Romidepsin (Istodax)

Number: 0865

Policy

1. Criteria for Initial Approval

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

   1. Cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome, primary cutaneous anaplastic large cell lymphoma)
   2. Peripheral T-cell lymphoma (PTCL) (see Appendix).

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections). 

2. Continuation of Therapy

   Aetna considers continuation of romidepsin (Istodax) therapy medically necessary for members with an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Romidepsin is available as generic (Teva Pharmaceuticals USA) or the brand, Istodax (Celgene), and are supplied as 10 mg of romidepsin lyophilized powder in single-dose vials for reconstitution. 

Cutaneous T-cell lymphoma (CTCL) or Peripheral T-cell lymphoma (PTCL): 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. Cycles should be repeated every 28 days provided that the individual continues to benefit from and tolerates the drug. 

Source: Celgene, 2020; Teva Pharmaceuticals USA, 2020

Experimental and Investigational

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

• Acute myeloid leukemia
• B-cell lymphoma (e.g., Burkitt lymphoma and indolent B-cell lymphoma) 
• Biliary tract cancer
• Bladder cancer
• Breast cancer (including triple-negative breast cancer)
• Chronic lymphocytic leukemia
• Colon cancer
• Dedifferentiated liposarcoma
• Endometrial cancer
• Glioblastoma
• Head and neck cancer
• Hepatocellular carcinoma
• Multiple myeloma
• Neuroblastoma
• Non-small cell lung cancer
• Ovarian cancer
• Pancreatic cancer
• Pulmonary fibrosis
• Rhabdomyosarcoma
• Small lymphocytic lymphoma
• Systemic ALCL
• Testicular germ cell tumors
• Thyroid cancer.

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Istodax is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy.

Compendial Uses

• Mycosis fungoides (MF)/Sézary syndrome (SS)
• Cutaneous anaplastic large cell lymphoma (ALCL)
• Peripheral T-Cell Lymphoma (PTCL)

Romidepsin, a histone deacetylase (HDAC) inhibitor, is a bicyclic depsipeptide. 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 have not been fully characterized.

Romidepsin, available as generic (Teva Pharmaceuticals USA) or by the brand Istodax (Celgene) carries the following warnings and precautions:

• Myelosuppression: can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts during treatment with Istodax; interrupt and/or modify the dose as necessary
• Infections: fatal and serious infections. Reactivation of DNA viruses (Epstein Barr and hepatitis B). Consider monitoring and prophylaxis in patients with evidence of prior hepatitis B
• Electrocardiographic (ECG) changes: consider cardiovascular monitoring in patients with congenital long QT syndrome, a history of significant cardiovascular disease, and patients taking medicinal products that lead to significant QT prolongation. Ensure that potassium and magnesium are within the normal range before administration of Istodax
• Tumor lysis syndrome: patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and appropriate precautions taken
• Embryo-fetal toxicity: fetal harm can occur when administered to a pregnant woman. Women should be advised to avoid becoming pregnant when receiving Istodax.

The most common adverse reactions were neutropenia, lymphopenia, thrombocytopenia, infections, nausea, fatigue, vomiting, anorexia, anemia, and ECG T-wave changes.

Romidepsin (Istodax) was approved by the Food and Drug Administration (FDA) for treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least 1 prior systemic therapy, and peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

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.

B-Cell Lymphoma / Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

In a phase I clinical trial, Holkova and colleagues (2017) determined the dose-limiting toxicities (DLT) and maximum-tolerated dose (MTD) for bortezomib followed by romidepsin on days 1, 8, and 15 in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), B-cell lymphoma or T-cell lymphoma.  A total of 18 treated patients were evaluable for response.  The MTD was 1.3 mg/m2 bortezomib and 10 mg/m2 romidepsin; median treatment duration was 3 cycles at this dose.  The DLT were grade-III fatigue, vomiting, and chills; 2 patients had partial responses (PR), 1 lasting greater than 2 years, 8 had stable disease (SD), and 8 had progressive disease.  The median duration of SD was 3.5 cycles.  Correlative studies examining expression of NF-кB, XIAP, Bcl-xL, and Bim yielded variable results.  The authors concluded that the safety profile was consistent with that reported for single-agent bortezomib and romidepsin.  They stated that this regimen had modest activity in heavily pre-treated patients with relapsed/refractory CLL or B- or T-cell lymphoma.

