PARIS--Low-dose therapy with the differentiation-inducing agent azaciti-dine
is transforming the formerly bleak prognosis for preleukemic myelodys-plastic
syndrome (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 who
were beyond the stage of refractory anemia, but has also proved to be cost
effective in reducing hospitalizations and transfusion requirements.
"When we started treating myelodys-plasia, we found that there
was 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 his
Mount Sinai colleague Dr. Lewis Silverman proceeded to evolve new definitions
By their definitions, a complete remission means that both the bone
marrow and the hemogram are normal; a partial remission describes a decrease
of at least 50% in bone marrow blasts with no peripheral blasts.
Most important, they defined a trilineage response, which is necessary
for a partial remission, as a more than 50% restoration of the initial
deficit in erythrocytes, granulocytes, and platelets, coupled with complete
elimination of transfusion requirements.
Patients who were somewhat improved, they noted, experienced a 50% restoration
of only one or two peripheral lineages and a 50% decrease in transfusion
In two CALGB studies, seven-day courses of azacitidine, 75 mg/m²/day,
were administered by continuous intravenous infusion or by subcutaneous
injection to MDS patients who had refractory anemia with excess blasts,
in some cases in transition to acute leukemia. Treatment was repeated at
monthly 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 subcutaneous
therapy, the complete remission rate was likewise 12%; the partial remission
rate, 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 four
or five months, as the cells progressively appear to differentiate."
Dr. Holland contrasted the one-year survival rates of 55% achieved with
subcutaneous azacitidine and 65% with intravenous azacitidine with the
roughly 30% rates previously reported with supportive treatment or low-dose
At Mount Sinai, he said, nearly 70% of 40 patients with MDS who were
treated by Dr. Silverman with azacitidine and intensive support survived
at least a year. He pointed out that two- and three-year survival rates,
respectively, were only 10% and 0% with low-dose cytarabine, but reached
20% and 10% with intravenous azacitidine, and 30% and 20% with subcutaneous
"I believe that, in fact, we have now added a drug to the armamentarium
for MDS treatment," Dr. Holland said. "Since the frequency of
MDS in the United States now approximates that of acute myelocytic leukemia,
we have hopes of persuading someone to make azacitidine available as a
Currently, the drug can be obtained only through the National Cancer
Institute, he said.
Dr. Silverman and his colleagues at Mount Sinai have studied azacitidine
in combination with a variety of other drugs and cytokines in vitro, and
will be mounting azacitidine-based combination therapy trials in the future.