Decitabine (Dacogen)

Number: 0868


  1. Criteria for Initial Approval

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

    1. Accelerated phase or blast myelofibrosis
    2. Acute myeloid leukemia (AML)
    3. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) - for the treatment of BPDCN when used in combination with venetoclax in either of the following settings:

      1. For the treatment of relapsed or refractory disease; or
      2. For the treatment of systemic disease with palliative intent
    4. Myelodysplastic syndromes (MDS)
    5. Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms - for treatment of MDS/MPN overlap neoplasms (i.e., chronic myelomonocytic leukemia (CMML), BCR-ABL negative atypical chronic myeloid leukemia (aCML), unclassifiable MDS/MPN, or MDS/MPN with ring sideroblasts and thrombocytosis).

    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 decitabine (Dacogen) therapy medically necessary for 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

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

Myelodysplastic Syndromes

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.

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

Source: Otsuka America Pharmaceutical, 2021

Experimental and Investigational

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

  • Alimentary tract cancer
  • 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.

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


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

Myelodysplastic Syndromes (MDS): Dacogen (decitabine) is indicated for treatment of adult 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.

Compendial Uses

  • Accelerated phase or blast phase myelofibrosis
  • Acute myeloid leukemia (AML)
  • Blastic plasmacytoid dendritic cell neoplasm (BPDCN)
  • Lower risk myelodysplastic syndromes (MDS) associated with thrombocytopenia, neutropenia, symptomatic anemia, or increased marrow blasts
  • Myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms

Decitabine is available as Dacogen (Otsuka America Pharmaceutical) and as generic decitabine. 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.

On May 2, 2006, the Food and Drug Administration (FDA) announced that: "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”.

The FDA approval of Dacogen was based on a randomized open-label, multicenter, controlled trial that evaluated adult patients with myelodysplastic syndromes (MDS) meeting French-American-British (FAB) classification criteria and International Prognostic Scoring System (IPSS) High-Risk, Intermediate-2 and Intermediate-1 prognostic scores. Kantarjian et al (2006) stated aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks (n=89 randomized; 83 received decitabine), or best supportive care (n=81). Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P = 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). The authors concluded that decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further.

In MDS clinical trials with Revlimid (lenalidomide), transfusion dependence was defined 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.

In 2001, the World Health Organization (WHO) submitted an alternative classification for MDS that was adapted from the original FAB classification criteria. Since that time, the WHO classification has been updated twice, once in 2008 and again in 2016. Currently, WHO guidelines represent six entities of MDS: MDS with single lineage dysplasia (MDS-SLD); MDS with ring sideroblasts (MDS-RS); MDS with multilineage dysplasia (MDS-MLD); MDS with excess blasts (MDS-EB); MDS with isolated del(5q) ± one other abnormality except -7/del(7q); and MDS unclassifiable (MDS-U). An additional provisional entity denoted as "refractory cytopenia of childhood" (RCC) is mentioned (NCCN, 2022b).

The Revised International Prognostic Scoring System (IPSS-R) was based on a cytogenic scoring methodology for MDS published in 2012. The IPSS-R served as a refinement of the original IPSS by integrating the following into the prognostic model: more detailed cytogenetic subgroups, separate subgroups within the "marrow blasts <5%" group, and a depth of cypopenias measurement with defined cutoffs for hemoglobin levels, platelet counts, and neutrophil counts. Additionally, the IPSS-R defines five risk groups (very low, low, intermediate, high, and very high) compared to the four groups in the initial IPSS (NCCN, 2022b).

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.

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.

Chronic Myeloid Leukemia (CML)

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.

