Guillermo Garcia-Manero, MD
Patients with relapsed/refractory acute myeloid leukemia (AML) have limited options for treatment, especially if they are not candidates for hematopoietic cell transplant or do not have targetable genetic mutations. Individuals with myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) face a similar challenge. Their treatment often includes hypomethylating agents, but many patients relapse after receiving this therapy.
Two randomized phase III clinical trials, ASTRAL-2 (NCT02920008) and ASTRAL-3 (NCT02907359), are designed to determine whether guadecitabine (SGI-110), a potent second-generation hypomethylating agent, could answer the unmet medical needs for these patient populations. Most patients with MDS or CMML do not respond to highdose chemotherapy, which is the first line of therapy, said Guillermo Garcia-Manero, MD, deputy chair of translational research in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. “Genetic screening for these patients has helped to find actionable mutations for targeted therapies, but there are a large number of patients who don’t have targetable mutations, and in that context, that’s where [guadecitabine] will be important.”
In ASTRAL-2, outcomes with guadecitabine are being compared with physician’s choice of therapy (Figure 1
): cytarabine in various doses and combinations; low-dose cytarabine or a hypomethylating agent different from guadecitabine; or best supportive care. Patients who are eligible must have AML previously treated with initial induction therapy using a standard intensive chemotherapy regimen, including cytarabine and an anthracycline, and must be refractory to initial induction (primary refractory) or in relapse after initial induction.
In ASTRAL-3, guadecitabine also is being compared with physician’s choice of therapy, but is using different regimens than ASTRAL-2, including a chemotherapy option and no hypomethylating agents other than the study drug (Figure 2
). The therapies are more appropriate for patients with MDS and CMML: low-dose cytarabine, standard intensive chemotherapy of a 7+3 regimen, or best supportive care. ASTRAL-3 is enrolling patients with MDS or CMML who were previously treated with at least 1 hypomethylating agent. The primary endpoint for both trials is overall survival (OS).