Best Practices in Hematologic Malignancies – December 2017 Vol 8

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Leukemia and Lymphoma

Targeted Therapy for Acute Myeloid Leukemia

After nearly 40 years of negligible drug development, 2017 saw the approval of 4 drugs by the FDA for the treatment of acute myeloid leukemia (AML). These novel regimens have been shown to decrease relapse rates in patients achieving a remission, improve response rates in patients with chemo­resistant phenotypes, and reduce short- and long-term toxicities associated with current strategies.

“2017 is the year of AML,” said Bruno C. Medeiros, MD, an associate professor of medicine and director of the inpatient hematology service at Stanford University Medical Center. “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.”

At the National Comprehensive Cancer Network 12th Annual Congress: Hematologic Malignancies, Dr Medeiros offered a brief overview of current and future agents in development for AML patients, with specific focus on targeted agents.

FLT3 Inhibitors

Approved by the FDA in April 2017 for FLT3-mutated AML, midostaurin is a multikinase inhibitor active against FLT3-ITD and FLT3-TKD. When added to conventional therapy in younger patients with untreated AML, midostaurin increased overall complete response (CR) rates (74% vs 66%; P = .01) with no added toxicity profile. Five-year survival also improved, 43% to 51%.

Crenolanib, another FLT3 inhibitor under investigation, inhibits both FLT3-ITD and FLT3-TKD mutations in the active conformation. In a small phase 2 trial, crenolanib added to standard “7+3” (Ida, Dauno60, Dauno90) induction therapy led to a CR rate of nearly 90% with no unexpected toxicities. Although median follow-up for patients was only 6 months, Dr Medeiros called the early look at overall survival (OS) rates “very promising.”

Two additional FLT3 inhibitors, quizartinib and gilteritinib, are currently being developed for patients with relapsed/refractory disease. Although median OS remains relatively limited, response rates have been encouraging. Randomized phase 3 studies versus salvage chemotherapy are ongoing, with results expected late next year or early 2019.

IDH Inhibitors

As Dr Medeiros reported, 6% to 12% of AML patients have IDH1 mutations and 8% to 18% have IDH2 mutations. Two agents that target these mutations are being developed in parallel, with similar trial designs. Response rates have been nearly identical for both trials, with an overall response rate (ORR) of 38% for the IDH1 inhibitor (ivosidenib) and 37% for the IDH2 inhibitor (enasidenib). Based on these results, the FDA approved enasidenib in August 2017, and approval for ivosidenib is expected by early next year. According to Dr Medeiros, however, investigators remain unable to predict which patients are likely to respond to these agents.

Immunotherapies in AML

Initially approved for relapsed/refractory AML, gemtuz­umab ozogamicin, an anti-CD33 antibody drug conjugate, was withdrawn from market in 2010 due to toxicity concerns. A number of large randomized trials, however, subsequently demonstrated that the addition of gemtuz­umab ozogamicin to standard induction chemotherapy is associated with significant improvement in OS, and the drug was approved for the treatment of newly diagnosed CD33-positive AML.

There are also several ongoing clinical trials examining the effectiveness of BiTE (bispecific T-cell engager) and DART (dual-affinity re-targeting) agents, which combine the binding specificities and biologic functions of 2 antibodies into 1 molecule, Dr Medeiros reported.

Although complicated by the lack of expression of nonrestricted AML-associated antigens, CAR T-cell therapies are also under investigation. Only very preliminary results are available, said Dr Medeiros, but “off-leukemia toxicity” has been an unwanted side effect of this approach. 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, he reported.

Novel Hypomethylating Agents

Two novel hypomethylating agents, guadecitabine and oral azacitidine, are also undergoing development. Phase 2 studies with guadecitabine demonstrated an increase in response rates (ORR, 57%; CR, 37%) compared with historical data. According to Dr Medeiros, promising median survival has been observed in responders, and a randomized study comparing guadecitabine with azacitidine completed enrollment late last year. In addition, oral azacitidine is currently being tested in 2 separate trials: as maintenance therapy for patients with AML not eligible for stem cell transplantation; and as maintenance therapy for patients with myelodysplastic syndromes or AML following stem cell transplantation.

“This oral agent may enhance patient convenience, eliminate injection-site reactions, and allow for alternative dosing and scheduling,” said Dr Medeiros, who noted that both trials are close to completing 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,” he concluded. “Hopefully, novel agents will continue to improve outcomes.”

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