Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2021009
Category:	Pharmacy
Initiated:	June 2021
Last Review:	February 2024

Romidepsin (e.g., ISTODAX)

Description:

Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in the modulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylated histones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect of romidepsin observed in nonclinical and clinical studies has not been fully characterized.

Regulatory

The FDA approved indications for Romidepsin (e.g., ISTODAX) include cutaneous and peripheral T-cell lymphoma in individuals that have received at least one prior therapy. The National Comprehensive Cancer Network® (NCCN) provides additional recommendations with a category 2A level of evidence for the use of Istodax. These include the use as primary treatment for Mycosis Fungoides/Sezary Syndrome which are subtypes of cutaneous T-cell lymphomas.

On July 30, 2021, Bristol Myers Squibb withdrew the indication for Romidepsin as treatment for relapsed or refractory peripheral T-cell lymphoma. The Food and Drug Administration granted approval under the accelerated approval process for Romidepsin on June 16, 2011. A confirmatory phase 3 study evaluated the addition of Romidepsin to CHOP as first-line treatment for peripheral T-cell lymphoma. The trial failed to meet its primary efficacy endpoint of PFS and Bristol Myers Squibb subsequently withdrew the peripheral T-cell lymphoma indication in accordance with FDA requirements for evaluating accelerated approvals that have not demonstrated sufficient clinical benefit.

Coding

See CPT/HCPCS Code section below.

Policy/
Coverage:

Prior approval is required for Romidepsin (e.g., Istodax).

The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart, or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.

Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.

Effective February 28, 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.

For off-label indications, authorizations will not exceed maximum recommended doses as outlined in dosage and administration section.

Romidepsin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:

FDA Approved Indications

INITIAL APPROVAL STANDARD REVIEW for up to 6 months:

1. Individual is 18 years of age or older (Istodax, 2021); AND

2. Indivudal has a diagnosis of cutaneous T-cell lymphoma (CTCL) (Istodax, 2021); AND

3. Individual has received at least one prior systemic therapy (Istodax, 2021); AND

4. Must be dosed in accordane with the FDA label.

CONTINUED APPROVAL for up to 12 months:

1. Individual continues to meet the initial approval criteria; AND

2. Tumor response with stabilization of disease or decrease in size of tumor or tumor spread (Istodax, 2021); AND

3. Individual is not experiencing unacceptable toxicity from the drug. Examples of unacceptable toxicity include the following: hematological abnormalities (e.g., neutropenia, anemia, leucopenia, thrombocytopenia, etc.), severe infections, severe tumor lysis syndrome, and ECG T-wave changes (Istodax, 2021).

Off Label Indications

STANDARD REVIEW for up to 12 months:

1. Primary Cutaneous Lymphomas (NCCN 2A)

a. Mycosis Fungoides/Sezary Syndrome

i. Preferred systemic therapy as primary treatment for:

1. Stage IB-IIA mycosis fungoides (MF), in combination with skin-directed therapy in selected cases

2. Stage IIB MF with limited tumor lesions, with or without local radiation therapy and with or without skin-directed therapy

3. Stage IIB MF with generalized tumor lesions, in combination with skin-directed therapy

4. Stage III MF, in combination with skin-directed therapy

5. Stage IVA1 or IVA2 Sezary syndrome, in combination with skin-directed therapy

6. Stage IVA2 non-Sezary or stage IVB visceral disease (solid organ), with or without radiation therapy for local control

7. Generalized cutaneous or extracutaneous lesions with large cell transformation (LCT), in combination with skin-directed therapy

ii. Preferred systemic therapy as subsequent treatment for:

1. Stage IA mycosis fungoides (MF) that is refractory to multiple previous therapies, in combination with skin-directed therapy in selected cases

2. Relapsed or persistent stage IB-IIA MF with a lower skin disease burden (e.g., predominantly patch disease), in combination with skin-directed therapy in selected cases

3. Stage IB-IIA MF with a higher skin disease burden (e.g., predominantly plaque disease) that is relapsed or persistent with T1-T2 disease, in combination with skin-directed therapy in selected cases

4. Stage IB-IIA MF that is refractory to multiple previous therapies, in combination with skin-directed therapy

5. Relapsed stage IIB T1-2 MF with limited tumor lesions, in combination with skin-directed therapy in selected cases

6. Relapsed stage IIB T3 MF with limited tumor lesions, with or without local radiation therapy and with or without skin-directed therapy

7. Persistent stage IIB T1-3 MF with limited tumor lesions, with or without local radiation therapy and with or without skin-directed therapy

