MRD Assessments in B-Cell ALL

Elias J. Jabbour, MD: It’s too late to cure ALL [acute lymphoblastic leukemia] when we wait for multiple failures. We have to tackle the disease from the beginning, and we need to look at minimal residual disease [MRD] from the beginning. Jae, can you give a brief summary of the role of MRD testing in ALL, where we stand today?

Jae Park, MD: Yes. One can argue that MRD is probably the single most important testing that we can do as ALL physicians. It can potentially change the course of the patients. MRD stands for measurable residual disease. It used to be minimal residual disease, but now we call it measurable residual disease because the sensitivity of detecting the disease is getting better. It simply refers to the depths of remission that we measure. What’s unique and remarkable in ALL is that we now have very good, robust data in multiple prospective clinical trials and a meta-analysis that demonstrate that MRD positivity at the end of induction and consolidation is highly prognostic of their long-term outcomes. They’re the harbinger of a relapse for these patients.

Even more importantly, in ALL and B-cell ALL, we have a drug that specifically works against and for MRD. Testing for MRD is very important for us to do. The timing to do MRD testing is variable because they vary in different frontline ALL regimens. The exact timing may vary, but we all mostly agree that about 3 months into the induction is an important decision-making time point to switch the therapy if someone is still persistently MRD positive. There are data in pediatric ALL. For example, if they’re MRD positive at day 14, day 28, or day 56, then those could also be prognostic markers. The earlier you enter into MRD negativity, the better the outcome is. That speaks to the chemosensitivity nature of the disease itself.

The typical time to test for MRD is at 3 months. There are largely 2 different ways to measure MRD. One is multiparameter flow cytometry, which is one of the most common ways in pediatric ALL. That’s the way we’re doing it at my center. But you need a good flow cytometrist. You also need to make sure you’re doing an MRD level of sensitivity with a 10-4 level sensitivity at the minimum in order to be called an MRD flow. That’s key. The second predominant way of getting them is by NGS [next-generation sequencing], which you can also get a deeper, more sensitive MRD measurement up to 10-6. In order to do that, 1 thing to keep in mind is you need a diagnostic material. You need original sequence to compare with your post treatment to see whether you’re still able to detect a genetic variability or the IGHV [immunoglobulin heavy chain variable] sequence after the treatment.

These are 2 ways to detect MRD. It’s an important marker because if you’re MRD positive at the end of induction consolidation, continuation of the same chemotherapy regimen that you initially committed these patients to wouldn’t be the best way to maintain. You won’t be able to convert MRD positive into MRD negative. If you don’t measure them, it will be too late. This will be leading to morphologic relapse. That’s the reason I say it’s decision-making time, because that’s the time you want to convert the therapy to something else.

Elias J. Jabbour, MD: I agree with you. When my patient comes to see me, there’s nothing minimal about minimal disease. It’s refractoriness. Whether you have 1 cell, 10 cells, or 50 cells, it’s refractoriness to treatment. There was a good meta-analysis with 13,000 patients in pediatric and adult ALL published by Dr Donald Berry [The University of Texas MD Anderson Cancer Center] in JAMA Oncology in 2017. It clearly showed that regardless of how you assess for MRD or at what time, if you’re MRD positive, you have a worse outcome when it comes to event-free survival and overall survival. Interestingly, the hazard ratio is identical in adults and pediatrics: 0.28.

Today, we have 2 kinds of risk. We have the baseline and dynamic. The baseline is the biology, and the dynamic is how the response was. We know from the old days that if we give steroids and we see response on day 7, it affects chemosensitivity. If somebody remains MRD positive, they’re refractory to treatment and we must change our therapy.

In fact, the FDA [Food and Drug Administration] agreed to consider MRD as a surrogacy for survival in approval of a drug. The first drug approved in that sense was blinatumomab [Blincyto]. If you’re MRD positive, the survival is only 12 months. If somebody is followed and becomes MRD positive, the survival is really short as well, because within a couple of months, they can declare their failure. Therefore, the best way to follow our patients with ALL today is to assess for MRD if we intervene. Because waiting for relapse [is too late]. I’ll give an example with blinatumomab. The TOWER trial showed that if you’re having a full relapse, the response rate is 40% and the survival is 7.7 months. In contrast, if somebody is MRD positive and you give blinatumomab, the response rate is 70% or 80% and the median survival in the long run is 36 months on average. Therefore, we must assess for MRD and act on it.

To add to Jae, we did a presentation at the ASH [American Society of Hematology] Annual Meeting the year before the last on the limitation of flow and NGS. Because when we do flow studies and we have an MRD, the threshold is 10-4 and our MRD negativity is 60% or 70% at the induction. If we do NGS, it’s 23% or 25%. That means patients who are considered to be negative by flow are positive by NGS and are relapsing. In fact, when we look at the outcome of NGS MRD negativity, those with MRD negativity by NGS had a survival of 95%. Therefore, it’s important to assess for MRD because it will allow us to tailor and shape our therapy and eventually use novel approaches—be it blinatumomab or eventually CAR [chimeric antigen receptor] T cell in the future—to reverse the refractoriness and improve the outcome.

Transcript edited for clarity.