AML Armamentarium Expands, Offering Hope for Consistent Cure

Justin M. Watts, MD

Based on advances in the understanding of the disease biology of acute myeloid leukemia (AML), numerous drugs have entered the treatment paradigm, resulting in better outcomes for particularly hard-to-treat patients, said Justin M. Watts, MD.

“Several new drug approvals have really changed the treatment landscape of AML in a way that we have never seen before and are really offering a lot of promising advances in terms of remission rates and even in overall survival (OS) for our patients,” said Watts, “including both those with newly diagnosed disease and those who have relapsed and whom we are still trying to get to allogeneic transplantation.”

In just the last 2 years, FLT3 inhibitors such as midostaurin (Rydapt) and gilteritinib (Xospata) have received regulatory approval, along with IDH1/2 inhibitors, such as enasidenib (Idhifa) and ivosidenib (Tibsovo). Venetoclax (Venclexta)-based combinations have also emerged, along with CPX-351 (Vyxeos), gemtuzumab ozogamicin (Mylotarg), and the hedgehog inhibitor glasdegib (Daurismo).

OncLive^®: What are the recently approved agents in AML and where they fit in the treatment paradigm?

In an interview with OncLive^® during the 2019 State of the Science Summit™ on Hematologic Malignancies, Watts, an assistant professor of medicine at the Sylvester Comprehensive Cancer Center, University of Miami Health System, shed light on these promising agents and their impact in the space, discussed remaining challenges, and expressed his hope for an era where most patients with AML will be cured.Watts: In younger patients with AML, who traditionally do better than those who are older, we are using these new agents—mostly in combination with induction chemotherapy, or, in some cases, as single agents in relapsed disease. There is gilteritinib if a patient has a FLT3 mutation, or the IDH1/2 inhibitors if they have an IDH1/2 mutation.

Midostaurin is the first FDA-approved FLT3 inhibitor and that's used in combination with 7+3 induction chemotherapy and consolidation therapy. That leads to an overall survival benefit; it's modest but very real. The [combination] is well tolerated and that is our standard of care if the patient has a FLT3 mutation, they’re being treated with upfront therapy, and if they’re younger than age 60.

Gilteritinib was more recently approved as a single agent for patients with relapsed/refractory FLT3-mutated AML based on an estimated 20% response rate in those patients. OS data comparing it with salvage chemotherapy are still pending.

In terms of the IDH1/2 inhibitors, there are enasidenib and ivosidenib. Both are FDA approved now for patients with those mutations with relapsed/refractory AML, based on response rates of around 20%, complete remissions (CRs), other responders with less complete but partial remissions, and many patients with prolonged periods of stable disease and so on. There are also several reports of patients who have had very long responses with those drugs as well. Those drugs have all been approved based on response rates, except for midostaurin. However, for some of them, we are still waiting for survival data or for those studies to be completed.

Venetoclax is another new exciting drug that has been approved, but for a different indication—not for relapsed disease, and it's not for a FLT3 or IDH1/2 mutation. It's approved for use in combination with azacitidine or decitabine in the frontline setting. That [regimen] was approved based on a very impressive 60% CR rate reported in a phase II study compared with about a 20% rate of azacitidine or decitabine alone. Venetoclax is also being studied in a variety of combinations for several indications given its suppressive activity; however, this activity seems to be far greatest in patients with treatment-naïve disease, regardless of setting.

Lastly, CPX-351 is the only other agent that has [improved] OS with randomized phase III data behind it. It’s also approved for patients [as a frontline treatment], but this is a much more intensive therapy. Venetoclax does increase adverse events (AEs) compared with azacitidine or decitabine alone, but CPX-351 is quite intensive chemotherapy. It is approved based on a survival benefit in a very difficult-to-treat population of older adults with secondary type AML, meaning they had a prior myelodysplastic syndrome or therapy-related AML. There was a fairly significant OS benefit, equating to a 31% decrease in the risk of death in those who received CPX-351 versus standard 7+3. Also, higher remission rates were observed and so on.

How will the field change over the next 5 to 10 years?

The one caveat here was although OS with CPX-351 was better, it is more toxic; the blood counts take longer to recover and that means bleeding and infection have to be considered. While it certainly has its place, patients do have to be selected based on those considerations.With some of these new oral agents—FLT3 inhibitors, IDH1/2 inhibitors, and venetoclax—we may be moving more of these targeted therapies to the frontline setting in older patients. This is where it's already being done to some extent, but also younger patients with or without traditional induction chemotherapy. We can possibly do this with hypomethylating agents, as a backbone agent that's less toxic. Perhaps we will be able to eliminate the use of chemotherapy in many of these patients, just like we eliminated its use in acute promyelocytic leukemia (APL).

That is a goal—to treat more of these patients as outpatient and to not only increase the response rates, but also to improve survival, get more durable remissions, and to have agents that we can use for long periods of time as maintenance. Perhaps we can even avoid the need for allogeneic stem cell transplantation in some patients.

What are some of the unanswered questions that still need to be addressed?

On the flip side, the older patient population has traditionally fared far more poorly than those who are younger for a variety of reasons—not just because they're older. However, many of these new drugs are helping those patients, such as the IDH1/2 inhibitors, venetoclax, and CPX-351.[We don’t know] how to best combine all of these new agents. No one really likes giving any patient with AML a single-agent drug, based on the nature of the disease and its genetic complexity. Most of these patients have several mutations, so why would targeting 1 work? It does work in some cases, as does azacitidine in some cases in older adults.

What is your take-home message to your colleagues working in the space?

Also, chemotherapy obviously does cure some younger adults, mostly those with favorable-risk features. How to combine these agents in the best way, in a rational way [is the question]. Yes, many of them are active as single agents and many of them can induce a CR as a single agent, but how durable are those CRs, and how do we make them more durable? [It will likely be] with combination therapy. However, how long do we use these combinations? How do we select them? These are all questions that need answering.The key takeaway is that we're making a lot of exciting therapeutic advances based on prior progress made in understanding the genetics and disease biology of AML. We’re catching up to some of the discovery made in the laboratory that we may have been a little behind on compared with some other diseases, such as chronic myeloid leukemia and chronic lymphocytic leukemia. This is very exciting. This is a tough disease; this is the hardest leukemia—at least in adults—to manage and deal with. It's a tough disease that most patients still don't survive. However, we know that these patients can be cured. Even the worst of the worst [cases] can be cured. Therefore, why can't we do it more often?

[We need to] understand how to use these new drugs in the right combinations and bring newer drugs into the clinic for those hard-to-treat subtypes, for example, those patients with p53 mutations. That may be the worst mutation a patient could have in AML, and there is another drug that may target that and refold the protein and restore its function.

That [agent] has shown very impressive activity in a phase I trial, and now it's already [being evaluated in] ongoing phase II and phase III studies. Therefore, that may be another new drug that we have at our disposal. Also, there are immunotherapy treatments in development as well, such as bispecific antibodies, such as blinatumomab (Blincyto) for acute lymphoblastic leukemia, or ones being developed for AML that seem to have good activity and also have AEs, such as cytokine release syndrome, that you would expect to see if they're active.

For each AML subtype—of which there are probably at least 11, and then there are subtypes within subtypes—we may need a specific therapy. Transplant may be what's needed for some, while high-dose cytarabine [may be needed for others]. APL has its own treatment, and now we have all these inhibitors and agents that may treat p53-mutated disease. Venetoclax may have a variety of uses that will make treating this disease more exciting. We're helping our patients more and [these agents] are going to get us to an era where we cure most AML cases just like we cure most, if not all, APLs.