Navigating Between High- and Low-Intensity Treatment Options in AML

Thomas W. LeBlanc, MD

The emergence of therapeutic options in the frontline and relapsed/refractory settings of acute myeloid leukemia (AML) has allowed for more personalized care, but understanding how to best navigate between high- and low-intensity treatments is still unclear, said Thomas W. LeBlanc, MD.

“For me, what is particularly exciting are the intensive therapy options. We are no longer just checking cytogenetic abnormalities just to be able to tell a patient what we think we might expect or whether or not they need a transplant,” said LeBlanc, an associate professor of medicine at Duke University Medical Center and a member of Duke Cancer Institute. “We can actually use those results to then recommend a particular therapy that might work better for them.”

Three agents were FDA approved for use in August/September 2017 as upfront intensive therapy, according to LeBlanc. The first was CPX-351 (Vyxeos), which is a fixed-combination of daunorubicin and cytarabine, for those with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes, based on an improvement in overall survival observed in a phase III trial.

Midostaurin (Rydapt), which is indicated for patients with newly diagnosed FLT3-positive disease in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation, followed later that month based on results from the phase III RATIFY trial. The antibody-drug conjugate gemtuzumab ozogamicin (Mylotarg) was also added to the armamentarium for use in patients aged ≥2 years with CD33-positive relapsed/refractory AML.

Beyond these agents, the IDH1/2 inhibitors ivosidenib (Tibsovo) and enasidenib (Idhifa), as well as the second-generation FLT3 inhibitor gilteritinib (Xospata), have also received regulatory approval in recent years for use as single agents in the relapsed/refractory setting.

Specific to ivosidenib, the FDA approved a supplemental new drug application for single-agent ivosidenib for the frontline treatment of adult patients with IDH1-mutant AML who are ≥75 years old or are ineligible to receive intensive chemotherapy.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, LeBlanc shared advice for community oncologists on to how to better navigate the complex treatment paradigm of AML.

OncLive: What are some of the exciting agents that have emerged in recent years?

LeBlanc: [In my presentation,] I had the difficult task of covering 5 of the 8 newly FDA-approved agents in AML; that's an exciting problem for us to have. I spoke about 3 agents that are now approved for upfront intensive therapy, so that would be midostaurin, the daunorubicin and cytarabine product, and also gemtuzumab ozogamicin, which is recently back on the market. I also covered the upfront, nonintensive options that have become available in the last year or so, such as venetoclax in combination with a hypomethylating chemotherapy or low-dose cytarabine. Furthermore, I discussed glasdegib (Daurismo) in combination with low-dose cytarabine.

If a patient has a FLT3 mutation, we would recommend midostaurin upfront in combination with 7+3 intensive induction. If they have an unfavorable cytogenetic profile and evidence of myelodysplasia-related changes or therapy-related AML, we would recommend liposomal daunorubicin and cytarabine. That approach has been associated with prolonged overall survival and patients getting to transplant.

For patients who don't have either of those abnormalities but have a favorable- or intermediate-risk profile, there is evidence that adding gemtuzumab ozogamicin to a standard 7+3 regimen will improve their outcomes. We are basically increasing personalized care in AML. Similarly, those who aren't fit for intensive induction chemotherapy now have a very exciting new standard of care, which is venetoclax (Venclexta) combine with another low-dose therapy. Regardless of which option you choose, these approaches are associated with effectively doubling or tripling our historical response rates. That is dramatically changing the [outcomes of patients] I see in my practice every day.

With this abundance of frontline agents, what are the sequencing challenges?

Sequencing of these drugs is increasingly becoming a problem. I will give you one example, but there are many of these. What happens when I see a patient who is newly diagnosed, and I might be considering them for intensive therapy, and they happen to have 1 or more targetable mutations? Most of the mutation-targeting treatments that have been approved by the FDA are single-agent drugs in the relapsed/refractory setting, not [available for use] in combination. For example, the 2 IDH1/2 inhibitors ivosidenib and enasidenib are both approved in the relapsed/refractory setting. Gilteritinib, the second-generation FLT3 inhibitor, is also approved for use as a single agent in this setting. Therefore, I would have to make a choice in that case. If that person has a FLT3 mutation, would I give them midostaurin and 7+3 upfront and ignore the IDH1/2 mutation they might have?

