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Azacitidine
Clinical data
Trade namesVidaza, Azadine, Onureg
Other names5-Azacytidine, Azacytidine, Ladakamycin, 4-Amino-1-β-D-ribofuranosyl-s-triazin-2(1H)-one, U-18496, CC-486
AHFS/Drugs.comMonograph
MedlinePlusa607068
License data
Pregnancy
category
  • AU: X (High risk)[1]
Routes of
administration		Subcutaneous, intravenous, by mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life4 hr.[8]
Identifiers
  • 4-Amino-1-β-D-ribofuranosyl-1,3,5-triazin-2(1H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.005.711 Edit this at Wikidata
Chemical and physical data
FormulaC8H12N4O5
Molar mass244.207 g·mol−1
3D model (JSmol)
  • O=C1/N=C(\N=C/N1[C@@H]2O[C@@H]([C@@H](O)[C@H]2O)CO)N
  • InChI=1S/C8H12N4O5/c9-7-10-2-12(8(16)11-7)6-5(15)4(14)3(1-13)17-6/h2-6,13-15H,1H2,(H2,9,11,16)/t3-,4-,5-,6-/m1/s1 checkY
  • Key:NMUSYJAQQFHJEW-KVTDHHQDSA-N checkY
  (verify)

Azacitidine, sold under the brand name Vidaza among others, is a medication used for the treatment of myelodysplastic syndrome, myeloid leukemia,[5][6] and juvenile myelomonocytic leukemia.[4][9] It is a chemical analog of cytidine, a nucleoside in DNA and RNA.[medical citation needed] Azacitidine and its deoxy derivative, decitabine (also known as 5-aza-2′-deoxycytidine) were first synthesized in Czechoslovakia as potential chemotherapeutic agents for cancer.[10]

The most common adverse reactions in children with juvenile myelomonocytic leukemia include pyrexia, rash, upper respiratory tract infection, and anemia.[9]

Medical uses

[edit]

Azacitidine is indicated for the treatment of myelodysplastic syndrome,[4] for which it received approval by the U.S. Food and Drug Administration (FDA) on 19 May 2004.[11][4][12] In two randomized controlled trials comparing azacitidine to supportive treatment, 16% of subjects with myelodysplastic syndrome who were randomized to receive azacitidine had a complete or partial normalization of blood cell counts and bone marrow morphology, compared to none who received supportive care, and about two-thirds of patients who required blood transfusions no longer needed them after receiving azacitidine.[13]

Azacitidine is also indicated for the treatment of myeloid leukemia[5][6][14] and juvenile myelomonocytic leukemia.[4][9] The combination of azacitidine and venetoclax is also approved for AML.[15]

Mechanism of action

[edit]

Azacitidine is a chemical analogue of the nucleoside cytidine, which is present in DNA and RNA. It is thought to have antineoplastic activity via two mechanisms – at low doses, by inhibiting of DNA methyltransferase, causing hypomethylation of DNA,[16] and at high doses, by its direct cytotoxicity to abnormal hematopoietic cells in the bone marrow through its incorporation into DNA and RNA, resulting in cell death. Azacitidine is a ribonucleoside, so it is incorporated into RNA to a larger extent than into DNA. In contrast, decitabine (5-aza-2'-deoxycytidine) is a deoxyribonucleoside, so it can only incorporate into DNA. Azacitidine's incorporation into RNA leads to the disassembly of polyribosomes, defective methylation and acceptor function of transfer RNA, and inhibition of the production of proteins. Its incorporation into DNA leads to covalent binding with DNA methyltransferases, which prevents DNA synthesis and subsequently leads to cytotoxicity. It has been shown effective against human immunodeficiency virus in vitro[17] and human T-lymphotropic virus.[18]

Inhibition of methylation

[edit]

