Decitabine (Dacogen)

Number: 0868

Policy

Aetna considers decitabine (Dacogen) medically necessary for members with the following indications:

• Acute myeloid leukemia (AML)
• Chronic myelomonocytic leukemia (CMML)
• Myelodysplastic syndrome (MDS)
• Myelofibrosis (MF)- MF accelerated phase or MF-blast phase/AML

Aetna considers decitabine experimental and investigational when used in combination with azacitidine (Vidaza) (both are DNA hypomethylators). 

Aetna considers decitabine experimental and investigational for the following indications (not an all-incluisve list):

• Alimentary tract cancer
• Chronic myelogenous leukemia (CML)
• Colon cancer
• Endometrial cancer
• Gastric cancer
• Guillain-Barre syndrome
• Glioblastoma
• Head and neck cancers
• Hepatobiliary cancers (e.g., cholangiocarcinoma and hepato-cellular carcinoma)
• Hodgkin lymphoma
• Lung cancer (e.g., non-small-cell lung cancer)
• Melanoma
• Multiple myeloma
• Neuroblastoma
• Ovarian cancer
• Sarcomas (e.g., Ewing's sarcoma, osteosarcoma and rhabdomyosarcoma)
• Sickle cell disease.

Background

Dacogen (decitabine) is an analogue of the natural nucleoside 2’‐deoxycytidine that is thought to achieve antineoplastic effects through inhibition of DNA methyltransferase. This inhibition causes a disruption in the function of genes that control cell differentiation and proliferation. Non‐proliferating cells are not affected by decitabine at normal concentrations.

Dacogen has been approved by the Food and Drug Adminstration (FDA) for myelodysplastic syndromes (MDS): "Decitabine for injection is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups”.

Transfusion dependence was defined (in Revlimid MDS clinical trials) as need for administration of two or more units of red blood cells [RBCs] in the previous eight weeks prior to initiation of lenalidomide treatment. Therefore, transfusion independence (for the purpose of demonstrating response and need for continuation of therapy) is defined as needing one or less units of RBCs in the previous eight weeks.

Guidelines from the National Comprehensive Cancer Network (2018) indicate Dacogen for the following indications:

• Myelofibrosis

  Myelofibrosis - Treatment of myelofibrosis (MF)-accelerated phase or MF-blast phase/acute myeloid leukemia

• Myelodysplastic syndromes (MDS)

  Myelodysplastic syndromes (MDS) -- Treatment in higher risk disease*, also 

  • in nontransplant candidates
  • in transplant candidates followed by hematopoietic stem cell transplant 
  • in transplant candidates as a bridge to transplant while awaiting donor availability
  • following relapse or no response after allogeneic hemopoietic stem cell transplant [2A]
    
    

• Myelodysplastic syndromes

  Myelodysplastic syndromes -- Treatment of lower risk disease** associated with
  
  
  • clinically relevant thrombocytopenia, neutropenia, or increased marrow blasts
  • clinically relevant thrombocytopenia, neutropenia, or increased marrow blasts, following disease progression or no response to immunosuppressive therapy or clinical trial
  • symptomatic anemia, without del(5q), with or without other cytogenetic abnormalities, with serum erythropoietin >500 mU/mL, and a poor probability to respond to immunosuppressive therapy [2A]
     

• Myelodysplastic syndromes

  Myelodysplastic syndromes -- Treatment in lower risk disease** associated with symptomatic anemia

  • with del(5q), with or without one other cytogenetic abnormality (except those involving chromosome 7), following no response or intolerance to lenalidomide
  • without del(5q), with or without other cytogenetic abnormalities, with serum erythropoietin >500 mU/mL following no response or intolerance to immunosuppressive therapy
  • without del(5q), with or without other cytogenetic abnormalities, with serum erythropoietin ≤500 mU/mL and ring sideroblasts <15% following no response to an erythropoiesis-stimulating agent (ESA) alone, followed by no response to an ESA in combination with lenalidomide with or without a granulocyte-colony stimulating factor (G-CSF)
  • without del(5q), with or without other cytogenetic abnormalities, with serum erythropoietin ≤500 mU/mL and ring sideroblasts ≥15% following no response to the combination of an ESA and G-CSF [2A]
     

• Acute myeloid leukemia (AML)

  Acute myeloid leukemia (AML) -- Used as a single agent in patients age greater than or equal to 60 years as

  • Lower-intensity induction therapy in candidates for intensive remission induction therapy with unfavorable cytogenetic or molecular markers/ antecedent hematologic disorder/ therapy-related AML
  • Lower-intensity treatment induction when not a candidate for intensive remission induction therapy or declines intensive therapy (preferred)
  • Post-remission therapy following response to previous lower intensity therapy
  • Post-remission maintenance therapy following complete response to prior intensive therapy [2A]
     

• Acute myeloid leukemia (AML)

  Acute myeloid leukemia (AML) -- Therapy for relapse or refractory disease

  • As a component of repeating the initial successful induction regimen if late relapse (≥12 months)
  • As a single agent (less aggressive therapy)
  • In combination with sorafenib (FLT3-ITD mutation positive) [2A]

* Higher risk defined as IPSS-R (Intermediate, High, Very High), IPSS (Intermediate-2, High), WPSS (High, Very High)

** Lower risk defined as IPSS-R (Very Low, Low, Intermediate), IPSS (Low/Intermediate-1), WPSS (Very Low, Low, Intermediate)

Dacogen (decitabine) should not be utilized in the following:

• During pregnancy/lactation (without risk vs. benefit discussion)
• In patients with a known hypersensitivity to decitabine or any other components of the product
• Patients less than 18 years of age.

