AML Field Advances With New Agents, But More Work Remains

Olga Frankfurt, MD

Olga Frankfurt, MD

The year 2017 saw 4 regulatory approvals in the field of acute myeloid leukemia (AML) that have made significant improvements in patient outcomes.

Most recently, in September, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of adults with newly diagnosed CD33-positive AML. In the approval, the antibody-drug conjugate was also indicated for patients aged 2 years and older with CD33-positive relapsed/refractory AML.

A month prior in August, the agency granted an approval to a fixed-combination of daunorubicin and cytarabine, known as CPX-351 (Vyxeos), for adult patients with newly diagnosed therapy-related AML or disease with myelodysplasia-related changes. That same month, the FDA approved enasidenib (Idhifa) for patients with relapsed/refractory IDH2-mutated AML.

In April, the FDA granted an approval to midostaurin (Rydapt) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adult patients with newly diagnosed FLT3-positive disease.

“This is indeed a very exciting time to be oncologists in general in acute myeloid leukemia,” according to Olga Frankfurt, MD. “There are 4 drugs that have been approved in the last several months. After about 40 years of no new drugs available for AML, now we have 4. We have to figure out how to use them and who to use them for, so it is indeed an exciting time.”

OncLive: We have seen much progress in the field of AML this past year. Can you highlight some of the advancements?

In an interview during the OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Frankfurt, an associate professor of medicine at the Feinberg School of Medicine, Northwestern University, discussed advances in the field of AML and challenges that lie ahead.Frankfurt: There have been 4 drugs that have received FDA approval, which includes midostaurin, a FLT3-targeted therapy given in combination with chemotherapy. This is obviously for FLT3-expressed patients who express FLT3 mutations.

We also talked about gemtuzumab ozogamicin which, as they say, “new is the well-forgotten old.” It is a resurrected antibody against the CD33 target, with calicheamicin attached to it. It also got approved in a slightly different schedule with chemotherapy and it has been shown to be effective in that combination.

Then, we talked about enasidenib, which is a drug that is FDA approved for IDH2-positive AML. This drug really changes our concept of how we treat AML, what the expectations are, what the targets are, and it effectively transforms acute disease into a possible chronic condition, so it’s a very unusual and interesting medication.

What is the prevalence of FLT3-mutant patients?

Lastly, we spoke about CPX-351, which comprises a liposomal combination of old and well-known 7+3, but it’s given in a specific ratio and it also has been shown to be more effective than 7+3 in the terrible patient population—refractory/resistant older adults with therapy-related secondary AML. There are different kinds of FLT3 mutations, and midostaurin is active in both of them. It depends on the study, but approximately 20% to 30% of patients express a FLT3 mutation.

What next steps are being taken in the field to go beyond the recently approved agents?

Other FLT3-targeted therapies are currently in clinical trials, so it is going to be very exciting to see 4 or 5 drugs available to choose from. We will have to see which ones are better. With all those drugs becoming FDA approved, now there are all various possible combinations being explored—in different settings, with transplant, and with maintenance therapy. All of these studies are in the process. There are other drugs that are very interesting and are being studied right now. There is a BCL-2 inhibitor that is currently FDA approved for CLL; it certainly has activity in AML and it has been studied extensively in combination with hypomethylating agents. Again, I’m not a fan of low-dose cytarabine, but the combination of the 2 seems to be effective in older adults with AML. That is awesome to have that option available.

What will the role of transplant be as more agents get approved?

What do you think the biggest therapy-related questions are that remain in the AML landscape?

The PD-1 inhibitors are currently making their way in combinations in the world of leukemia and myelodysplastic syndrome. Those drugs are already available and are FDA approved for many lymphomas and solid malignancies. It is, again, very exciting to see which way this is going to go. As a transplant physician, I like that you asked me this question. I hope that transplant will go away, will not be needed, and we'll have a more sophisticated way of activating the immune system and making it do what it’s supposed to do, which is to fight leukemia. Honestly, I do not see transplant going away quite now. However, as of today, we have drugs that give a better and deeper remission and it’s imminent that we will have a good maintenance mediation that we can give after transplant to decrease the rate of relapse and improve cure and survival. No doubt it is exciting to have all these 4 new drugs approved for AML. However, I feel that both gemtuzumab ozogamicin and CPX-351 offer an incremental change—an important but only incremental change and incremental improvement over standard therapy. I do think that targeted therapy, FLT3 inhibition and IDH2 inhibition, offer a new paradigm in the treatment of AML. But again, they are not known to cure the disease unless they’re given after or before a stem cell transplant. I am afraid there is still a lot of work that needs to be done. Again, most of our patients have more options today than they had a year ago.