After azanucleosides such as azacitidine have been metabolized to 5-aza-2′-deoxycytidine-triphosphate (aka, decitabine-triphosphate), they can be incorporated into DNA and azacytosine can be substituted for cytosine. Azacytosine-guanine dinucleotides are recognized as substrate by the DNA methyltransferases, which catalyze the methylation reaction by a nucleophilic attack. This results in a covalent bond between the carbon-6 atom of the cytosine ring and the enzyme. The bond is normally resolved by beta-elimination through the carbon-5 atom, but this latter reaction does not occur with azacytosine because its carbon-5 is substituted by nitrogen, leaving the enzyme covalently bound to DNA and blocking its DNA methyltransferase function. In addition, the covalent protein adduction also compromises the functionality of DNA and triggers DNA damage signaling, resulting in the degradation of trapped DNA methyltransferases. As a consequence, methylation marks become lost during DNA replication.[19][20]

Toxicity

[edit]

Azacitidine causes anemia (low red blood cell counts), neutropenia (low white blood cell counts), and thrombocytopenia (low platelet counts), and patients should have frequent monitoring of their complete blood counts, at least prior to each dosing cycle. The dose may have to be adjusted based on nadir counts and hematologic response.[4]

It can also be hepatotoxic in patients with severe liver impairment, and patients with extensive liver tumors due to metastatic disease have developed progressive hepatic coma and death during azacitidine treatment, especially when their albumin levels are less than 30 g/L. It is contraindicated in patients with advanced malignant hepatic tumors.[4]

Kidney toxicity, ranging from elevated serum creatinine to kidney failure and death, have been reported in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for conditions other than myelodysplastic syndrome. Renal tubular acidosis developed in five patients with chronic myelogenous leukemia (an unapproved use) treated with azacitidine and etoposide, and patients with renal impairment may be at increased risk for renal toxicity. Azacitidine and its metabolites are primarily excreted by the kidneys, so patients with chronic kidney disease should be closely monitored for other side effects, since their levels of azacitidine may progressively increase.[4]

Based on animal studies and its mechanism of action, azacitidine can cause severe fetal damage. Sexually active women of reproductive potential should use contraception while receiving azacitidine and for one week after the last dose, and sexually active men with female partners of reproductive potential should use contraception during treatment and for three months following the last dose.[4]

A study undertaken to evaluate the immediate and long-term effects of a single-day exposure to Azacytidine (5-AzaC) on neurobehavioral abnormalities in mice found, that the inhibition of DNA methylation by 5-AzaC treatment causes neurodegeneration and impairs extracellular signal-regulated kinase (ERK1/2) activation and the activity-regulated cytoskeleton-associated (Arc) protein expression in neonatal mice and induces behavioral abnormalities in adult mice, as DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function.[21]

Azacitidine can also cause nausea, vomiting, fevers, diarrhea, redness at its injection sites, constipation, bruising, petechiae, rigors, weakness, abnormally low potassium levels in the bloodstream, and many other side effects, some of which can be severe or even fatal.[4]

History

[edit]

The efficacy of azacitidine to treat juvenile myelomonocytic leukemia was evaluated in AZA-JMML-001 (NCT02447666), an international, multicenter, open-label study to evaluate the pharmacokinetics, pharmacodynamics, safety, and activity of azacitidine prior to hematopoietic stem cell transplantation in 18 pediatric patients with juvenile myelomonocytic leukemia.[9]

Research

[edit]

Azacitidine can be used in vitro to remove methyl groups from DNA. This may weaken the effects of gene silencing mechanisms that occur prior to methylation. Certain methylations are believed to secure DNA in a silenced state, and therefore demethylation may reduce the stability of silencing signals and confer relative gene activation.[22]

Azacitidine induces tumor regression on isocitrate dehydrogenase-1 mutant glioma xenografts in mice.[23]

In research, 5-azacitidine is commonly used for promoting cardiomyocyte differentiation of adult stem cells. However, it has been suggested that this drug has a compromised efficacy as a cardiac differentiation factor because it promotes the transdifferentiation of cardiac cells to skeletal myocytes.[24]

Azacitidine also has antiviral effects in animal studies as well as its anti-cancer actions, but has not been tested for clinical use.[25][26]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Azacitidine