Kantarjian et al (2003) evaluated the activity and toxicity of decitabine in different phases of chronic myelogenous leukemia (CML).  A total of 130 patients with CML were treated: 123 with Philadelphia chromosome (Ph)-positive CML (64 blastic, 51 accelerated, 8 chronic) and 7 with Ph-negative CML.  Decitabine was given at 100 mg/m(2) over 6 hours every 12 hours x 5 days (1,000 mg/m(2) per course) in the first 13 patients, 75 mg/m(2) in the subsequent 33 patients, and 50 mg/m(2) in the remaining 84 patients.  A total of 552 courses were given to the 130 patients.  Only 4 patients (3 %) died during the first course from myelosuppressive complications (3 patients) or progressive disease (1 patient).  Of 64 patients in the CML blastic phase, 18 patients (28 %) achieved objective responses.  Of these 18 patients, 6 achieved complete hematologic responses (CHR), 2 achieved partial hematologic responses (PHR), 7 achieved hematologic improvements (HI), and 3 returned to the second chronic phase (second CP).  Five patients (8 %) had cytogenetic responses.  Among 51 patients in the accelerated phase, 28 patients (55 %) achieved objective responses (12 CHR, 10 PHR, 3 HI, and 3 second CP).  Seven patients (14 %) had cytogenetic responses.  Among 8 patients treated in the chronic phase, 5 (63 %) had objective responses.  Of 7 patients treated for Ph-negative CML, 4 (57 %) had objective responses.  There was no evidence of a dose-response effect.  The estimated 3-year survival rate was less than 5 % in the blastic phase and 27 % in the accelerated phase.  The only significant toxicity reported was severe myelosuppression, which was delayed, prolonged, and dose-dependent.  With decitabine 50 to 75 mg/m(2), the median time to granulocyte recovery above 0.5 x 10(9)/L was about 4 weeks.  Myelosuppression-associated complications included febrile episodes in 37 % and documented infections in 34 %.  The authors concluded that decitabine appeared to have significant anti-CML activity.  They stated that future studies should evaluate lower-dose, longer-exposure decitabine schedules alone in imatinib-resistant CML, as well as combinations of decitabine and imatinib in different CML phases.

In a phase I study, Fang et al (2010) examined the effects of low-dose decitabine combined with carboplatin in patients with recurrent, platinum-resistant ovarian cancer.  Decitabine was administered intravenously daily for 5 days, before carboplatin (area under the curve, 5) on Day 8 of a 28-day cycle.  By using a standard 3 + 3 dose escalation, decitabine was tested at 2 dose levels: 10 mg/m(2) (7 patients) or 20 mg/m(2) (3 patients).  Peripheral blood mononuclear cells (PBMCs) and plasma collected on Days 1 (pre-treatment), 5, 8, and 15 were used to assess global (LINE-1 repetitive element) and gene-specific DNA methylation.  Dose-limiting toxicity (DLT) at the 20-mg/m(2) dose was grade 4 neutropenia (2 patients), and no DLTs were observed at 10 mg/m(2).  The most common toxicities were nausea, allergic reactions, neutropenia, fatigue, anorexia, vomiting, and abdominal pain, the majority being grades 1 to 2.  One complete response was observed, and 3 additional patients had stable disease for greater than or equal to 6 months.  LINE-1 hypomethylation on Days 8 and 15 was detected in DNA from PBMCs.  Of 5 ovarian cancer-associated methylated genes, HOXA11 and BRCA1 were demethylated in plasma on Days 8 and 15.  The authors concluded that repetitive low-dose decitabine was tolerated when combined with carboplatin in ovarian cancer patients, and demonstrated biological (i.e., DNA-hypomethylating) activity, justifying further testing for clinical efficacy.

In a phase II clinical trial, Glasspool et al (2014) tested the hypothesis that decitabine can reverse resistance to carboplatin in women with relapsed ovarian cancer.  Patients progressing 6 to 12 months after previous platinum therapy were randomized to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone.  The primary objective was response rate in patients with methylated hMLH1 tumor DNA in plasma.  After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination.  Responses by GCIG criteria were 9 out of 14 versus 3 out of 15 and by RECIST were 6 out of 13 versus 1 out of 12 for carboplatin and carboplatin/decitabine, respectively.  Grade 3/4 neutropenia was more common with the combination (60 % versus 15.4 %) as was G2/3 carboplatin hypersensitivity (47 % versus 21 %).  The authors concluded that with this schedule, the addition of decitabine appeared to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer; and was difficult to deliver.  The authors stated that patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.