Issa et al (2005) determined the activity of decitabine, a DNA methylation inhibitor, in imatinib-refractory or intolerant chronic myelogenous leukemia. Thirty-five patients were enrolled in this phase II study (12 in chronic phase, 17 in accelerated phase, and six in blastic phase).  Decitabine was administered at 15 mg/m2 intravenously over 1 hour daily, 5 days a week for 2 weeks. DNA methylation was measured using a LINE1 bisulfite/pyrosequencing assay. Complete hematologic responses were seen in 12 patients (34%) and partial hematologic responses in seven patients (20%), for an overall hematologic response rate of 54% (83% in chronic phase, 41% in accelerated phase, and 34% in blastic phase). Major cytogenetic responses were observed in six patients (17%), and minor cytogenetic responses were seen in 10 patients (29%) for an overall cytogenetic response rate of 46%. Median response duration was 3.5 months (range, 2 to 13+ months). Myelosuppression was the major adverse effect, with neutropenic fever in 28 (23%) of 124 courses of therapy. LINE1 methylation decreased from 71.3% +/- 1.4% (mean +/- standard error of the mean) to 60.7% +/- 1.4% after 1 week, 50.9% +/- 2.4% after 2 weeks, and returned to 66.5% +/- 2.7% at recovery of counts (median, 46 days). LINE1 methylation at the end of week 1 did not correlate with subsequent responses. However, at day 12, the absolute decrease in methylation was 14.5% +/- 3.0% versus 26.8% +/- 2.7% in responders versus non-responders (P = .007). The authors concluded that decitabine induces hypomethylation and has clinical activity in imatinib refractory chronic myelogenous leukemia. The authors hypothesize that the inverse correlation between hypomethylation 2 weeks after therapy and response is due to a cell death mechanism of response, whereby resistant cells can withstand more hypomethylation. 

Oki et al (2007) stated resistance to imatinib is a frequent clinical problem in advanced phase chronic myelogenous leukemia (CML). A Phase II study was performed on low-dose decitabine, a DNA methyltransferase inhibitor, in combination with imatinib in patients with CML in accelerated phase (AP) and myeloid blastic phase (BP). Patients received decitabine 15 mg/m(2) intravenously daily, 5 days a week for 2 weeks, and imatinib 600 mg orally daily. Global DNA methylation was measured by long interspersed nucleotide element (LINE) bisulfite/pyrosequencing. Twenty-eight patients were enrolled (25 with imatinib resistance; 18 in AP, 10 in BP). A total of 91 cycles (median, 2.5 cycles per patient) was administered. Complete hematologic responses, partial hematologic responses, and hematologic improvement were observed in 9 (32%), 1 (4%), and 2 (7%) patients. Major and minor cytogenetic responses were observed in 5 (18%) and 3 (11%) patients. The hematologic response rate was higher in patients without BCR-ABL kinase mutations (10 of 19, 53%) than in those with mutations (1 of 7, 14%). Median duration of hematologic response was 18 (range, 4 to 107+) weeks. Myelosuppression was the major adverse effect, with neutropenic fever in 9 patients (32%). LINE methylation decreased from 71.6% +/- 0.9% (mean +/- standard error of the mean) to 60.4% +/- 2.0% on Day 5, 60.5% +/- 1.8% on Day 12, and returned to 68.8% +/- 1.4% at peripheral blood recovery. A decrease in LINE methylation tended to be greater in non-responders than in responders on Days 5 and 12. The authors concluded that combination therapy with decitabine and imatinib is well tolerated and active in advanced phase CML without BCR-ABL kinase mutations. 

Chronic Myelomonocytic Leukemia (CMML)

Chronic myelomonocytic leukemia (CMML) is a malignant hematopoietic stem cell disorder with clinical and pathological characteristics of both a myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS). CMML is characterized by a peripheral blood monocytosis accompanied by bone marrow dysplasia along with cytopenias, constitutional symptoms, and/or splenomegaly frequently occurring. CMML is among the most aggressive chronic leukemias, with a tendency for progression to acute myeloid leukemia (AML). Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for patients with CMML, but however carries substantial complications, including acute and chronic graft-versus-host disease (GVHD), non relapse mortality (NRM), and disease relapse. For those who are not candidates for allogeneic HCT and who decide not to participate in a clinical trial, the authors suggest symptom-directed therapy with either hydroxyurea or hypomethylating agents (e.g., azacitidine, decitabine) (UpToDate, Padron; reviewed 2020). 