8. Stage IIB MF with limited tumor lesions that is refractory to multiple previous therapies, in combination with skin-directed therapy

9. Relapsed stage IIB T1-2 MF with generalized tumor lesions, in combination with skin-directed therapy in selected cases

10. Relapsed stage IIB T3 MF with generalized tumor lesions, in combination with skin-directed therapy

11. Persistent stage IIB T1-3 MF with generalized tumor lesions, in combination with skin-directed therapy

12. Stage IIB MF with generalized tumor lesions that is refractory to multiple previous therapies, in combination with skin-directed therapy

13. Relapsed or persistent stage III MF, in combination with skin-directed therapy

14. Stage III MF that is refractory to multiple previous therapies, in combination with skin-directed therapy

15. Relapsed or persistent stage IVA1 or IVA2 Sezary syndrome, in combination with skin-directed therapy

16. Relapsed or persistent stage IVA2 non Sezary or stage IVB visceral disease (solid organ), with or without radiation therapy for local control

17. Limited cutaneous lesions with large cell transformation (LCT) that is refractory to multiple previous therapies, in combination with skin-directed therapy

18. Relapsed or persistent generalized cutaneous or extracutaneous lesions with LCT, in combination with skin-directed therapy

iii. Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders:

1. Therapy for primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions, or cutaneous ALCL with regional node (N1) (excludes systemic ALCL), as a single agent for relapsed/refractory disease

2. T-Cell Lymphomas (NCCN 2A)

a. Peripheral T-Cell Lymphomas:

i. Initial palliative intent therapy or second-line and subsequent therapy for relapsed/refractory peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (preferred), enteropathy-associated T-cell lymphoma (EATL) (preferred), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) (preferred), angioimmunoblastic T-cell lymphoma (AITL) (preferred), nodal peripheral T-cell lymphoma with TFH phenotype (PTCL, TFH) (preferred) and follicular T-cell lymphoma (FTCL) (preferred), or anaplastic large cell lymphoma (ALCL), as a single agent

b. Breast Implant-Associated Anaplastic Large Cell Lymphoma (ALCL):

i. Second-line and subsequent therapy for relapsed/refractory disease, as a single agent

c. Hepatosplenic T-Cell Lymphoma:

i. Preferred therapy as a single agent for refractory disease after 2 first-line therapy regimens

d. Extranodal NK/T-Cell Lymphomas:

i. Therapy as a single agent for relapsed/refractory disease following additional therapy with an alternate combination chemotherapy regimen (asparaginase-based) not previously used

The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Romidepsin is 14 mg per square meter of body surface area administered intravenously (IV) over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the individual continues to benefit from and tolerates the drug.

Discontinue or interrupt treatment (with or without dose reduction to 10 mg per square meter of body surface area) to manage drug toxicity.

Reduce starting dose in individuals with moderate and severe hepatic impairment.

Romidepsin is available as 10 mg lyophilized powder in a single-dose vial for reconstitution.

Off Label Dosing per disease:

1. Mycosis Fungoides/Sezary Syndrome

a. Romidepsin 14 mg per square meter of body surface area as a 4-hour IV infusion on days 1, 8, and 15 of each 28-day cycle for up to 6 cycles for Stage IB-IVA (NCCN; Whittaker, 2010)

2. Peripheral T-Cell Lymphomas

a. Romidepsin 14 mg per square meter of body surface area as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles for individuals who have relapsed from or were refractory to 1 or more prior systemic therapies; individuals with response or stable disease could continue romidepsin beyond 6 cycles. (Coiffier, 2014)

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Romidepsin, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of romidepsin, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective March 2023 to February 27, 2024

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of Romidepsin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:

Treatment of cutaneous T-cell lymphoma (CTCL)in adult patients (age 18 years and older) who have received at least one prior systemic therapy (FDA 2018, NCCN 2A).
Treatment of Mycosis Fungoides or Sézary Syndrome (NCCN 2A).
Must be dosed in accordance with the FDA label.

INITIAL APPROVAL will be for 6 months.

CONTINUED APPROVAL

Patient continues to meet the criteria as previous approval; AND
Tumor response with stabilization of disease or decrease in size of tumor or tumor spread (FDA, 2018); AND
Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include the following: hematological abnormalities (e.g., neutropenia, anemia, leucopenia, thrombocytopenia, etc.), severe infections, severe tumor lysis syndrome, and ECG T-wave changes (FDA, 2018);

Dosage and Administration

Dosing per FDA Guidelines

The recommended dose of Romidepsin is

14 mg/m2 administered intravenously (IV) over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the patient continues to benefit from and tolerates the drug.