Xia et al (2014) explored the safety and tolerability of combining 2 epigenetic drugs: decitabine (a DNA methyltransferase inhibitor) and panobinostat (a histone deacetylase inhibitor), with chemotherapy with temozolomide (an alkylating agent).  The purpose of such combination was to evaluate the use of epigenetic priming to overcome resistance of melanoma to chemotherapy.  This phase I clinical trial enrolled patients aged 18 years or older, with recurrent or unresectable stage III or IV melanoma of any site.  Patients were treated with subcutaneous decitabine 0.1 or 0.2 mg/kg 3 times weekly for 2 weeks (starting on day 1), in combination with oral panobinostat 10, 20, or 30 mg every 96 h (starting on day 8), and oral temozolomide 150 mg/m(2)/day on days 9 through 13. In cycle 2, temozolomide was increased to 200 mg/m(2)/day if neutropenia or thrombocytopenia had not occurred.  Each cycle lasted 6 weeks, and patients could receive up to 6 cycles.  Patients who did not demonstrate disease progression were eligible to enter a maintenance protocol with combination of weekly panobinostat and thrice-weekly decitabine until tumor progression, unacceptable toxicity, or withdrawal of consent.  A total of 20 patients were initially enrolled, with 17 receiving treatment.  The median age was 56 years; 11 (65 %) were males, and 6 (35 %) were females.  Eleven (64.7 %) had cutaneous melanoma, 4 (23.5 %) had ocular melanoma, and 2 (11.8 %) had mucosal melanoma.  All patients received at least 1 treatment cycle and were evaluable for toxicity.  Patients received a median of two 6-week treatment cycles (range of 1 to 6).  None of the patients experienced DLT; MTD was not reached.  Adverse events attributed to treatment included grade 3 lymphopenia (24 %), anemia (12 %), neutropenia (12 %), and fatigue (12 %), as well as grade 2 leukopenia (30 %), neutropenia (23 %), nausea (23 %), and lymphopenia (18 %).  The most common reason for study discontinuation was disease progression.  The authors concluded that this triple agent of dual epigenetic therapy in combination with traditional chemotherapy was generally well-tolerated by the cohort and appeared safe to be continued in a phase II trial.  No DLTs were observed, and MTD was not reached.

Lou et al (2014) stated that despite recent advances in the treatment of human colon cancer, the chemotherapy efficacy against colon cancer is still unsatisfactory.  In the present study, effects of concomitant inhibition of the epidermal growth factor receptor (EGFR) and DNA methyltransferase were examined in human colon cancer cells.  These researchers demonstrated that decitabine (a DNA methyltransferase inhibitor) synergized with gefitinib (an EGFR inhibitor) to reduce cell viability and colony formation in SW1116 and LOVO cells.  However, the combination of the 2 compounds displayed minimal toxicity to NCM460 cells, a normal human colon mucosal epithelial cell line.  The combination was also more effective at inhibiting the AKT/mTOR/S6 kinase pathway.  In addition, the combination of decitabine with gefitinib markedly inhibited colon cancer cell migration.  Furthermore, gefitinib synergistically enhanced decitabine-induced cytotoxicity was primarily due to apoptosis as shown by Annexin V labeling that was attenuated by z-VAD-fmk, a pan caspase inhibitor.  Concomitantly, cell apoptosis resulting from the co-treatment of gefitinib and decitabine was accompanied by induction of BAX, cleaved caspase 3 and cleaved PARP, along with reduction of Bcl-2 compared to treatment with either drug alone.  Interestingly, combined treatment with these 2 drugs increased the expression of XIAP-associated factor 1 (XAF1), which play an important role in cell apoptosis.  Moreover, small interfering RNA (siRNA) depletion of XAF1 significantly attenuated colon cancer cells apoptosis induced by the combination of the 2 drugs.  The authors stated that these findings suggested that gefitinib in combination with decitabine exerted enhanced cell apoptosis in colon cancer cells were involved in mitochondrial-mediated pathway and induction of XAF1 expression.  These investigators concluded that based on the observations from this study, they suggested that the combined administration of these 2 drugs might be considered as a novel therapeutic regimen for treating colon cancer.

Maes et al (2014) noted that DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) are under investigation for the treatment of cancer, including the plasma cell malignancy multiple myeloma (MM). Evidence exists that DNA damage and repair contribute to the cytotoxicity mediated by the DNMTi decitabine. Here, we investigated the DNA damage response (DDR) induced by decitabine in MM using 4 human MM cell lines and the murine 5T33MM model. In addition, we explored how the HDACi JNJ-26481585 affects this DDR. Decitabine induced DNA damage (gamma-H2AX foci formation), followed by a G0/G1- or G2/M-phase arrest and caspase-mediated apoptosis. JNJ-26481585 enhanced the anti-MM effect of decitabine both in vitro and in vivo. As JNJ-26481585 did not enhance decitabine-mediated gamma-H2AX foci formation, we investigated the DNA repair response towards decitabine and/or JNJ-26481585. Decitabine augmented RAD51 foci formation (marker for homologous recombination (HR)) and/or 53BP1 foci formation (marker for non-homologous end joining (NHEJ)). Interestingly, JNJ-26481585 negatively affected basal or decitabine-induced RAD51 foci formation. Finally, B02 (RAD51 inhibitor) enhanced decitabine-mediated apoptosis. Together, we report that decitabine-induced DNA damage stimulates HR and/or NHEJ. JNJ-26481585 negatively affects RAD51 foci formation, thereby providing an additional explanation for the combinatory effect between decitabine and JNJ-26481585.

