Aaron Logan, MD, PhD, Associate Professor of Clinical Medicine at the University of California, San Francisco, and Elias Jabbour, MD, Professor in the Department of Leukemia, Division of Cancer Medicine, at MD Anderson Cancer Center in Houston, discussed whether measurable residual disease (MRD) negativity indicates a cure in patients with acute lymphoblastic leukemia or if an allogeneic hematopoietic stem cell transplant is still necessary.
Dr. Logan: MRD represents the residual cancer cells in the bone marrow of somebody who is in a complete remission (CR) after treatment for acute lymphoblastic leukemia (ALL) or sometimes other blood cancers.
There are several methods available for quantifying MRD. We know from various studies that MRD that is quantified at a level of greater than 0.01%, or one leukemia cell out of 10,000 bone marrow cells, is strongly indicative of a future relapse after initial therapy, even if a CR is achieved. We also know that patients who achieve less than 10−4, or 0.01% disease burden, after therapy, have a significantly lower but non-negligible risk of relapse. We now have newer techniques that can get us down to a sensitivity of 10−6, or one leukemia cell out of a million.
There are emerging data that show this higher level of sensitivity gives us better prognostication about the potential outcome of our patients, including their risk of relapse, but the data are still maturing. We don’t have very large studies yet using this approach with next-generation sequencing (NGS) and high-sensitivity MRD quantification to verify that achievement of MRD negativity at that level is in fact a cure. That leads to the question, “How should we use current MRD techniques that are very sensitive to guide our decision-making regarding continuing consolidation or maintenance therapies versus taking patients to a consolidative allogeneic stem cell transplant?”
Dr. Jabbour: When we look at the meta-analysis published by Berry et al, even among patients who are MRD-negative, they’re still relapsing. We know patients who were MRD-positive don’t do well, but those who were MRD-negative are still relapsing and that speaks to the limitation of the current assays to test for MRD. We hope that with the application of NGS and having an assessment of the depth of the response, that can tease out the outliers in whom transplant may not be needed. The U.S. Food and Drug Administration used the data of the meta-nalysis to accept MRD as a surrogate for outcome and approve a drug for MRD-positive ALL, which is the first one. In the BLAST trial, where patients at 10−3 disease burden are given blinatumomab, the endpoint was to convert them into MRD negativity and be able to transplant the majority of them.
Historically, those who were MRD-positive had a median survival of only 12 months, and in the BLAST trial, the survival for the whole cohort of 113 patients was 36 months, which is triple what it used to be at baseline. Those who responded had an even better outcome. At three to four years, survival was at 50%, which is what we see in somebody who is MRD-negative or responding at the beginning. In the trial, a median of two courses of blinatumomab were administered, and those who responded had a transplant. The study was not designed to assess the impact of transplant—whether or not it was needed. The majority of patients (75%) received transplantation. The researchers did the landmark analysis to assess the impact of transplant in first CR, and there was no positive impact, meaning there was no difference in outcomes between those who had a transplant and those who did not.
In fact, those who had a transplant had less relapse, but there was transplant-related mortality that nullified the advantage seen. This is where the question comes in: “Do we use transplant for everybody?” Of course, the standard answer is, “let’s randomize patients to transplant versus no transplant, and we can know the answer.” But that will not happen in our lifetime. You can try to transplant based on donor availability, but no one will do that. At MD Anderson Cancer Center, for example, we try to use blinatumomab at a very early stage at 10−4—which is not in line with the drug’s label—and instead we said, “We’re going to give more courses—four or five courses—and if we don’t transplant, we’re going to do a maintenance approach.”
The exposure is prolonged, and we are intervening earlier. It is important to monitor for MRD using a better technique, such as NGS. We’ve shown that we can have a better survival than the BLAST trial, at a 10−4 intervention, giving more blinatumomab. We’ve shown as well that although the numbers are smaller, transplant may not be needed because we do not see a difference in outcomes. Here, the question is, “Is transplant needed or not?” Of course, the standard of care says transplant is needed, but I think if we can get to a level where we can get early responses, get NGS negativity, and develop a maintenance program, transplant may not be needed. We know, for example, in a pilot trial published by Topp and colleagues before the BLAST trial, that in 20 patients, there were six outliers who did not have a transplant and were surviving the longest.