We don't have mature data yet indicating that we can safely combine 3 drugs together and that it would improve efficacy. Many of us believe that these data will probably come very soon in AML. Many of those studies are ongoing, but until we have approved indications, we are sort of left using treatments we feel won't be as effective in the near future.

Could you expand on any of those ongoing studies?

At the 2018 ASH Annual Meeting, I was really excited to see some preliminary data coming out regarding intensive therapy combinations with IDH1/2 inhibitors, looking at 7+3 induction in combination with either ivosidenib or enasidenib. Is that approach safe and tolerable, or does that dramatically improve toxicity? We don't know, and this is needs to be looked at further. When that study reports out fully, I hope it will answer this question. At least the preliminary evidence that has come out suggests that it probably does improve the efficacy of 7+3. If you take the average person with AML and not parse out any abnormalities or look at differences by age and such, we are typically getting half of patients or more into a complete remission (CR) with an intensive induction regimen; the rate may be as high as 70% or 80% in certain subsets. Some of the preliminary data with combination studies are showing 90% CR rates. Will that pan out in the more mature data looking at OS? It's still yet to be shown. However, that was still impressive for me to see; this could improve the standard of care.

Also, the signals that have been described in those studies so far have not suggested any additive toxicity. That's important because we know AML is a very clonally heterogeneous disease, and just giving regular old chemotherapy is not enough to cure it. At the same time, just targeting one mutation is not enough either. We need to combine these therapies and hit the disease from multiple angles. Will that be too much for the patient? Hopefully not.

Do any of these agents approved in the relapsed/refractory setting have the potential to be explored in other settings or combinations?

The 3 agents [ivosidenib, enasidenib, and gilteritinib], to me, are really exciting possibilities for a combination with any upfront therapy. There are data that have started to emerge about intensive treatment. There are similar studies going on looking at low-intensity treatment. For example, could you take a hypomethylating drug, combine it with venetoclax, and then add an IDH1/2 or FLT3 inhibitor? We don't know this yet, but hopefully we will in the relatively near future.

Many of us are excited about this possibility because targeting some of those mutations that may be drivers for making the leukemia grow could be the key. It's an exciting idea and probably a better way of addressing this disease. We know outcomes have not been great with just induction therapy or just hypomethylating agents. The venetoclax combination is exciting because it's improving upon the old hypomethylating drugs story; however, it's still not enough. We don't know the long-term outcomes of this approach or if this is curing patients.

What are some unanswered questions with venetoclax?

One of the challenges we're facing, now that venetoclax has emerged as a new standard of care in patients who are ineligible for chemotherapy, is this question of whether it could be as good as intensive chemotherapy and come at a lower risk to the patient. We know that even in the best hands, at really experienced centers, there is still a small risk of death in the first 60 days of induction. Our hope and expectations are that this risk is lower with a low-intensity regimen, but we are also finding that venetoclax-based regimens are actually pretty myelosuppressive.

Recently, the FDA shut down the myeloma aspect of this program due to infection. That's sad and sobering, and we don't want this to happen in AML. Yet when we give this treatment, patients have pancytopenia for quite a while. We are learning that many of them get into remission very quickly. Many of us are starting to do bone marrow biopsies after 1 month because many of those patients are in remission. Now that patients are being treated in the real world off of rigorous study protocol that require more frequent bone marrow assessments, we need to be paying close attention this.

We need to also figure out the right dose of venetoclax when we are giving antifungal prophylaxis, which is also lifesaving in AML. When a patient has no neutrophils for 2 or 3 months, if they are on a myelosuppressive regimen like venetoclax, they are probably benefitting from antifungal prophylaxis.

How do we balance all this? I do have some worries about the safety of using this kind of regimen in the community setting where a community practitioner won't see too many AML cases in a year. There's a lot of complicated supportive care that goes along with treating these patients. The piece that is really close to home for me is the patient experience with any of these new therapies. Unfortunately, we historically have very little data for what it's like for patients to go through these treatments.

We know a little bit about what symptoms patients experience based on data from rigorous studies, and, of course, from our own observation. However, we really don't know much about how a venetoclax regimen compares with another regimen. When I sit down with patients, I can tell them about the adverse events seen in clinical trials, but that's still a few steps beyond what patients want to know.