Relapsed/Refractory B-Cell ALL: Adopting MRD Testing into Routine Practice

Elias J. Jabbour, MD: Blinatumomab [Blincyto] is the only drug approved for MRD [minimal residual disease]. At the ASH [American Society of Hematology] Annual Meeting, we had inotuzumab [Besponsa] in a small pivotal trial with 17 patients treated, with a 60% response rate. But in this cohort of patients, they already received blinatumomab and we gave them inotuzumab after. It’s a proof of concept that inotuzumab can work, but it has a different mechanism of action compared with blinatumomab. We’ll see whether we can build on that. If blinatumomab doesn’t work, inotuzumab can be a good option as well. The problem today is when we get patients in the clinic and they don’t get MRD assessment. Is it the same by you, Jae?

Jae Park, MD: Yes.

Elias J. Jabbour, MD: In the community setting, MRD assessment isn’t part of the routine, maybe because ALL [acute lymphoblastic leukemia] is a rare disease or because of the lack of knowledge about the concept of MRD. More work needs to be done. There are 6000 patients with ALL in the United States. Half of them are pediatric and half are adult. They should be referred to academia, not be treated in a community setting. There are a lot of things we need to be aware of.

The NCCN [National Comprehensive Cancer Network] is adopting the recommendation to do MRD assessment, and dialogue between community and academia is necessary to deliver the best care and education about MRD, not to send a blood sample for MRD and debate about the blood or bone marrow. The best sample is given from bone marrow and should be the first pull, not the last one. There are data comparing blood with bone marrow. If you do flow cytometry, you must do bone marrow in the first sample. If you’re doing NGS [next-generation sequencing], bone marrow is better than blood. But the blood NGS is better than bone marrow for flow. We have tools and we need to have dialogue about that.

Jae, tell me about how you’re using MRD in your treatment today. When you follow your patients at Memorial Sloan Kettering Cancer Center [New York, New York], what’s your algorithm in how you manage MRD? How does it dictate your choice of therapy?

Jae Park, MD: To echo your point, I feel so strongly about MRD measurements and that patients need to be seen by an ALL expert or in ALL specialty centers. Even in the large centers where they see a lot of hematological malignancy, they may not see a lot of ALL and may not think about MRD because MRD isn’t as critical in all hematological disease. Whereas in ALL, it’s so critical because it directly impacts the survival. It’s always easier. It’s easier to treat and cure ALL the first time before the morphologic relapse, so you have a very limited window to intervene. I feel very strongly that it has to be seen and should be measured. If you don’t, it’s a disservice to patients and bordering on mismanagement.

I’ll talk about how I use MRD in the frontline setting first. In the frontline setting, the timing depends on the regimen they get, whether it’s a pediatric ALL regimen, young adult regimen, or a pediatric-inspired chemotherapy regimen that we also use in some adults. Typically, we get the first bone marrow on usually either day 14 or 28, and every time we do a bone marrow, we assess for MRD. We assess it again at 1 month and 3 months, as you mentioned. Those are usually the critical times.

The other important point is that even after you achieve MRD negativity and therefore continue on original therapy, it doesn’t mean that you should stop checking for MRD. As you said, it’s a dynamic process. Relapses can happen, and early relapse is always more challenging. That’s also the critical time that relapses can also occur, so we monitor for them. Depending on the regimen, it usually falls every 2 or 3 months after each cycle of the chemotherapy that we’re repeating the bone marrow biopsy. Every time we do that, we assess for MRD. If at any point they’re becoming MRD positive, we also switch therapy to blinatumomab and think about consolidative allogeneic transplant for those patients.

During the maintenance part of treatment of ALL, there’s also typically 2 years of oral chemotherapy they do and then we measure the MRD during the time frame when we do a bone marrow assessment. As you said, in the future, we may do more of a blood NGS to avoid frequent bone marrow biopsies for the convenience of our patient as well. After allogeneic transplant, when they do a surveillance bone marrow biopsy, it’s also important to measure for MRD at the level because the relapse after transplant is even more challenging. But if you don’t assess for MRD, we can also miss the big opportunity to change the immunosuppressive therapy for the patients, or the DLIs [donor lymphocyte infusions], CAR [chimeric antigen receptor] T cells, or others. You want to measure the MRD even after allogeneic transplant.

In the relapsed setting, we don’t follow these patients long-term, because the goal is to get them into remission, hopefully MRD negative, and then go to transplant for those patients. The way that we measure and use MRD is to assure and hopefully achieve MRD-negative remission before they proceed to allogeneic transplant. Because we also know that MRD pre-transplant predict a worse outcome post-transplant. Now that we have a different type of immunotherapy available for our patients, we want to do our best whenever feasible to achieve MRD negativity prior to going into the allogeneic transplant.

Elias J. Jabbour, MD: Let me tell you about our experience at The University of Texas MD Anderson Cancer Center [Houston, Texas]. We use hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone] when we’re going to integrate blinatumomab in the frontline setting. Our strategy has been to assess for bone marrow on days 21 and 28 and assess for MRD. We do it monthly until we get MRD negativity, and then every 3 months thereafter. We used to use flow cytometry. Though we still use 6- to 8-color flow, we’re also using NGS on a regular basis as of 2021. When it comes to treatment decisions, do I use MRD to make treatment changes? We published that the dynamic of MRD matters. If you have MRD negativity from CR [complete response], you have the best outcome. But if you’re MRD positive at 3 months, you should go to blinatumomab therapy and then discuss transplantation.

Essentially, we send the high-risk patients to transplant based on cytogenetic abnormalities, complex hypodiploidy, TP53, and ATP ALL. The question of MRD is questionable because the standard of care is to do blinatumomab and allo [allogeneic] transplantation. But we’re exploring the role of NGS to see if we can get into MRD negativity, in which case transplant may not be needed. We showed data at EHA [European Hematology Association Congress] that if we give blinatumomab for MRD positivity and then convert them into MRD negativity for 2 cycles, and we give them the maintenance approach—4 course of blinatumomab and then we maintenance over the year—patients eventually can spare the need for allo [allogeneic] transplant, especially if they’re MRD negative by NGS. But it’s a small series and provocative data.

Here’s the role of maintenance with some of our therapy. I’m not saying it’s standard of care, but it’s something to further be explored to look for the outcome. The indications for transplant today are changing. We know that in Ph [Philadelphia chromosome]-positive ALL, everybody would receive transplant. We’re basing our decision on MRD. If you have CMR [complete molecular response], no disease, transplant isn’t needed. Another high-risk subset is the Ph-like ALL, where essentially, they remain MRD positive in the vast majority. These patients should get blinatumomab and then transplantation. But not all Ph-like are similar. The worst group is Ph-like, CRLF2, JAK2, which should get transplant. But maybe there are others. If we add TKIs [tyrosine kinase inhibitors] or we use blinatumomab upfront, we can convert into MRD negativity, and transplant may not be needed.

When it comes to relapse, we have some provocative data where we use mini-CVD [cyclophosphamide and dexamethasone at 50% dose reduction], no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses, inotuzumab, and blinatumomab and we go for allo [allogeneic] transplant. We have a series with 100 patients. Half of them didn’t get a transplant. Among responders in salvage 1, it was shown that if you’re MRD negative by NGS, transplant doesn’t add much. But this is a small series at a single institution. The message I’m trying to convey here is if we have MRD negativity to a very low level, it may dictate the choice of therapy.

Finally, I’d like to say that assessing for MRD is critical. We can’t treat ALL without assessing for MRD. In the future, assessment for MRD may shape our treatment. It may allow us to de-escalate or intensify therapy. Of course, with the data we have today, MRD alone isn’t enough. We should put MRD in the context of biology. But with very good therapy, like blinatumomab, inotuzumab, CAR T cells, and very good assays, like NGS, we may be able to overcome the biology and rely on dynamic parameters and then shape therapy accordingly.

Transcript edited for clarity.