A phase II trial,r compared azacitidine (AZA) with best supportive care in patients with intermediate-high risk and high risk myelodysplasia (MDS) and acute myeloid leukaemia (AML) with 20 to 30% blasts, as well as patients with refractory anaemia (RA) and refractory anaemia with ringed sideroblasts (RARS) with associated cytopenias. Patients were allowed to cross over. AZA was given for seven days every four weeks (75 mg/m2/day IV). This study showed AZA resulted in reduced transfusion, and improved quality of life. Most importantly AZA delayed both transformation to acute myeloid leukaemia (AML) and death. A further analysis of this trial and two other trials with AZA was performed and published.r All patients had been treated with AZA 75 mg/m2/day IV or SC for seven days, every four weeks. This indicated, in patients with MDS, 10% to 17% of patients had a complete response and 23% to 36% with haematological improvement. In patients with AML, 7% achieved CR or PR compared to 0% on the standard care arm. Time to any responses occurred after 3 cycles (range 1 to 17 cycles) although 90% of responders achieved a response by cycle 6.r
A phase III, international, multicentre, controlled, open-label trial, was conducted for patients with higher- risk myelodysplastic syndromes (AZA-001). These included patients “with higher-risk myelodysplastic syndromes (an international prognosis scoring system rating of intermediate-2 or high risk) and FAB-defined refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation, or chronic myelomonocytic leukaemia with at least 10% bone marrow blasts and a white-blood-cell count lower than 13×109 cells/L”.r They were to receive AZA (75 mg/m2 SC per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy). The primary endpoint was overall survival. Erythroid stimulating hormones were prohibited. Patients were treated with a median of 9 cycles. This study confirmed that “treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care".r Most experts concur that ongoing therapy is appropriate for patients who are experiencing hematologic responses. The survival benefit appears to extend beyond patients who achieve complete and partial responses”.r
The landmark trial (Fenaux 2009)r showed that after a median follow-up of 21 months, median overall survival was significantly improved in the AZA arm compared to the conventional care group; 24 months versus 15 months. At 2 years, on the basis of Kaplan-Meier estimates, 51% of patients in the AZA group were alive compared with 26% on conventional care. Improved survival was seen in all subgroups including cytogenetic subgroups. AZA also lowers the risk of progression to acute myeloid leukaemia in patients with higher-risk myelodysplastic syndrome compared with treatment with conventional care regimens. However, the difference in survival between the azacitidine and intensive chemotherapy groups was not significant, “possibly because of the small number of patients in this analysis.”r
© Lancet 2009
Myelosuppression is the main toxicity observed. Significant worsening of neutropenia occurred in 58% and significant worsening of thrombocytopenia in 52%. Nausea and vomiting occurred in 4%, and treatment related infection occurred in 20%.r Myelotoxicity is worst in the first two cycles. Nadir was seen in the second and third weeks after treatment. Adverse events were almost twice as common in the best supportive care arm compared to the AZA arm. Treatment with AZA did not increase the rate of infection or bleeding.r The most common treatment-related non-haematological adverse events with AZA included injection site reactions, nausea, vomiting, fatigue, and diarrhoea.r AZA has renal excretion. Dose adjustment for moderate renal impairment is recommended but data is not available to guide adjustment. AZA is contraindicated in severe renal impairment (Creatinine clearance <30 mL/min).