Therapeutic Developments in AML Lead to Sequencing Questions

Robert L. Redner, MD

The FDA approval of 8 new agents in the acute myeloid leukemia (AML) paradigm in the past 3 years has offered more options for targeted treatment, leading to further trials on combination and sequencing strategies, explained Robert L. Redner, MD.

“[Finding combinations and sequencing] probably will not be easy,” said Redner, a medical oncologist and hematologist, and professor of medicine, at the University of Pittsburgh Hillman Cancer Center. “It's still unclear what the best combinations are for second-, third-, or fourth-line therapy. Hopefully, if we get things right, we won't need second- or third- or fourth-line therapy. However, there are still a lot of clinical trials that need to happen.”

Despite the tremendous progress, there have also been therapeutic setbacks. In June 2019, the FDA issued a complete response letter to Daiichi Sankyo informing the company that its new drug application for quizartinib would not be approved for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive AML.

In an interview with OncLive, Redner highlighted some of the newer available agents in AML and ongoing studies that could impact clinical practice.

OncLive: What are your thoughts on the current AML treatment paradigm?

Redner: This is a very exciting time to be treating patients with AML. Since the early 1980s, we've all been using anthracycline plus cytarabine, which is a very toxic therapy and overall does not have great results. Over the past 3 years, there are now 8 new agents that have been approved by the FDA for targeted treatment in AML. This is going to be a very exciting time for doctors who treat these patients because now we have bullets in our armamentarium, and we'll be able to figure out what combinations are best, what sequencing is best, and hopefully improve outcomes for this patient population.

What are your thoughts on the potency of gilteritinib (Xospata) and what do you think its role will be in the treatment of AML?

Gilteritinib has been approved for folks with FLT3-positive AML; it's a FLT3 inhibitor. FLT3 is a tyrosine kinase growth factor receptor on normal hematopoietic cells and it is commonly mutated. It's probably the most common driver mutation in patients with poor-risk AML. In the past, outcomes have been very poor for this population. Midostaurin (Rydapt) was the first FLT3 inhibitor that was approved, though it's [indicated] in the setting of upfront treatment in combination with an anthracycline and cytarabine.

Gilteritinib is approved as a single agent, which is quite different from midostaurin. As a single agent, gilteritinib has significant activity and has been approved for patients with relapsed/refractory AML who have either the FLT3-ITD mutation or the FLT3 tyrosine kinase domain mutation. It's very active, and the future [question is] whether it is more effective than midostaurin. There has not been a comparison whether it is more useful in combinations with other chemotherapies. Overall, its role depends on whether or not it can be used in upfront therapy.

Could you discuss the negative ODAC vote for quizartinib?*

The QuANTUM-R study compared this drug with salvage chemotherapy. It also had transplant outcomes within it, which is different than the other studies that have been done with other FLT3 inhibitors. The primary endpoint was OS. In OS, there was a significant improvement, but [the duration of the efficacy results] was approximately 6 weeks. Based upon that, the ODAC lost enthusiasm.

There is still a role for this. One of the important facts to remember is there was a significantly greater number of patients who were able to get to transplant when taking the drug. That is an area that is very important in treating patients with AML—to try and get them to transplant and hopefully long-term survival. The story is not closed yet on this drug.

Could you give us your thoughts on IDH1/2 inhibitors?

They work great. They are both approved as single agents, which is quite remarkable. The IDH1 inhibitor ivosidenib (Tibsovo) has been approved for not only relapsed/refractory AML, but also for upfront treatment for patients who are not candidates for intensive induction chemotherapy. There are now trials ongoing to see how they work in combination with chemotherapy. As I mentioned earlier, the new challenge will be sequencing these drugs and combining them with other agents we know work to try and improve outcomes.

What are your thoughts on the activity with venetoclax (Venclexta) in AML?

Venetoclax has opened a number of doors in the world of targeted therapy; it was the first [targeted agent] that works very well in the elderly population. It was approved in combination with either [azacitidine or decitabine or low-dose cytarabine]. For the combination with either decitabine or azacitidine, the response rates are very high; the complete response rate is somewhere around 70%. The question now is, “How durable will these remissions be?” They're approved now for upfront treatment for the elderly population. The nice thing about it is, aside from initial few days in the hospital, the treatment is very well tolerated, and it's primarily outpatient therapy.

What additional research is ongoing in AML that you would like to highlight?

There's lots of interesting stuff going on in the world of AML. Primarily, the new buzzword across oncology is "immunotherapy." There are a number of new agents, both approved and not yet approved, that comprise antibody-directed therapies. There are ongoing, international studies; we're doing some of them here at University of Pittsburgh Medical Center. We're using bispecific T-cell engager (BiTE) technology and there is a lot of early enthusiasm that CAR T-cell therapy might have a role in treating patients with AML. The challenge now is to find the best target for AML, but there are early ongoing trials.

Could you expand on the BiTE technology?

It's basically a “poor man's CAR T-cell therapy.” The antigen targeting region of immunoglobulins are cloned into a vector, which produces a protein that at one end has the antigen recognition site to latch onto a T cell, such as CD3.

On the other end, it has antigen receptor region that can latch onto the domain of choice. The major example is blinatumomab (Blincyto), which is very useful and approved for targeting patients with CD19-targeted acute lymphoblastic leukemia. There are now ongoing trials with similar strategies trying to target CD30 or CD123 or other potential cell surface antigens that are expressed on AML cells.

*Editor’s Note: This interview was conducted prior to the FDA issuing a complete response letter to Daiichi Sankyo regarding its new drug application for quizartinib.