Colon Cancer

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.

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.

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.


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.

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.

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.

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.

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.

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.


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.

Multiple Myeloma

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, the authors investigated the DNA damage response (DDR) induced by decitabine in MM using 4 human MM cell lines and the murine 5T33MM model. In addition, they 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, they 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, they authors 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.

Myelodysplastic syndrome/Myeloproliferative neoplasms (MDS/MPNs)

The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a type of myeloid malignancies that present with both myelodysplastic and myeloproliferative phenotypic features. MDS-like features include cytopenias and dysplasia of various cell lines and MPN-like features include constitutional symptoms (e.g. night sweats and/or weight loss), elevated blood counts as well as extramedullary infiltration. The 2008 World Health Organization (WHO) classification added the category of MDS/MPN neoplasms, which includes chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), atypical chronic myeloid leukemia (aCML), MDS/MPN unclassifiable (MDS/MPN-U), and refractory anemia with ring sideroblasts and thrombocytosis (RARS-T). Diagnosis and classification remain clinicopathologic, based on laboratory, morphological, and clinical parameters (Clara, 2016; Orazi, 2008; Vardiman, 2009).

Multiple prognostic scores have been validated specifically for CMML in the past 5 years. These incorporate somatic mutations, with ASXL1 mutations repeatedly correlating with poor prognosis. Accurate prognostication can guide treatment. Hypomethylating agents (HMAs) and curative allogeneic blood or marrow transplantation (BMT) remain the most available standard treatments. Recently, a number of novel approaches using unapproved therapies (i.e., lenalidomide, ruxolitinib, sotatercept, and tipifarnib) have demonstrated some efficacy in CMML. Increased recognition and interest in CMML have led to the development of a number of new prognostic models and potential treatment options. Standard treatment options remain limited and clinical trials should be strongly considered whenever available (Elmariah 2019)

Chronic myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm in which treatment strategies with the capacity to improve survival are currently lacking. Clinical features are heterogeneous and although the overall prognosis is poor, survival can vary significantly between individuals. This reflects the need for an individualized treatment approach which incorporates accurate risk stratification. Though numerous prognostic scores exist, newer CMML-specific models incorporating molecular data should be favored. While asymptomatic, low-risk patients should be observed until their disease progresses, the majority of patients will require treatment. Due to a deficiency in treatments with disease-modifying capacity, any patient who requires treatment should be considered for enrollment in clinical trials evaluating novel therapeutic approaches. Allogeneic stem cell transplant (allo-SCT) remains the only current therapy with the potential to cure the disease and should be considered in most patients with intermediate- to high-risk disease. However, substantial risks are involved and, in part, because of advanced age at diagnosis, a minority of patients are candidates. Hypomethylating agents (HMAs) have become a preferred treatment approach, and should be used in those with cytopenias. Patients presenting with proliferative features can be treated with hydroxyurea to manage their symptoms and control leukocytosis, though HMAs can be incorporated as well, particularly in patients with higher risk disease. HMAs should also be considered in patients with a high burden of disease prior to proceeding with allo-SCT. Induction chemotherapy should be reserved for younger, healthy patients who have transformed to acute myeloid leukemia to induce remission prior to transplant. Supportive care utilizing transfusion support, erythropoiesis-stimulating agents, and infection prevention measures should be incorporated into the care of all patients (Hunter 2018).

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.

Ovarian Cancer

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.

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.