Biliary Tract Cancer

Mayr and colleagues (2021) noted that inhibition of HDACs is a promising anti-cancer approach. For biliary tract cancer (BTC), only limited therapeutic options are currently available. These investigators carried out a comprehensive examination of HDAC expression and pharmacological HDAC inhibition into a panel of 8 established BTC cell lines. The screening results indicated a heterogeneous expression of HDACs across the studied cell lines. They next tested the effect of 6 established HDAC inhibitors (HDACi) covering pan- and class-specific HDACis on cell viability of BTC cells and found that the effect was dose- and cell-line-dependent; did not correlate with HDAC isoform expression; and was most pronounced for romidepsin (a class I HDACi), showing the highest reduction in cell viability with IC50 values in the low-nM range. Further analyses showed that romidepsin induced apoptosis in BTC cells, reduced HDAC activity, and increased acetylation of histone 3 lysine 9 (H3K9Ac). Similar to BTC cell lines, HDAC 1/2 proteins were heterogeneously expressed in a cohort of resected BTC specimens (n = 78), and their expression increased with tumor grading. The survival of BTC patients with high HDAC-2-expressing tumors was significantly shorter. The authors concluded that HDAC class I inhibition in BTC cells by romidepsin was highly effective in-vitro and encouraged further in-vivo evaluation in BTC. These researchers suggested that romidepsin can be an additional option regarding the treatment of BTC.

The authors stated that this study had several drawbacks. Although the kit used in the current study was more specific to HDAC 2 than HDAC 1 and other HDAC isoforms, these researchers could not exclude that the activity of other HDACs influenced the results of their measurements. In addition, these data were based on an in-vitro model and retrospective analysis of BTC patient samples. These investigators suggested that further prospective, in-vivo studies are needed to extend the knowledge regarding romidepsin as an anti-BTC substance.

Colon Cancer

Wang and associates (2017) stated that romidepsin (FK228) is one of the most promising HDAC inhibitors due to its potent anti-tumor activity, and has been used for cancer therapy.  However, FK228-induced changes in protein modifications and the cross-talk between different modifications has not been reported.  To better understand the underlying mechanisms of FK228-related cancer therapy, these investigators examined the acetylome, phosphorylation, and cross-talk between modification data-sets in colon cancer cells treated with FK228 by using stable-isotope labeling with amino acids in cell culture and affinity enrichment, followed by high-resolution liquid chromatography tandem mass spectrometry analysis.  In total, 2,728 protein groups, 1,175 lysine-acetylation sites, and 4,119 lysine-phosphorylation sites were quantified.  When the quantification ratio thresholds were set to greater than 2.0 and less than 0.5, respectively, a total of 115 and 38 lysine-acetylation sites in 85 and 32 proteins were quantified as increased and decreased targets, respectively, and 889 and 370 lysine-phosphorylation sites in 599 and 289 proteins were quantified as increased and decreased targets, respectively.  Furthermore, these researchers identified 274 proteins exhibiting both acetylation and phosphorylation modifications.  The authors concluded that these findings indicated possible involvement of these proteins in FK228-related treatment of colon cancer and provided insight for further analysis of their biological function.  They noted potential interactions between the acetylome, phosphorylation levels, and the proteome based on positive regulation between the acetylome and phosphorylation events.  However, further experiments are needed to enhance validation and interpretation of the predicted mechanisms.