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from Grokipedia
Azacitidine is a pyrimidine nucleoside analogue of cytidine with antineoplastic activity, functioning primarily as a DNA hypomethylating agent. It is incorporated into DNA and RNA, where it inhibits DNA methyltransferases, leading to reduced DNA methylation, reactivation of silenced genes, and cytotoxicity against abnormal hematopoietic cells. Chemically, azacitidine has the formula C₈H₁₂N₄O₅ and a molecular weight of 244 Da, differing from cytidine by the replacement of carbon at the 5-position with nitrogen. First approved by the U.S. (FDA) in 2004 under the brand name Vidaza for the treatment of specific subtypes of myelodysplastic syndromes (MDS)—including refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and —azacitidine marked the first drug specifically indicated for MDS. Subsequent approvals expanded its use, including an oral formulation (Onureg) in 2020 for maintenance therapy in (AML) following induction chemotherapy, and in 2022 for newly diagnosed juvenile myelomonocytic leukemia (JMML) in pediatric patients aged one month and older. Administered via subcutaneous injection, intravenous infusion, or orally, it is typically given in cycles of 75 mg/m² daily for 7 days every 28 days, with treatment continued as long as clinical benefit is observed. Azacitidine's dual mechanism—epigenetic modulation through hypomethylation and direct via interference with synthesis—distinguishes it from conventional chemotherapies and has demonstrated benefits such as improved , reduced transfusion dependence, and hematologic improvement in higher-risk MDS patients compared to supportive care. While generally well-tolerated, common adverse effects include gastrointestinal disturbances, myelosuppression, and injection-site reactions, necessitating monitoring for and renal impairment. As a cornerstone in the management of myeloid neoplasms, azacitidine exemplifies targeted epigenetic therapy in .

Medical Uses

Approved Indications

Azacitidine, marketed as Vidaza for the injectable formulation, is approved by the U.S. (FDA) for the treatment of adult patients with the following French-American-British (FAB) subtypes of myelodysplastic syndromes (MDS): refractory (RA) or refractory with ringed sideroblasts (RARS) if accompanied by or , or requiring transfusions; refractory with excess blasts (RAEB); RAEB in transformation (RAEB-t); and (CMML). These indications correspond to intermediate-2 and high-risk MDS per the International Prognostic Scoring System (IPSS). The oral formulation of azacitidine, known as Onureg (CC-486), received FDA approval in July 2020 for maintenance therapy in adult patients with (AML) who achieved first complete remission following induction with or without consolidation. Azacitidine is also approved in combination with for the initial treatment of newly diagnosed AML in adults who are 75 years of age or older, or who have comorbidities that preclude the use of intensive induction ; this approval was granted in October 2020 based on data from the phase 3 VIALE-A trial demonstrating improved overall survival. In pediatric patients, azacitidine is indicated for the treatment of newly diagnosed juvenile myelomonocytic leukemia (JMML) in those aged 1 month and older; this approval, issued in May 2022, was supported by data from the AZA-JMML-001 trial showing a confirmed clinical response rate of 50% (95% CI: 26-74). Clinical benefits of azacitidine include delaying progression to AML in higher-risk MDS, improving overall survival in AML maintenance settings, and reducing red blood cell transfusion dependence. In the pivotal phase 3 AZA-001 trial, azacitidine significantly prolonged median overall survival to 24.5 months versus 15.0 months with conventional care regimens and delayed the time to AML transformation (hazard ratio 0.54). For oral azacitidine maintenance in AML, the phase 3 QUAZAR AML-001 trial reported a median overall survival of 24.7 months compared to 14.8 months with placebo, establishing its role in prolonging remission.