Now, we do not know what these patients received, but should we develop a plan for maintenance in the case that transplant may not be needed? We’re assessing for MRD eradication from the early point of time. For example, if you can get MRD negativity at complete response, survival is better than if you have MRD negativity down the road. If you integrate your best-approach immune therapy into the frontline setting to deepen the responses, then a transplant may not be needed, and we can overcome the issue of transplant. In fact, we’ve shown that by having MRD negativity by NGS on day 21, the long-term survival is almost 100%. Eradication of MRD early on can eventually nullify the poor biology and improve the outcome.
Are we ready for prime time? The answer is “not yet,” but I think we are making progress. I can tell you, for example, in a Philadelphia chromosome (Ph)-positive disease, if you get MRD negativity, transplant is not needed. In Ph-like ALL, there’s a group of patients with CRLF2-positive, JAK2-negative, the achievement of MRD negativity by NGS may alleviate the need for allogeneic stem cell transplantation, which is not the case for those who are JAK2- and CRLF2-positive, where transplant is still needed. We are moving from transplant for everybody who is MRD-positive to identifying a group of patients who may not need transplant if we deepen the response.
Finally, when we look at the NGS impact, for example, of chimeric antigen receptor (CAR) T-cells in the relapsed setting, there is a recent paper published by Pulsipher and colleagues, where they look at the impact of three-month NGS MRD negativity, and those who are MRD-negative by NGS at 10−7 had a very low risk of relapse, and transplant may not be needed. In contrast, those who are MRD-positive had the highest rate of relapse, and transplant may need to be offered. I think we are at the time when we can use good NGS techniques to identify good responders, and we can identify patients in whom transplant is needed versus not needed, and instead of escalation of therapy, we deescalate therapy.
Dr. Logan: I agree with a lot of what Dr. Jabbour said, including that hopefully the use of NGS and high-sensitivity MRD quantification will give us better predictions of who is at risk for relapse. But, for instance, the BLAST study used a threshold of 10−4 for eradication of disease, and even in patients who achieved MRD negativity by that threshold, about 60% relapsed if they didn’t go to transplant, and only 20% relapsed if they went to transplant. This was not a randomized comparison, but there was a much higher risk of relapse without transplant. But there was, as mentioned, an offset based on treatment-related mortality associated with transplant, which was substantially higher. It was about 30% in patients who were transplanted in the BLAST trial versus less than 10% treatment-related mortality if they didn’t get a transplant.
After five years of follow-up, there were about 45% of patients alive if they got blinatumomab followed by transplant, and there were about 30% alive if they got blinatumomab with no transplant. That may not have been statistically significantly different given the relatively small numbers, but it was numerically suggestive that there’s a benefit to transplant, even in patients who achieve MRD negativity after blinatumomab.
What we don’t know about the patients in the BLAST study is their genomics. Dr. Jabbour has already invoked that there are certain subsets that have a much higher risk of future relapse, including Ph-like disease and patients with translocation t(4;11), mixed-lineage leukemia (MLL or KMT2A) rearrangements, and those with complex cytogenetics. My current practice is to use MRD to guide who not to transplant unless they have some of these high-risk features. We know, for instance, that blinatumomab, inotuzumab, and even CAR T-cell therapy do not work very well for patients who relapse with some of these high-risk features.
I don’t want to lose the opportunity to get them in the best available remission, and if they happen to be MRD-negative after their induction or consolidation, and they have an MLL rearrangement or another high-risk lesion, I still want to take them to transplant because I believe that is the best, gold-standard, evidence-based way to achieve long-term disease-free remission in these types of patients. We know from older data, such as the UKALL XII study, which looked specifically at some of the patients who had translocation t(4;11), that the outcomes were actually pretty good in those who got to transplant. Survival was better than 50% if they were transplanted, but it was in the 20% range if they didn’t get a transplant.
I think the abundance of evidence of the presence of high-risk cytogenetic abnormalities or molecular abnormalities still suggests that we should take some of these patients to transplant, even if they achieve MRD negativity. But hopefully we’ll learn more about using the NGS approach and maybe even further subdivide the CRLF2 patients based on the molecular mutations they have and decide which ones to transplant. Right now, I do take those patients with high-risk genetic lesions to transplant, even if they achieve MRD negativity.
