Combination Therapies Potentially Address Controversies Over Optimal AML Management

Richard M. Stone, MD

Richard M. Stone, MD

Several new agents have been introduced to the treatment landscape of acute myeloid leukemia (AML), including FLT3 and IDH1/2 inhibitors for patients withFLT3andIDH1orIDH2mutations. Although these advancements are improving the landscape for AML offering a wealth of new treatment options, these new additions can cause questions among oncologists over preferred approaches in each setting.

Single-agent ivosidenib (Tibsovo), an IDH1 inhibitor, was approved in May 2019 for the treatment of adult patients withIDH1-mutant AML. The IDH2 inhibitor enasidenib (Idhifa) was previously approved in 2017 for the treatment of relapsed/refractory patients harboring theIDH2mutation. In addition to the IDH inhibitors, the FLT3 inhibitor gilteritinib (Xospata) received its approval in November 2018, for the treatment of adult patients with relapsed/refractoryFLT3-mutant AML.

The specific role of these agents is still unknown in the relapsed/refractory setting. More prospective trials are needed to define the patient population where these inhibitors would be most beneficial. For instance, researchers are currently investigating the combination of an IDH inhibitor with venetoclax (Venclexta), a BCL-2 inhibitor, for patients witIDHmutations and poor risk factors.

In the frontline setting, physicians still rely on the combination of fludarabine, cytarabine, and granulocyte-colony stimulating factor with idarubicin (FLAG-IDA), or the standard induction chemotherapy regimen of 3+7. However, clinical trials are also investigating the combination of either of these agents with venetoclax as well.

“Venetoclax has opened up a lot of possibilities,” said Richard M. Stone, MD. He believes clinical trials like this will lead to a greater understanding of the disease and how to manipulate more than just 1 genetic abnormality at a time.

In an interview withTargeted Oncology, Richard M. Stone, MD, the chief of staff and director of translational research and the Adult Leukemia Program at Dana-Farber Cancer Institute, and a professor of medicine at Harvard Medical School, discussed the biggest controversies across a number of patient populations in AML. He also highlighted some areas of research he finds particularly exciting for the treatment of patients with AML.

TARGETED ONCOLOGY: How does the current treatment landscape look for AML?

Stone:The treatment landscape for AML is undergoing some major changes, in major part due to the approval of around 8 new drugs over the past couple of years. We tend to see some controversy about where these new drugs should be brought into the therapeutic algorithm, but I will say that we generally consider very strongly host and disease factors when deciding on therapy for newly diagnosed patients with AML. We look at host factors such as fitness for chemotherapy, age, and comorbid diseases. We also look very closely at disease factors including the type of AML and, quite specifically, the cytogenetic and molecular profile.

TARGETED ONCOLOGY: What are the current treatment options for younger patients? What are the controversies in this space?

Stone:For younger adults with favorable risk disease and without a history of myelodysplastic syndrome (MDS), we will generally still use a standard induction regimen of 3+7 or FLAG-IDA. For patients withFLT3mutations, eitherFLT3-ITD orFLT3-TKD, we use 3+7 and midostaurin (Rydapt) in accordance with the RATIFY trial that was published a couple of years ago in theNew England Journal of Medicine. Those patients generally go into remission, and then hopefully get transplanted while they’re in remission, which is the best hope for cure for those patients, according to that paper.

For patients who happen to have a history of MDS, we will at least consider the use of CPX-351 (cytarabine and daunorubicin; Vyxeos), which is approved for patients with a history of MDS or therapy-related leukemia or myelodysplasia-related changes, chromosomal or even morphologically. That’s a bit of a controversy since the trial to get this approved was only done in people aged 60 to 75, but the approval extends below age 60.

For all the other patients, we generally use the 3+7 or FLAG-IDA-based regimen to get them into remission, then we will transplant them in first remission. [For patients with]favorable-risk AML, for many patients [we] will add gemtuzumab ozogamicin (Mylotarg) to the 3+7, based on the ALFA 0701 trial that was done a few years ago. A few of the MRC trials that led to the re-approval of gemtuzumab for use in conjunction with chemotherapy at the new dose of 3 mg/m²on days 1, 4, and 7. The data support doing it, I believe.

Again, for younger adults with favorable risk based on core binding factor abnormalities, we use 3+7. ForFLT3mutations, we use 3+7 plus midostaurin. For everybody else we use 3+7 or FLAG-IDA with the possible exception of those with an MDS-type history or cytogenetics, in which case we might use something else.

TARGETED ONCOLOGY: What is different about treating older patients with AML? What challenges arise in this patient population as opposed to in younger adults?

Stone:For older adults, the situation is evolving even more rapidly. For those who can tolerate chemotherapy, we’ll use the same algorithm that I had mentioned before, although there is a lot more people in this age group that have a history of MDS or leukemia, so those people might get Vyxeos. The real big thing is the advent of the combination of hypomethylating agents or low-dose cytarabine with venetoclax, the BCL-2 inhibitor. The combination of Ara-C (cytarabine) with venetoclax or azacitidine (Vidaza) has been approved by the FDA for use in people who are over age 75, or those who have other comorbidities that are making them not eligible for intensive chemotherapy.

