Novel Agents, Combo Regimens Poised to Dominate AML Treatment

Alexander Edward Perl, MD, MS

Several novel agents have gained FDA approval for use in patients with acute myeloid leukemia (AML), which Alexander Edward Perl, MD, MS, believes should be used in combination to create the most effective and least toxic regimens for patients.

“This field is moving so fast after many years of being a lot of study of biology and not a lot of improvements in the clinic. It's a really exciting time to be in the field involved with novel therapeutics; we've been given a whole new set of tools for the toolbox. I prefer to see these not as single agents, but as building blocks for regimens because we're just starting to get drugs that we can finally combine,” said Perl.

“We could start thinking more broadly and asking what new backbones are going to be used that are the most active and best tolerated drugs that work the best in combination without increasing toxicity.”

In an interview during the 2019 OncLive State of the Science Summit on Hematologic Malignancies, Perl, an associate professor of medicine at the Hospital of the University of Pennsylvania, discussed advancements in AML treatment and future approaches in the field.

OncLive: Could you provide an overview of some recent advances in AML treatment?

Perl: The novel formulation of daunorubicin and cytarabine, called CPX-351 (Vyxeos), was proven to be superior to standard induction. It is the first time that any therapy in a head-to-head trial was shown to be superior against traditional cytarabine and daunorubicin, which was known as 7+3.

There are two major advances in terms of better therapy in both the frontline and relapsed/refractory settings, both of which are supported by phase III data. For FLT3-mutated patients, there are randomized data showing that adding a FLT3 inhibitor [gilteritinib (Xospata)] to frontline therapy is superior. Additionally, a placebo-controlled trial showed that midostaurin (Rydapt) improved survival and ultimately improved cure rates in AML.

The CPX-351 data showed that high-risk, older patients who had prior myelodysplastic syndrome, therapy-related leukemia, or genetics indicative of mild dysplasia-related AML had improved survival when they use a newer form of induction chemotherapy [with CPX-351]. We're seeing improvements in outcomes in terms of better response rates and higher cure rates. It's a different kind of therapy because we're able to give many patients less toxic therapy that works better.

Additionally, there are very similar data giving low-dose cytarabine plus venetoclax (Venclexta), which seems to be very tolerable and has higher response rates than any other low-intensity therapy. [The results] are also comparable to what we see with high-intensity therapy. We're waiting on phase III data, which will first compare [the combination] to a hypomethylating agent alone.

Perhaps we will ultimately see a comparison in fit patients between low intensity but high activity therapy, such as venetoclax plus either a hypomethylating agent or low-dose cytarabine versus 7+3. We can imagine that study might have very similar outcomes, but less toxicity or maybe even better outcomes. The response rates and survival with venetoclax combinations are transformative. They're better than anything we've seen on any other single-arm study. We're waiting for the randomized data, but most people are expecting positive results.

The gilteritinib data are a similar story in the relapsed setting. Gilteritinib, a targeted inhibitor of FLT3, was more active and improved survival with less toxicity compared with investigator's choice of chemotherapy in patients with relapsed/refractory FLT3-mutated AML. That's a very exciting finding that has transformed how we approach patients with relapsed AML.

This is a game changer, because we no longer have to bring these patients with aggressive FLT3-mutated AML in the hospital and insist upon giving them the most aggressive, toxic therapies in order to achieve a response that is often a very short duration and does not lead to long-term survival. If we're trying to treat these patients to get them to transplant, we do so more often with lower-intensity therapy with fewer adverse events (AEs).

What factors do you consider when deciding which drug to give a patient?

Our approach to how we assess a patient for what therapy has changed. It used to be one-size-fits-all, meaning if you were fit for induction therapy, you received induction therapy. If you were unfit for induction, we used something of lower intensity—typically a hypomethylating agent or low-dose cytarabine. We provided supportive care alone if patients were not fit for any therapy.

Nowadays, we're not making these decisions based on just fitness; we're also looking at the genetic complement of the leukemia. We might still use fitness to decide intensive- versus low-intensity therapy. Using a different induction strategy can improve survival for patients with therapy-related leukemia, myelodysplastic syndrome—related leukemia, and FLT3-mutated AML. FLT3-mutated patients make up one-third of all AML cases; core-binding factor leukemia make up about 15% to 20% of all patients with AML. There are more patients who are getting a different approach than 7+3. It's no longer one-size-fits-all therapy.

In core-binding factor patients, we embrace the addition of gemtuzumab ozogamicin (Mylotarg), which showed a 15% to 20% improvement in overall survival, which is quite substantial and rare. These data are pulled from meta-analysis data from multiple trials with thousands of patients treated.

There was a substantial improvement in outcome when you add gemtuzumab ozogamicin to frontline therapy, which has become our standard. We give fractionated gemtuzumab ozogamicin on days 1, 4, and 7 at much lower doses than in the past. The reduction in dose is important because it mitigates the toxicity concerns that have been made about gemtuzumab ozogamicin, including that it could be associated with higher induction mortality or higher hepatic toxicity, particularly patients who go on to transplant afterwards. It's less of an issue for core-binding factor patients, because we typically use chemotherapy only in frontline therapy and don't go to transplant as often.

What other novel approaches are moving through the pipeline?

The big questions with these drugs are, “What's the best target? What's the best payload? Should you use the immune system or a targeted drug delivery?” Treatments like CAR T cells that work very well in acute lymphocytic leukemia (ALL) are much harder to do in AML because the antigen specificity for a tumor cell is easier to get away. The antigens that are on myeloblast are shared with normal hematopoietic elements. If you design a drug that is very effective at killing those cells, you'll see a lot of extra marrow toxicity against normal cells that you want to preserve. That is why it's been harder to develop targeted immunotherapeutics or CAR T-cell approaches that work on those antigens in AML.

We are making some real strides and there is quite interesting activity, but it's still very early in development. We would love to say that immuno-oncology is ready to move forward in AML, but it's still a work in progress. There have been studies looking at checkpoint inhibitors and CTLA-4 blockade, but those still need to be proven to show that they are an important part of the regimen. They are tolerable, but we still need to figure out how much value they add.

What does the future of AML treatment look like?

We're already testing FLT3 inhibitors with venetoclax. We will soon be doing studies combining FLT3 inhibitors and IDH inhibitors for the people who have both mutations. You can look outside of that realm to create combinations outside of 7+3. There are other ways we can address the problem. I don't have the right answer to all of this yet because we're still doing the studies. If we have more drugs to kind of design these regimens, we can be intelligent about saying who would benefit from one approach versus the other.

I don't think we have gotten rid of chemotherapy because there is a role for it. I hope we can ultimately get chemotherapy that works better with fewer AEs and eventually need [lower doses] of toxic therapies and treatment modalities that we use now, because we really have nothing better.

Allogeneic stem cell transplantation has a lower relapse rate than anything else I can give patients. However, I don't like the toxicities of the treatment modality. If there is a way to see that kind of treatment benefit without all the AEs, we would use it. I'm hopeful that in the future, we will use less-toxic transplants or no transplant in [frontline] therapy. We would reserve [transplant] for patients who have the highest-risk disease or patients whose frontline therapy doesn't work. My hope for AML is that we are able to make this disease easier to treat and treatments more effective in order to use toxic therapies less often.