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The epigenetic modifier CC-486 (an oral formulation of azacitidine)1 is a cytidine nucleoside analogue that is incorporated into newly synthesized DNA as well as RNA.2-4 Once incorporated, CC-486 may deplete DNA methyltransferase 1 (DNMT1), induce DNA damage, and promote hypomethylation of DNA.2,5 The antineoplastic effects of CC-486 are hypothesized to result from this DNA hypomethylation and the ultimate unsilencing of genes involved in cell cycle regulation.2,5
CC-486 Hypothesized Mechanism of Action
CC-486 is an epigenetic modifier hypothesized to induce malignant cell death through the inhibition of protein synthesis or the activation of DNA damage response pathways in hematologic malignancies.
Rationale for Investigation of CC-486 in Hematologic Malignancies
Post-induction AML maintenance
Preclinical studies suggest that the antileukemic effects of CC-486 include direct cytotoxicity due to inhibition of protein synthesis and DNA damage and the re-expression of aberrantly silenced tumor suppressor genes due to DNA hypomethylation.2,5-7 In vitro studies have shown that serial cycles of DNA replication are required to induce hypomethylation, and extensive demethylation requires prolonged exposure.2,3,8 Extended dosing with CC-486 may prolong drug exposure, which is hypothesized to allow more opportunity for incorporation into cycling malignant cells.9
Most patients with acute myeloid leukemia (AML) will relapse following achievement of remission with intensive chemotherapy, and it has been shown that duration of remission is predictive of long-term outcomes.10,11 Stem cell transplant is associated with the lowest rates of relapse.11 However, not all patients are candidates for stem cell transplant, and relapse remains a significant problem even for patients who do receive a transplant.12,13 There is an unmet need to prolong duration of remission following intensive chemotherapy with or without stem cell transplant.
Angioimmunoblastic T-cell lymphoma
Preclinical studies suggest that CC-486 has antitumor effects that include direct cytotoxicity due to activation of DNA damage response pathways, inhibition of protein synthesis, and re-expression of aberrantly silenced tumor suppressor genes due to DNA hypomethylation.2,5-7 One study in lymphoma cell lines has suggested that this hypomethylation may lead to re-expression of antitumor genes that are commonly silenced in non-Hodgkin lymphoma.14
Post hypomethylating agent (HMA) failure
Similar to the effects described in AML, CC-486 has exhibited antileukemic effects in preclinical studies.2,5-7 Additionally, prolonged exposure to CC-486 may allow more opportunity for incorporation into cycling malignant cells.2,3,8
Approximately two-thirds of patients with myelodysplastic syndromes (MDS) present with lower-risk disease that is generally viewed as having a favorable prognosis and is often treated with only supportive care.15,16 However, many patients with lower-risk disease have poor prognostic features and could benefit from early active treatment.15,17 The only potential cure for most patients with MDS remains stem cell transplant, which is generally reserved for younger patients with higher-risk disease.17 However, even patients who receive a transplant often relapse.17 There is an unmet need for additional treatment options in the post-transplant setting to improve disease-free survival.