Combined Decitabine and Venetoclax for the Treatment of Acute Myeloid Leukemia

Maiti et al (2021a) stated that R/R-AML has poor outcomes.  Although lower-intensity venetoclax-containing regimens are standard for older/unfit patients with newly diagnosed AML, it is unknown how such regimens compare with intensive chemotherapy (IC) for R/R-AML.  Outcomes of R/R-AML patients treated with 10-day decitabine and venetoclax (DEC10-VEN) were compared with IC-based regimens including idarubicin with cytarabine, with or without cladribine, clofarabine, or fludarabine, with or without additional agents.  Propensity scores derived from patient baseline characteristics were used to match DEC10-VEN and IC patients to minimize bias.  A total of 65 patients in the DEC10-VEN cohort were matched to 130 IC recipients.  The median ages for the DEC10-VEN and IC groups were 64 and 58 years, respectively, and baseline characteristics were balanced between the 2 cohorts.  DEC10-VEN conferred significantly higher responses compared with IC including higher ORR (60 % versus 36 %; OR, 3.28; p < 0.001), CR with incomplete hematologic recovery (CRi, 19 % versus 6 %; OR, 3.56; p = 0.012), minimal residual disease (MRD) negativity by flow cytometry (28 % versus 13 %; OR, 2.48; p = 0.017), and lower rates of refractory disease.  DEC10-VEN led to significantly longer median event-free survival (EFS) compared with IC (5.7 versus 1.5 months; hazard ratio, 0.46; 95 % CI: 0.30 to 0.70; p < 0.001), as well as median OS (6.8 versus 4.7 months; hazard ratio, 0.56; 95 % CI: 0.37 to 0.86; p = 0.008).  DEC10-VEN was independently associated with improved OS compared with IC in multi-variate analysis.  Exploratory analysis for OS in 27 subgroups showed that DEC10-VEN was comparable with IC as salvage therapy for R/R-AML.  The authors concluded that DEC10-VEN represented an appropriate salvage therapy and may offer better responses and survival compared with IC in adults with R/R-AML.

Maiti and et al (2021b) noted that hypo-methylating agents (HMA) with venetoclax is a new standard for older/unfit patients with AML; however, it is unclear how HMA with venetoclax compared to IC in patients who are "fit" or "unfit" for IC.  These researchers compared outcomes of older patients with newly diagnosed AML receiving 10-day DEC10-VEN versus IC.  DEC10-VEN consisted of daily venetoclax with decitabine 20 mg/m2 for 10 days for induction and decitabine for 5 days as consolidation.  The IC cohort received regimens containing cytarabine greater than or equal to 1 g/m2 /day.  A validated treatment-related mortality score (TRMS) was used to classify patients at high-risk or low-risk for TRM with IC.  Propensity scores were used to match patients to minimize bias.  Median age of the DEC10-VEN cohort (n = 85) was 72 years (range of 63 to 89) and 28 % patients were at high-risk of TRM with IC.  The comparator IC group (n = 85) matched closely in terms of baseline characteristics.  DEC10-VEN was associated with significantly higher CR/CRi compared to IC (81 % versus 52 %, p < 0.001), and lower rate of relapse (34 % versus 56 %, p = 0.01), 30-day mortality (1 % versus 24 %, p < 0.01), and longer OS (12.4 versus 4.5 months, hazard ratio = 0.48, 95 % CI: 0.29 to 0.79, p < 0.01).  In patients at both at high-risk and low-risk of TRM, DEC10-VEN showed significantly higher CR/CRi, lower 30-day mortality, and longer OS compared to IC.  Patients at both high-risk and low-risk of TRM had comparable outcomes with DEC10-VEN.  The authors concluded that DEC10-VEN offered better outcomes compared to IC in older patients with newly diagnosed AML, especially in those at high-risk of TRM.