Glioblastoma

Everson et al (2016) stated that immunotherapy is an ideal treatment modality to specifically target the diffusely infiltrative tumor cells of malignant gliomas while sparing the normal brain parenchyma. However, progress in the development of these therapies for glioblastoma has been slow due to the lack of immunogenic antigen targets that are expressed uniformly and selectively by gliomas. These researchers utilized human glioblastoma cell cultures to induce expression of New York-esophageal squamous cell carcinoma (NY-ESO-1) following in-vitro treatment with the demethylating agent decitabine. They then investigated the phenotype of lymphocytes specific for NY-ESO-1 using flow cytometry analysis and cytotoxicity against cells treated with decitabine using the xCelligence real-time cytotoxicity assay. Finally, these investigators examined the in-vivo application of this immune therapy using an intra-cranially implanted xenograft model for in-situ T cell trafficking, survival, and tissue studies. These studies showed that treatment of intra-cranial glioma-bearing mice with decitabine reliably and consistently induced the expression of an immunogenic tumor-rejection antigen, NY-ESO-1, specifically in glioma cells and not in normal brain tissue. The up-regulation of NY-ESO-1 by intra-cranial gliomas was associated with the migration of adoptively transferred NY-ESO-1-specific lymphocytes along white matter tracts to these tumors in the brain. Similarly, NY-ESO-1-specific adoptive T cell therapy demonstrated anti-tumor activity after decitabine treatment and conferred a highly significant survival benefit to mice bearing established intracranial human glioma xenografts. Transfer of NY-ESO-1-specific T cells systemically was superior to intra-cranial administration and resulted in significantly extended and long-term survival of animals. The authors concluded that these results revealed an innovative, clinically feasible strategy for the treatment of glioblastoma.

Head and Neck Cancers

Viet and colleagues (2014) stated that cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study these investigators hypothesized that methylation of key genes mediates cisplatin resistance. They determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. These researchers showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. They then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier these researchers quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When these investigators quantified methylation and expression of genes in the classifier in HNSCC cells in-vitro, they showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The authors concluded that the findings of this study provided direct evidence that decitabine restored cisplatin sensitivity in in-vitro and in-vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduced HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.

National Comprehensive Cancer Network’s clinical practice guideline on “Head and neck cancers” (Version 1.2015) does not list decitabine as a therapeutic option.

Hepatobiliary Cancers

Wang et al (2014) noted that decitabine (DAC), an inhibitor of DNA methyltransferase, demonstrates anti-tumor activities in various types of cancer. However, its therapeutic potential for cholangiocarcinoma (CCA) remains to be explored. The present study investigated the anti-proliferative effects of DAC on CCA cells in-vitro and in-vivo. Human CCA cell lines, TFK-1 and QBC939, were used as models to investigate DAC on the cell growth and proliferation of CCA. Cell proliferation was evaluated by Cell Counting Kit-8 assay combined with clonogenic survival assay. Flow cytometry, Hoechst 33342/propidium iodide staining and green fluorescent protein-tagged MAP-LC3 detection were applied to determine cell cycle progression, apoptosis and autophagy. Nude mice with TFK-1 xenografts were evaluated for tumor growth following DAC treatment. Decitabine was observed to significantly suppress the proliferation of cultured TFK-1 and QBC939 cells, accompanied with enhanced apoptosis, autophagy and cell cycle arrest at G2/M phase. In TFK-1 mouse xenografts, DAC retarded the tumor growth and increased the survival of CCA tumor-bearing mice.

In an open-label, single-arm, phase I/II study, Mei et al (2015) determined the safety and effectiveness of lower-dose decitabine-based therapy in pre-treated patients with advanced hepato-cellular carcinoma (HCC). The administered dose of decitabine was 6 mg/m2/day intravenously on days 1 to 5 of a 28-day cycle. Additional therapies were given based on their disease progression status. The end-point was to ensure the safety, hepatotoxicity, clinical responses, progression-free survival (PFS) and pharmacodynamics assay of lower-dose decitabine. A total of 15 patients were enrolled. The favorable adverse events and liver function profiles were observed. The most beneficial responses were 1 complete response (CR), 6 stable disease (SD), and 8 progressive disease (PD); MRI liver scans post-treatment indicated a unique and specific characteristic. The immunohistochemistry result from the liver biopsy exhibited noteworthy cytotoxic lymphocytes (CTLs) responses. Median PFS was 4 months (95 % confidence interval [CI]: 1.7 to 7.0), comparing favorably with existing therapeutic options. Expression decrement of DNA methyltransferase DNMT1 and global DNA hypo-methylation were observed in PBMCs after lower-dose decitabine treatment. The authors concluded that the lower-dose decitabine-based treatment resulted in beneficial clinical response and favorable toxicity profiles in patients with advanced HCC. They stated that prospective evaluations of decitabine administration schemes and tumor tissue-based pharmacodynamics effect are needed in future trials.

Furthermore, NCCN’s clinical practice guideline on “Hepatobiliary cancers” (Version 2.2015) does not list decitabine as a therapeutic option

