5-Azacytidine is a pyrimidine nucleoside analog of cytidine that undergoes incorporation into DNA and blocks DNA methyltransferase leading to hypomethylation and potentially beneficial re-expression of abnormally silenced genes. It is the first agent approved for use in patients with myelodysplastic syndromes (MDSs) based on its improvement in overall survival as monotherapy. Evidence of efficacy in combination with other agents is also accumulating. Our understanding of the molecular basis and pathogenesis of MDS continues to evolve rapidly. 5-Azacytidine has been shown to improve both overall survival and quality of life in patients with high-risk MDS. Currently, the oral route of administration is undergoing evaluation in clinical trials. Used as a monotherapy and also in novel combinations, 5-azacytidine has the potential to further improve the prognosis of some patients with MDS. [1]

Azacitidine is the first drug in a new class of compounds, known as DNA hypomethylating agents, to receive FDA-approved labeling for the treatment of myelodysplastic syndromes. It exerts its antineoplastic activity by causing a direct cytotoxic effect on abnormally proliferating hematopoietic cell lines by interfering with nucleic acid metabolism. Azacitidine is rapidly absorbed following subcutaneous injection, with peak plasma concentrations achieved within 30 minutes of administration. Based on promising results in Phase I-II testing, azacitidine entered Phase III testing in all subtypes of myelodysplastic syndromes. Azacitidine was compared with best supportive care, the previous standard therapy for myelodysplastic syndromes, demonstrating improvements in hematologic response, delaying time to progression to acute myelogenous leukemia, and increasing overall survival. Azacitidine is available as sterile lyophilized powder in single-use vials for reconstitution. The recommended dosage of azacitidine for the first treatment cycle is 75 mg/m(2) daily for seven days. The treatment cycle should be repeated every four weeks for a minimum of four cycles. [2]

Azacitidine is the first drug FDA-approved for the treatment of myelodysplastic syndromes that has demonstrated improvements in overall survival and delaying time to progression to acute myelogenous leukemia. The recommended dosage of azacitidine is 75 mg/m(2) daily for 7 days, with different treatment schedules validated. It appears to be well tolerated, with the most common adverse effects being myelosuppression. Several other off-label recommendations were also analyzed. Acute myeloid leukemia (AML) is a complex hematological malignancy predominantly affecting the elderly, with a median diagnosis age of 68 years. Despite advances in treatment, elderly AML patients face suboptimal survival outcomes, with an estimated 5-year survival rate below 20 %. Epigenetic dysregulation, notably DNA methylation, is a key factor in the progression of myelodysplastic syndromes (MDS) to AML. This review examines various combination regimens involving azacitidine (AZA), including those with lenalidomide, histone deacetylase inhibitors (HDACi), kinase inhibitors, metabolic enzyme inhibitors, monoclonal antibodies, immune checkpoint inhibitors, and anti-apoptotic protein inhibitors. Notable among these are the combinations with venetoclax, which has demonstrated remarkable efficacy in phase III trials, and the emerging IDH inhibitors ivosidenib and enasidenib, which have shown significant clinical benefits in patients with IDH mutations. While combination therapies with AZA hold great promise, challenges persist, including translating in vitro synergies to in vivo efficacy and identifying optimal regimens for specific patient populations. [3]

Venetoclax, in combination with azacitidine, decitabine, or low-dose cytarabine (LDAC), received confirmatory approval in 2020 by the US Food and Drug Administration for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged 75 years or older or who are ineligible for intensive induction chemotherapy. The economic value associated with response to venetoclax combinations compared with other treatments for this patient population has not been comprehensively evaluated. The analysis used treatment effect estimates (ie, complete remission [CR] + CR with incomplete blood count recovery [CRi]) from a network meta-analysis and annual cost estimates from a prior budget impact model. The model considered the total cost of care including the costs of drug and administration, adverse events, hospitalization, disease monitoring, blood transfusions, and subsequent AML management when patients discontinued active treatment. Costs per patient achieving CR + CRi associated with venetoclax + azacitidine, venetoclax + LDAC, azacitidine, decitabine, LDAC, and best supportive care (ie, treatment given with the intent to maximize quality of life without specific antileukemic intent, such as blood transfusion products and antibiotics) were calculated as the annual total cost of care per patient divided by the CR + CRi rate. [4]

The myelodysplastic syndromes (MDS) encompass a heterogeneous group of malignant hematologic disorders characterized by ineffective hematopoiesis, peripheral cytopenias, frequent karyotypic abnormalities and significant risk for transformation to acute myeloid leukemia (AML). The prognosis of patients with intermediate- or high-risk MDS is very poor. This is due to the fact that standard therapeutic options are largely palliative. Neither autologous stem cell transplantation (SCT) nor chemotherapeutic regimens have been shown to prolong survival in patients with MDS. Allogeneic SCT, while potentially curative, is only available to a selected group of patients and is associated with high morbidity and mortality in elderly patients, which constitute the majority of patients with MDS. Hypermethylation of tumor-suppressor genes has been invoked as an important pathogenetic mechanism in MDS. The pyrimidine nucleoside analog azacitidine, which inhibits DNA methyltransferases, has recently become the first therapeutic to prolong survival in patients with MDS, thus changing the natural history of these malignancies. The activity of azacitidine in MDS has spurred the development of combinations of this agent with other epigenetic modifiers for the treatment of MDS and AML. [6]

Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and a propensity to transform into acute myeloid leukemia. There are few treatment options available for patients with MDS. Studies into the molecular biology of MDS have demonstrated abnormal patterns of DNA methylation that lead to silencing of tumor-suppressor genes. Hypomethylating agents are compounds that have the potential to reverse the aberrant DNA methylation and increase the expression of silenced genes, leading to cellular differentiation and/or apoptosis. Decitabine is a cytidine analogue that has activity as a hypomethylating agent and has been evaluated in the therapy of patients with high-risk MDS. Several studies have confirmed the clinical activity of low-dose decitabine in patients with high-risk MDS, leading to responses in approximately 50% of patients, with low treatment-related mortality. Responses have even been seen in patients with high-risk cytogenetic abnormalities, and some studies have demonstrated increased re-expression of genes that were previously silenced by hypermethylation, such as CDKN2B/p15INK4B. There are still some issues concerning the ideal dose and schedule of decitabine for treating patients with MDS. This article focuses on the most recent clinical studies of decitabine for therapy of MDS. [7]

A search of the published medical literature revealed 1 study investigating the researchable question:

What are the therapeutic alternatives for Azacitidine Injection?

C - Multiple studies with limitations or conflicting results  Read more→