Discontinue or interrupt treatment (with or without dose reduction to 10 mg/m2) to manage drug toxicity.

Reduce starting dose in patients with moderate and severe hepatic impairment.

Romidepsin is available as 10 mg lyophilized powder in a single-dose vial for reconstituion.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Romidepsin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving for any indication or circumstance other than those outlined above.

For members with contracts without primary coverage criteria, the use of romidepsin any condition or circumstance other than listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective March 2, 2022 to February 2023

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of Romidepsin meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:

Treatment of cutaneous T-cell lymphoma (CTCL)in adult patients (age 18 years and older) who have received at least one prior systemic therapy (FDA 2018, NCCN 2A).
Treatment of Mycosis Fungoides or Sézary Syndrome (FDA 2018, NCCN 2A).

INITIAL APPROVAL will be for 6 months.

CONTINUED APPROVAL

Patient continues to meet the criteria as previous approval; AND
Tumor response with stabilization of disease or decrease in size of tumor or tumor spread (FDA, 2018); AND
Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include the following: hematological abnormalities (e.g., neutropenia, anemia, leucopenia, thrombocytopenia, etc.), severe infections, severe tumor lysis syndrome, and ECG T-wave changes (FDA, 2018);

Dosage and Administration

14 mg/m2 administered intravenously (IV) over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the patient continues to benefit from and tolerates the drug.
Discontinue or interrupt treatment (with or without dose reduction to 10 mg/m2) to manage drug toxicity.
Reduce starting dose in patients with moderate and severe hepatic impairment.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Romidepsin does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any other indication than those outlined above.

For members with contracts without primary coverage criteria, the use of romidepsin any other condition than listed above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective June 1, 2021 to March 1, 2022

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

The use of Romidepsin (Istodax) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:

Treatment of cutaneous T-cell lymphoma (CTCL)in adult patients (age 18 years and older) who have received at least one prior systemic therapy (FDA 2018, NCCN 2A).
Treatment of peripheral T-cell lymphoma (PTCL) in adult patients (age 18 years and older) who have received at least one prior therapy. This indication is approved under accelerated approval based on response rate (FDA 2018, NCCN 2A).
Treatment of Mycosis Fungoides or Sézary Syndrome (FDA 2018, NCCN 2A).

INITIAL APPROVAL will be for 6 months.

CONTINUED APPROVAL

Patient continues to meet the criteria as previous approval; AND
Tumor response with stabilization of disease or decrease in size of tumor or tumor spread (FDA, 2018); AND
Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include the following: hematological abnormalities (e.g., neutropenia, anemia, leucopenia, thrombocytopenia, etc.), severe infections, severe tumor lysis syndrome, and ECG T-wave changes (FDA, 2018);

Dosage and Administration

14 mg/m2 administered intravenously (IV) over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the patient continues to benefit from and tolerates the drug.

Discontinue or interrupt treatment (with or without dose reduction to 10 mg/m2) to manage drug toxicity.

Reduce starting dose in patients with moderate and severe hepatic impairment.

Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Romidepsin does not meet member benefit certificate primary coverage criteria for any other indication.

Rationale:

Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).

Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.

Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).

Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication. (Coiffier B, Pro B, Prince HM, et. al., 2012)

A phase I/II multicenter study evaluated romidepsin treatment in Japanese patients with relapsed/refractory peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Patients aged ≥20 years received romidepsin via a 4-h intravenous infusion on days 1, 8, and 15 of each 28-day cycle. Phase I used a 3 + 3 design to identify any dose-limiting toxicity (DLT) for regimens of romidepsin 9 and 14 mg/m2. The primary endpoints for phase I and II were DLT and overall response rate (ORR), respectively. Intent-to-treat patients were those who received ≥1 romidepsin dose (PTCL, n = 48; CTCL, n = 2). In phase I, none of the patients (n = 3, 9 mg/m2; n = 6, 14 mg/m2) exhibited DLT. In phase II, 40 patients with PTCL were treated with 14 mg/m2 romidepsin. The most common treatment-emergent grade ≥3 adverse events were lymphopenia (74%), neutropenia (54%), leukopenia (46%), and thrombocytopenia (38%). Patients in phase II showed a 43% ORR, including 25% complete responses. Median progression-free survival was 5.6 months and median duration of response was 11.1 months. This phase I/II study identified a well-tolerated dose of romidepsin, with an acceptable toxicity profile and clinically meaningful efficacy in Japanese patients with relapsed/refractory PTCL. ClinicalTrials.gov Identifier NCT01456039. (Maruyama D, Tobinai K, Ogura M, et.al., 2017)

2022 Update

A randomized phase III study of Ro-CHOP versus CHOP in adult patients with previously untreated PTCL was conducted as a confirmatory trial. All patients received CHOP in 3-week cycles for six cycles. Romidepsin, 12 mg/m2, was administered intravenously over a 4-hour period on days 1 and 8 of each 3-week cycle for six cycles. The primary end point was progression-free survival (PFS) according to International Working Group 1999 criteria.

