Romidepsin (Istodax)

Number: 0865


Aetna considers romidepsin (Istodax) medically necessary for the following indications:

  • Adult T-cell leukemia/lymphoma
  • Cutaneous T-cell lymphoma (CTCL) in persons who have received at least 1 prior systemic therapy
  • Mycosis fungoides/Sezary syndrome
  • Relapsed or refractory primary cutaneous anaplastic large cell lymphoma (ALCL) with multifocal lesions and cutaneous ALCL with regional nodes (excludes systemic ALCL)
  • Relapsed or refractory peripheral T-cell lymphomas (PTCL) (includes angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma, or enteropathy-associated T-cell lymphoma).

Aetna considers romidepsin experimental and investigational for all other indications includingthe following (not an all-inclusive list):

  • Breast cancer
  • Glioblastoma
  • Head and neck cancer
  • Multiple myeloma
  • Non-small cell lung cancer
  • Ovarian cancer
  • Pancreatic cancer
  • Systemic ALCL
  • Thyroid cancer

Selection criteria are presented in the background section.


Istodax was approved by the Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma in patients who have received at least 1 prior systemic therapy.

Guidelines from the National Comprehensive Cancer Network (2014) recommend romidepsin for the following indications:

  • Adult T-cell leukemia/lymphoma - Therapy for nonresponders to first-line therapy for acute disease or lymphoma [2A]
  • Mycosis fungoides/Sezary syndrome - Systemic biologic therapy as a
    • Single agent or in combination with skin-directed therapy for stage I-IIA and stage III MF with blood involvement
    • Single agent or in combination with skin-directed therapies for stage I-IIA MF with histologic evidence of folliculotropic or large cell transformed or stage IIB MF with limited extent tumor disease
    • Single agent or in combination with systemic retinoids, interferons, or photopheresis for stage IA-IIB with histologic evidence of folliculotropic or large cell transformed MF, stage IIB MF with generalized extent tumor, transformed, and/or folliculotropic disease, or SS [2A; 2B for stage I-IIA with blood involvement]
  • Mycosis fungoides/Sezary syndrome - May be used as adjuvant systemic biologic therapy after total skin electron beam therapy for stage IIB MF generalized extent tumor, transformed, and/or folliculotropic disease or after chemotherapy for stage IV non-Sezary or visceral disease [2A]
  • Mycosis fungoides/Sezary syndrome - Systemic biologic therapy for refractory or progressive stage IA-IIA or stage IIB (patch or plaque) MF [2A]
  • Peripheral T-Cell Lymphoma - Second-line therapy for relapsed or refractory angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma not otherwise specified, anaplastic large cell lymphoma, or enteropathy-associated T-cell lymphoma [2A]
  • 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) [2A]

Haigentz et al (2012) noted that patients with advanced squamous cell carcinoma of the head and neck (SCCHN) have limited treatment options.  Inhibition of histone deacetylases (HDACs) represents a novel therapeutic approach warranting additional investigation in solid tumors.  These researchers performed a phase II trial of single agent romidepsin in 14 patients with SCCHN who provided consent for pre- and post-therapy samples of accessible tumor, blood and uninvolved oral mucosa.  Romidepsin was administered at 13 mg/m(2) as a 4-hour intravenous infusion on days 1, 8 and 15 of 28-day cycles, with response assessment by Response Evaluation Criteria In Solid Tumors (RECIST) every 8 weeks.  Objective responses were not observed, although 2 heavily pre-treated patients had brief clinical disease stabilization.  Observed toxicities were expected, including frequent severe fatigue.  Immunohistochemical analysis of 7 pre- and post-treatment tumor pairs demonstrated induction of p21(Waf1/Cip1) characteristic of HDAC inhibition, as well as decreased Ki67 staining.  Exploratory microarray analyses of mucosal and tumor samples detected changes in gene expression following romidepsin treatment that were most commonly associated with regulation of transcription, cell cycle control, signal transduction, and electron transport.  Treatment with romidepsin did not alter the extent of DNA methylation of candidate gene loci (including CDH1 and hMLH1) in SCCHN tumors.  The authors concluded that single agent romidepsin has limited activity for the treatment of SCCHN; but can effectively achieve tumor-associated HDAC inhibition.  Moreover, they stated that although tolerability of romidepsin in this setting may be limiting, further evaluation of other HDAC inhibitors in combination with active therapies may be justified.