Dr. Jabbour: I agree with Dr. Logan. In the old days when we used suboptimal treatment, of course we had higher relapses leading to transplant, but when we are integrating all the best effective therapies upfront—and maybe one day CAR T cells upfront for high-risk patients, then what we know now as high risk may not be high risk anymore and things will change.
We’re not ready yet, but there are phase II trials moving toward this goal to give better treatment upfront and improve outcomes. For example, the combination of hyperfractionated CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy plus blinatumomab and now inotuzumab in young patients, with several of them having adverse features, is producing very promising results, with a three-year survival rate of 84%. Things are changing. What was poor risk in the past may not be any more today and definitely not in the future.
I agree today to transplant people who are MRD-negative, who have poor biology, such as hypodiploidy, complex karyotype, and Ph-like, JAK2-positive disease, but I think we are tuning our treatment armamentarium and strategy to decrease the need for allogeneic transplant and intensive approaches toward more targeted therapy and using immunotherapy and CAR T cells.
Dr. Logan: I hope to see studies like those that Dr. Jabbour and his colleagues are conducting ultimately lead to a replacement for allogeneic transplant for some patients with high-risk genetic abnormalities. I think the approach of incorporating blinatumomab in maintenance therapy is an excellent idea, because then we get some continued immunologic consolidation, which is otherwise lacking from chemotherapy-only maintenance. We know that one of the reasons allogeneic transplant works is you get continuous immunologic activity against residual leukemia cells. I think we need to replace that in one way or another, whether it’s going to be CAR T cells or maintenance with quarterly blinatumomab or some other immune-active agent will remain to be seen. I think there’s the potential to replace transplant, but based on the current state of the data, I think that we should be transplanting the patients with high-risk genetic lesions, even if they achieve MRD negativity.
Dr. Jabbour: I would like to go back to the BLAST trial and what Dr. Logan is saying about transplant. In the BLAST trial, the number of courses given were only two, and Dr. Logan knows that’s something very important—maintenance therapy. It’s not that we give one or two courses of blinatumomab and then you’re done; we know the short half-life of the drug. These patients are going to relapse unless we go for transplant. But if you want to get rid of transplant, we have to replace it with something smarter. Dr. Logan mentioned maintenance therapy, and I’m all for it. Use immunotherapy as maintenance, as a booster, to maintain the remission and keep the clones suppressed.
We are in a great time today, because there are a lot of great things happening, and we are walking away from the traditional approach of intensive chemotherapy and allogeneic transplant. We are not yet ready to get rid of all transplants, but there are some subgroups of patients in whom we can spare transplant. Further understanding of the biology, assessment of MRD by better tools, and integration of immunotherapy and novel agents upfront may spare patients from transplant. I think down the road, patients will require less transplant.
Dr. Logan: I think MRD is currently allowing us to select patients with standard-risk disease who don’t need a transplant in first remission, but based on the available data, I think high-risk patients should likely still be allografted in their first remission. We know the outcome of an allogeneic transplant is best when a patient goes into the transplant MRD-negative. In these patients with high-risk genetic abnormalities, if they are lucky enough to achieve MRD negativity with chemotherapy with or without blinatumomab and inotuzumab, we don’t want to miss the opportunity to take them to a potentially curative allogeneic transplant, because if they relapse after receiving all of those agents upfront, they’re going to have very limited opportunities to get back into remission.
Dr. Jabbour: I think we are in a time of treatment à la carte. MRD is here to stay, and it allows us to treat à la carte—we take from the menu what is suitable to the patient based on their biology, MRD, and treatment available. I think one treatment that fits all is not relevant anymore.
Dr. Logan: I’ve long been an advocate of using MRD to personalize therapy for patients, because we’re measuring, in a serial fashion, hopefully, how each patient is responding to their therapy and making sure that we’re achieving eradication of the disease. I commend Dr. Jabbour and his colleagues for pushing this field forward and identifying alternative approaches using the novel agents, such as inotuzumab and blinatumomab, to achieve deeper MRD-negative remissions at the NGS 10−6 level and developing maintenance strategies that potentially can replace transplant. I think we need to see their data mature to verify the rate of long-term disease-free remissions without transplant before people outside of the clinical trial setting opt not to transplant patients with high-risk ALL.
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