Dosage and Administration

Azacitidine is available in two primary formulations: Vidaza, a lyophilized powder for reconstitution as an injectable suspension administered subcutaneously or intravenously, and Onureg, oral tablets for . For the treatment of myelodysplastic syndromes (MDS) in adults, the standard dosing regimen is 75 mg/m²/day administered subcutaneously or intravenously for 7 days, repeated every 28 days. typically continues for a minimum of 4 to 6 cycles, with potential extension to 6 to 12 cycles or longer if clinical benefit is observed, and dose escalation to 100 mg/m²/day may be considered after two cycles if no response occurs. For initial treatment of newly diagnosed AML in adults 75 years or older or with comorbidities precluding intensive , azacitidine is administered at 75 mg/m²/day subcutaneously or intravenously on days 1 through 7 of each 28-day cycle in combination with (ramped up to 400 mg orally once daily starting on day 1 after azacitidine administration). Therapy continues until disease progression or unacceptable toxicity. For maintenance therapy in adult patients with acute myeloid leukemia (AML) who have achieved complete remission, the oral formulation is dosed at 300 mg once daily on days 1 through 14 of each 28-day cycle, continuing until disease progression or unacceptable toxicity. In newly diagnosed juvenile myelomonocytic leukemia (JMML) for patients aged 1 month and older, dosing is 75 mg/m²/day intravenously for those ≥1 year old and weighing ≥10 kg, or 2.5 mg/kg/day for those <1 year old or weighing <10 kg, administered daily on days 1 through 7 of a 28-day cycle for a minimum of 3 cycles and up to 6 cycles. Subcutaneous administration is often preferred over intravenous to reduce the incidence of and , with patients premedicated using prior to dosing for both routes; for , an is recommended 30 minutes before each dose during the first two cycles. The reconstituted injectable solution should be administered within 1 hour of preparation, via into the , , or upper arm, or as a short intravenous over 10 to 40 minutes. Oral tablets must be swallowed whole with or without food at the same time each day, without splitting, crushing, or chewing; missed doses are omitted, and after a dose requires skipping that day's intake. Dose adjustments are required for myelosuppression, renal or hepatic impairment, and other toxicities. For injectable azacitidine in MDS, reduce the dose by 50% if absolute neutrophil count (ANC) falls below 500/µL or platelets below 25,000/µL during nadir periods, and delay cycles if recovery is incomplete; hold therapy if ANC is below 500/µL at the start of a cycle. In AML maintenance with oral azacitidine, interrupt dosing for severe neutropenia (ANC <500/µL on day 1 or <1,000/µL with fever) or grade 3/4 gastrointestinal toxicity, resuming at 200 mg/day upon recovery, with further reductions in cycle duration (e.g., to 7 days) if toxicity recurs, and discontinuation if unresolved. For renal impairment, no initial adjustment is needed for mild to severe cases (creatinine clearance ≥15 mL/min), but monitor closely and reduce dose by 50% or delay if serum creatinine or blood urea nitrogen elevates significantly; hepatic impairment requires caution in moderate to severe cases, with no specific adjustment for mild impairment, and contraindication in advanced malignant hepatic tumors. In JMML, no dose reductions occur for hematologic toxicity in the first three cycles, but discontinue if neutrophil count is below 500/µL at the end of cycle 3 or on day 1 of cycles 5 or 6. For the venetoclax combination, dose modifications follow guidelines for each agent based on toxicities such as tumor lysis syndrome or myelosuppression. Monitoring includes weekly complete blood counts during the first two cycles of therapy, followed by assessments prior to each subsequent cycle, with more frequent checks after dose reductions; and serum creatinine should also be evaluated regularly to detect or renal issues early. For the combination, additional monitoring for is required, including hydration and anti-hyperuricemics. Special considerations include contraindications for to azacitidine or , and avoidance in patients with advanced renal or hepatic disease; azacitidine is classified as D due to potential fetal harm, requiring effective contraception during and for at least 6 months after treatment in females of reproductive potential and for 3 months in males. For the combination, additional contraindications and precautions from venetoclax apply.

