Читать книгу Pathy's Principles and Practice of Geriatric Medicine - Группа авторов - Страница 634

Azacitidine (5‐azacytidine, 5‐aza, Vidaza) is a pyrimidine nucleoside analogue of cytidine whose mechanism of action is thought to be DNA hypomethylation in addition to a direct cytotoxic effect on the haematopoietic elements of the bone marrow. Another hypomethylating agent, decitabine (5‐aza−2–deocytidine), has also demonstrated promise as an agent for MDS. Chemically it is closely related to azacitidine. Both compounds are approved for use in MDS in the US; only azacytidine has been approved by EMA.

Two phase 3 clinical trials comparing azacitidine with best supportive care demonstrated this drug's clinical efficacy in treating MDS.^97,98 Azacitidine treatment (75 mg/m² per day for seven days, then once a week by subcutaneous injection) was continued in the absence of progression or unacceptable toxicity, and the median number of cycles administered was nine. Complete and partial remission rates for the azacitidine arm were superior to conventional care, at 29 versus 21%, respectively. With a median follow‐up of 21.1 months, the median overall survival was 24.5 months for the azacitidine arm compared with 15 months for the conventional care arm (p = 0.0001).

A phase 3 randomized trial of decitabine versus best supportive care in high‐risk MDS showed similar results, although a survival benefit was not demonstrated, probably due to a higher‐risk study population.⁹⁹ Even though no prospective comparative analysis has been carried out between the two drugs, a retrospective analysis suggests equivalent efficacy between azacitidine and decitabine.¹⁰⁰

Hypomethylating agents offer limited response: complete response/partial response/hematologic improvement is achieved in 40–50% of high‐risk patients. This benefit could be even smaller in real‐world experience. In general, response is slow, so both agents should be given for four to six cycles before the treatment is considered a failure. Generally, these treatments are well tolerated, with the most relevant side effects being worsening of cytopenias (which usually improve during treatment), nausea, and fatigue. Patients who respond are recommended to continue therapy indefinitely until progression, as response is quickly lost after treatment discontinuation, and outcome after stopping the drug is dismal.¹⁰¹

It has been suggested the hypomethylating agents offer a benefit in quality of life, as they improve fatigue, dyspnoea, physical function, and psychological well‐being. However, these data have not been replicated by other studies. It should also be considered that patients require intensive monitoring and frequent attendance to an outpatient clinic.