Between January 2013 and December 2017, 421 patients were enrolled (Ro-CHOP, n = 211; CHOP, n = 210). The median PFS for Ro-CHOP versus CHOP was 12.0 months (95% CI, 9.0 to 25.8) versus 10.2 months (95% CI, 7.4 to 13.2) with a hazard ratio of 0.81 (P = .096). In the Ro-CHOP versus CHOP arms, the median overall survival was 51.8 versus 42.9 months and the objective response rate was 63% versus 60% with complete response plus unconfirmed complete response rates of 41% versus 37% (P > .1 in all comparisons), respectively. Grade 3 or 4 treatment-emergent adverse events occurring in ≥ 30% of patients in the Ro-CHOP arm included thrombocytopenia (50% v 10% in the Ro-CHOP v CHOP arms, respectively), neutropenia (49% v 33%), anemia (47% v 17%), and leukopenia (32% v 20%).

The addition of romidepsin to CHOP did not improve PFS, response rates, nor overall survival and increased the frequency for grade ≥ 3 treatment-emergent adverse events. Ro-CHOP does not represent a significant advance in the standard of care for patients with previously untreated PTCL. (Bachy E, Camus V, Thieblemont, et.al., 2022)

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement.

2024 Update

Annual policy review completed with a literature search using the MEDLINE database through February 2024. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:

References:

U.S. Food and Drug Administration (FDA).(2018) 2018 ROMIDEPSIN. Prescribing Information. (2009 [Revised 2/2018]). https://www.accessdata.fda.gov/drugsatfda_docs/label

Bachy E, Camus V, Thieblemont C, et.al.,(2022) Romidepsin Plus CHOP Versus CHOP in Patients With Previously Untreated Peripheral T-Cell Lymphoma: Results of the Ro-CHOP Phase III Study (Conducted by LYSA). J Clin Oncol. 2022 Jan 20;40(3):242-251. doi: 10.1200/JCO.21.01815. Epub 2021 Nov 29. PMID: 34843406.

Coiffier B, Pro B, Prince HM, et. al.,(2012) 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 Feb 20;30(6):631-6. doi: 10.1200/JCO.2011.37.4223. Epub 2012 Jan 23. PMID: 22271479.

Coiffier B, Pro B, Prince HM, Foss F, Sokol L, Greenwood M, Caballero D, Morschhauser F, Wilhelm M, Pinter-Brown L, Padmanabhan Iyer S, Shustov A, Nielsen T, Nichols J, Wolfson J, Balser B, Horwitz S.(2014) Romidepsin for the treatment of relapsed/refractory peripheral T-cell lymphoma: pivotal study update demonstrates durable responses. J Hematol Oncol. 2014 Jan 23;7:11. doi: 10.1186/1756-8722-7-11. PMID: 24456586; PMCID: PMC4016573.

Istodax [package insert]. Summit, NJ; Celgene, July 2016. Accessed February 2021.

Maruyama D, Tobinai K, Ogura M, et. al.,(2017) Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. Int J Hematol. 2017 Nov;106(5):655-665. doi: 10.1007/s12185-017-2286-1. Epub 2017 Jun 29. PMID: 28664499.

National Comprehensive Cancer Network (NCCN).(2020) Istodax. NCCN Drugs and Biologics Compendium. Fort Washington, PA: NCCN, 2020.

National Comprehensive Cancer Network (NCCN).(2021) Romidepsin. NCCN Drugs & Biologics Compendium®. https://www.nccn.org/professionals/drug_compendium/content/

NCCN Drugs & Biologics Compendium® for Romidepsin (e.g., Istodax). © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed [February 14, 2024]. To view the most recent and complete version of the Compendium, go online to NCCN.org.

Whittaker SJ, Demierre MF, Kim EJ, et al.(2010) Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010;28:4485-4491. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20697094.

Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2024 American Medical Association.