Pharmacology

Mechanism of Action

Azacitidine is a pyrimidine nucleoside analog of cytidine, characterized by the replacement of the carbon atom at position 5 of the pyrimidine ring with a nitrogen atom. This structural modification allows it to mimic cytidine and be recognized by cellular enzymes involved in nucleic acid synthesis. Upon cellular uptake via nucleoside transporters, azacitidine is phosphorylated by uridine-cytidine kinase to its monophosphate form and subsequently to the diphosphate and triphosphate derivatives. Approximately 80-90% of the azacitidine triphosphate is incorporated into RNA, while 10-20% is converted by ribonucleotide reductase to 5-aza-2'-deoxycytidine triphosphate for incorporation into DNA. The cytotoxic effects of azacitidine primarily arise from its interference with nucleic acid metabolism in rapidly proliferating cells. Incorporation into RNA disrupts polyribosome assembly, inhibits RNA processing, and impairs protein synthesis, leading to cellular stress and reduced proliferation. When integrated into DNA, azacitidine causes chain termination during replication and induces DNA strand breaks, triggering apoptosis particularly in the G1 and S phases of the cell cycle. These actions are more pronounced in high-proliferating malignant cells, contributing to the drug's antineoplastic activity. In addition to , azacitidine exerts epigenetic modulation by targeting . Once incorporated into DNA, it forms covalent adducts with DNA methyltransferases (, DNMT3A, and DNMT3B), trapping and depleting these enzymes through proteasomal degradation. This depletion results in passive DNA hypomethylation during subsequent replication cycles, reversing the hypermethylation of promoter regions in tumor suppressor genes that are often silenced in cancer cells. Consequently, hypomethylation reactivates these genes, restoring normal and growth control. The therapeutic effects of azacitidine are dose-dependent, with low doses (typically 2-8 μmol/L) predominantly inducing hypomethylation and gene reactivation without overwhelming , while higher doses (e.g., 16 μmol/L) enhance direct cell killing through extensive disruption. This dual mechanism provides specificity for hematologic malignancies like myelodysplastic syndromes (MDS) and (AML), where aberrant hypermethylation in leukemic stem cells drives disease progression; azacitidine preferentially targets these epigenetically dysregulated cells while sparing slowly dividing normal hematopoietic cells.

Pharmacokinetics

Azacitidine exhibits route-dependent absorption characteristics. Following , it is rapidly absorbed with a peak plasma concentration of approximately 750 ng/mL occurring at 0.5 hours and a of about 89% relative to intravenous administration based on area under the curve (AUC). Intravenous administration provides immediate and complete . Oral azacitidine has a lower of approximately 11% compared to subcutaneous dosing, primarily due to extensive first-pass , though steady-state plasma levels achieved with adjusted dosing schedules are sufficient to support clinical efficacy. The drug is widely distributed in tissues following administration, with a mean volume of distribution of 76 L after intravenous dosing. Azacitidine is rapidly taken up by bone marrow and liver tissues, reflecting its targeted effects on hematopoietic cells and potential hepatic processing. Azacitidine crosses the blood-brain barrier, with studies showing achievement of cytotoxic concentrations in cerebrospinal fluid. Metabolism of azacitidine occurs primarily through spontaneous and rapid by cytidine deaminase to form 5-azauridine, with the majority of metabolites eliminated renally. There is no significant involvement of enzymes in its metabolism. Elimination of azacitidine is rapid, with a plasma half-life of about 4 hours for total radioactivity following , though the parent compound has a shorter of 41 minutes. Less than 1% is excreted unchanged in the urine, with the majority eliminated as metabolites primarily via urinary within 24 hours. Differences in administration routes influence pharmacokinetic profiles. Subcutaneous injection achieves similar overall exposure (AUC) to intravenous but with a slower time to peak concentration. necessitates higher and more frequent dosing to achieve equivalent AUC compared to parenteral routes due to lower . In special populations, azacitidine clearance is reduced in patients with severe renal impairment ( clearance <30 mL/min), resulting in approximately 70% higher exposure after a single dose and 41% higher after multiple doses, warranting monitoring for . For pediatric patients with juvenile myelomonocytic (JMML) receiving intravenous dosing at 75 mg/m² or 2.5 mg/kg, peak plasma concentrations average 4510 ng/mL, with an AUC of 1550 ng·h/mL and a of 0.3 hours. No major dose adjustments are required for hepatic impairment, as its effects on have not been shown to significantly alter exposure.