Dedifferentiated Liposarcoma

Seligson and colleagues (2019) stated that dedifferentiated liposarcoma (DDLPS) is a highly morbid mesenchymal tumor characterized and driven by genomic amplification of the MDM2 gene.  Direct inhibition of MDM2 has shown promise pre-clinically, but has yet to be validated in clinical trials.  Early in-vitro studies have demonstrated that pan-histone deacetylase (HDAC) inhibition may have anti-MDM2 effects.  These investigators presented in-silico, in-vitro, and mouse xenograft studies that suggested that specifically targeting HDAC2 reduced MDM2 expression and had anti-tumor affects in DDLPS.  Two independent data-sets, the Cancer Genome Atlas (TCGA; n = 58) and the Memorial Sloan-Kettering Cancer Center Dataset (MSKCC; n = 63), were used to identify the co-expression between class I HDACs and MDM2, and their clinical impact.  HDAC2 was highly co-expressed with MDM2 (TCGA: Spearman's coefficient = 0.29, p = 0.03; MSKCC: Spearman's coefficient = 0.57, p < 0.001).  As both a continuous and dichotomous predictor, elevated HDAC2 expression was associated with worsened disease-free survival (DFS) in the TCGA (Continuous: hazard ratio (HR) 1.7; 95 % confidence interval [CI]: 0.97 to 2.9; p = 0.06; Dichotomous: HR 7.1, 95 % CI: 2.5 to 19.8, p < 0.001) and distant recurrence-free survival (RFS) in the MSKCC (Continuous: HR 2.2; 95 % CI: 1.1 to 4.8; p = 0.04; Dichotomous: HR 2.8, 95 % CI: 1.2 to 6.4, p = 0.02).  In-vitro, treatment of DDLPS cell lines with the HDAC inhibitors MI-192 (HDAC2/3 inhibitor) or romidepsin (HDAC1/2 inhibitor) reduced MDM2 expression and induced apoptosis.  In a murine DDLPS xenograft model, romidepsin reduced tumor growth and lowered tumor MDM2 expression.  RNA-sequencing of romidepsin treated mouse tumors demonstrated markers of TP53 reactivation.  The authors stated that this was the first report of romidepsin's activity in MDM2-amplified tumors.  These findings suggested a potential role for HDAC2 inhibition in DDLPS as a modulator of the MDM2:p53 pathway; further clinical trials are needed to verify this hypothesis.

Endometrial Cancer

Li and co-workers (2016) examined the anti-cancer effects of romidepsin and the associated mechanism(s) in endometrial carcinoma (EC).  Ishikawa and HEC-1-A endometrial cancer cells were treated with 8 nM concentration of romidepsin and cell growth was measured by XTT assay (cell proliferation assay).  The cell cycle distribution and cell death were measured by flow cytometry, immunofluorescence, respectively.  The mNRA and protein expressions were analyzed by quantitative real-time polymerase chain reaction (RT-PCR) and Western blot, respectively.  Based on assays performed in EC cell lines, it was observed that romidepsin inhibited EC cell proliferation in a dose- and time-dependent manner.  Furthermore, following treatment with romidepsin for 48 hours, there were significant induction of apoptosis and cell cycle arrest at G0/G1 phase in EC cells.  Moreover, treatment with romidepsin significantly increased the mRNA and protein expressions of p53, p21, cleaved caspases such as 3, 7 and 8 and PARP.  Furthermore, romidepsin increased the levels of acetylated histone H3 and H4 that confirmed the HDAC inhibition.  The authors concluded that romidepsin inhibited EC tumor cell proliferation and induced apoptosis by activation caspase/PARP via the induction of p53/p21 signaling cascades, suggesting that it is a potential therapeutic agent for EC.

Glioblastoma

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.

Hepatocellular Carcinoma

Sun and colleagues (2017) examined the effect of romidepsin in hepato-cellular carcinoma (HCC) by inducing G2/M phase arrest via Erk/cdc25C/cdc2/cyclinB pathway and apoptosis through JNK/c-Jun/caspase3 pathway in-vitro and in-vivo.  Human HCC cell lines were cultured with romidepsin and dimethyl sulfoxide (DMSO; negative control) and 5-fluorouracil (5FU; positive control).  Then the cells' viability and apoptosis were determined by cell proliferation assay and flow cytometry.  Protein concentrations and expression changes were measured by Western blot.  Subsequently, Huh7 cells were subcutaneously inoculated into the nude mice, which were employed to further probe the tumor-suppressive effect of romidepsin in-vivo.  Romidepsin treatment led to a time- and dose-dependent induction of cell cycle arrest in the G2/M phase and apoptosis.  G2/M phase arrest inhibited the proliferation of HCC cells by alterations in p21/cdc25C/cdc2/cyclinB proteins.  Increased concentrations of Erk and JNK phosphorylations were observed in a dose-dependent manner in the romidepsin group, but p38 phosphorylation was not affected.  G2/M phase arrest and the apoptosis of HCC cells induced by romidepsin were mediated by the activation of Erk/MAPK pathways and JNK/MAPK pathways.  The tumor size was significantly larger in the negative control group compared to romidepsin group and no significant loss in body weight was observed in the romidepsin group.  The authors concluded that these findings offered proof-of-concept for use of romidepsin as a novel class of chemotherapy in the treatment of HCC.