Lung Cancer

Yan and colleagues (2015) stated that lung cancer cells are sensitive to 5-aza-2'-deoxycytidine (decitabine) or midostaurin (PKC412), because decitabine restores the expression of methylation-silenced tumor suppressor genes, whereas PKC412 inhibits hyperactive kinase signaling, which is essential for cancer cell growth. These researchers demonstrated that resistance to decitabine (decitabine(R)) or PKC412 (PKC412(R)) eventually results from simultaneously re-methylated DNA and re-activated kinase cascades. Indeed, both decitabine(R) and PKC412(R) displayed the up-regulation of DNMT1 and tyrosine-protein kinase (KIT), the enhanced phosphorylation of KIT and its downstream effectors, and the increased global and gene-specific DNA methylation with the down-regulation of tumor suppressor gene epithelial cadherin CDH1. Interestingly, decitabine(R) and PKC412(R) had higher capability of colony formation and wound healing than parental cells in-vitro, which were attributed to the hyperactive DNMT1 or KIT, because inactivation of KIT or DNMT1 reciprocally blocked decitabine(R) or PKC412(R) cell proliferation. Further, DNMT1 knockdown sensitized PKC412(R) cells to PKC412; conversely, KIT depletion synergized with decitabine in eliminating decitabine(R). Importantly, when engrafted into nude mice, decitabine(R) and PKC412(R) had faster proliferation with stronger tumorigenicity that was caused by the re-activated KIT kinase signaling and further CDH1 silencing. The authors concluded that these findings identified functional cross-talk between KIT and DNMT1 in the development of drug resistance, implying the reciprocal targeting of protein kinases and DNA methyltransferases as an essential strategy for durable responses in lung cancer.

Zhang and associates (2017) stated that epithelial-mesenchymal transition (EMT) is a crucial driver of tumor progression.  Tumor growth factor-beta 1 (TGF-β1) is an important factor in EMT induction in tumorigenesis.  The targeting of EMT may, therefore, represent a promising approach in anti-cancer treatment.  In this study, these researchers determined the effect of decitabine, a DNA methyltransferase inhibitor, on TGF-β1-induced EMT in non-small-cell lung cancer (NSCLC) PC9 and A549 cells.  They also evaluated the involvement of the miR-200/ZEB axis.  Decitabine reversed TGF-β1-induced EMT in PC9 cells, but not in A549 cells.  This phenomenon was associated with epigenetic changes in the miR-200 family, which regulated EMT by altering the expression of ZEB1 and ZEB2.  TGF-β1 induced aberrant methylation in miR-200 promoters, leading to EMT in PC9 cells.  Decitabine attenuated this effect and inhibited tumor cell migration in-vitro and in-vivo.  In A549 cells, however, neither TGF-β1 nor decitabine exhibited an effect on miR-200 promoter methylation.  The authors concluded that these findings suggested that epigenetic regulation of the miR-200/ZEB axis was responsible for EMT induction by TGF-β1 in PC9 cells; decitabine inhibited EMT in NSCLC cell PC9 through its epigenetic-based therapeutic activity.  These preliminary findings need to be further investigated.

Neuroblastoma and Sarcomas

Krishnadas et al (2013) stated that patients with relapsed stage 4 neuroblastoma have an extremely poor long-term prognosis, making the investigation of new agents of interest.  These investigators reported the outcome of the first patient treated in a phase I study for relapsed neuroblastoma, using the chemotherapy agent decitabine to up-regulate cancer testis antigen expression, followed by a dendritic cell vaccine targeting the cancer testis antigens MAGE-A1, MAGE-A3, and NY-ESO-1.  This patient had persistent tumor in his bone marrow after completion of standard therapy for neuroblastoma, including multi-agent chemotherapy, tumor resection, stem cell transplantation, radiation therapy, and anti-GD2 monoclonal antibodies.  His marrow disease persisted despite chemotherapy, which was given while the vaccine was being produced.  After 3 cycles of decitabine and vaccine, this patient achieved a complete remission (CR) and is now 1 year from his last treatment, with no evidence of tumor in his bone marrow or other sites.  This patient was noted to have an increase in MAGE-A3-specific T cells.  The authors noted that this was the first report combining demethylating chemotherapy to enhance tumor antigen expression followed by a cancer antigen vaccine.  Well-designed studies are needed to ascertain the effectiveness of decitabine in the treatment of neuroblastoma.

Krishnadas et al (2015) noted that antigen-specific immunotherapy was studied in a multi-institutional phase I/II study by combining decitabine (DAC) followed by an autologous dendritic cell (DC)/MAGE-A1, MAGE-A3 and NY-ESO-1 peptide vaccine in children with relapsed/refractory solid tumors. Patients aged 2.5 to 15 years with relapsed neuroblastoma, Ewing's sarcoma, osteosarcoma and rhabdomyosarcoma were eligible to receive DAC followed by DC pulsed with overlapping peptides derived from full-length MAGE-A1, MAGE-A3 and NY-ESO-1. The primary end-points were to assess the feasibility and tolerability of this regimen. Each of 4 cycles consisted of week 1: DAC 10 mg/m(2)/day for 5 days and weeks 2 and 3: DC vaccine once-weekly. A total of 15 patients were enrolled in the study, of which 10 were evaluable. Generation of DC was highly feasible for all enrolled patients. The treatment regimen was generally well-tolerated, with the major toxicity being DAC-related myelosuppression in 5/10 patients; 6 of 9 patients developed a response to MAGE-A1, MAGE-A3 or NY-ESO-1 peptides post-vaccine. Due to limitations in number of cells available for analysis, controls infected with a virus encoding relevant genes have not been performed. Objective responses were documented in 1/10 patients who had a complete response. Of the 2 patients who had no evidence of disease at the time of treatment, 1 remained disease-free 2 years post-therapy, while the other experienced a relapse 10 months post-therapy. The authors concluded that the chemoimmunotherapy approach using DAC/DC-CT vaccine was feasible, well-tolerated and resulted in anti-tumor activity in some patients. Moreover, they stated that future trials to maximize the likelihood of T cell responses post-vaccine are needed.