Adverse Effects

Common Adverse Effects

The common adverse effects of azacitidine, defined as those occurring in more than 30% of patients in clinical trials, primarily involve gastrointestinal, hematologic, and general symptoms, which are typically manageable with supportive measures and do not usually require discontinuation of . These effects are observed across subcutaneous and intravenous administration routes, with subcutaneous being the most common. Gastrointestinal disturbances are highly prevalent, affecting up to 81% of patients with all-grade events in the AZA-001 trial. occurs in 71% of patients, in 54%, in 36%, and in 34%. These symptoms often arise early in treatment cycles and can be mitigated with prophylactic antiemetics such as or laxatives like for constipation. Hematologic toxicities, often dose-limiting due to the drug's myelosuppressive action, include in 70% of patients, in 66%, and in 32%. is also common at 48%. Management typically involves monitoring complete blood counts, dose delays or reductions, and supportive interventions such as or platelet transfusions. General adverse effects encompass pyrexia in 52% of patients and injection site reactions, including and , in 35% to 70% depending on the study population. Real-world studies in elderly patients report similar or slightly elevated rates of these events compared to trial data.

Serious Adverse Effects

Azacitidine treatment is associated with myelosuppression, which can lead to severe infections due to grade 3-4 occurring in approximately 20-30% of patients, often resulting in or . This cytotoxic incorporation into precursors contributes to prolonged , exacerbating infection risk in patients with high tumor burden. , a potentially life-threatening complication, has also been reported in cases of high-burden disease, necessitating close monitoring of levels and renal function during initial cycles. Hepatotoxicity, including elevated and ALT levels, has been reported, with higher risk in those with preexisting , including advanced malignant hepatic tumors where azacitidine is contraindicated. , including renal failure, has been reported, particularly with intravenous administration; regular monitoring of creatinine clearance is essential to detect early tubular dysfunction. Pulmonary complications include rare interstitial pneumonitis (reported in <0.1% of patients), presenting as drug-induced lung injury that may be more frequent with the intravenous route compared to subcutaneous, and may progress to requiring . Other serious effects encompass rare cardiac events such as in less than 1% of cases, often linked to postmarketing reports. Azacitidine is teratogenic and causes embryo-fetal lethality, representing an absolute during ; females of reproductive potential and males must use effective contraception for specified periods post-treatment. Risk factors for serious adverse effects include advanced age in elderly patients, who experience heightened myelosuppression and rates, as well as combination therapies that amplify incidence of grade 3-4 events. A 2025 pharmacovigilance analysis reported high prevalence of serious adverse events, including cytopenias and s, in patients with MDS or AML. Management involves discontinuing azacitidine for grade 4 toxicities, administering corticosteroids such as or dexamethasone for to achieve resolution, and initiating for severe renal failure.

History

Discovery and Development

Azacitidine, a analog of , was first synthesized in 1964 by Alois Pískala and František Šorm at the Institute of Organic Chemistry and Biochemistry of the Czechoslovak Academy of Sciences in . Independently, it was isolated as an from the culture filtrates of the bacterium Streptoverticillium ladakanus in 1966, highlighting its natural occurrence and initial interest as a potential agent. In preclinical studies during the , azacitidine demonstrated antileukemic activity in animal models, notably inhibiting tumor growth in the L1210 mouse model through cytotoxic effects on rapidly dividing cells. However, early investigations revealed significant , including myelosuppression and gastrointestinal issues, which limited its therapeutic window despite promising in vitro and in vivo. Phase I and II clinical trials launched in the and continuing through the 1980s tested azacitidine primarily for solid tumors and acute leukemias, such as (AML), but results showed modest response rates overshadowed by dose-limiting toxicities. Development pivoted toward myelodysplastic syndromes (MDS) in the 1990s, driven by emerging insights into azacitidine's epigenetic effects, particularly its ability to inhibit DNA methyltransferases and induce hypomethylation at lower doses, which reduced toxicity while reactivating silenced genes. Key challenges included the drug's chemical in aqueous solutions, where it rapidly hydrolyzes to inactive forms, necessitating specialized lyophilized formulations and immediate reconstitution for administration. Initial applications for approval in non-MDS cancers, including AML and solid tumors, faced rejection due to insufficient evidence of survival benefits in pivotal trials. Commercial advancement accelerated when Pharmion Corporation acquired global marketing rights to azacitidine from Pharmacia in July 2001, enabling focused efforts on its reformulation and clinical validation for MDS, culminating in the 2004 launch of Vidaza as the branded injectable product.