Inflammatory Breast Cancer (IBC)

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.

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.

Neuroblastoma

Hegarty and colleagues (2017) stated that neuroblastoma is the most common extra-cranial pediatric solid tumor, arising from the embryonic sympatho-adrenal lineage of the neural crest, and is responsible for 15 % of childhood cancer deaths.  Although survival rates are good for some patients, those children diagnosed with high-risk neuroblastoma have survival rates as low as 35 %.  As a result, neuroblastoma remains a significant clinical challenge and the development of novel therapeutic strategies is essential.  Given that there is widespread epigenetic dysregulation in neuroblastoma, epigenetic pharmacotherapy holds promise as a therapeutic approach.  In recent years, HDAC inhibitors have been shown to be potent chemotherapeutics for the treatment of a wide range of cancers.  These researchers examined the ability of romidepsin, a selective HDAC1/2 inhibitor, to act as a cytotoxic agent in neuroblastoma cells.  Treatment with romidepsin at concentrations in the low nM range induced neuroblastoma cell death through caspase-dependent apoptosis.  Romidepsin significantly increased histone acetylation, and significantly enhanced the cytotoxic effects of the cytotoxic agent 6-hydroxydopamine, which has been shown to induce cell death in neuroblastoma cells through increasing reactive oxygen species.  Romidepsin was also more potent in MYCN-amplified neuroblastoma cells, which is an important prognostic marker of poor survival.  The authors concluded that he findings of this study demonstrated that romidepsin has a potent caspase-dependent cytotoxic effect on neuroblastoma cells, whose effects enhance cell death induced by other cytotoxins, and suggested that romidepsin may be a promising chemotherapeutic candidate for the treatment of neuroblastoma.

Non-small Cell Lung Cancer (NSCLC)

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. 

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.

Okuni and colleagues (2022) noted that although improvement has been made in therapeutic strategies against pancreatic carcinoma, OS has not significantly enhanced over last 10 years; therefore, the establishment of better therapeutic regimens remains a high priority. In this study, pancreatic cancer cell lines were incubated with romidepsin and tamoxifen, and their effects on cell growth, signaling and gene expression were analyzed. Xenografts of human pancreatic cancer CFPAC1 cells were medicated with romidepsin and tamoxifen to evaluate their effects on tumor growth. The inhibition of the growth of pancreatic cancer cells induced by romidepsin and tamoxifen was effectively reduced by N-acetyl cysteine and α-tocopherol, respectively. The combined treatment greatly induced reactive oxygen species production and mitochondrial lipid peroxidation, and these effects were prevented by N-acetyl cysteine and α-tocopherol. Tamoxifen enhanced romidepsin-induced cell senescence. FOXM1 expression was markedly down-regulated in pancreatic cancer cells treated with romidepsin, and tamoxifen further reduced FOXM1 expression in cells treated with romidepsin. Siomycin A, an inhibitor of FOXM1, induced senescence in pancreatic cancer cells. Similar results were obtained in knockdown of FOXM1 expression by siRNA. The authors concluded that since FOXM1 is used as a prognostic marker and therapeutic target for pancreatic cancer, a combination of the clinically available drugs romidepsin and tamoxifen might be considered for the treatment of patients with pancreatic cancer.

Pulmonary Fibrosis

Conforti and colleagues (2017) noted that idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people.  It has a poor prognosis and there are limited therapies.  Since epigenetic alterations are associated with IPF, HDAC inhibitors offer a novel therapeutic strategy to address the unmet medical need.  These investigators examined the potential of romidepsin as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials.  The anti-fibrotic effects of romidepsin were evaluated both in-vitro and in-vivo together with any harmful effect on alveolar type II cells (ATII).  Broncho-alveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX).  In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression; ATII cell numbers and their lamellar bodies were unaffected.  In-vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression; LOX was significantly elevated in BALF of IPF patients compared to controls.  The authors concluded that the potent anti-proliferative and anti-fibrotic properties of romidepsin in-vitro and in-vivo support progression of romidepsin towards a clinical trial to evaluate its potential as a new therapy for IPF.  Moreover, they stated that identification of LOX as secreted protein whose levels were increased in IPF lung and whose production was modulated by romidepsin support its evaluation as a companion biomarker with the actual physiological end-points for assessing the early proof-of-mechanism of romidepsin in study patients.

