Evolving Treatment Approaches Pre- and Post-Transplant

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Peer Exchange | <b>Acute Myeloid Leukemia: 2021 Perspectives on Testing, Systemic Therapies, and Transplantation</b>

Vinod Pullarkat, MD, leads a detailed discussion on evolving treatment approaches using MRD pretransplant, and panelists consider recent therapeutic advances for the post-transplant setting.

Harry Erba, MD, PhD: Vinod, how are you using MRD [minimal residual disease]? Does it impact who you take to transplant or the preparative regimen?

Vinod Pullarkat, MD: This has also evolved. There was a time when we would take patients with some degree of disease to transplant knowing the outcome wouldn’t be good. Then we were focused on complete remission. Now the question is, should we try to make the MRD negative before we take the transplant, knowing that the transplant outcomes will be better? I alluded to this earlier. Let’s say a patient who had 7+3 in this cycle of HiDAC [high dose cytarabine] still has MRD. We need to consider whether you should give them venetoclax and make them MRD negative, and then take the transplant. We don’t know the answer to the question, but the prognostic value of MRD is well established in treating ALL [acute lymphocytic leukemia] and AML [acute myeloid leukemia].

If you take patients who have MRD, then the question is whether we should do something on the other side after the transplant to try to minimize the risk of relapse. There’s an ongoing study using lower doses of an HMA [hypomethylating agent] and venetoclax as a false transplant maintenance, considering both if they have actionable mutations, and whether we should add those agents down the line. My preference would be to take them to transplant in an MRD-negative state. If we do additional therapy, that doesn’t add to the toxicity and the nonrelapse mortality of transplant. HMA is an example that doesn’t cause the tissue damage that Mark was talking about. You possibly are in a better situation in an MRD-negative state, and you haven’t delayed the transplant too much because the response is quick.

Harry Erba, MD, PhD: Mitchell Horwitz here at Duke [Cancer Institute] led a trial of reduced intensity vs myeloablative preparative regimens in transplant for AML, and there was no benefit. In fact, the myeloablative preparative regimen looked better. Then Chris Hourigan did double-stranded DNA sequencing on many of those samples and found that there was a benefit of the myeloablative preparative regimen, and those patients were still positive using his double-stranded DNA sequencing. Do those data affect your choice of preparative regimen?

Vinod Pullarkat, MD: No. There was a trial that was stopped prematurely—I think it was for the CTN [Clinical Trials Network]—where the myeloablative arm performed better to reduce intensity for AML. Those were before the MRD days, so I’m assuming that myeloablative regimens, to some extent, can overcome the MRD positivity, but with the new assessments for MRD, we have to question, especially for patients who are right at the border and could take either regimen, whether you’d have to build it to a myeloablative regimen.

Harry Erba, MD, PhD: When the transplanters come back to me and say, “That’s too much disease for me to transplant”—whatever the number is, MRD positive or negative—I always worry, what am I going to be able to give them now, to get them into that deeper remission without beating them up? I often wonder, why don’t we just transplant them and then do something, as you said, Vinod, on the other side? Mark, what about maintenance regimens after transplant?

Mark Levis, MD, PhD: That’s well and good, but we’re looking at FLT3. If you go into transplant with a detectable FLT3, you’re going to relapse fast that maintenance is not going to do you any good. In Chris Hourigan’s own study, all 10 of the detectable FLT3-ITDs in that study died. It didn’t matter whether you used myeloablative or nonmyeloablative regiments. You can’t go back and cure the sins of MRD with post-transplant maintenance. In other words, MRD pretransplant is a big deal. We don’t know what that threshold is. We don’t know what to do about it when we see it, but I don’t believe maintenance will fix the problem. Maintenance will fix a lot of sins, and that’s where the field is heading: maintenance with IDH, maintenance with venetoclax. We’re looking at all sorts of maintenance. We’re doing maintenance with bispecific antibodies but not MRD. I don’t think it fixes MRD, at least MRD by our ability to measure.

Courtney DiNardo, MD: The challenge is you never know, in the post-transplant setting, who’s going to be able to get maintenance because there are so many moving parts of a transplant that require engraftment and no graft-vs-host disease and the recovery of counts. Not everyone you want to start on a maintenance regimen—like a FLT3-mutated patient—is quickly able to do that.