Kim and colleagues (2021) noted that TP53 mutation (TP53mut ) confers an adverse prognosis in AML.  Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggested that TP53mut confers resistance to venetoclax.  These investigators examined the outcomes of patients with TP53mut AML who were treated with a 10-day DEC10-VEN.  Patients with newly diagnosed AML received decitabine 20 mg/m2 for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response.  The venetoclax dose was 400 mg daily.  TP53mut was identified in bone marrow samples using next-generation sequencing (NGS), with sensitivity of 5 %.  Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.  Among 118 patients (median age of 72 years; age range of 49 to 89 years), 63 (53 %) had secondary AML, 39 (33 %) had AML with complex karyotype, and 35 (30 %) had TP53mut AML.  The median TP53 variant allele frequency was 32 % (inter-quartile range [IQR], 16 % to 65 %), 8 patients (23 %) had only a single TP53 mutation, 15 (43 %) had multiple mutations, and 12 (34 %) had mutation and deletion.  Outcomes were significantly worse in patients who had TP53mut AML compared with those who had wild-type TP53 AML, with an ORR of 66 % versus 89 % (p = 0.002), a CR/CRi of 57 % versus 77 % (p = 0.029), and a 60-day mortality of 26 % versus 4 % (p < 0.001), respectively.  Patients with TP53mut versus wild-type TP53 had shorter OS at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95 % CI: 2.44 to 8.93; p < 0.0001), and shorter relapse-free survival (RFS) at 3.4 versus 18.9 months (hazard ratio, 4.80; 95 % CI: 1.97 to 11.69; p < 0.0001), respectively.  Outcomes with DEC10-VEN in patients with TP53mut AML were comparable to historical results with 10-day decitabine alone.  The authors concluded that patients with TP53mut AML have lower response rates and shorter survival with DEC10-VEN.


Table: Classification of the Myelodysplastic Syndromes
FAB Classification Blasts in Bone Marrow (%) Other Findings
Refractory anemia (RA) < 5 < 1% circulating blast cells
RA with ring sideroblasts < 5 < 1% circulating blast cells; 15% ring sideroblasts in bone marrow
RA with excess blasts 5 - 20 < 5% circulating blasts
Chronic myelomonocytic leukemia < 20 1 x 109/liter monocytes and promonocytes in peripheral blood
RA with excess blasts in transformation 20 - 30 5% circulating blast cells; Auer rods

FAB = French-American-British

Source: Doll, List, 1989

Table: 2016 WHO Classification of MDS
Subtype Blood Bone Marrow
MDS with single lineage dysplasia Single or bicytopenia Dysplasia in ≥ 10% of one cell line, < 5% blasts
MDS with ring sideroblasts (MDS-RS) Anemia, no blasts ≥ 15% of erythroid precursors w/ring sideroblasts, or ≥ 5% ring sideroblasts if SF3B1 mutation present
MDS with multilineage dysplasia Cytopenia(s), < 1 x 109/L monocytes Dysplasia in ≥ 10% of cells in ≥ 2 hematopoietic lineages, < 15% ring sideroblasts (or < 5% ring sideroblasts if SF3B1 mutation present), < 5% blasts
MDS with excess blasts-1 Cytopenia(s), ≤ 2% - 4% blasts, < 1 x 109/L monocytes Unilineage or multilineage dysplasia, 5% - 9% blasts, no Auer rods
MDS with excess blasts-2 Cytopenia(s), 5% - 19% blasts, < 1 x 109/L monocytes Unilineage or multilineage dysplasia, 10% - 19% blasts, ± Auer rods
MDS, unclassifiable Cytopenias, ±1% blasts on at least 2 occasions Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, < 5% blasts
MDS with isolated del(5q) Anemia, platelets normal or increased Unilineage erythroid dysplasia, isolated del(5q), < 5% blasts ± one other abnormality except -7/del(7q)
Refractory cytopenia of childhood (Provisional WHO category) Cytopenias, < 2% blasts Dysplasia in 1 - 3 lineages, < 5% blasts

Source: NCCN, 2022b

Table: International Prognostic Scoring System (IPSS)
Survival and AML Evolution
Score Value
Prognostic Variable






Marrow Blasts (%)