Rhabdomyosarcoma

Rossetti and colleagues (2021) described the in-vitro and in-vivo activity of romidepsin in counteracting and radio-sensitizing embryonal (ERMS, fusion-negative) and alveolar (ARMS, fusion-positive) rhabdomyosarcoma (RMS). RH30 (ARMS, fusion-positive) and RD (ERMS, fusion-negative) cell lines and human multipotent mesenchymal stromal cells (HMSC) were used. Flow cytometry analysis, RT-qPCR, Western blots and enzymatic assays were carried out. Irradiation was delivered by using an x-6 MV photon linear accelerator. Romidepsin (1.2 mg/kg) in-vivo activity, combined or not with radiation therapy (2 Gy), was evaluated in murine xenografts. Compared to HMSC, RMS expressed low levels of class I HDACs. In-vitro, romidepsin, as single agents, reversibly down-regulated class I HDACs expression and activity and induced oxidative stress, DNA damage and a concomitant growth arrest associated with PARP-1-mediated transient non-apoptotic cell death. Surviving cells up-regulated the expression of cyclin A, B, D1, p27, Myc and activated PI3K/Akt/mTOR and MAPK signaling, known to be differently involved in cancer chemoresistance. Interestingly, while no radio-sensitizing effects were detected, in-vitro or in-vivo, on RD cells, romidepsin markedly radio-sensitized RH30 cells by impairing antioxidant and DSBs repair pathways in-vitro. Furthermore, romidepsin when combined with RT in-vivo significantly reduced tumor mass in mouse RH30 xenografts. The authors concluded that romidepsin did not show anti-tumor activity as a single agent while its combination with RT resulted in radio-sensitization of fusion-positive RMS cells; thus, representing a possible strategy for the treatment of the most aggressive RMS subtype.

Squamous Cell Carcinoma of the Head and Neck (SCCHN)

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.

Testicular Germ Cell Tumors

Jostes and colleagues (2017) noted that type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumors in young men (20 to 40 years) and are classified as seminoma or non-seminoma.  TGCTs are commonly treated by orchiectomy and chemo- or radiotherapy.  However, a subset of metastatic non-seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel therapeutic options.  Recent studies have shown effective application of the small-molecule inhibitor JQ1 in tumor therapy, which interferes with the function of “bromodomain and extra-terminal (BET)” proteins.  JQ1-treated TGCT cell lines displayed up-regulation of genes indicative for DNA damage and cellular stress response and induced cell cycle arrest.  Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, displayed down-regulation of pluripotency factors and induction of mesodermal differentiation.  In contrast, seminoma-like TCam-2 cells tolerated higher JQ1 concentrations and were resistant to differentiation.  ECs xeno-grafted in-vivo showed a reduction in tumor size, proliferation rate and angiogenesis in response to JQ1.  Moreover, the combination of JQ1 and romidepsin allowed for lower doses and less frequent application, compared with monotherapy.  The authors proposed that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.  They stated that clinical trials will reveal, whether the combination of JQ1 + romidepsin is suitable for treatment of (mixed) TGCTs.

Triple-Negative Breast Cancer

Pattarawat and colleagues (2019) noted that triple-negative BC (TNBC) is an aggressive, lethal, and heterogeneous subtype of BCs, tending to have lower 5-year survival rates than other BC subtypes in response to conventional chemotherapies.  These investigators identified advanced regimens to effectively control TNBC tumor development.  They examined the combination of the DNA synthesis inhibitor gemcitabine, the DNA-damaging agent cisplatin, and the histone deacetylase inhibitor romidepsin to control a variety of breast cells in-vitro.  These researchers studied the toxicity of drug doses and administration schedules to determine tolerable combination regimens in immune-deficient nude and -competent BALB/c mice.  They then studied the efficacy of tolerable regimens in controlling TNBC cell-derived xenograft development in nude mice.  By reducing clinically equivalent doses of each agent in combination, these investigators formulated tolerable regimens in animals.  They verified that the tolerable triple combination gemcitabine plus romidepsin + cisplatin regimen was more efficacious than double combination regimens in controlling xenograft tumor development in nude mice.  A triple combination of gemcitabine + romidepsin + cisplatin synergistically induced death of the TNBC M.D. Anderson-Metastatic Breast cancer (MDA-MB) 231 and MDA-MB468, as well as Michigan Cancer Foundation (MCF) 7, MCF10A, and MCF10A-Ras cells.  Cell death induced by gemcitabine + romidepsin + cisplatin was in a reactive oxygen species-dependent manner.  The authors concluded that considering the high costs for developing a new anti-cancer agent, these researchers used the FDA-approved drugs gemcitabine, romidepsin (is approved for T-cell lymphoma and is under clinical trial for TNBC), and cisplatin to economically formulate a safe and effective combinational regimen.  The highly effectives gemcitabine plus romidepsin + cisplatin regimen should be poised for translation into clinical trials, ultimately contributing to reduced mortality and improved quality of life (QOL) for TNBC patients.

