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ATLANTA -- Oral azacitidine (Vidaza) given for up to 21 days per 4-week cycle for myelodysplastic syndrome (MDS) appeared safe and effective in patients with lower-risk disease, a researcher said here.

Some 40% of patients receiving the drug orally at 300 mg/day for 14 or 21 days per 4-week cycle achieved hematologic responses, and about one-quarter needed no transfusions for at least 12 weeks, said Guillermo Garcia-Manero, MD, of the MD Anderson Cancer Center in Houston.

Some 15% of patients discontinued treatment because of adverse events such as grade 3-4 diarrhea, vomiting, and hematologic toxicities, he reported at the American Society of Hematology's annual meeting.

Overall, Garcia-Manero said, the regimens were "active and well-tolerated."

Currently, azacitidine is approved as an injectable drug for MDS, administered for 7 days per 4-week treatment cycle.

Its manufacturer, Celgene, is now developing an oral formulation of the drug that it believes will be more acceptable to patients, and possibly more effective.

Not only would an oral drug be more convenient, but it would eliminate injection-site reactions. The company also thinks that it can be given in longer schedules than possible with the injectable version, increasing its therapeutic effects.

Garcia-Manero said an initial study had demonstrated that the oral formulation was effective and well tolerated in patients with MDS and certain leukemia types when given for 7 days per 4-week cycle.

The current study sought to determine if it remained safe and effective in MDS patients when given for longer periods in each cycle.

It enrolled 53 patients with MDS considered low-risk according to standard prognostic indicators. Inclusion criteria included a requirement for dependence on red cell and platelet transfusions or significant deficits in hemoglobin (9 g/L or less) and platelet counts (50,000/mL or less).

The drug was given at a fixed dose of 300 mg daily. Patients were assigned 1:1 to take it for 14 or 21 days per cycle. Treatment continued until patients no longer wanted it, had intolerable side effects, died, or did not respond.

Median patient age was 73 (range 70 to 77) in the 14-day arm and 70 (range 60 to 76) in the 21-day arm. More than half of both groups were dependent on red cell transfusions at baseline, but only four patients overall were regularly receiving platelet transfusions.

Median platelet counts were about 57,000/mL and median hemoglobin was 8.7 g/L. About two-thirds were classified under the IPSS prognostic system with "intermediate-1" risk, the rest with low risk.

Up to 17 treatment cycles were delivered, with medians of seven in the 14-day arm and five in the 21-day arm.

Two-thirds of both groups discontinued azacitidine, for the following reasons:

• Treatment failure: 14-day arm, 27%; 21-day arm, 19%
• Adverse event: 14-day arm, 15%; 21-day arm, 15%
• Proceeded to stem cell transplant: 14-day arm, 4%; 21-day arm, 15%
• Withdrew consent: 14-day arm, 8%; 21-day arm, 11%
• Death: 14-day arm, 4%; 21-day arm, 0%
• Other: 14-day arm, 12%; 21-day arm, 0%

Almost all patients reported gastrointestinal problems such as diarrhea, nausea, and vomiting, and about half had infections.

Grade 3-4 events were reported in two-thirds of both arms. These included diarrhea, vomiting, pneumonia, and cellulitis on the nonhematologic side. Neutropenia (with or without fever), thrombocytopenia, and anemia remained significant in from 4% to 19% of each study arm.

But Garcia-Manero indicated that substantial numbers of patients responded well to oral azacitidine, without much difference in efficacy between the two dosing schedules.

A composite of complete remission, partial remission, any hematologic improvement, and transfusion independence was achieved by 42% and 37% of the 14- and 21-day arms, respectively.

Improvement in erythrocyte, platelet, and neutropenia counts were seen in 17% to 30% of the 14-day arm and in 20% to 30% of the 21-day arm.

Red cell transfusion independence sustained for 8 weeks was seen in 54% and 40% of the 14- and 21-day arms, respectively. Independence sustained for 12 weeks occurred in 20% and 33% of the two arms, respectively.

There also appeared to be a positive relationship between clinical response and a decrease in genomic methylation with treatment, Garcia-Manero said. Aberrant DNA methylation has been noted in connection with MDS and may contribute to the condition's pathogenesis.

Clinical nonresponders showed a mean reduction in highly methylated loci of ab0ut 2.7 percentage points during therapy, compared with 5 percentage points in the responders (P=0.011).

A phase III trial of the extended dosing schedules is now under way, Garcia-Manero said.

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