< 5

5 - 10

11 - 20

21 - 30








0 / 1

2 / 3




Table: International Prognostic Scoring System (IPSS)
IPSS Risk Category (% IPSS pop.) Overall Score Median Survival (y) in the Absence of Therapy 25% AML Progression (y) in the Absence of Therapy
Low (33) 0 5.7 9.4
Intermediate-1 (38) 0.5 - 1.0 3.5 3.3
Intermediate-2 (22) 1.5 - 2.0 1.1 1.1
High (7) ≥ 2.5 0.4


Source: Greenberg et al., 1997

Table: Revised International Prognostic Scoring System (IPSS-R)
Score Value
Prognostic Variable 0 0.5  1   1.5  2  3   4
Cytogenetic Very good  —  Good  —  Intermediate Poor Very poor
Marrow blasts (%) ≤ 2  —  > 2 - < 5  —   5 - 10  > 10  — 
Hemoglobin ≥ 10  —   8 - < 10 < 8  —   —   — 
Platelets ≥ 100 50 - < 100 < 50  —   —   —   — 
ANC ≥ 0.8 < 0.8  —   —   —   —   — 

Table: Revised International Prognostic Scoring System (IPSS-R)
IPSS-R Risk Category (% IPSS-R pop.) Overall Score Median Survival (y) in the Absence of Therapy 25% AML Progression (y) in the Absence of Therapy  
Very low (19) ≤ 1.5 8.8 Not reached
Low (38) > 1.5 - ≤ 3.0 5.3 10.8
Int (20) > 3.0 - ≤4.5 3 3.2
High (13) > 4.5 - ≤6.0 1.6 1.4
Very high (10) > 6.0 0.8 0.7

Source: Greenberg et al., 2012

Myelodysplastic Syndromes: Supportive Care

  • Clinical monitoring
  • Psychosocial support
  • Quality-of-life assessment
  • Transfusions: RBC transfusions (CMV-safe) are recommended for symptomatic anemia, and platelet transfusions are recommended for thrombocytopenic bleeding. However, they should not be used routinely in patients with thrombocytopenia in the absence of bleeding unless platelet count less than 10,000/mcL. Irradiated products are suggested for transplant candidates.
  • Antibiotics are recommended for bacterial infections, but no routine prophylaxis is recommended except in patients with recurrent infections.
  • Aminocaproic acid or other antifibrinolytic agents may be considered for bleeding refractory to platelet transfusions or profound thrombocytopenia.
  • Iron chelation: If less than 20 to 30 RBC transfusions have been received, consider daily chelation with deferoxamine subcutaneously or deferasirox orally to decrease iron overload, particularly for patients who have lower-risk MDS or who are potential transplant candidates (LOW/INT-1). For patients with serum ferritin levels less than 2500 ng/mL, aim to decrease ferritin levels to less than 1000 ng/mL (See Discussion). Patients with low creatinine clearance (less than 40 mL/min) should not be treated with deferasirox or deferoxamine.
  • Cytokines:

    • EPO - EPO refers to the following agents: epoetin alfa and epoetin alfa-epbx.
    • G-CSF:

      • G-CSF refers to the following agents: filgrastim, filgrastim-sndz, and tbo-filgrastim. Not recommended for routine infection prophylaxis.
      • Consider use in neutropenic patients with recurrent or resistant infections.
      • Combine with EPO for anemia when indicated.
      • Platelet count should be monitored.

    • Clinically significant thrombocytopenia - In patients with lower-risk MDS who have severe or life-threatening thrombocytopenia, consider treatment with a thrombopoietin-receptor agonist.

Source: NCCN, 2022b

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

Other HCPCS codes related to the CPB:

Venetoclax - no specific code:

ICD-10 codes covered if selection criteria are met:

C86.4 Blastic plasmacytoid dendritic cell neoplasm (BPDCN) [relapsed or refractory]
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
C94.6 Myelodysplastic disease, not classified
D46.0 - D46.9 Myelodysplastic syndrome (MDS)
D47.1 Chronic myeloproliferative disease

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
D57.00 - D57.819 Sickle-cell disorders
G61.0 Guillain-Barre syndrome

The above policy is based on the following references:

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