Combination Therapies

Combination of Romidepsin and Bendamustine for Relapsed / Refractory Peripheral T-Cell Lymphoma

Nachmias and colleagues (2019) stated that the treatment of relapsed / refractory (R/R) peripheral T-cell lymphoma (PTCL) is limited to a few agents.  Romidepsin was approved for PTCL treatment as a single-agent in the R/R setting, yet with partial efficacy.  Several attempts to combine romidepsin with other chemotherapy regimens have been reported, however, with significant toxicity.  These researchers examined the romidepsin-bendamustine combination in PTCL in an attempt to maximize efficacy while minimizing toxicity.  They reported on a series of 7 heavily pre-treated PTCL patients (2 to 5 previous lines of therapy) treated with a romidepsin-bendamustine combination; 4 patients were not previously exposed to either drug.  Of these, 2 achieved complete remission (CR); 1 patient continued treatment with a prolonged progression-free survival (PFS) of more than 4 years.  Toxicity was minimal and no treatment-related deaths (TRDs) or discontinuation were noted.  Significant nausea and vomiting were reported in over 50 % of patients.  Hematological toxicity was mild and lower than that reported for other romidepsin-chemotherapy combinations and was correlated with bone marrow involvement by lymphoma.  The authors concluded that although reporting a small number of patients, these findings suggested that the combination of romidepsin and bendamustine may be a feasible therapeutic option in R/R PTCL patients and merits further study.

Combination of Romidepsin and Dexamethasone for Germ Cell Tumors

Nettersheim and colleagues (2019) noted that testicular germ cell tumors (GCTs) mostly affect young men at aged 17 to 40 years.  Although high cure rates can be achieved by orchiectomy and chemotherapy, GCTs can still be a lethal threat to young patients with metastases or therapy resistance.  Therefore, alternative therapeutic options are needed.  Based on studies utilizing GCT cell lines, romidepsin is a promising therapeutic option, showing high toxicity at very low-doses towards cisplatin-resistant GCT cells, but not fibroblasts or Sertoli cells.  In this study, these researchers extended their analysis of the molecular effects of romidepsin to deepen their understanding of the underlying mechanisms.  Patients will benefit from these analyses, since detailed knowledge of the romidepsin effects allows for a better risk and side-effect assessment.  These investigators screened for changes in histone acetylation of specific lysine residues and analyzed changes in the DNA methylation landscape after romidepsin treatment of the GCT cell lines TCam-2, 2102EP, NCCIT and JAR, while human fibroblasts were used as controls. In addition, these researchers focused on the role of the dehydrogenase/reductase DHRS2, which was strongly up-regulated in romidepsin treated cells, by generating DHRS2-deficient TCam-2 cells using CRISPR/Cas9 gene editing.  They showed that DHRS2 is dispensable for up-regulation of romidepsin effectors (GADD45B, DUSP1, ZFP36, ATF3, FOS, CDKN1A, ID2) but contributed to induction of cell cycle arrest.  Finally, the authors showed that a combinatory treatment of romidepsin plus the glucocorticoid dexamethasone further boosted expression of the romidepsin effectors and reduced viability of GCT cells more strongly than under single-agent treatment.  These researchers stated that romidepsin and dexamethasone might represent a new combinatorial approach for treatment of GCT.

