferred systemic therapy as treatment for
    • stage IA mycosis fungoides (MF) with B1 blood involvement that is relapsed, persistent, or refractory to multiple previous therapies, with or without skin-directed therapy
    • relapsed or persistent stage IB-IIA MF with a higher disease burden (eg, predominantly plaque disease), with or without skin-directed therapy
    • relapsed or persistent stage IIB MF with limited tumor lesions, with or without local radiation therapy
    • stage IIB MF with limited tumor lesions refractory to multiple previous therapies, with or without skin-directed therapy
    • relapsed or persistent stage IIB MF with generalized tumor lesions, with or without skin-directed therapy
    • stage IIB MF with generalized tumor lesions refractory to multiple previous therapies
    • relapsed or persistent stage III MF, with or without skin-directed therapy
    • stage III MF that is refractory to multiple previous therapies, with or without skin-directed therapy
    • relapsed or persistent stage IV Sezary syndrome, with or without skin-directed therapy
    • relapsed or persistent stage IV non Sezary or visceral disease (solid organ), with or without radiation therapy for local control
    • large cell transformation (LCT) with limited cutaneous lesions that is refractory to multiple previous therapies
    • relapsed or persistent LCT with generalized cutaneous or extracutaneous lesions, with or without skin-directed therapy
• NHL- Peripheral T-cell 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
• NHL - 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)
• T-Cell Lymphomas - Extranodal NK/T-Cell Lymphoma, nasal type
  • Preferred therapy as a single agent for relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used
• T-Cell Lymphomas - Hepatosplenic Gamma-Delta T-Cell Lymphoma
  • Preferred second-line and subsequent therapy as a single agent for refractory disease after 2 primary treatment regimens
E. Romidepsin (Istodax®) is considered investigational in other conditions including, but not limited to, the following:
• Large B-cell lymphoma
• Mesothelioma
• Head and neck cancer (including thyroid cancer)
• Ovarian and peritoneal carcinoma
• Glioblastoma multiforme
• Metastatic breast cancer
• Non-Small Cell Lung Cancer
• Multiple myeloma
• Bladder cancer
• Prostate cancer
• Colorectal cancer
• Pancreatic cancer
• Chronic Myeloid Leukemia
• Acute Myelogenous Leukemia
• Mantle Cell Lymphoma
• Myelodysplastic syndrome
• Lung cancer
• Renal cancer
• Follicular lymphoma
• Gastric cancer
• Hodgkin’s lymphoma
• HIV infection

Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for this service. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy.

Medicaid Coverage:

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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:
Histone Deacetylase Inhibitor(s) [Romidepsin (Istodax®)]
Histone Deacetylase Inhibitor
Vorinostat
Zolinza
Romidepsin
Istodax

References:
1. AHFS Drug Information. American Society of Health-System Pharmacists, Inc. 2019.

2. Blumenschein GR, Kies MS, Papadimitrakopoulou VA et al. Phase II trial of the histone deacetylase inhibitor vorinostat (ZolinzaTM, suberoylanilide hydroxamic acid, SAHA) in patients with recurrent and/or metastatic head and neck cancer. Invest New Drugs 2008;26:81-87.

3. Crump M, Coiffier B, Jacobsen ED et al. Phase II trial of oral vorinostat (suberoylanilide hydroxamic acid) in relapsed diffuse large B-cell lymphoma. [Abstract] Ann Oncol 2008, Feb.

4. Galanis E, Jaeckle KA, Maurer MJ et al. N047B : NCCTG phase II trial of vorinostat (suberoylanilide hydroxamic acid) in recurrent glioblastoma multiforme (GBM). [Abstract] 2007 ASCO Annual Meetings Proceedings:25(18S),2007:2004.

5. Krug LM, Curley T, Schwartz L et al. Potential role of histone deacetylase inhibitore in mesothelioma : clinical experience with suberoylanilide hydroxamic acid. [Abstract] Clin Lung Cancer 2006;7(4):257-61.

6. Luu TH, Leong L, Morgan R et al. Vorinostat (suberoylanilide hydroxamic acid) as salvage therapy in metastatic breast cancer (MBC): A California Cancer Consortium phase Ii study. [Abstract] 2007 ASCO Annual Meetings Proceedings:25(18S),2007:11502.

7. Micromedex Health Series. Thomson Gateway. [Available at: http://www.thomsonhc.com/hcs/librarian/PFPUI/AH1fgpoxqU9YR]

8. Modesitt SC, Sill M, Hoffman JS et al. A Phase II study of vorinostat in the treatment of persistent or recurrent epithelial ovarian or primary peritoneal carcinoma: A Gynecologic Oncology Group study. [Abstract] Gyn Oncol 2008, Feb.

9. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Central Nervous System Cancers. Version 2.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/cns.pdf.

10. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Breast Cancer. Version 2.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.

11. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf

12. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Head and Neck Cancers. Version.2020 Available at http://www.nccn.org/professionals/physician_gls/PDF/head-and-neck.pdf

13. National Comprehensive Cancer Network (NCCN). Practice Guidelines in Oncology: Ovarian Cancer. Version 2.2020. Available at http://www.nccn.org/professionals/physician_gls/PDF/ovarian.pdf

14. Traynor AM, Dubey M, Eickhoff J et al. A phase II study of vorinostat (NSC 701852) in patients with relapsed non-small cell lung cancer (NSCLC). [Abstract] 2007 ASCO Annual Meetings Proceedings:25(18S),2007:18044.

15. Zolinza® (Vorinosat) Prescribing Information. Merck & Co. Whitehouse Station, NJ: 04/2013