Wilson et al (2012) stated that romidepsin (FK228) was recently approved by the FDA for the treatment of cutaneous and peripheral T cell lymphoma.  These researchers have previously shown in-vitro efficacy of FK228 in ovarian cancer; they evaluated FK228 combined with cisplatin in ovarian cancer in-vitro and in-vivo.  Ovarian cancer cell lines were treated with cisplatin, FK228 or the combination of drugs.  Colorimetric assays were used to determine cytotoxicity in-vitro.  Mice engrafted with 5 × 10(6) SKOV-3 ovarian cancer cells were treated with cisplatin, FK228 or the combination, and tumor weights and volumes were measured.  These investigators assessed molecular markers of proliferation (mib-1), apoptosis (cleaved PARP and cleaved caspase 3) and DNA damage (pH2AX, RAD51 and 53BP1).  FK228 enhanced the cytotoxic effects of cisplatin in ovarian cells compared to vehicle-treated controls or each drug alone.  Mice treated with FK228, cisplatin and both drugs showed reduced tumor weights and volumes.  Drug-treated tumors showed decreased mib-1 and increased cleaved-caspase 3 expression levels.  The number and intensity of pH2AX stained cells was greatest in tumors exposed to the combination of FK228 and cisplatin.  The authors concluded that FK228 causes DNA damage-induced apoptosis and enhanced the anti-tumor effects of cisplatin.  They stated that the DNA damage mark pH2AX was activated by FK228 and cisplatin and may be a useful pharmacodynamic marker of these effects.

Amiri-Kordestani et al (2013) noted that romidepsin is a potent histone deacetylase inhibitor (HDI) with activity in T-cell lymphoma.  Given pre-clinical data showing greater induction of gene expression with longer exposures to HDIs, a phase I study of a day 1, 3, and 5 romidepsin schedule was evaluated.  A secondary objective was to assess the effect of romidepsin on radioactive iodine (RAI) uptake in thyroid cancers.  In this open-label, single-arm, phase I, 3 + 3 dose escalation study, romidepsin was administered as a 4-hour infusion on days 1, 3, and 5 of a 21-day cycle.  Pharmacokinetics (PK) and pharmacodynamics (PD) were assessed, including histone acetylation in peripheral blood mononuclear cells (PBMC), RAI uptake in refractory thyroid cancer, and HDI-related ECG changes.  A total of 28 patients with solid tumors, including 11 patients with thyroid cancer were enrolled.  Six dose levels were explored, and 7 mg/m(2) on days 1, 3, and 5 was identified as tolerable.  No RECIST-defined objective responses were recorded although 9 patients had stable disease a median 30 weeks (range of 21 to 112) including 6 with thyroid cancer a median of 33 weeks.  Pharmacodynamics studies detected acetylated histones in PBMCs and ECG changes beginning at low dose levels.  Follow-up RAI scans in patients with RAI refractory thyroid cancer did not detect meaningful increases.  The authors concluded that a romidepsin dose of 7 mg/m(2) administered on days 1, 3, and 5 was found tolerable and resulted in histone acetylation in PBMCs.  They stated that although there were no objective responses with romidepsin alone, this schedule may be useful for developing combination studies in solid tumors.

Robertson et al (2013) stated that inflammatory breast cancer (IBC) is the most metastatic variant of locally advanced breast cancer; IBC has distinctive characteristics including invasion of tumor emboli into the skin and rapid disease progression.  Previous studies suggested that HDAC inhibitors have promise in targeting IBC.  The present study revealed that romidepsin potently induced destruction of IBC tumor emboli and lymphatic vascular architecture associated with inhibition of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1alpha, (HIF1alpha) proteins in the Mary-X pre-clinical model of IBC.  Romidepsin treatment induced clinically relevant biomarkers in including induction of acetylated histone 3 (Ac-H3) proteins, apoptosis, and increased p21WAF1/CIP1.  Romidepsin, alone and synergistically when combined with paclitaxel, effectively eliminated both primary tumors and metastatic lesions at multiple sites formed by the SUM149 IBC cell line.  The authors concluded that this was the first report of the ability of an HDAC inhibitor to eradicate IBC tumor emboli, to destroy the integrity of lymphatic vessel architecture and to target metastasis.  They stated that  romidepsin, in combination with a taxane, warrants evaluation as a therapeutic strategy that may effectively target the skin involvement and rapid metastasis that are hallmarks of IBC.

