After a prolonged period of stagnation where the progress in treating patients with acute myeloid leukemia (AML) was limited at best, we have seen significant advances in understanding the biology of the disease and the molecular processes underlying its pathogenesis. This improved understanding is already being translated to the discovery and development of new agents with promising activity some of which have already been approved by the FDA.
Although the initial description of the transmembrane receptor, FLT3, and its role in normal and malignant hematopoiesis dates back to several decades ago, inhibitors of the FLT3 kinase activity have been of interest for the past 15-20 years. However, the approval of midostaurin in combination with chemotherapy in the initial therapy of patients with FLT3 mutated AML has generated further interest in this class of agents. A number of more potent FLT3 inhibitors such as quizartinib, gilteritinib, and crenolanib are being investigated in randomized trials designed to determine their efficacy in patients with relapsed FLT3-mutated AML.
Other recurring molecular aberrations have been identified in AML and although, at present time, some are of more interest for their prognostic value, others have been targets for drug development. Mutations of the genes encoding for the intracellular isocitrate dehydrogenase (IDH) enzymes have been described in about 20 percent of patients with AML and inhibitors of IDH1 and IDH2, enasidenib and ivosidenib, have been evaluated in large phase I and II studies. Both oral drugs are relatively non-toxic and well-tolerated in general and produce about 40 percent overall response rate. Enasidenib has been approved by the FDA for the treatment of patients with relapsed IDH2-mutated AML and ivosidenib data have been submitted for approval. Potential benefits of combining these drugs with chemotherapy or with hypomethylating agents are being investigated in ongoing trials.
Venetoclax, a potent inhibitor of BCL2 protein, important in regulation of the cellular apoptotic mechanisms, was approved for patients with relapsed 17p deletion chronic lymphocytic leukemia. Initial studies in relapsed AML showed modest activity, but studies combining venetoclax with low-dose cytarabine or with hypomethylating agents, decitabine and azacytidine, have demonstrated impressive activity in untreated eldely patients with AML. These combinations have been well-tolerated and have produced response rates at least comparable to those achieved by cytarabine plus anthracycline-based induction regimens, with these responses being durable. Ongoing clinical trials will further establish the role of these regimens in the frontline therapy of elderly and unfit patients with AML, but it is likely that these regimens will have a significant role in this setting.
Other targeted strategies that may have potential promise are antibody-based agents. The re-approval of gemtuzumab ozogamicin for the frontline therapy of patients with AML in combination with chemotherapy has further generated interest in monoclonal antibody—toxin conjugates and a number of such agents are in development. Furthermore, with the success of immunotherapy in solid tumors and the efficacy of blinatumomab in acute lymphoblastic leukemia, several immune reactivating antibodies and bi-specific antibodies directed at myeloid specific antigens are undergoing evaluation in early phase clinical trials.
Overall, with the recent FDA approvals of several drugs in AML and with the availability of several drugs with promising initial activity, the outlook for patients with AML is improving significantly. Many challenges remain including ways to rapidly identify patients who will likely benefit from specific strategies, and novel designs of trials that would demonstrate quickly the potential efficacy and benefit of multiple drugs in development.
FARHAD RAVANDI, MD, is the Janiece and Stephen A. Lasher Professor of Medicine, and Chief, Section of Developmental Therapeutics, Department of Leukemia, at the University of Texas MD Anderson Cancer Center, Houston.