Combination of Romidepsin and Pralatrexate for Relapsed / Refractory Peripheral T-Cell Lymphoma

Amengual and colleagues (2018) noted that PTCL are a group of rare malignancies characterized by chemotherapy resistance and poor prognosis.  Romidepsin and pralatrexate were approved by the FDA for patients with R/R PTCL, exhibiting response rates of 25 % and 29 % respectively.  Based on synergy in pre-clinical models of PTCL, these researchers performed a phase-I clinical trial of pralatrexate plus romidepsin in patients with R/R lymphoma.  This was a single-institution, dose-escalation study of pralatrexate plus romidepsin designed to determine the DLTs, MTD, pharmacokinetic profile, and response rates.  Patients were treated with pralatrexate (10 to 25 mg/m2) and romidepsin (12 to 14 mg/m2) on 1 of 3 schedules: every week × 3 every 28 days, every week × 2 every 21 days, and every other week every 28 days.  Treatment continued until progression, withdrawal of consent, or medical necessity.  A total of 29 patients were enrolled and evaluable for toxicity.  Co-administration of pralatrexate and romidepsin was safe, well-tolerated, with 3 DLTs across all schedules (grade-3 oral mucositis × 2; grade-4 sepsis × 1).  The recommended phase-II dose was defined as pralatrexate 25 mg/m2 and romidepsin 12 mg/m2 every other week; 23 patients were evaluable for response.  The overall response rate (ORR) was 57 % (13/23) across all patients and 71 % (10/14) in PTCL.  The authors concluded that this phase-I clinical trial of pralatrexate plus romidepsin resulted in a high response rate in patients with previously treated PTCL; a phase-II clinical trial will determine the efficacy of this combination in patients with PTCL.

Combined Romidepsin and Azacitidine for the Treatment of Acute Myeloid Leukemia

Loke and colleagues (2022) stated that azacitidine (AZA) is important in the management of patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. Romidepsin (ROM) is a histone deacetylase inhibitor that synergizes with AZA in-vitro. The ROMAZA Trial established the maximum tolerated dose (MTD) of combined ROM/AZA therapy in patients with AML, as ROM 12 mg/m2 on Days 8 and 15, with AZA 75 mg/m2 administered for 7/28 day cycle; 9 of the 38 (23.7 %) patients treated at the MTD were classified as responders by Cycle 6 (best response: CR/incomplete CR [n = 7]; PR [n = 2]). The authors concluded that the findings of this study established a MTD for combined ROM/AZA therapy that is safe and clinically active within adults with relapsed AML. Moreover, these researchers stated that further studies are needed to compare the clinical activity of ROM/AZA directly to a comparator treatment arm.

Combined Romidepsin and Simvastatin for the Treatment of Bladder Cancer

Okubo and colleagues (2021) noted that the HMG-CoA reductase inhibitor simvastatin activates AMP-activated protein kinase (AMPK) and thereby induces histone acetylation. These researchers postulated that combining simvastatin with the HDACi romidepsin would kill bladder cancer cells by inducing histone acetylation cooperatively. The combination of romidepsin and simvastatin induced robust apoptosis and killed bladder cancer cells synergistically. In murine subcutaneous tumor models using MBT-2 cells, a 15-day treatment with 0.5 mg/kg romidepsin and 15 mg/kg simvastatin was well-tolerated and inhibited tumor growth significantly. Mechanistically, the combination induced histone acetylation by activating AMPK. The combination also decreased the expression of HDACs; thereby, further promoting histone acetylation. This AMPK activation was essential for the combination's action because compound C, an AMPK inhibitor, suppressed the combination-induced histone acetylation and the combination's ability to induce apoptosis. These investigators also found that the combination increased the expression of peroxisome proliferator-activated receptor (PPAR) γ, leading to reactive oxygen species production. In addition, the combination induced endoplasmic reticulum (ER) stress and this ER stress was shown to be associated with increased AMPK expression and histone acetylation; therefore, playing an important role in the combination's action. Our study also suggests there is a positive feedback cycle between ER stress induction and PPARγ expression.

The authors stated that this study had several drawbacks. First, these investigators examined the in-vivo efficacy of the combination using the mice allograft model. Fortunately, they could prove the same mechanism of action both in-vitro and in-vivo using the same mouse cells (MBT-2); however, xenograft models would be preferable to show the anti-neoplastic effects of the combination more precisely on human bladder cancer. Second, these researchers did not examine the interaction that the drugs may have on their blood concentrations. In-vivo experiments using mice models without tumor burden would be the appropriate method and might be the next step. Third, although the safety of each drug has been established, what interaction they might have is unknown; thus, careful drug monitoring should be carried out when testing the combination in clinical settings.