Karthik et al (2014) noted that HDAC inhibitors have been proven to be effective therapeutic agents to kill cancer cells through inhibiting HDAC activity or altering the structure of chromatin.  These researchers recently reported that chemotherapy by the HDAC inhibitor, romidepsin, activated the anti-apoptotic transcription factor NF-κB in A549 non-small cell lung cancer (NSCLC) cells and failed to induce significant levels of apoptosis.  They also demonstrated that NF-κB inhibition with proteasome inhibitor bortezomib enhanced HDAC inhibitor induced mitochondrial injury and sensitize A549 NSCLC cells to apoptosis through the generation of reactive oxygen species.  In this study, these investigators examined if combined treatment with romidepsin and bortezomib would induce apoptosis in A549 NSCLC cells by activating cell cycle arrest, enhanced generation of p21 and p53, down-regulation of matrix metalloproteinases (MMPs) 2 and 9 also altering the acetylation status of histone proteins.  The data showed that combination of romidepsin and bortezomib caused cell cycle arrest at Sub G0-G1 transition, up-regulation of cell cycle protein p21 and tumor suppressor protein p53.  In addition, romidepsin down-regulated the expression of MMP-2,9 and hyper-acetylation of histone H3 and H4 in bortezomib sensitized A549 NSCLC cells.  The authors concluded that romidepsin and bortezomib co-operatively inhibited A549 NSCLC cell proliferation by altering the histone acetylation status, expression of cell cycle regulators and MMPs.  They stated that romidepsin along with bortezomib might be an effective treatment approach for A549 NSCLC cells. 


Bezecny (2014) noted that epigenetic mechanisms are increasingly recognized as a major factor contributing to pathogenesis of cancer including glioblastoma, the most common and most malignant primary brain tumor in adults. Enzymatic modifications of histone proteins regulating gene expression are being exploited for therapeutic drug targeting. Over the last decade, numerous studies have shown promising results with HDAC inhibitors (HDACIs) in various malignancies. The author provided a brief overview of mechanism of anti-cancer effect and pharmacology of HDACIs and summarized results from pre-clinical and clinical studies in glioblastoma. It analyzed experience with HDACIs as single agents as well as in combination with targeted agents, cytotoxic chemotherapy and radiotherapy. Hallmark features of glioblastoma, such as uncontrolled cellular proliferation, invasion, angiogenesis and resistance to apoptosis, have been shown to be targeted by HDACIs in experiments with glioblastoma cell lines. Vorinostat is the most advanced HDACI that entered clinical trials in glioblastoma, showing activity in recurrent disease. Multiple phase II trials with vorinostat in combination with targeted agents, temozolomide and radiotherapy are currently recruiting. While the results from pre-clinical studies are encouraging, early clinical trials showed only modest benefit and the value of HDACIs for clinical practice will need to be confirmed in larger prospective trials. The author concluded that further research in epigenetic mechanisms driving glioblastoma pathogenesis and identification of molecular subtypes of glioblastoma is needed; and hopefully this will lead to better selection of patients who will benefit from treatment with HDACIs.

Lee and colleagues (2015) stated that glioblastoma is the most common and deadliest of malignant primary brain tumors (Grade IV astrocytoma) in adults. Current standard treatments have been improving but patient prognosis still remains unacceptably devastating. Glioblastoma recurrence is linked to epigenetic mechanisms and cellular pathways. Thus, greater knowledge of the cellular, genetic and epigenetic origin of glioblastoma is the key for advancing glioblastoma treatment. One rapidly growing field of treatment, epigenetic modifiers; HDACIs, has now shown much promise for improving patient outcomes through regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. Histone deacetylase inhibitors have been shown, in a pre-clinical setting, to be effective anti-cancer agents via multiple mechanisms, by up-regulating expression of tumor suppressor genes, inhibiting oncogenes, inhibiting tumor angiogenesis and up-regulating the immune system. There are many HDACIs that are currently in pre-clinical and clinical stages of investigation for various types of cancers. This review explained the theory of epigenetic cancer therapy, identified HDACIs that are being investigated for glioblastoma therapy, explained the mechanisms of therapeutic effects as demonstrated by pre-clinical and clinical studies and described the current status of development of these drugs as they pertain to glioblastoma therapy.

