Melissa L. Larson, MD
After decades of few advances and stagnant treatment approaches, which mainly comprised 7+3 chemotherapy, the acute myeloid leukemia (AML) paradigm now has several agents approved, and plenty of ongoing trials are exploring other novel therapies alone and in combination, according to Melissa L. Larson, MD.
Several of these research efforts are focused on targeting molecular drivers of disease, such as FLT3
“We have very good momentum now going forward with the research. There have been such great strides made in identifying all of the different mutations that you can have in AML,” said Larson. “It's just a matter of putting the time and money into the research, looking at how we can target some of these other mutations in order to improve our outcomes. With the use of next-generation sequencing, we are getting a lot more information about the biology of the disease and, with time, we will be able to get a result that will personalize the treatment that each individual patient is going to need for their leukemia.”
In an interview during the 2019 OncLive®
State of Science Summit™ on Hematologic Malignancies, Larson, an associate professor of medicine at Rush University Medical Center, discussed available treatments for patients with AML, as well as others that are in the pipeline.OncLive: How has the AML paradigm evolved in recent years?Larson
: This has been a very exciting time for leukemia doctors, given the number of new drug approvals over the last couple of years. We have used standard 7+3 chemotherapy for over 40 years. The last 2 years has brought new drugs, which have changed the treatment paradigm. We are now looking at individual disease characteristics and specific molecular mutations that help guide our treatment decisions with these newer drugs.
For patients who are older, we are able to treat many more patients than we used to. It used to be that patients over the age of 80—sometimes even over the age of 70—would be put on hospice because they were diagnosed with AML. Now, we have tolerable treatment options that are effective for these patients.In the current paradigm, is high-intensity treatment necessary to achieve responses?
For younger patients in particular, we still need to use intensive chemotherapy in order to achieve responses, but we are able to improve the response rates over what we traditionally saw with these intensive agents by adding certain targeted agents. Currently, midostaurin (Rydapt), a FLT3 inhibitor, has been approved as an addition to intensive induction with cytarabine and daunorubicin. This has really changed—not so much the response rates, but— the overall survival (OS) of these patients. Patients are living longer and disease free.
We're seeing some of the other targeted agents now being evaluated in clinical trials, such as enasidenib (Idhifa) and ivosidenib (Tibsovo), the IDH1/2 inhibitors that are now also being added upfront to chemotherapy. In the older patient population, we are seeing very good responses with low-intensity treatments; decitabine or azacitidine in combination with venetoclax (Venclexta) has shown great promise in the older patient population. We are seeing responses within 1 to 2 months of treatment and that they are improving their OS.There are some questions about the tolerability of venetoclax in other diseases. Is venetoclax tolerable in AML?
It is. Even when we're adding [venetoclax] to these other agents, we're not seeing much in the way of adverse events. We do, however, see prolonged cytopenia. These patients are taking longer to recover their [mature blood cell] counts and this can lead to some delays with subsequent cycles.What patients, if any, are perhaps not suited to receive venetoclax?
I am using this particular combination in older patients, typically those who I wouldn't consider fit for induction chemotherapy. There are still some older patients who could tolerate an intensive induction regimen. It's very important to assess each patient individually, including their goals for therapy, before deciding on a treatment strategy.
In the younger patient population, we aren't using it as commonly. However, I have used it in the relapsed setting for patients who are failing more traditional chemotherapy agents. The benefit is that you're using agents with completely different mechanisms of action compared with traditional cytotoxic chemotherapy. In that patient population, we are able to potentially get a response to get those younger patients on to stem cell transplant.