Aetna considers decitabine (Dacogen) medically necessary for members with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

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

• Chronic myelogenous leukemia (CML)
• Colon cancer
• Melanoma
• Multiple myeloma
• Neuroblastoma
• Ovarian cancer

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”.

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

• Myelodysplastic syndromes (MDS) -- Treatment in higher risk patients who

  • Are not candidates for high-intensity therapy
  • Are high-intensity therapy candidates awaiting improved patient status or donor availability

  • Relapse after allogeneic hemopoietic stem cell transplant [2A]

• Myelodysplastic syndromes -- Treatment in lower risk patients with symptomatic anemia, del(5q) with or without other cytogenetic abnormalities, and serum erythropoietin levels greater than 500 mU/ml with no response or intolerance to lenalidomide and low probability of response to immusuppressive therapy [2A]

• Myelodysplastic syndromes -- Initial treatment in lower risk patients with

  • Symptomatic anemia and serum erythropoietin levels greater than 500 mU/ml with no del(5q) with or without other cytogenetic abnormalities and a low probability of response to immunosuppressive therapy
  • Clinically relevant thrombocytopenia or neutropenia, or increased marrow blasts [2A]
     

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

  • Induction therapy
  • Post-remission therapy [2A]
     

• Acute myeloid leukemia (AML) -- Used as a single agent in patients who cannot tolerate more agressive regimens for

  • Post-induction therapy in patients age less than 60 years with induction failure
  • Salvage chemotherapy [2A]

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.

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.

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.

Appendix

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

Source: NCCN, 2013; Dacogen prescribing information.

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

Score Values

Outcomes According to IPSS 

Source: NCCN, 2013, Dacogen prescribing information.  

Table 3:  Supportive Care Measures for Myelodysplastic Syndrome