Chronic Myelomonocytic Leukemia

Per the Prescribing Information, Dacogen (decitabine) is indicated for treatment of patients with MDS including previously treated and untreated, de novo and secondary MDS of all French-American-British (FAB) subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.

Gastric Cancer

Nakamura and associates (2017) examined the effect of a DNA demethylating agent, decitabine, against Epstein-Barr virus-associated gastric cancer (EBVaGC).  Decitabine inhibited cell growth and induced G2/M arrest and apoptosis in EBVaGC cell lines.  The expression of E-cadherin was up-regulated and cell motility was significantly inhibited in the cells treated with decitabine.  The promoter regions of p73 and RUNX3 were demethylated, and their expression was up-regulated by decitabine.  They enhanced the transcription of p21, which induced G2/M arrest and apoptosis through down-regulation of c-Myc.  Decitabine also induced the expression of BZLF1 in SNU719.  Induction of EBV lytic infection was an alternative way to cause apoptosis of the host cells.  The authors concluded that this study was the first report to reveal the effectiveness of a demethylating agent in inhibiting tumor cell proliferation and up-regulation of E-cadherin in EBVaGC.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Gastric cancer” (Version 3.2016) does not mention decitabine as a therapeutic option.

Hodgkin Lymphoma

Swerev and colleagues (2017) stated that DNA methylation is an epigenetic control mechanism that contributes to the specific phenotype and to the oncogenic program of virtually all tumor entities.  Although the effectiveness of demethylating agents in classical Hodgkin lymphoma (cHL) was not specifically tested, a case of regression of relapsed metastatic cHL was described as a fortunate side effect of the demethylating agent 5-azacytidine in a patient with MDS.  These researchers examined the molecular mechanisms of decitabine (5-Aza-dC) anti-tumor activity in cHL using gene expression profiling followed by gene set enrichment analysis.  They found that 5-Aza-dC inhibited growth of cHL cell lines at clinically relevant concentrations of 0.25 to 2 µM.  The anti-tumor effect of 5-Aza-dC was associated with induction of genes, which negatively regulate cell cycle progression (e.g., CDKN1A and GADD45A).  These investigators also observed significant enrichment of pro-survival pathways like MEK/ERK, JAK‑STAT and NF‑κB, as well as signatures comprising transcription-activating genes.  Among the up-regulated pro-survival genes were the anti-apoptotic genes BCL2 and BCL2L1, as well as genes involved in transduction of growth and survival signals like STAT1, TLR7, CD40 and IL-6.  These researchers therefore analyzed whether interference with these pro-survival pathways and genes would potentiate the anti-tumor effect of 5-Aza-dC.  They could show that the BCL2/BCL2L1 inhibitor ABT263, the JAK‑STAT inhibitors fedratinib and SH‑4‑54, the AKT inhibitor KP372‑1, the NF‑κB inhibitor QNZ, as well as the bromodomain and extra-terminal (BET) family proteins inhibitor JQ1 acted synergistically with 5-Aza-dC.  The authors concluded that targeting of oncogenic pathways of cHL may improve effectiveness of DNA-demethylating therapy in cHL.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hodgkin lymphoma” (Version 3.2016) does not mention decitabine as a therapeutic option.

Primary Myelofibrosis

National Comprehensive Cancer Network’s Drugs & Biologics Compendium (2017) list “Myeloproliferative Neoplasms -- Primary Myelofibrosis and Post-PV or Post-ET MF” as a recommended indication of decitabine -- treatment of myelofibrosis (MF)-accelerated phase or MF-blast phase/acute myeloid leukemia (2A Recommendation).

Endometrial Cancer

Li and co-workers (2016) examined the effect of the demethylation drug 5-Aza-CdR on endometrial carcinoma xenografted in nude mice.  Mice were randomly assigned into decitabine (AZA), cisplatin (DDP), medroxyprogesterone acetate (MPA), AZA+DDP, AZA+MPA, DDP+MPA and model groups (3 in each group) after building the models of xenografted tumor by transplanting the HEC-1B cells on nude mice, and dealt them respectively with corresponding drugs (1 μg/g, single or combination) in the experiment groups and normal saline in model group (injected per 3 days, 8 injections in total).  Tumor inhibitory rates in different groups were calculated.  The methylation and protein expression of RASSF1A gene was estimated by methylation specific PCR (MSP) and Western blot, respectively, and apoptosis situation of carcinoma cell was estimated by tunel.  Inhibitory rate in AZA+DDP group was the highest, and the lowest was AZA group.  RASSF1A gene promoter region methylation levels of AZA, AZA+DDP, and AZA+MPA groups significantly reduced and showed obvious demethylation stripes while other groups mainly showed the methylation stripes.  The differences of RASSF1A protein expression among AZA, AZA+DDP, and AZA+MPA groups were not statistical significant (p > 0.05),but the 3 were higher than model group (p < 0.05); there was no statistically significant difference in the DDP, MPA, DDP+MPA groups compared with that of model group (p > 0.05).  In the comparison of apoptosis index, model group was the lowest, followed by the 3 single medicine groups, and the highest was 3 combination groups (p < 0.05).  The authors conclude that demethylation drug 5-Aza-CdR in endometrial cancer treatment has a great potential clinical application value by reversing the abnormal methylation of RASSF1A gene, restoring biological functions of RASSF1A protein and strengthening the efficacy of DDP and MPA. These findings need to be further investigated in clinical trials.

