Back Back
New Targeted Agents in AML
How I Use New Targeted Agents to Improve Outcomes for My Patients With AML

Released: October 12, 2017

Expiration: October 11, 2018

Activity Information

Activity

Progress
1
Course Completed
Continue

The landscape for the treatment of acute leukemias is undergoing dramatic evolution with the approval in 2017 of 4 new drugs to treat acute myeloid leukemia (AML). One of these drugs, CPX-351, is a chemotherapy-based approach, with a liposomal formulation of cytarabine and daunorubicin. It was discussed by Jeff Lancet, MD, in a previous ClinicalThought. In this commentary, I will discuss the 3 newly approved targeted therapies—gemtuzumab ozogamicin (CD33), midostaurin (FLT3), and enasidenib (IDH2)—that have been developed for patients with certain mutations or cell surface markers. Each of these targeted agents should be considered independently to understand how they might be incorporated into traditional regimens or whether they should be considered as monotherapy.

Gemtuzumab Ozogamicin 
Gemtuzumab ozogamicin is an antibody–drug conjugate targeting CD33 that mirrors a traditional cytotoxic drug, in the sense that it delivers a DNA-damaging toxin to tumor cells. CD33 is a common surface marker on AML cells, and this drug comprises an anti-CD33 monoclonal antibody linked with a protease-cleavable linker to the cytotoxin calicheamicin. Once the monoclonal antibody binds to the CD33 receptor, it is internalized into the tumor cell and transported to lysosomes, where the calicheamicin is released, damaging the cell DNA and initiating apoptosis.

The current approval of gemtuzumab ozogamicin in combination with chemotherapy was based on the French ALFA-0701 trial, which was a randomized, open-label phase 3 study of patients aged 50 to 70 years (N = 271) with newly diagnosed AML. Patients were randomly assigned (1:1) to receive induction therapy with 7 days of cytarabine and 3 days of an anthracycline (also known as the 7+3 regimen) with or without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7. The estimated median event-free survival time was 17.3 months for patients receiving gemtuzumab ozogamicin vs 9.5 months for those receiving chemotherapy alone (HR: 0.56; 95% CI: 0.42-0.76).

The single-agent trials included the phase 3 AML-19 trial, which was a randomized, open-label study (N = 237) comparing gemtuzumab ozogamicin monotherapy vs best supportive care among patients with newly diagnosed AML who were older than 75 years of age, or 61 to 75 years of age with a performance status lower than 2 or unwilling to receive intensive chemotherapy. Gemtuzumab ozogamicin induction dosing was 6 mg/m2 on day 1 and 3 mg/m2 on day 8, with continuation on gemtuzumab ozogamicin for patients without disease progression or significant toxicities. The median OS was 4.9 months vs 3.6 months for gemtuzumab ozogamicin vs best supportive care, respectively (HR: 0.69; 95% CI: 0.53-0.90; P = .005).

Originally, gemtuzumab ozogamicin was believed to be highly specific for CD33-positive cells because it only released the chemotherapy inside the cell, which is considered less toxic to the surrounding healthy cells. However, it was found that calicheamicin is also released systemically, which increases the toxicity risk, so the conjugate was temporarily withdrawn from the market in 2010. Adverse events associated with gemtuzumab ozogamicin include cytopenias, gastrointestinal toxicity, and hepatic sinusoidal obstruction syndrome. The latter toxicity is more common among patients who subsequently receive allogeneic stem cell transplantation.

With the new approval, these risks have been partially mitigated, with a lower recommended dose of gemtuzumab ozogamicin and a different schedule than that of the earlier approval, as well as a different patient population. It has become an important part of AML treatment in 3 areas:

Midostaurin 
Midostaurin is a small-molecule agent that targets FLT3 internal tandem duplication and FLT3 point mutations—both of which are commonly seen in AML. Of note, midostaurin is the first drug to be approved by the FDA that specifically targets mutated FLT3.

Midostaurin has been approved for AML in combination with traditional chemotherapy—namely the 7+3 regimen—based on survival improvements observed in the phase III RATIFY trial. In that study, patients in the midostaurin/chemotherapy arm showed a significant improvement in median disease-free survival of 25.9 months vs 14.4 months in the placebo/chemotherapy arm (P = .002), and a median OS of 74.7 months vs 25.6 months, respectively. Although midostaurin was not shown to be effective against AML for patients with FLT3 point mutations in other studies, in the RATIFY study, these patients saw a similar benefit to those with the more commonly seen internal tandem duplication.

A benefit with midostaurin was also seen among patients who underwent autologous stem cell transplantation. An important question being explored is whether midostaurin can serve as a long-term maintenance strategy for patients with AML, because it is not currently approved or indicated as maintenance in this setting. Additional midostaurin research includes seeking the best ways to combine this agent with traditional chemotherapy or the newly approved CPX-351; how to combine it with other agents for patients who are not well enough or fit enough to undergo traditional chemotherapy such as hypomethylating agents; the optimal use in the context of autologous stem cell transplantation; and whether midostaurin should be used as maintenance therapy for high-risk patients.

Newer FLT3-targeted drugs (quizartinib, gilteritinib, and others) are being investigated in ongoing clinical trials, both as monotherapies and in combination with chemotherapies, in hopes of understanding if there are better agents for FLT3-mutated AML. For now, midostaurin is the sole FLT inhibitor used in combination with traditional chemotherapy as induction therapy, with the aim to improve long-term outcomes for patients with AML and FLT3 mutations.

Enasidenib
Multiple isocitrate dehydrogenase (IDH) isoforms are important for cellular metabolism, and both IDH1 and IDH2 are commonly mutated in patients with AML—approximately 20% of patients have either of these mutations. Multiple agents targeting IDH1 or IDH2 mutations are under investigation, including novel inhibitors that have the potential to inhibit both enzymes.

Enasidenib is a small-molecule inhibitor of IDH2, and it is currently indicated and approved to treat patients with relapsed IDH2-positive leukemia. Approval was based on an open-label, single-arm trial of 100 mg/day enasidenib among 199 adults with relapsed or refractory AML with an IDH2 mutation. After a median follow-up time of 6 months, 19% of patients had a CR, lasting a median of 8.2 months. Of the patients who required transfusions at trial initiation (n = 157), 34% did not require transfusions for at least 56 days on enasidenib, and 76% of patients who did not require transfusions at the start of the trial maintained transfusion independence.

Enasidenib is very effective at targeting IDH2-mutated AML resulting in improved blood counts and even complete remission in some patients. As in the case of FLT3 inhibitors, enasidenib is being studied in combination with traditional chemotherapy for patients with the IDH2 mutation in hopes to show a similar impact as midostaurin. In addition, the novel mechanism of action of agents targeting IDH1/IDH2 mutations raise the possibility that patients may experience long-term benefits from improved marrow function even outside of the traditional response criteria for CRs or PRs.

Summary
It is exciting to now have multiple targeted therapies available for the treatment of AML. Each of the novel agents appear to offer clinical benefits to targeted groups: gemtuzumab ozogamicin’s CD33 targeting in combination with chemotherapy appears to benefit patients with core-binding factor AMLs; midostaurin in combination with chemotherapy shows benefit in patients with FLT3 mutations; and enasidenib is currently indicated for relapsed patients with IDH2 mutations. These are encouraging advances for patients with AML, although the best long-term use of these agents has yet to be determined.

How have you started using any of these targeted agents in your practice? Please leave a comment below.

Continue

Poll

1.
Which of the following agents are you using or do you intend to use in your treatment of patients with AML?
Submit