Multiple Myeloma:

Genadieva-Stavric et al (2014) stated that multiple myeloma (MM) is still an incurable disease with pattern of regression and remission followed by multiple relapses rising from the residual myeloma cells surviving even in the patients who achieve complete clinical response to treatment. New anti-myeloma drugs such as thalidomide, lenalidomide, and bortezomib have dramatically changed treatment paradigm leading to both tumor reduction and tumor suppression. Much progress has been made, but still many unsolved questions remain. In the mode of sequencing treatment for patients with MM, old drugs such as the alkylating agent melphalan, which continues to play a central role in the transplantation setting, are still being used. The authors noted that newer drugs are now emerging and are being tested including HDACIs (romidepsin), monoclonal antibodies (elotuzumab and daratumumab), proteasome inhibitors (carfilzomib, ixazomib, oprozomib, and marizomib), and signal transduction modulator( perifosine). They stated that many advances have been made, but there is still a long way to go.

El-Amm and Tabbara (2015) noted that the treatment of MM has evolved significantly over the past 2 decades due to the use of high-dose chemotherapy and autologous stem cell transplantation, and the subsequent introduction of the immunomodulatory agents (thalidomide and lenalidomide) and the proteasome inhibitor (bortezomib). The median overall survival (OS) of MM patients has increased significantly with patients younger than age 50 years experiencing a 10-year survival rate of around 40 %. However, despite the increased effectiveness of the first-line agents, the majority of patients will eventually relapse and become drug- resistant. Promising novel therapies have recently emerged and are being used to treat relapsed and refractory patients. These researchers presented the clinical data regarding these emergent therapies that include new generation of HDACIs, immunomodulatory drugs, monoclonal antibodies, proteasome inhibitors, and signal transduction modulator.

Pancreatic Cancer:

Feng et al (2014) stated that pancreatic cancer is a devastating disease with a dismal prognosis. Surgical resection is the only curative option but is heavily hampered by delayed diagnosis. Due to few therapeutic treatments available, novel and effective therapy is urgently needed. Histone deacetylase inhibitors are emerging as a prominent class of therapeutic agents for pancreatic cancer and have exhibited significant anti-cancer potential with negligible toxicity in pre-clinical studies. Clinical evaluations of HDACIs are currently underway; HDACIs as monotherapy in solid tumors have proven less effective than hematological malignancies, the combination of HDACIs with other anti-cancer agents have been assessed for advanced pancreatic cancer. These researchers described the molecular mechanism, which underpin the anti-cancer effect of HDACIs in pancreatic cancer and summarized the recent advances in the rationale for the combination strategies incorporating HDACIs.

Damaskos et al (2015) noted that pancreatic carcinoma is one of the leading causes of cancer death. Current standard treatments include surgical resection, chemotherapy and radiotherapy but patient's prognosis remains poor and present severe side-effects. Contemporary oncology found a wide variety of novel anticancer drugs that regulate the epigenetic mechanisms of tumor genesis. Histone deacetylases are enzymes with pleiotropic activities that control critical functions of the cell through regulation of the acetylation states of histone proteins and other non-histone protein targets. They are divided into 4 groups, each with different localization in the cell, role and structure. Histone deacetylase inhibitors are substances, which inhibit the function of HDACs. These researchers recognize 4 leading groups (hydroxamic acid, cyclic tetrapeptide, benzamide, aliphatic acid). There are many HDACIs currently in pre-clinical and 2 (vorinostat, romidepsin) in clinical stages of investigation for pancreatic cancer. Numerous studies argued for the use HDACIs as monotherapy, others suggested that combination of HDACIs with other anti-tumor drugs has better therapeutic results.