Alimentary Tract Cancer

Chen and associates (2018) stated that the pressing need for improved therapeutic outcomes provides a good rationale for identifying effective strategies for alimentary tract (AT) cancer treatment.  The potential re-sensitivity property to chemo- and immuno-therapy of low-dose decitabine has been evident both pre-clinically and in previous phase-I clinical trials.  These investigators conducted a phase Ib/II clinical trial evaluating low-dose decitabine-primed chemo-immunotherapy in patients with drug-resistant relapsed/refractory (R/R) esophageal, gastric or colorectal cancers.  A total of 45 patients received either the 5-day decitabine treatment with subsequent re-administration of the previously resistant chemotherapy (decitabine-primed chemotherapy, D-C cohort) or the afore-mentioned regimen followed by cytokine-induced killer cells therapy (D-C and cytokine-induced killer [CIK] cell treatment, D-C + CIK cohort) based on their treatment history.  Grade 3 to 4 adverse events (AEs) were reported in 11 (24.4 %) of 45 patients.  All AEs were controllable, and no patient experienced a treatment-related death.  The objective response rate (ORR) and disease control rate (DCR) were 24.44 % and 82.22 %, respectively, including 2 patients who achieved durable CRs.  Clinical response could be associated with treatment-free interval and initial surgical resection history; ORR and DCR reached 28 % and 92 %, respectively, in the D-C + CIK cohort.  Consistently, the PFS of the D-C + CIK cohort compared favorably to the best PFS of the pre-resistant unprimed therapy (p = 0.0001).  The toxicity and ORRs exhibited were non-significantly different between cancer types and treatment cohort.  The authors concluded that the safety and efficacy of decitabine-primed re-sensitization to chemo-immunotherapy was attractive and promising.  They stated that these data warrant further large-scale evaluation of drug-resistant R/R AT cancer patients with advanced stage disease.

Guillain-Barre Syndrome

Fagone and colleagues (2018) noted that Guillain-Barre syndrome (GBS) is an immune-mediated acute disorder of the peripheral nervous system.  Despite treatment, there is an associated mortality and severe disability in 9 to 17 % of the cases.  Decitabine (DAC) is a hypo-methylating drug used in MDS, that has been shown to exert immunomodulatory effects.  These researchers examined the effects of DAC in 2 rodent models of GBS, the experimental allergic neuritis (EAN).  Both prophylactic and therapeutic treatment with DAC ameliorated the clinical course of EAN, increasing the numbers of thymic regulatory T cells and reducing the production of pro-inflammatory cytokines.  The authors concluded that these findings suggested the possible use of decitabine for the treatment of GBS.

Sickle Cell Disease

Molokie and co-workers (2017) stated that sickle cell disease (SCD), a congenital hemolytic anemia that exacts terrible global morbidity and mortality, is driven by polymerization of mutated sickle hemoglobin (HbS) in red blood cells (RBCs).  Fetal hemoglobin (HbF) interferes with this polymerization, but HbF is epigenetically silenced from infancy onward by DNA methyltransferase 1 (DNMT1).  To pharmacologically re-induce HbF by DNMT1 inhibition, this first-in-human clinical trial combined 2 small molecules-decitabine to deplete DNMT1 and tetrahydrouridine (THU) to inhibit cytidine deaminase (CDA), the enzyme that otherwise rapidly deaminates/inactivates decitabine, severely limiting its half-life, tissue distribution, and oral bioavailability.  In a randomized, phase-I clinical trial, oral decitabine doses, administered after oral THU 10 mg/kg, were escalated from a very low starting level (0.01, 0.02, 0.04, 0.08, or 0.16 mg/kg) to identify minimal doses active in depleting DNMT1 without cytotoxicity.  Patients were SCD adults at risk of early death despite standard-of-care, randomized 3:2 to THU-decitabine versus placebo in 5 cohorts of 5 patients treated 2X/week for 8 weeks, with 4 weeks of follow-up.  The primary end-point was greater than or equal to grade 3 non-hematologic toxicity.  This end-point was not triggered, and AEs were not significantly different in THU-decitabine-versus placebo-treated patients.  At the decitabine 0.16 mg/kg dose, plasma concentrations peaked at approximately 50 nM (Cmax) and remained elevated for several hours.  This dose decreased DNMT1 protein in peripheral blood mononuclear cells by greater than 75 % and repetitive element CpG methylation by approximately 10 %, and increased HbF by 4 % to 9 % (p < 0.001), doubling HbF-enriched red blood cells (F-cells) up to approximately 80 % of total RBCs.  Total hemoglobin increased by 1.2 to 1.9 g/dL (p = 0.01) as reticulocytes simultaneously decreased; that is, better quality and efficiency of HbF-enriched erythropoiesis elevated hemoglobin using fewer reticulocytes.  Also indicating better RBC quality, biomarkers of hemolysis, thrombophilia, and inflammation (LDH, bilirubin, D-dimer, C-reactive protein [CRP]) improved.  As expected with non-cytotoxic DNMT1-depletion, platelets increased and neutrophils concurrently decreased, but not to an extent requiring treatment holds.  As an early phase study, drawbacks included small patient numbers at each dose level and narrow capacity to evaluate clinical benefits.  The authors concluded that the use of oral THU-decitabine to patients with SCD was safe in this study and, by targeting DNMT1, up-regulated HbF in RBCs.  Moreover, they stated that further studies should examine clinical benefits and potential harms not identified to-date.

