Establishing MRD's Role in ALL Management


Max S. Topp, MD: The BLAST trial was unique because it was the first time that we had a primary endpoint of conversion of MRD [minimal residual disease] positive to MRD negative. So it was the first time the regulatory agencies, both in the United States as well as in Europe, have accepted a primary endpoint based on MRD testing. Recognizing this endpoint is pivotal for us, because looking at other disease settings—in hematology at least—it is very clear that MRD is very important. It’s going to be an endpoint for other disease settings. So this trial really has pioneered the awareness within our society—the hematology field but also with regulatory agencies—that there is something beyond complete remission, beyond OS [overall survival] or PFS [progression-free survival]. We have now established MRD as a way to analyze that. So I think apart from the clinical benefit and the unique mechanism of action that it has, this is really, in my mind, a key outcome for us hematologists.

Anyone who remains MRD positive after consolidation is chemotherapy refractory. So it is a key point in making the decision to continue therapy with standard therapy, chemotherapy, maintenance therapy, etc; or to branch off to give the patient blinatumomab and transplant; or in an elderly patient, just blinatumomab. Similarly, if a patient becomes MRD negative during consolidation maintenance or after in the observation period, that also would change the way we treat the patient. So we’d stop consolidation straightaway if the patient becomes MRD positive during consolidation. And the same goes for maintenance therapy.

If you use maintenance therapy and a patient becomes MRD positive during that period of maintenance therapy, we’d straightaway switch over and expose the patient to blinatumomab and sequentially a transplantation. In the observation period there’s a very similar sequence, and we would at least offer them blinatumomab in that context, and potentially you have to take them to transplant.

So every time, MRD positivity or negativity is going to decipher whether you stay on track with what you’ve been doing, or if you’re MRD positive, you have to do something different. Because once you’re MRD positive, 95% of your patients, despite continuing therapy, will be relapsing with full-blown relapse. And then you are in a much more uncomfortable situation. If you catch it earlier, you have a very high response rate, bearing in mind that blinatumomab is also licensed for refractory ALL [acute lymphoblastic leukemia], so there won’t be a full-blown relapse. Response rates are lower. They’re just 43%, 44%. And also looking at that patient population—looking at the patients with high tumor burden and low tumor burden—of the ones with even high tumor burden, which is the majority of them, just 30% will have a response. So it’s very obvious that catching it early results in an 80% response rate versus on the deep end. There’s only a 30% response rate once the patients really develop full-blown relapse with 80% blast counts in the bone marrow.

Maintenance therapy we will offer to every patient irrespective of age, and we try to get away with that by looking in a particularly favorable patient population who had become MRD negative very early onward after treatment and then remained MRD negative for 1 year. And then we asked the question, can we take away maintenance therapy for these MRD-negative patients? But unfortunately, what happened is that there was a higher relapse rate. So MRD testing is great, but it’s not the whole story, because if you look at it, MRD is a reduction of only maybe 5 or 6 logs of tumor burden. So that patient, when he enters the arena, presents himself with 1x1012 leukemic cells, so if you reduce by 6 logs and you’re below the detection range, you still have a huge space to cover. We don’t know what’s happening down there, so maintenance therapy is absolutely necessary for leukemia patients, in ALL at least.

Transcript Edited for Clarity

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