Hypomethylating agents (HMAs) are cytidine nucleoside analogues—azacitidine (5-azacytidine) and decitabine (5-aza-2′-deoxycytidine)—that act as DNA methyltransferase (DNMT) inhibitors and form the backbone of therapy for myelodysplastic syndromes (MDS) and older/unfit patients with acute myeloid leukemia (AML).
They are also active in chronic myelomonocytic leukemia (CMML) and, in combination with venetoclax, are now standard for newly diagnosed AML in patients ineligible for intensive chemotherapy.
After cellular uptake via nucleoside transporters, both drugs undergo sequential phosphorylation to active triphosphate metabolites and are incorporated into nucleic acids during S-phase.
Decitabine is incorporated exclusively into DNA, whereas ~80–90% of azacitidine is incorporated into RNA (with only 10–20% entering DNA), giving azacitidine additional RNA-dependent effects.
Once in DNA, the 5-aza modification traps and covalently binds DNMT1 (and DNMT3A/3B), preventing β-elimination and leading to enzyme degradation and progressive, replication-dependent global DNA hypomethylation.
Downstream effects include re-expression of aberrantly silenced tumor suppressor genes, activation of endogenous retroviral elements producing a viral mimicry/interferon response, DNA damage, differentiation, and apoptosis.
At higher doses they also act as classical cytotoxic agents; the lower “epigenetic” doses used clinically maximize demethylation with better tolerability.
Azacitidine: 75 mg/m²/day SC or IV for 7 days every 28 days.
Decitabine (IV): 20 mg/m²/day for 5 days every 28 days (an alternative 3-day regimen exists).
Oral decitabine/cedazuridine (DEC-C): 35 mg/100 mg daily for 5 days every 28 days; cedazuridine is a cytidine deaminase inhibitor that allows oral bioavailability, and DEC-C is an accepted substitute for IV decitabine in IPSS Intermediate-1 and higher disease.
An oral azacitidine formulation (Onureg) is approved for maintenance therapy in AML.
Efficacy in MDS
In higher-risk MDS, the pivotal AZA-001 trial showed median overall survival of 24.5 vs 15 months for azacitidine versus conventional care, with delayed AML transformation and reduced transfusion dependence; the benefit held across age, blast percentage, and karyotype.
Decitabine improves response rates and progression-free survival but has not demonstrated an overall survival benefit over best supportive care in randomized trials (e.g., ~10.1 vs 8.5 months, not significant).
Azacitidine is often preferred as front-line therapy in higher-risk MDS, though response rates for the two agents are similar.
Responses are typically delayed with median 2–3 months, patients should receive at least 4–6 cycles before being deemed refractory unless clearly progressing, and responders continue treatment until progression or toxicity.
In lower-risk MDS, low-dose HMA regimens are an option for symptomatic cytopenias; a randomized comparison found higher response rates with low-dose decitabine but no significant difference in event-free or overall survival versus low-dose azacitidine.
Compared with conventional care, HMAs improve response rates in AML but did not consistently improve OS in early trials; in older patients, median OS was longer with HMAs (14.4 months) than high-intensity therapy (10.8 months), establishing them as standard for this population.
HMA + venetoclax has transformed care of newly diagnosed AML unfit for intensive chemotherapy, achieving hematologic remission in roughly two-thirds of patients.
HMAs are not curative—they do not eradicate the founder clone—and complete responses to monotherapy are limited and often non-durable.
Principal toxicity is myelosuppression (neutropenia, thrombocytopenia, anemia) with associated infection/bleeding risk; comparative data suggest decitabine causes more grade 3/4 anemia, febrile neutropenia, and leukopenia than azacitidine.
Biallelic TP53-mutated disease portends a poor outcome even with HMA therapy, though HMAs are still often preferred over intensive chemotherapy in TP53-mutant MDS/AML.
The NCCN Myelodysplastic Syndromes guideline positions HMAs as preferred therapy for higher-risk, transplant-ineligible disease.
Place on site