Appendix

PTCL Subtypes

• Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS)
• Angioimmunoblastic T-cell lymphoma (AITL)
• Anaplastic large cell lymphoma (ALCL)
• Breast implant-associated anaplastic large cell lymphoma (BIA- ALCL)
• Enteropathy-associated T-cell lymphoma (EATL)
• Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL)
• Nodal peripheral T-cell lymphoma with TFH phenotype (PTCL, TFH)
• Follicular T-cell lymphoma (FTCL)
• Extranodal NK/T-cell lymphoma (ENKL)
• Hepatosplenic T-cell lymphoma (HSTCL)

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
96401 - 96549	Chemotherapy Administration
HCPCS codes covered if selection criteria are met:
J9318	Injection, romidepsin, non-lyophilized, 0.1 mg
J9319	Injection, romidepsin, lyophilized, 0.1 mg
ICD-10 codes covered if selection criteria are met:
C82.00 - C82.99	Follicular lymphoma [relapsed or refractory follicular T-cell lymphoma]
C84.00 - C84.09	Mycosis fungoides
C84.10 - C84.19	Sezary's disease
C84.40 - C84.49	Peripheral T-cell lymphoma [nodal peripheral T-cell lymphoma with TFH phenotype]
C84.60 - C84.79	Anaplastic large cell lymphoma [multifocal lesions or regional nodes] [including breast implant-associated]
C84.A0 - C84.A9	Cutaneous T-cell lymphoma, unspecified
C86.0	Extra-nodal NK/T cell lymphoma, nasal type
C86.1	Hepatosplenic T-cell lymphoma
C86.2	Enteropathy-type (intestinal) T-cell lymphoma [relapsed or refractory monomorphic epitheliotropic intestinal T-cell lymphoma]
C86.5	Angioimmunoblastic T-cell lymphoma
C86.6	Primary cutaneous CD30-positive T-cell proliferations
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C17.0 - C17.9	Malignant neoplasm of small intestine
C18.0 - C18.9	Malignant neoplasm of colon
C19	Malignant neoplasm of rectosigmoid junction
C22.0 - C22.9	Malignant neoplasm of liver and intrahepatic bile ducts
C24.0 - C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C26	Malignant neoplasm of intestinal tract, part unspecified
C34.00 - C34.92	Malignant neoplasm of the bronchus and lung [non small cell]
C48.0 - C48.8	Malignant neoplasm retroperitoneum and peritoneum [dedifferentiated liposarcoma]
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue
C50.011 - C50.929	Malignant neoplasm of breast
C54.1	Malignant neoplasm of endometrium
C56.1 - C56.9	Malignant neoplasm of ovary
C62.00 - C62.92	Malignant neoplasm of testis [testicular germ cell tumors]
C67.0 - C67.9	Malignant neoplasm of bladder
C73	Malignant neoplasm of thyroid gland
C74.00 - C74.90	Malignant neoplasm of adrenal gland [neuroblastoma]
C76.0	Malignant neoplasm of head, face, and neck
C83.00 - C83.19	Small cell B-cell lymphoma [small lymphocytic lymphoma]
C83.30 - C83.39	Diffuse large B-cell lymphoma
C85.10 - C85.19	Unspecified B-cell lymphoma
C85.20 - C85.29	Mediastinal (thymic) large B-cell lymphoma
C91.10 - C91.12	Chronic lymphocytic leukemia of B-cell type
C92.00 - C92.92	Myeloid leukemia
D01.0 - D01.1	Carcinoma in situ of colon and rectosigmoid junction
D01.40	Carcinoma in situ of unspecified part of intestine
D01.49	Carcinoma in situ of other parts of intestine
D01.5	Carcinoma in situ of liver, gallbladder and bile ducts
D07.0	Carcinoma in situ of endometrium
D07.69	Carcinoma in situ of other male genital organs [testicular germ cell tumors]
D09.0	Carcinoma in situ of bladder
J84.10 - J84.17	Other interstitial pulmonary diseases with fibrosis

The above policy is based on the following references: