Measuring MRD Imperative to Guide ALL Treatment Decisions

Noelle Frey, MD, MS

It should be a standard of care to measure minimal residual disease (MRD) throughout the treatment course of patients with acute lymphocytic leukemia (ALL), said Noelle Frey, MD, MS, as the biomarker can provide insight into disease prognosis and used to guide care.

“For patients who are MRD-positive, a subset of their disease is chemotherapy-resistant,” said Frey, the director of clinical cellular therapy and associate professor of medicine at the Hospital of the University of Pennsylvania. “We have incredible tools available to us now that work very differently from chemotherapy that can go after this part of their disease that's not responding.”

One such tool is the bispecific T-cell engager blinatumomab (Blincyto), which was granted an accelerated approval by the FDA in March 2018 for the treatment of adult and pediatric patients with B-cell precursor ALL in first or second complete remission with MRD ≥.01%. This was the first FDA-approved treatment for patients with MRD-positive ALL. CAR T-cell therapies are also generating excitement in the space, said Frey, who added that this approach may be particularly beneficial in patients who have a later relapse of MRD-positive disease.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Frey highlighted various therapies available to patients with ALL and the importance of measuring MRD.

OncLive: Could you discuss the importance of measuring MRD in patients with ALL?

Frey: [Measuring MRD] throughout the treatment course should be a standard of care for all of our patients with ALL. The reason for that is, MRD has extreme importance in terms of helping the patient and physician understand the [disease] prognosis. When patients are MRD-positive, even when they're in a complete remission, their chances of relapsing are very high. That’s important to know, as that information can impact how we take care of patients.

There are newer agents that work very differently than traditional chemotherapy. One of the most important agents to consider [in this space] is blinatumomab, which was approved by the FDA to specifically treat patients [with ALL] who are MRD-positive.

How is MRD measured?

There are many ways to measure MRD; there is no standardized process in place in the United States. The most important thing is to understand how sensitive [the tests that you’re using] are and to do a little research. You should use a test that has been validated specifically to test for MRD. The tools that we use are similar to those that we use in traditional assessments for leukemia and other malignancies.

One way to assess for MRD is flow cytometry. Certain laboratories are validated to use a flow cytometry technique to detect very low levels of ALL. That's a helpful way to assess MRD because it gives us information about the disease that can inform treatment. For example, when you do flow cytometry, you're going to learn if the blasts are CD19-, CD20-, or CD22-positive, which can inform treatment decisions.

The use of a quantitative polymerase chain reaction—based method is another way to assess for MRD. That has been the traditional way that we've used to measure MRD in patients who have Philadelphia chromosome (Ph)–positive ALL, but it can also be a tool to follow patients with Ph-negative ALL and those with T-cell ALL. The tricky part is you need to identify a leukemia-specific abnormality to follow along the patient's course. You need to identify that at diagnosis.

What is the future role of chemotherapy in the treatment paradigm now that new therapies have emerged in the paradigm?

I think [chemotherapy] will definitely be phased out somewhat, especially the intensity and chronicity of it. The treatment for ALL is a multiagent chemotherapy approach that's very intense; it's probably the most intensive chemotherapy that we give in all of oncology. [This treatment approach] lasts over several years, it’s not curative for every patient, and many adult patients simply can't tolerate it.

The advent of immunotherapy offers the potential for better, longer remissions, and oftentimes, with less toxicity. I believe that chemotherapy will always have some part of the treatment for ALL, but we need to learn how to combine it effectively with immunotherapy. [We need to] use immunotherapy earlier in the treatment course, not use it just as a salvage regimen. [We need to] do the right clinical trials to see and understand the benefit of adding [immunotherapy] to initial therapy. It's going to take some time and large cooperative group studies, but hopefully we can get to a point where we have more effective and less toxic therapies than what we have now.

What treatment advances have been made in ALL? Could you expand on the promise seen with CAR T-cell therapies?

As I mentioned, we do have the FDA-approved indication with blinatumomab, which is an immunotherapy. Additionally, CAR T cells are a very exciting area for ALL. [This approach] hasn't been used in the up-front setting for patients who have ALL, so that is an interesting area to pursue for certain high-risk patients where you don't have a lot of hope in traditional chemotherapy approaches. For patients who have a later relapse of MRD-positive disease, considering CAR T cells at that point is very reasonable, ideally as part of a clinical trial. Studies to compare that type of approach with more off-the-shelf technologies like blinatumomab or inotuzumab ozogamicin (Besponsa) [are warranted] because, at that point, chemotherapy is not going to help.

How has the treatment of this disease evolved over the years, and where should future research focus?

You can see the change happening in real-time with CAR T cells and other types of immunotherapy, which is pretty incredible. Understanding the biology of cancer, up until this point, has been focused on learning why these cancer cells become chemotherapy-resistant or why they are inherently chemotherapy-resistant. Using a completely different mechanism of action, which is immunotherapy, shoots that out of the water and offers a completely different approach.

Now we're asking questions, such as, "Why are some tumors more responsive to immunotherapies and others are not? What can we do to overcome barriers to immunotherapy? Why are CAR T cells a ‘home run’ in ALL but less effective, with the potential to be very effective, in [diseases] like chronic lymphocytic leukemia?" We are learning that these therapies are successful, but in a parallel way, we're understanding more about the immune system and cancer to ultimately improve these therapies even more within the next 5 years.