There’s still a lot of controversy over what’s the best way to treat people who are aged between 65 and 75 who don’t have comorbid diseases, thus not being eligible for the aforementioned combination of azacitidine plus venetoclax. The way that poor-chromosomal and poor-risk abnormalities might not do very well with 3+7-based therapies, there is a lot of controversy. Some of those patients could also get a Vyxeos; for 65- to 75-year-old patients have adverse-risk features, but you can give it as well, either CPX-351 or fixed dose, but potentially even a combination with venetoclax. There’s a lot of controversy there.

For relapsed AML, there’s a new FLT3 inhibitor that was recently approved called gilteritinib. It beat chemotherapy in a trial of relapsed AML. There are IDH1 and IDH2 inhibitors that have also been approved for relapsed and refractoryIDH-mutant refractory AML. The IDH1 drug is called ivosidenib and the IDH2 drug is called enasidenib.

We have a lot of new therapies for relapsed AML and a bunch of controversies in the upfront setting. It’s a bit of a complicated landscape right now.

TARGETED ONCOLOGY: What would you say are the biggest challenges in this space?

Stone:There are many [more issues]. To start, let’s look at relapsed AML. InFLT3-mutant AML, should gilteritinib as a single-agent be used alone as per the approval, or [combined with] physician’s choice of chemotherapy in that setting? Is it likely that gilteritinib as a single-agent is going to be wonderful? No. Maybe it should be combined, but we just don’t have the data yet. There are some folks down at MD Anderson Cancer Center who routinely do that without data, and it makes sense but needs to be proven prospectively.

The other thing is the controversy that exists around how to treat patients who you might think would benefit from venetoclax and azacitidine or venetoclax with decitabine, but there aren’t any approved indications yet. Patients get it off protocol, but if they do get it, how long should they get it for? Should they stay on until minimal residual disease (MRD) negativity, or stay on indefinitely? Furthermore, there is also a regimen called decitabine 10-day plus venetoclax, for which there is a lot of interest based on some early reports from MD Anderson and based on the original gemcitabine data in P53-mutant patients; that was published in theNew England Journal of Medicinea few years ago.

Of course, the upfront issue is whether FLAG-IDA really is better than 3+7. No one knows. There was some strong evidence, but no prospective randomized trial that demonstrates the increased toxicity. The role of stem cell transplantation is a big one, especially in the context of MRD. The whole idea of MRD in AML is super controversial but super interesting. We know that the people who go on to stem cell transplantation with MRD-positive disease, based on the full cytometry or molecular studies, don’t do well with the transplant, so how important is it to beat someone down to the MRD-negativity and then do the transplant? There are many controversies in AML.

TARGETED ONCOLOGY: Is there any research you’re particularly excited for in this field?

Stone:Yes, there are lots. First of all, [there’s] combination venetoclax with standard chemotherapy. MD Anderson is doing a trial with FLAG-IDA plus venetoclax in both upfront and relapsed patients. We at Dana-Farber are doing a trial in collaboration with MD Anderson combining 3+7, the most commonly used induction regimen in the United States, with venetoclax. That is going on right now.

We are also interested in many combination studies combining some of the available agents, such as venetoclax and an IDH inhibitor forIDH-mutant patients who indeed need triplet therapy. [There is] venetoclax, IDH inhibitor, and azacitidine for newly diagnosed older adults withIDH1-orIDH2-mutant AML, so we’re interested in understanding whether patients who have bad cytogenetics who may be fit for chemotherapy should maybe get Vyxeos, 3+7, or azacitidine plus venetoclax. There’s going to be a trial that will answer that question, hopefully done within the United States and not too far into the distant future.

Another fascinating piece of research is in core-binding factor AML; is it a good idea to add a TET inhibitor to 3+7 or 3+7 plus gemtuzumab, which are becoming the standard of care for AML in many centers?

I didn’t even get into the new drugs, but that’s just a smattering of some of the research going on right now.

TARGETED ONCOLOGY: Where do you see the field headed in the decade or so?

Stone:One exciting development might be the ability to change AML to a more acute promyelocytic leukemia—like situation where we won’t even have to use cytotoxic chemotherapy. I may be dreaming a little bit, but in my opinion, it may be possible that we treat AML with gemtuzumab and a TET inhibitor, and adding venetoclax so virtually all patients [will benefit], including certain adults with a FLT3mutation and a FLT3 inhibitor, maybe with venetoclax and chemotherapy. Same for IDH inhibitors.

Venetoclax has opened up a lot of possibilities. Hopefully we will be able to understand how to manipulate MRD in a better way so we can make patients better candidates for transplant, and we will understand how to attack people with multiple genetic abnormalities, which is the norm rather than the exception for newly diagnosed AML. In other words, if you have aFLT3mutation, anIDH2mutation, and aTET2