Appendix

Dosing Recommendations for Myelodysplastic Syndrome

Decitabine is available as Dacogen and as generic decitabine in 50mg single dose vials.

There are two regimens for Dacogen administration. With either administration it is recommended that members be treated for a minimum of 4 cycles; however, a complete or partial response may take longer than 4 cycles.

• Treatment Regimen‐ Option 1: Administer Dacogen at a dose of 15mg/m2 by continuous intravenous infusion over 3 hours repeated every 8 hours for 3 days. Repeat cycle every 6 weeks.
• Treatment Regimen‐ Option 2: Administer Dacogen at a dose of 20mg/m2 by continuous intravenous infusion over 1 hour repeated daily for 5 days. Repeat cycle every 4 weeks.

For Treatment Regimen‐ Option 1

For Treatment Regimen‐ Option 1:

If hematologic recovery (ANC ≥1,000/ μL and platelets ≥50,000/ μL) from a previous Dacogen (decitabine) treatment cycle requires more than 6 weeks, then the next cycle of Dacogen (decitabine) therapy should be delayed and dosing temporarily reduced by following the below algorithm:

• Recovery requiring more than 6, but less than 8 weeks‐ Dacogen (decitabine) dosing to be delayed for up to 2 weeks and the dose temporarily reduced to 11mg/m² every 8 hours (33mg/m²/day, 99mg/m²/cycle) upon restarting therapy.
• Recovery requiring more than 8, but less than 10 weeks‐ patients should be assessed for disease progression (by bone marrow aspirates); in the absence of progression, the Dacogen (decitabine) dose should be delayed up to 2 more weeks and the dose reduced to 11mg/m² every 9 hours (33mg/m²/day, 99mg/m²/cycle) upon restarting therapy, then maintained or increased in subsequent cycles as clinically indicated.

For Treatment Regimen‐ Option 2

For Treatment Regimen‐ Option 2:

If myelosuppression is present, subsequent treatment cycles of Dacogen (decitabine) should be delayed until there is hematologic recovery (ANC ≥ 1,000/μL platelets ≥ 50,000/μL).

Table 1. French-American- British (FAB) Classification of MDS

Subtype	% Blasts in Peripheral Blood	% Blasts in Bone Marrow	Survival in Months
Refractory Anemia (RA)	<1	<5	19-64
Refractory Anemia with Ringed Sideroblasts (RARS)	<1	<5	21-76
Refractory Anemia with Excess Blasts (RAEB)	<5	5-20	7-15
Refractory Anemia with Excess Blasts in Transformation (RAEB-t)	>5	21-30	5-12
Chronic Myelomonocytic Leukemia (CMML)	<5	5-20	8-60+

Source: NCCN, 2013; Dacogen prescribing information.

Table 2: International Prognostic Scoring System (IPSS) for MDS

Score Values

Table 2: International Prognostic Scoring System (IPSS) for MDS Score Values

Prognostic Variable	0	0.5	1.0	1.5	2
BM Blast (%)	<5	5-10	N/A	11-20	21-30
Karyotype	Good	Intermediate	Poor
Cytopenias	0-1	2 or 3

Table 2: International Prognostic Scoring System (IPSS) for MDS Outcomes According to IPSS 

		N = 816		N = 759
Prognosis Score	IPSS Subgroup	Patients (%)	Median Survival (yrs) in absence of therapy	Patients (%)	Median AML transformation (yrs)
0	Low	33	5.7	31	9.4
0.5-1.0	Int-1	38	3.5	39	3.3
1.5-2.0	Int-2	22	1.2	22	1.1
≥2.5	High	7	0.4	8	0.2

Source: NCCN, 2013, Dacogen prescribing information.  

Supportive Care Measures for Myelodysplastic Syndrome

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:
96360 - 96368	Intravenous infusion
96374 - 96379	Therapeutic, prophylactic, or diagnostic injection; intravenous push
HCPCS codes covered if selection criteria are met:
J0894	Injection, decitabine, 1 mg
ICD-10 codes covered if selection criteria are met:
C92.00 - C92.02 C92.40 - C92.A2	Acute myeloid leukemia (AML)
C92.20	Atypical chronic myeloid leukemia, BCR/ABL-negative, not having achieved remission
C93.00 - C93.02	Acute monoblastic/monocytic leukemia
C93.10 - C93.12	Chronic myelomonocytic leukemia
C94.00 - C94.22	Acute erythroid and megakaryoblastic leukemia
D46.0 - D46.9	Myelodysplastic syndrome (MDS)
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach
C18.0 - C18.9	Malignant neoplasm of colon
C26.0 - C26.9	Malignant neoplasm of other and ill-defined digestive organs [alimentary tract cancer]
C43.0 - C43.9	Malignant melanoma of skin
C54.1	Malignant neoplasm of endometrium
C56.1 - C56.9	Malignant neoplasm of ovary
C81.90 - C81.99	Hodgkin lymphoma, unspecified
C90.00 - C90.02	Multiple myeloma
C92.10	Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission
C92.12	Chronic myeloid leukemia, BCR/ABL-positive, in relapse
D57.00 - D57.819	Sickle-cell disorders
G61.0	Guillain-Barre syndrome

The above policy is based on the following references: