Although the standard treatment for acute myeloid leukemia (AML) involves intensive induction chemotherapy, many diagnosed patients are ineligible because of advanced age and preexisting comorbidities. (1) Lower-intensity regimens, such as monotherapy with a hypomethylating agent (HMA) or low-dose cytarabine, were traditionally given to patients who were ineligible for chemotherapy; however, HMAs are associated with low rates of remission and short overall survival. (1) In an interview with CancerNetwork[R], Eytan M. Stein, MD, director of Drug Development in Leukemia at Memorial Sloan Kettering Cancer Center, New York, New York, discussed recent advances in standard of care for patients diagnosed with first-line chemotherapy-ineligible AML, data on combination therapy with venetoclax plus an HMA, predictive and prognostic factors of outcomes in AML, practical considerations for venetoclax and HMA therapy, and promising future therapeutic approaches.
According to Stein, the majority of patients with a diagnosis of AML who are ineligible for chemotherapy traditionally received supportive care alone, which led to an overall survival of approximately 3 to 6 months. Use of HMAs such as 5-azacitadine and decitabine increased starting in 2009, but the low rates of remission (approximately 20%) and long time to response (4-6 cycles) are major limitations, according to Stein.
"The longer a patient is not in remission, the longer they have to get an infection, which might cause severe morbidity or mortality," said Stein. "Or [they may] have a bleeding event from thrombocytopenia that could lead also to morbidity and mortality," said Stein.
Stein noted that small molecule inhibitors, such as venetoclax, are being used as monotherapy or in combination with HMAs in chemotherapy-ineligible patients with promising efficacy: "The use of venetoclax in combination with HMAs ... has really revolutionized how we treat newly diagnosed patients who are ineligible to receive intensive induction chemotherapy."
Single-agent therapies approved for relapsed or refractory AML, including gilteritinib (for patients with FLT3 mutations), ivosidenib (for patients with IDH1 mutations), and enasidenib (for patients with IDH2 mutations), have also changed treatment for relapsed and refractory AML harboring specific genetic mutations, according to Stein. Although Stein noted that currently available immunotherapeutic approaches, such as checkpoint inhibitors, chimeric antigen receptor T cell therapy, and bispecific T cell-engaging antibodies, have been largely unsuccessful for AML, he said that the anti-CD47 monoclonal antibody magrolimab combined with azacitidine has shown promise in clinical trials of AML. "This drug reactivates macrophages," said Stein. "It allows macrophages to recognize myeloid leukemia blasts and then phagocytose those myeloid leukemia blasts."
Stein added that another promising approach lies in the development of new, bispecific, T cell-engaging antibodies that transport the myeloid blasts close to T cells, which eradicate the blasts. Flotetuzumab, a bispecific, antibody-based molecule that targets CD3[member of] and CD123 in a dual-affinity retargeting antibody format, led to complete remissions (with full or partial hematologic recovery) in 18% of patients with AML who had primary induction failure or relapse within 6 months and received the recommended phase 2 dose. (2)
Stein also pointed out the importance of selecting clinically relevant and expedient end points...