Regulatory Approvals

Azacitidine received its initial approval from the U.S. Food and Drug Administration (FDA) on May 19, 2004, as Vidaza for injectable suspension, indicated for the treatment of patients with the following French-American-British (FAB) subtypes of myelodysplastic syndromes (MDS): refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS) (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). This approval was granted under the accelerated approval pathway based on hematologic response rates from controlled trials (CALGB 9221, 8421, and 8921). The subsequent phase 3 AZA-001 trial confirmed a survival benefit, with median overall survival of 24.5 months with azacitidine versus 15.0 months with conventional care regimens in higher-risk MDS patients, supporting conversion to full approval. The European Medicines Agency (EMA) granted marketing authorization for Vidaza on December 17, 2008, for the treatment of intermediate-2 and high-risk MDS, as well as acute myeloid leukemia (AML) with 20-30% blasts. In other regions, azacitidine was approved in on January 21, 2011, by the Ministry of Health, Labour and Welfare for the treatment of MDS, following a licensing agreement established in 2006. approved azacitidine in 2018 for intermediate-2/high-risk MDS and AML with excess blasts. By 2020, versions, such as azacitidine betapharm, received EMA approval on March 24, 2020, expanding access in the . Subsequent expansions included the FDA approval of oral azacitidine (Onureg) on September 1, 2020, for in adult patients with AML in first complete remission following induction . This was based on the phase 3 QUAZAR AML-001 , which showed a of 0.69 for overall survival with oral azacitidine versus (median 24.7 months vs. 14.8 months). In October 2020, the FDA granted full approval for the combination of azacitidine with for newly diagnosed AML in patients aged 75 years or older, or those ineligible for intensive induction due to comorbidities. The EMA followed with approval for Onureg as frontline oral in AML on June 18, 2021. Further indications included FDA approval on May 20, 2022, for azacitidine in pediatric patients aged 1 month and older with newly diagnosed juvenile myelomonocytic leukemia (JMML), based on response rates from a single-arm trial. In 2023, the label for oral azacitidine (Onureg) was updated to include strengthened warnings for interstitial pneumonitis based on post-marketing reports. Ongoing post-marketing surveillance continues to monitor safety and efficacy across approved indications. The drug's development advanced following Celgene's acquisition of Pharmion Corporation in 2008, which facilitated global commercialization. In November 2019, Bristol Myers Squibb completed its acquisition of Celgene Corporation, further supporting the global development and marketing of azacitidine formulations.

