Bruno C. Medeiros, MD
After nearly 40 years with little in the way of drug development for the treatment of acute myeloid leukemia (AML), four new drugs have been approved by the US Food and Drug Administration (FDA) in 2017 for AML, and several promising agents are in development.
Bruno C. Medeiros, MD, a director at the Stanford Comprehensive Cancer Center, in California, discussed the modern landscape of the treatment of AML at the NCCN 12th Annual Congress: Hematologic Malignancies in San Francisco.1
Midostaurin (Rydapt) is a multi-tyrosine kinase inhibitor active against FLT3-ITD and FLT3-TKD that was approved by the FDA in April 2017 for the treatment of FLT3
-mutated AML. When added to conventional induction chemotherapy in younger patients with untreated AML, midostaurin improved the overall rate of complete response (CR) from 66% to 74%, extended median overall survival (OS) from 25.6 months to 74.7 months, and improved 5-year survival from 43% to 51% without additional toxicity.2
Medeiros discussed other FLT3 inhibitors that are under investigation.
One is crenolanib, a highly selective FLT3 inhibitor under development that inhibits both FLT3
-ITD and FLT3
-TKD mutations in the active conformation. “It is a specific inhibitor and therefore has little activity against cKIT, which should minimize some of the myelosuppression associated with other FLT3 inhibitors that are also KIT inhibitors, and it is thought for this reason to be an optimal partner for combination therapies with induction therapy,” said Medeiros. When crenolanib was added to standard 7 + 3 induction therapy, CR was achieved in 88% of patients with no unexpected toxicities.3
Other FLT3 inhibitors in development that target relapsed/refractory AML are quizartinib and gilteritinib, both of which have demonstrated encouraging response rates and are currently being assessed in randomized phase 3 studies. Mutations in IDH1 and IDH2 are seen in 6% to 18% of patients with AML. The presence of these mutations leads to formation of oncometabolites to hydroxyglutarate, leading to an absence of differentiation of hematopoietic progenitors. The FDA approved enasidenib (Idhifa) in August 2017 and is expected to approve AG-120 (ivosidenib) in the second quarter of 2018. In parallel studies, the overall response rates were similar with these agents, nearing 40%, and the CR rate approached 20%.4
“It is interesting to note that, to date, we are not able to predict which patients are likely to respond to these agents,” said Medeiros.
He shifted to a discussion of new delivery methods of existing therapies. CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin designed to maintain a 5:1 molar ratio. These features lead to favorable pharmacokinetic properties with increased leukemia blast exposure. “In phase I and phase II clinical trials, this agent was found to have particular activity in those patients that have a very chemoresistant phenotype, such as those patients that have secondary AML, therapy-related AML, or de novo AML with myelodysplastic-related cytogenetic abnormalities,” he said. Sixty-day mortality was lower with CPX-351 compared with standard 7 + 3 therapy, and the risk of death was reduced by 30%.5
The survival benefit was particularly impressive in patients undergoing allografts during post-remission therapy. This agent was approved in August 2017 for the treatment of high-risk AML patients.
Medeiros then moved to immunotherapeutic options, starting with the anti-CD33 antibody drug conjugate gemtuzumab ozogamacin (Mylotarg), which had been withdrawn from the market in 2010. Since then, a number of large clinical trials have demonstrated that the addition of the drug to standard induction chemotherapy led to a significant improvement in OS.6
The agent appears to improve OS in patients regardless of age and has a preferential effect in patients who have intermediate- or favorable-risk cytogenetics and in those with favorable molecular abnormalities.
Other investigational agents that can target CD33 include bispecific T-cell engager (BITE) and dual-affinity retargeting (DART), which combine the binding specificities and biologic functions of two antibodies into one molecule, bringing tumor cells into close proximity to the effectors. Clinical trials of BITES/DARTs designed to target CD33 or CD123 are ongoing.7