Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS:Results from the nordic NMDSG08A phase II trial

This prospective phase II study evaluated the efficacy of azacitidine (Aza) + erythropoietin (Epo) in transfusion-dependent patients with lower-risk myelodysplastic syndrome (MDS). Patients ineligible for or refractory to full-dose Epo + granulocyte colony stimulation factors for 48 weeks and a transfusion need of ≥ 4 units over 8 weeks were included. Aza 75mgm -2 d-1, 5/28 days, was given for six cycles; non-responding patients received another three cycles combined with Epo 60 000 units per week. Primary end point was transfusion independence (TI). All patients underwent targeted mutational screen for 42 candidate genes. Thirty enrolled patients received ≥ one cycle of Aza. Ten patients discontinued the study early, 7 due to adverse events including 2 deaths. Thirty-eight serious adverse events were reported, the most common being infection. Five patients achieved TI after six cycles and one after Aza + Epo, giving a total response rate of 20%. Mutational screening revealed a high frequency of recurrent mutations. Although no single mutation predicted for response, SF3A1 (n = 3) and DNMT3A (n = 4) were only observed in nonresponders. We conclude that Aza can induce TI in severely anemic MDS patients, but efficacy is limited, toxicity substantial and most responses of short duration. This treatment cannot be generally recommended in lower-risk MDS. Mutational screening revealed a high frequency of mutations

5-Azacytidine/5-Azacitidine

The hypomethylating agent 5-Azacytidine epigenetically modulates various genes, including tumor suppressor genes. For many years, the "new agent", which was first discovered in the 1960s, remained fairly unobtrusive in the rank of salvage treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). When the significance of epigenetics in tumorigenesis became clear, 5-Azacytidine attracted new attention. Finally, it was the first drug approved for the treatment of all categories of MDS, and its survival benefit over best conventional care was confirmed. Today, in many clinical situations, when aggressive therapies including allogeneic hematopoietic cell transplantation are not an option, 5-Azacytidine is the first treatment of choice. Preliminary data on combinations of the hypomethylating agent with other new drugs are promising, and innovative strategies involving immune modulation and regenerative tissue repair hold a broad potential for future developments