Research

Combination Therapies

Azacitidine, a hypomethylating agent central to the treatment of myelodysplastic syndromes (MDS) and (AML), is frequently combined with targeted therapies to enhance efficacy through synergistic mechanisms. These combinations leverage azacitidine's DNA hypomethylation to reactivate silenced genes and promote differentiation, while pairing it with agents that induce or inhibit specific oncogenic pathways, leading to improved response rates and survival in unfit or high-risk patients. One established regimen is azacitidine combined with , a inhibitor, for frontline treatment of AML in patients ineligible for intensive . In the phase 3 VIALE-A trial, this combination achieved a composite complete remission (CR) rate of 66.4% compared to 28.3% with azacitidine alone, with median overall survival of 14.7 months versus 9.6 months. The U.S. (FDA) approved this regimen in October 2020 based on these results. Combinations with IDH1 inhibitors have also shown promise in IDH1-mutated AML and MDS. The phase 3 AGILE trial demonstrated that plus azacitidine improved median overall survival to 24.0 months versus 7.9 months with plus azacitidine in newly diagnosed IDH1-mutant AML, with a complete remission rate of 47.2%. The FDA approved this combination in May 2022 for adults aged 75 years or older, or those with comorbidities precluding intensive therapy. For mutant IDH1 MDS, phase 2 data on olutasidenib plus azacitidine reported an overall response rate of 59%, including 27% complete remissions, in higher-risk patients, highlighting durable remissions in this subgroup. Emerging triplet regimens incorporate menin inhibitors for genetically defined AML subsets. In NPM1-mutant AML unfit for intensive therapy, bleximenib combined with and azacitidine yielded composite CR rates of 93% in phase 1b data presented at the European Hematology Association 2025 congress, demonstrating deep responses in relapsed/ and newly diagnosed patients. Long-term follow-up from the phase 3 , updated in June 2025, evaluated plus azacitidine versus azacitidine monotherapy in higher-risk MDS. While the primary endpoint of overall survival was not met ( 0.91), the combination showed superiority in ( 0.55) and higher modified overall response rates, supporting its role in achieving deeper, more durable responses. The rationale for these combinations stems from azacitidine's hypomethylating effects, which sensitize leukemic cells to targeted induction by or pathway-specific inhibitors like IDH and menin blockers, resulting in enhanced tumor and reduced clonal evolution. Safety profiles generally include increased myelosuppression, such as and , compared to monotherapy; however, these are manageable through dose ramp-up (e.g., 100 mg day 1, 200 mg day 2, 400 mg day 3 onward) and supportive care, with early 30-day mortality rates around 9% in trials.

Investigational Applications

Azacitidine's epigenetic mechanism, which involves to reactivate silenced genes, underpins its exploration in non-hematologic malignancies and other conditions. In solid tumors, phase I/II trials have investigated azacitidine combined with PD-1 inhibitors such as to enhance immunogenicity in advanced cases, including and cancers. For instance, the ECHO-206 study (NCT02959437) evaluated azacitidine sequenced with epacadostat and in patients with advanced solid tumors, reporting an overall response rate of 5.7% and stable disease in 18.6%, with partial responses observed in subsets like urothelial and , though specific data were not stratified. In , pilot studies have explored azacitidine with other agents like all-trans to delay progression, demonstrating feasibility but limited efficacy as a monotherapy alternative in hormone-refractory settings. For central nervous system malignancies, intrathecal administration of azacitidine combined with nivolumab is under evaluation in phase 1 trials targeting leptomeningeal disease associated with recurrent high-grade gliomas. The ongoing NCT06896110 trial, a single-arm dose-escalation study, assesses safety and maximum tolerated dose, with enrollment continuing as of 2025 and preliminary data indicating feasibility for concurrent intrathecal delivery without dose-limiting toxicities reported to date. In autoimmune diseases, low-dose azacitidine has shown promise in phase II trials for steroid-refractory systemic inflammatory disorders. A prospective phase II study in patients with steroid-dependent autoimmune conditions demonstrated clinical responses via epigenetic modulation. Beyond these, azacitidine is being probed as a monotherapy alternative in (CMML) and higher-risk myelodysplastic syndromes (MDS), where real-world studies report response rates of 16-22% in treatment-naïve higher-risk cases, with retrospective data supporting its use in lower-risk subsets to delay progression without intensive . Additionally, preclinical and early-phase investigations explore azacitidine for epigenetic priming to enhance CAR-T in lymphomas, showing improved antitumor activity in leukemia models by upregulating target antigens prior to infusion. Challenges in expanding azacitidine's applications include its chemical in novel administration routes, such as oral or intrathecal, leading to rapid degradation and low (around 17% orally). As of 2025, nanoparticle formulations, including lipid-based and nanoparticles loaded with azacitidine, have demonstrated improved stability, controlled release, and enhanced oral in preclinical models, with up to 90% drug release over 8 hours and reduced . Future directions emphasize trials targeting hypermethylated tumors across histologies, building on phase I/II data from epigenetic modifier studies in solid tumors to identify responsive subsets via multi-omics stratification.

References

  1. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/azacitidine
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