Targeted Therapy Approvals Spur Increased Biomarker Research in AML

Alice Mims, MD

The introduction of targeted therapies in acute myeloid leukemia (AML) has motivated research efforts dedicated to identifying biomarkers in the newly diagnosed and relapsed/refractory settings to better find optimal treatments for both populations, explained Alice Mims, MD.

Although several agents have gained approval in recent years to treat patients with both mutation-driven and nondriver AML, no curative treatment exists yet. Mims recommends that patients with AML continue to be considered for clinical trials investigating novel agents or strategies.

“We're making lots of progress with AML. With having all the information at our hands, we're finally starting to see clinical breakthroughs, but we still want to do a better job. It is really important to still consider clinical trials for patients and make sure that we're offering therapies even to patients who are older because there are new therapies that are more tolerable. Even if they're not curative, they can buy patients better quality of life and longer time living with this disease.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Mims, a medical oncologist at The Ohio State University Comprehensive Cancer Center—James, discussed biomarker research and therapeutic developments in AML.

OncLive: What are some recent changes in the AML field?

Mims: One of the big changes has been the introduction of targeted therapies, both IDH inhibitors and FLT3 inhibitors. Ivosidenib (Tibsovo) is an IDH1 inhibitor that has been approved for newly diagnosed patients who are ineligible for intensive chemotherapy or who are ages 75 or older. Enasidenib (Idhifa) is for [the treatment of patients with] IDH2-mutated relapsed/refractory disease. There is also the FLT3 inhibitor gilteritinib (Xospata), which has been approved for FLT3-ITD— or FLT3-TKD—mutated relapsed/refractory AML.

Is molecular testing at diagnosis being conducted up front for patients with AML?

The National Comprehensive Cancer Network and other guideline panels recommend performing molecular testing at diagnosis. There is controversy regarding whether one should wait for those results to return, because some patients [require active treatment] due to the unsafe progression of their disease.

However, if patients have disease that is not very proliferative, they may be able to wait for those [molecular testing results] to return. That would be ideal in figuring out treatment options that may be more targeted and individualized for a particular patient, rather than a “blanket” chemotherapy given to all patients up front.

What do you recommend for patients who are too symptomatic to wait for their test results to return?

It would depend on what their molecular profile showed. Patients who have very proliferative disease where they have high white blood cell counts, require leukapheresis, or have symptoms of disseminated intravascular coagulation may want to start treatment because it's not safe to wait for those results to come back.

For most patients, it takes at least 1 week to receive molecular profiling. Midostaurin (Rydapt), which is approved for patients with newly diagnosed, FLT3-mutated AML, is not started until day 8 after 7+3 therapy starts; therefore, you could wait to start [targeted therapy]. For other targeted therapeutics, [the timing of starting therapy] depends on the setting.

What questions remain with biomarker research in this space?

We are seeing new patients that have all these different varieties of mutations. How do they work together? How do we best target those mutations with the new therapies that are being explored? What is the best setting [to target] those mutations? Are there subsets that respond better to agents, such as glasdegib (Daurismo) or venetoclax (Venclexta)? Right now, it's not quite clear.

How do you optimally manage resistance in AML?

We are still learning about [resistance] in AML. We know the most about IDH- and FLT3-mutated patients. For IDH-mutated AML, it appears that patients have other mutations, such as RAS and FLT3 mutations. They may not respond as well to IDH1/2 inhibitors, which is being explored. Are there better combination therapies for those patients upfront? There are patients who develop resistance mutations with IDH1/2 [inhibitors]. They may have an IDH1 mutation, then develop an IDH2 [mutation], and it can go back and forth. It's really important that when patients are not responding to disease, you look and repeat molecular profiling to see if [the patient] has developed new mutations. For example, for FLT3 mutations, there are mutations that arise and make [the patient] not responsive to gilteritinib and you would want to determine whether that has happened.

What are some of the investigational combinations that are currently being studied?

A lot of people are interested in targeted therapy combinations. There are ongoing studies looking at venetoclax with IDH inhibitors, as well as venetoclax with FLT3 inhibitors in patients with those respective mutations. We are also looking at studies examining combinations with chemotherapy, including 7+3 plus new FLT3 inhibitors, IDH inhibitors, or hypomethylating agents.

What regimens are approved for older patients with AML?

A lot of the new approvals have been for newly diagnosed, older patients who are 75 years or older with comorbidities. Ivosidenib was approved for patients with IDH1-mutated AML. Venetoclax plus either hypomethylating agents or low-dose cytarabine has been approved for that same population. Glasdegib, which is a Hedgehog inhibitor, is also approved in combination with subcutaneous cytarabine for that population.

What are your recommendations for future AML research?

A lot of these new therapies are exciting, but none of them seems to be curative for patients. We still need to do a better job in trying to figure out how to cure patients with AML instead of prolonging the inevitable. One study that's looking at [curing AML] is the Beat AML Master Trial, which is with the Leukemia and Lymphoma Society. It's [looking at] an older population of patients with AML, mostly those who are 60 years and older. Patients undergo molecular testing and results are received within 1 week. Patients who have dominant clones are put on particular therapies. If [the patient] doesn’t have mutations that can be targeted, they are given experimental therapy. That is showing some exciting results and, hopefully, will lead to new therapies in that patient population.