Expert Gives an Overview of New Drugs to Treat AML

For the past four decades, there have been few advances in the treatment field of acute myeloid leukemia (AML). However, in the year 2017, there have been four new drugs approved by the FDA to treat the disease, with even more promising agents in the pipeline.

Bruno C. Medeiros, M.D., 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.

Rydapt (midostaurin) is a multi-tyrosine kinase inhibitor active against FLT3-ITD and FLT3-TKD genes 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, Rydapt improved the overall rate of complete response (CR) from 66 percent to 74 percent, extended median overall survival (OS) from 25.6 months to 74.7 months, and improved five-year survival from 43 percent to 51 percent without additional toxicity.

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 percent of patients with no unexpected toxicities.

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 percent to 18 percent 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 Idhifa (enasidenib) 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 percent, and the CR rate approached 20 percent. “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. Vyxeos (CPX-351) 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 1 and phase 2 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 percent. 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 Mylotarg (gemtuzumab ozogamacin), 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. 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.

Novel hypomethylating agents in development include guadecitabine and oral Vidaza (azacytidine), which is already approved to treat myelodysplastic syndrome. Guadecitabine is a dinucleotide of decitabine and deoxyguanosine that protects decitabine from degradation within the intracellular compartment. Phase 2 studies with guadecitabine demonstrated increases in response rates compared with historical data and promising median OS in responders. A randomized study comparing guadecitabine to Vidaza in patients with previously untreated AML who could not tolerate induction chemotherapy completed accrual in late 2016. Oral Vidaza is currently being tested as maintenance therapy for patients with AML who are not eligible for stem cell transplant and as maintenance therapy for patients with advanced myeloid malignancies in the post-transplant setting.

The bcl-2 inhibitor Venclexta (venetoclax) has limited single-agent activity in AML, but response rates were much improved when combined with hypomethylating agents in patients not fit for induction chemotherapy; 75 percent of patients achieved a CR or CR with incomplete marrow recovery (Cri) with a median time to CR/Cri of 29.5 days.

E-selectin is an adhesion molecule expressed in AML cells. GMI-1271 is a novel E-selectin antagonist that enhances responses to chemotherapy. In a phase 2 study in AML patients older than 60 years, GMI-1271 in combination with cytarabine plus mitoxantrone and etoposide led to a CR/CRi rate of 75 percent in those with de novo AML and 67 percent in those with secondary AML. “This agent is undergoing further development in a broader patient population,” Medeiros said.

Chimeric antigen receptor (CAR) T cell therapy is complicated by the lack of expression of nonrestricted AML-associated antigens, leading to unwanted on-target, off-leukemia toxicity. Dual targeting approaches (CD33 and CD123) may result in reduced off-leukemia toxicity, he said.