The Evolving Disease Managing Patterns in Acute Myeloid Leukemia

Rajneesh Nath, MD

As more research around acute myeloid leukemia (AML) is conducted, oncologists have better ways of managing the disease in most patient subgroups. According to Rajneesh Nath, MD, treating AML today is much better for oncologists and their patients than it was just a decade prior.

“In the last few years, there have been a lot of exciting advancements that have happened in acute myeloid leukemia. We have had more than 10 new drugs that have been brought to the market and there are several drugs in late stage of their development, we have had a new testing to evaluate residual disease after the treatment has been completed…So, we have exciting times ahead of us in the field of acute myelogenous leukemia,” said Nath, section chief of cellular therapy/stem cell transplant & leukemia at Banner MD Anderson Cancer Center.

In an interview with Targeted Oncology™, Nath, discussed the evolution of risk stratification, molecular testing, and treatment of AML.

TARGETED ONCOLOGY: What have been the latest updates around AML risk stratification and management of the disease?

Nath: More than 10 years ago, the classic stratification for acute myelogenous leukemia was based mostly on cytogenetics. Patients would be classified into high risk, intermediate risk, and low risk groups based on how many cytogenetic abnormalities they had and what those cytogenetic abnormalities were. The only tool we had at that time was conventional cytogenetics, and FISH analysis. Recently, through the next-generation sequencing studies, we have found several new molecular targets that are not picked up by conventional cytogenetics. This has changed the field of risk stratification and acute myeloid leukemia, based on that European Leukemia Network-developed risk stratification scheme, which they had published in Blood in 2017. I think based on that, we now combine both molecular studies, and cytogenetic FISH data to risk stratify our patients. And there are several patients who are risk stratified as poor prognostis based on the molecular studies.

Can you discuss the new therapies brought into the landscape over the past few years?

There have been several new therapies. One of the prognostic factors that we have for acute myeloid leukemia, which has been brought into the market in the last 3 to 5 years are the FLT3 inhibitors. FLT3 either internal tandem duplication or tyrosine kinase mutations have been prognostic in acute myeloid leukemia. So, we have had 3 FLT3 inhibitors brough to the market for this particular indication, and 1 of them is for another indication, but physicians frequently use it.

Besides that, there is also gemtuzumab, which was in the market more than 10 years ago but was taken off the market because of toxicity and more recently, was brought back into and was approved at a much lower dosage. That is also there for another target in acute myelogenous leukemia with specific mutations that we call the poor binding factors leukemia. There have been data to show that if we combine induction chemotherapy with gemtuzumab or short-term gemtuzumab, that there is a much better survival in this group of patients. This has also been utilized in elderly patients for acute myelogenous leukemia, and most of the elderly have poor prognostic cytogenetics.

What toxicities should oncologists look out for in these agents?

With these newer agents, oncologists need to be aware of their drug-to-drug interactions. Thinking especially of FLT3 inhibitors, some agents have very specific toxicity. So, for example, one of them is gilteritinib [Xospata] results in the prolongation of QT interval. So, it needs to be used with caution in patients who have prolonged QT interval. Lastly, there may be some drug-to-drug interaction azoles and oncologists may want to consider reducing the dosage. Also, because some azoles cause prolongation of QT interval, physicians need to be cautious of using those along with this FLT3 inhibitors.

The other one that we used frequently and has been shown in randomized studies to prolong both disease-free and overall survival is sorafenib [Nexavar], which has actually not been approved for acute myelogenous leukemia. But there are several studies both as either a phase 2 or even one of them as randomized phase 3 that is showing both responses and survival advantage, But, the drug has issues with rash and a gastrointestinal toxicity like diarrhea. Even though these 2 toxicities happen very frequently, by adjusting the drug dosage and just being aware of it, and it can be used. Also, other drugs can be used to mitigate these adverse events, and physicians can carry on with these medications for an extended period of time. We certainly know that these medications do help in this setting in the patients who have FLT3-ITD mutations. There is also targeted therapy.

Aside from FLT3 mutations, what novel biomarkers are being explored?

There is an ongoing study for patients that have spliceosome mutations, which about 20% to 25% of patients with acute myeloid leukemia carry. There is a component that specifically targets these mutations. The study is conducted by a company called Prelude and they will have a poster during the [2021] American Society of Hematology Annual Meeting. So, that is one of the things that comes to mind currently.

Thinking further about biomarkers, what are your recommendation for molecular testing in AML?

I think in 2021, all newly-diagnosed patients with acute myeloid leukemia should have a testing performed by cytogenetics and FISH studies. Once you have a diagnosis, I frequently asked the pathologist if there is suspicion for acute promyelocytic leukemia [PML]. And if there is a suspicion for acute promyelocytic leukemia, I quickly asked my geneticist to do FISH for PML. With the probes that are available for this, one should be able to provide an answer in about 12 hours or less, because that's a big probe they can run. If we have a diagnosis of acute promyelocytic leukemia, you have your answer there, and you can do the targeted therapy.

Outside of acute promyelocytic leukemia, we are able to then make a diagnosis of good risk leukemias also by FISH analysis. This is for inversion 16 and translocation 821, which are the core binding factor leukemias. At the same time of stratifying risk and doing FISH studies, physicians should get next-generation sequencing, and here are some companies that can give results within 72 hours. I recommend that every patient with newly diagnosed acute myeloid leukemia should be tested for FLT3, and it should be independent of the next-generation sequencing, because it can miss some of the FLT3s.

It also is helpful to work with a lab to follow up on a patient for minimal residual disease, as treatment for AML is continued. There are 2 ways that you can do MRD testing. One way is by flow cytometry, which brings the sensitivity down to .01, or with a PCR test that helps to detect disease at 10-6. We now know that for most of these patients with certain mutations, it is important to evaluate MRD at an undetectable level because if there is persistent MRD, it would be a short time before these patients relapse.

What strides have been made in understanding disease management for the elderly AML population?

The elderly population is a specific population who don't tolerate the chemotherapy very well. And if they get chemotherapy, they frequently do not go into remission. So traditionally, all patients whom we thought could tolerate chemotherapy were given induction chemotherapy. More recently, based on the VIALE-A study, we are able to treat elderly patients with a combination of an HMA, which could be dexamethasone or azacitidine, and we can combine it with venetoclax [Venclexta]. This combination can [induce complete remission in] about 60% of elderly patients…within about a month and a half. So, after this, for the patients who are eligible and can tolerate a stem cell transplant, we frequently will take them to an allogenic stem cell transplant.

Now, the problem comes when the elderly patients don't get into remission, either with a standard induction chemotherapy or in the combination I just spoke about, there is an ongoing randomized study, the SIERRA study, which has recently completed its accrual. We anxiously await the data, whether patients who have refractory/relapsed acute myelogenous leukemia who were given transplant utilizing this new technology with Iomab-B have an advantage over the standard of care. We expect the results of the study sometime in fall of 2022.

Generally, can you describe the current state of AML management?

In the last few years, there have been a lot of exciting advancements that have happened in acute myeloid leukemia. We have had more than 10 new drugs that have been brought to the market and there are several drugs in late stage of their development, we have had a new testing to evaluate residual disease after the treatment has been completed. I mentioned a couple of them, but several others are in the process of being developed, including the droplet digital PCR and liquid biopsies, which are able to detect small amounts of disease in the blood or the bone marrow. So, we have exciting times ahead of us in the field of acute myelogenous leukemia.