Researchers at Moffitt Cancer Center have completed a phase II clinical trial to determine the safety and efficacy of dasatinib for patients with higher-risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia, or acute myeloid leukemia resulting from MDS and have failed treatment with azanucleosides.
The therapy may not be effective for all patients, but those with trisomy 8 chromosomal disorder have higher rates of stable disease and respond better to treatment with dasatinib, the study shows.
Myelodysplastic syndromes are disorders of the stem cell in bone marrow. The marrow does not produce enough normal blood cells for the body. As the number of quality blood-forming cells declines, blood production is impaired.
According to the researchers, stem cell transplantation is the only potentially curative option for MDS but also has risks of morbidity and mortality. A class of medication called azanucleosides is the only approved medication for patients with an advanced stage of this disease. The outcome after failure of azanucleosides is poor. Therefore, new therapies for MDS are needed, said the study authors.
Dasatinib, a multikinase inhibitor, has been approved by the Food and Drug Administration for patients with chronic myelogenous leukemia. The drug has promising potential because of its activity against a broad spectrum of tyrosine kinases, including those in the Src family. Src pathways have been found to play a role in the increased activation of cell migration, proliferation, survival, invasion and angiogenesis (tumor blood vessel growth).
“Given the evidence for the role of Src kinases in myeoblast proliferation and the laboratory tested inhibitory activity of dasatinib on Src, especially on the Lyn kinase, we conducted a phase II study to assess the overall response to 100 mg per day dasatinib in patients with higher risk MDS who had failed previous treatments,” said study corresponding author Rami S. Komrokji, M.D., clinical director of Hematologic Malignancies and member of the Chemical Biology and Molecular Medicine Program at Moffitt.
The researchers found that although dasatinib was relatively “well-tolerated” with limited toxicities, it had only “modest activity.”
“Among 18 patients treated, three patients responded, four had stable disease, and 10 experienced disease progression,” wrote the researchers.
They noted that four of the five participants with trisomy 8, a disorder caused by having three copies of chromosome 8, had stable disease.
“Of particular interest is that the Lyn kinase gene is encoded on the long arm of chromosome 8,” explained Komrokji. “The gene duplication may augment kinase response capacity and proliferation. What looks like preferential activity of dasatinib in patients with trisomy 8 could be due to the suppression of Lyn, a kinase that appears to aid in proliferation of the disease.”
The researchers concluded that the trisomy 8 observation warrants further investigation.