San Francisco, CA—After nearly 40 years of negligible drug development, in 2017 the FDA approved 4 drugs for acute myeloid leukemia (AML). These novel therapies have been shown to decrease relapse rates, improve response rates in patients with specific mutations, and reduce short- and long-term adverse reactions associated with current treatment strategies.
“2017 is the year of AML,” said Bruno C. Medeiros, MD, Director, Cancer Center ITA services, Stanford Comprehensive Cancer Center, CA, at the 2017 NCCN Hematologic Malignancies Congress. “For the first time in decades, we have a lot of exciting news to share. Now that we have all these drugs commercially available, however, the challenge is to figure out how to use these agents optimally,” he added.
Dr Medeiros offered a brief overview of approved drugs and other agents in development for patients with AML, with specific focus on targeted agents.
FLT3 Inhibitors
Midostaurin (Rydapt), a multityrosine kinase inhibitor that is active against FLT3-ITD and FLT3-TKD, was approved by the FDA in April 2017 for the treatment of patients with AML associated with FLT3 mutation. When added to conventional chemotherapy in younger patients with newly diagnosed AML, midostaurin increased complete response rates compared with conventional chemotherapy plus placebo (74% vs 66%, respectively; P = .01), without additional toxicity. The 5-year survival improved from 43% with chemotherapy plus placebo to 51% with midostaurin plus chemotherapy.
Crenolanib is an investigational FLT3 inhibitor that inhibits FLT3-ITD and FLT3-TKD mutations in the active conformation. In a small phase 2 clinical trial, crenolanib added to the standard “7+3” (idarubicin, daunorubicin 60 mg/m2, daunorubicin 90 mg/m2) induction regimen led to a complete response rate of nearly 90%, with no unexpected adverse reactions. Although the median follow-up at that point was only 6 months, an early analysis of the data showed “very promising” overall survival (OS), said Dr Medeiros.
Two additional FLT3 inhibitors—quizartinib and gilteritinib—are currently in development for the treatment of relapsed or refractory AML. Although the median OS remains relatively limited, the response rates have been encouraging, according to Dr Medeiros.
Randomized phase 3 clinical trials with quizartinib and with gilteritinib versus salvage chemotherapy are ongoing, with results expected in late 2018 or in early 2019.
New IDH Inhibitors
Overall, 6% to 12% of patients with AML have IDH1 mutations, and 8% to 18% have IDH2 mutations. Two agents that target these mutations have been developed in parallel, with similar clinical trial designs—enasidenib and ivosidenib. The response rates were nearly identical in the respective study for each of these 2 agents.
In August 2017, the FDA approved enasidenib (Idhifa) as the first agent for patients with AML associated with IDH2 mutation, based on the results of the clinical trial showing a 37% overall response rate. A similar response rate (38%) was seen with ivosidenib, which is expected to receive FDA approval for AML with IDH1 mutation in early 2018, based on these results.
Immunotherapy for AML
Initially approved for relapsed or refractory AML, gemtuzumab ozogamicin (Mylotarg), an anti-CD33 antibody drug conjugate, was withdrawn from the market in 2010 because of safety concerns. However, several large randomized clinical trials using a lower dose of the drug subsequently demonstrated that the addition of lower-dose gemtuzumab ozogamicin to standard induction chemotherapy is associated with significant improvement in OS.
In September 2017, the FDA approved low-dose gemtuzumab ozogamicin for the treatment of adults with newly diagnosed CD33-positive relapsed AML, and for CD33-positive AML in patients aged ≥2 years.
Several ongoing clinical trials are examining the effectiveness of BiTE (bispecific T-cell engager) and DART (dual-affinity retargeting) agents, which combine the binding specificities and biologic functions of 2 antibodies into 1 molecule, reported Dr Medeiros.
Although complicated by the lack of expression of nonrestricted AML-associated antigens, chimeric antigen receptor (CAR) T-cell therapies are also under investigation. Only very preliminary results are available, but “off-leukemia toxicity” has been an unwanted side effect of CAR T-cell therapy. In the future, investigators will look to increase the specificity of this technology, while decreasing off-target effects, possibly with dual targeting of CD33 and CD123, reported Dr Medeiros.
Novel Hypomethylating Agents
Two investigational hypomethylating agents—guadecitabine and oral azacitidine—are in development for AML. Phase 2 clinical trials with guadecitabine demonstrated an increase in overall response rate (57%) and complete response rate (37%).
Promising median survival data have been reported in patients who responded to these agents, and a randomized clinical trial that compares guadecitabine and azacitidine completed patient enrollment in late 2016.
In addition, oral azacitidine is being studied as maintenance therapy in 2 separate clinical trials, (1) for patients with AML who are not eligible for stem-cell transplant, and (2) for patients with myelodysplastic syndrome or AML after stem-cell transplant.
“This oral agent may enhance patient convenience, eliminate injection-site reactions, and allow for alternative dosing and scheduling,” said Dr Medeiros, adding that both studies are close to completing patient accrual.
“All of us in the community feel that this is just the beginning of great things to come for patients who suffer from this condition. Hopefully, novel agents will continue to improve outcomes,” concluded Dr Medeiros.