MRD: A Key Predictor of Clinical Outcomes in Acute Lymphoblastic Leukemia

Annie Im, MD, discusses the importance of minimal residual disease in acute lymphoblastic leukemia, the role of transplant, and novel treatment approaches under investigation.

Annie Im, MD

Assessing for minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) is imperative, as it can be used to predict clinical outcomes, such as relapse and survival in patients, said Annie Im, MD.

“With the techniques that we have currently for MRD, we’re learning that this is a really important test for us to be able to predict outcomes for patients and that can help us change our treatment strategies as well, such as whether or not we recommend something like an allogeneic stem cell transplant,” said Im, an assistant professor of medicine at the University of Pittsburgh School of Medicine, hematologist/medical oncologist, Division of Hematology/Oncology, Hillman Cancer Center.

In those who are ineligible for transplant, other exciting approaches have emerged in the space, such as blinatumomab (Blincyto), which received an accelerated approval from the FDA in March 2018 for the treatment of adult and pediatric patients with B-cell precursor ALL who are in remission but still have MRD.

This decision was based on data from the phase II BLAST study, in which treatment with the agent led to a nearly 80% complete MRD response rate in patients with MRD-positive ALL in hematologic complete remission. The agent is now being studied in combination with chemotherapy in the upfront setting in a phase III trial (NCT02003222).

Another exciting approach that has gained traction in ALL is CAR T-cell therapy.

“It has been really exciting. In fact, patients [with ALL] were some of the first patients who were treated with CAR T cells,” said Im. “Some of the sickest patients with very relapsed/refractory disease were cured [with this approach], and so it’s pretty amazing.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Hematologic Malignancies, Im discussed the importance of MRD in ALL, the role of transplant, and novel treatment approaches under investigation.

OncLive: What is the importance of MRD in predicting clinical outcomes in ALL?

Im: We’re learning that MRD is actually one of the most important prognostic factors in ALL, even independent of some of the traditional clinical risk factors. We’re also learning that transplant can help patients who have MRD positivity with ALL after induction chemotherapy. In addition to that, there are nontransplant strategies, such as blinatumomab or immunotherapies that we can utilize to eradicate MRD for these patients as well.

In terms of how you’re determining MRD, are there different assays or tools available that you’re using to predict those outcomes?

There are several different techniques that we’re using to assess MRD. There are some older techniques, such as quantitative polymerase chain reaction (PCR) of either a T-cell receptor or immunoglobulin genes. There is also PCR of fusion genes that may exist. Another common strategy is multiparameter or multicolor flow cytometry.

However, one of the newer techniques that we’re using is actually next-generation sequencing. There is actually an FDA-approved test now called ClonoSEQ that being used; this is commercially available for sites that may not have access to some of the other techniques. This is great because now this [testing] is widely applicable.

Could you expand on how MRD is being used in relation to transplant?

We can actually use MRD as a way to determine who might be eligible for a stem cell transplant. For these patients, we know that the risk of relapse is going to be higher with just standard chemotherapy. Therefore, we would think that the benefit of the transplant outweighs the potential risks. As such, for these patients we would we normally recommend allogeneic transplant.

With the various approved and emerging therapies in ALL, do you believe that transplant will continue to have a role in the treatment of these patients?

That’s a good question. We may get to the point someday where we see that some of these immunotherapies, blinatumomab, CAR T-cell therapies, etc. that are coming down the pike may be able to take the place of stem cell transplant in terms of being able to maintain long-term remissions.

However, for right now, we are still utilizing stem cell transplant in conjunction with these therapies. I believe that right now the best strategy is to use them together. However, someday we’ll see if some of these [approaches] may [replace transplant in the paradigm].

What available options would you recommend to transplant-ineligible patients?

Blinatumomab is a nice strategy for patients who are not eligible for an allogeneic transplant; it’s relatively safe and can be used for these patients to eradicate the MRD and hopefully help decrease their risk of relapse, but still be a safer therapy.

Blinatumomab is currently FDA approved for use as a single agent. What are some of the next steps with this drug?

[Blinatumomab] is actually being studied in combination with chemotherapy as a strategy for patients [in the upfront setting]. We’ll see if that’s enough to eradicate MRD upfront. I believe it’s also being studied in other settings as well to see if we can maximize how we use it. Because, as you say, it’s currently just approved for as a single agent [in this space].

Could you speak to some of the advances that have been made with CAR T-cell therapies in ALL over the years?

Right now, it’s a nice bridge to transplant for some of these patients—those who are never able to get into a remission to be able to go to transplant. For some patients, [this approach] can even take the place of [transplant]. It has been pretty exciting to see miraculous outcomes with CAR T-cell therapies for patients who otherwise would not have options.

What are some of the overarching questions that remain with CAR T-cell therapy in this field?

Whether or not CAR T-cell therapies can take the place of transplant is a big question; [the answer to] that is something we’ll hopefully learn as further studies are being done. To be able to essentially cure this disease, when it’s very refractory to standard treatments, would be something that we need to learn more about. This is because there are patients who can get into remission and still relapse after CAR T-cell therapies. Therefore, [determining] whether or not that’s [an approach that] that could cure patients effectively down the line would be great.

FDA Briefing Document Oncologic Drugs Advisory Committee Meeting BLA 125557 S-013 Blincyto (blinatumomab) Applicant: Amgen, Inc. Published March 29, 2018. Accessed July 2, 2019.