Differentiation Agent Improves Myelodysplasia Survival Rates

PARIS--Low-dose therapy with the differentiation-inducing agent azaciti-dineis transforming the formerly bleak prognosis for preleukemic myelodys-plasticsyndrome (MDS), reported James Holland, MD, of Mount Sinai Medical Center,NY, at the Seventh International Congress on Anti-Cancer Treatment.

Azacitidine has not only doubled survival rates in MDS patients whowere beyond the stage of refractory anemia, but has also proved to be costeffective in reducing hospitalizations and transfusion requirements.

"When we started treating myelodys-plasia, we found that therewas a total lack of agreement on how to structure the assessment of response,"Dr. Holland said. To bring some measure of order to the chaos, he and hisMount Sinai colleague Dr. Lewis Silverman proceeded to evolve new definitionsof response.

By their definitions, a complete remission means that both the bonemarrow and the hemogram are normal; a partial remission describes a decreaseof at least 50% in bone marrow blasts with no peripheral blasts.

Most important, they defined a trilineage response, which is necessaryfor a partial remission, as a more than 50% restoration of the initialdeficit in erythrocytes, granulocytes, and platelets, coupled with completeelimination of transfusion requirements.

Patients who were somewhat improved, they noted, experienced a 50% restorationof only one or two peripheral lineages and a 50% decrease in transfusionrequirements.

In two CALGB studies, seven-day courses of azacitidine, 75 mg/m²/day,were administered by continuous intravenous infusion or by subcutaneousinjection to MDS patients who had refractory anemia with excess blasts,in some cases in transition to acute leukemia. Treatment was repeated atmonthly intervals and continued in patients who responded after four courses.

The intravenous regimen yielded complete remissions in 12% of patients,partial remissions in 25%, and trilineage responses in 12%. With subcutaneoustherapy, the complete remission rate was likewise 12%; the partial remissionrate, 15%; and the trilineage response rate, 27%.

"In contrast to acute leukemia, this is a slow response,"Dr. Holland cautioned. "The median time to remission is about fouror five months, as the cells progressively appear to differentiate."

Dr. Holland contrasted the one-year survival rates of 55% achieved withsubcutaneous azacitidine and 65% with intravenous azacitidine with theroughly 30% rates previously reported with supportive treatment or low-dosecytarabine.

At Mount Sinai, he said, nearly 70% of 40 patients with MDS who weretreated by Dr. Silverman with azacitidine and intensive support survivedat least a year. He pointed out that two- and three-year survival rates,respectively, were only 10% and 0% with low-dose cytarabine, but reached20% and 10% with intravenous azacitidine, and 30% and 20% with subcutaneousazacitidine.

"I believe that, in fact, we have now added a drug to the armamentariumfor MDS treatment," Dr. Holland said. "Since the frequency ofMDS in the United States now approximates that of acute myelocytic leukemia,we have hopes of persuading someone to make azacitidine available as acommercial product."

Currently, the drug can be obtained only through the National CancerInstitute, he said.

Dr. Silverman and his colleagues at Mount Sinai have studied azacitidinein combination with a variety of other drugs and cytokines in vitro, andwill be mounting azacitidine-based combination therapy trials in the future.