Coverage Policy Manual
Policy #: 2021009
Category: Pharmacy
Initiated: June 2021
Last Review: March 2022
  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 patients 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
 
J9315     Injection, romidepsin
J9318     Injection, romidepsin, non-lyophilized, 0.1 mg
J9319     Injection, romidepsin, lyophilized, 0.1 mg
C9065    Injection, romidepsin, non lyophilized (e.g. liquid), 1 mg (term 6/30/2021)
 

Policy/
Coverage:
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 March 2, 2022
 
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:
 
  1. 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).
  2. 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);  
 
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
 
  • 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:
 
  1. 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).
  2. 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).
  3. 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);  
 
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
 
    • 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.
 
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.

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)

CPT/HCPCS:
C9065Injection, romidepsin, non lypohilized (e.g. liquid), 1mg
J9315Injection, romidepsin, 1 mg
J9318Injection, romidepsin, non-lyophilized, 0.1 mg
J9319Injection, romidepsin, lyophilized, 0.1 mg

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.

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/


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.
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