CPT Codes / HCPCS Codes / ICD-10 Codes
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
ICD-10 codes will become effective as of October 1, 2015:
Other CPT codes related to the CPB:
96401 - 96549 Chemotherapy Administration
HCPCS codes covered if selection criteria are met:
J9315 Injection, romidepsin, 1 mg
ICD-10 codes covered if selection criteria are met:
C84.A0 - C84.A9 Cutaneous T-cell lymphoma, unspecified
C84.00 - C84.09 Mycosis fungoides
C84.10 - C84.19 Sezary's disease
C84.40 - C84.49 Peripheral T-cell lymphoma
C84.60 - C84.79 Anaplastic large cell lymphoma [multifocal lesions or regional nodes]
C91.50 - C91.52 Adult T-cell lymphoma/leukemia (HTLV-1-associated)
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C34.00 - C34.92 Malignant neoplasm of the bronchus and lung [non small cell]
C50.011 - C50.929 Malignant neoplasm of breast
C56.1 - C56.9 Malignant neoplasm of ovary
C73 Malignant neoplasm of thyroid gland
C76.0 Malignant neoplasm of head, face, and neck

The above policy is based on the following references:
    1. Celgene Corporation. Istodax (romidepsin) for injection. Prescribing Information. ISTBAXPPI.006. Summit, NJ: Celgene; revised October 2014.
    2. National Comprehensive Cancer Network (NCCN). Romidepsin. NCCN Drugs and Biologics Compendium. Fort Washington, PA: NCCN; 2014.
    3. McEvoy GK, Snow ED, eds. Romidepsin. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2012.
    4. Haigentz M Jr, Kim M, Sarta C, et al. Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer. Oral Oncol. 2012;48(12):1281-1288.
    5. Wilson AJ, Lalani AS, Wass E, et al. Romidepsin (FK228) combined with cisplatin stimulates DNA damage-induced cell death in ovarian cancer. Gynecol Oncol. 2012;127(3):579-586.
    6. Amiri-Kordestani L, Luchenko V, Peer CJ, et al. Phase I trial of a new schedule of romidepsin in patients with advanced cancers. Clin Cancer Res. 2013;19(16):4499-4507.
    7. Robertson FM, Chu K, Boley KM, et al. The class I HDAC inhibitor Romidepsin targets inflammatory breast cancer tumor emboli and synergizes with paclitaxel to inhibit metastasis. J Exp Ther Oncol. 2013;10(3):219-233.
    8. Karthik S, Sankar R, Varunkumar K, Ravikumar V. Romidepsin induces cell cycle arrest, apoptosis, histone hyperacetylation and reduces matrix metalloproteinases 2 and 9 expression in bortezomib sensitized non-small cell lung cancer cells. Biomed Pharmacother. 2014;68(3):327-334.
    9. Genadieva-Stavric S, Cavallo F, Palumbo A. New approaches to management of multiple myeloma. Curr Treat Options Oncol. 2014;15(2):157-170
    10. Feng W, Zhang B, Cai D, Zou X. Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer. Cancer Lett. 2014;347(2):183-190
    11. Bezecny P. Histone deacetylase inhibitors in glioblastoma: Pre-clinical and clinical experience. Med Oncol. 2014;31(6):985
    12. Lee P, Murphy B, Miller R, et al. Mechanisms and clinical significance of histone deacetylase inhibitors: Epigenetic glioblastoma therapy. Anticancer Res. 2015;35(2):615-625
    13. El-Amm J, Tabbara IA. Emerging therapies in multiple myeloma. Am J Clin Oncol. 2015;38(3):315-321
    14. Damaskos C, Karatzas T, Nikolidakis L, et al. Histone deacetylase (HDAC) inhibitors: Current evidence for therapeutic activities in pancreatic cancer. Anticancer Res. 2015;35(6):3129-3135.

You are now leaving the Aetna website.

Links to various non-Aetna sites are provided for your convenience only. Aetna Inc. and its subsidiary companies are not responsible or liable for the content, accuracy, or privacy practices of linked sites, or for products or services described on these sites.

Continue >