Vinod Pullarkat, MD: The pan-specific profile of these agents is different after transplant, so that’s another problem.

Harry Erba, MD, PhD: I completely agree with what all my learned colleagues have just said. However— 

Mark Levis, MD, PhD: But—

Harry Erba, MD, PhD: What our audience is hearing is that there are so many reasons why a transplanter might say no to your patient, that when I see the data coming from single-arm transplant studies with incredible outcomes, they give me pause about the selection of those patients and don’t really reflect the people I’m seeing in my clinic on a day-to-day basis. I hope I didn’t ruffle any feathers. I believe in transplant. I love what you guys do.

Mark Levis, MD, PhD: Transplanters will routinely pick an Olympic athlete in an MRD-negative remission and say, “That’s the 1 I’m going to do.”

Harry Erba, MD, PhD: There you go. I tell my fellows, “I take the patients who I’ve already cured and then cure them.”

Mark Levis, MD, PhD: That said, at MSKCC, Memorial Sloan Kettering [Cancer Center], they’re transplanting 50% of patients with AML who walk in the door, as are we [at Johns Hopkins University School Sidney Kimmel Comprehensive Cancer Center]. We’re not being quite so selective.

Harry Erba, MD, PhD: I’m glad I saw the job as a nontransplanter, so that’s good. Thank you for not taking them all. There’s something for me to do. Along those lines, there’s something new for me to do because we’ve been looking for some therapy that might extend relapse-free and overall survival in our patients with AML who cannot go onto transplant. Now we have oral azacytidine. Based on the QUAZAR study that was done in patients who were 55 years of age and older—who got intensive chemotherapy for their AML; they couldn’t have a core binding factor leukemia—they went into remission. Eighty percent got consolidation, and 20% did not. They got randomized to oral maintenance with azacytidine or a placebo, and there was a survival benefit. There was an improvement in median survival of just over 2 years in the patients who got the maintenance, and it was statistically better than placebo.

There are patients I see who get intensive therapy who I’ll offer that regimen to. One of the places I’ll use it is for the patient who got intensive chemotherapy and got beaten up. I have 2 patients like this right now. I’m worried about giving them HiDAC, but I want to get them to a transplant. I’ve used, orally, cytidine in that situation to get them to the transplant. It does seem that there’s clear MRD in some of the patients, although the placebo also cleared MRD in some of them too. This is shows 1 of the caveats about all these fancy MRD assessments that we do that we don’t have time to talk about.

Let me move on and talk about something new in terms of allogeneic stem cell transplant. This is something that my colleague Mitchell Horwitz has been involved with, as have many of you guys, many of the transplanters: the omidubicel. I can say it, so maybe someday I could be a transplanter. Vinod, why don’t you tell us about it?

Vinod Pullarkat, MD: The data look amazing because, as everyone in this audience knows, there are still patients who don’t have matches, who are on the wait list for donors, or who aren’t candidates for haploidentical transplant. They may still need an alternative donor source and umbilical cord blood is readily available. There have been many strategies trying to expand the use of cord blood with them. The challenge is that they don’t really shorten engraftment. This technology, the NAD technology, gets meaningful expansions of the CD34 progenitors. Most important, the neutrophil engraftment in this study is really short, like 10 to 12 days, which is remarkable for cord blood. If you do a haploidentical transplant with post-transplant Cytoxan [cyclophosphamide], you have much more delayed engraftment, which may be a problem for many patients. If these data were to be in larger studies—if this is true—then this is a major advance because we still struggle with some of our older patients who don’t have siblings or unrelated donors or who may have antibodies against donor antigens.

This is a major advance in this field. If this is true, we may have a donor for almost every patient, and we can do cord-blood transplant. This study was good; it looked like other donor sources. Importantly, the bacterial infection—infection risk is a big problem for these patients, especially among the relapsed patients; and if you’re engrafting neutrophils in 10 to 12 days, that should have a major impact on bacterial and fungal infections. I don’t know about the T-cell engraftment, but 1 problem with a haploidentical transplant is often their…reconstitution is delayed, so we’ll have to see those data, but they look very promising. The differences aren’t minimal; they’re significant.