Cross Q&A: Team Moffitt Marrowvingians


The Memorial Sloan Kettering team gets the opportunity to question the clinical trial data presented by the H. Lee Moffitt team.

Steven Frommeyer: Thank you, Marrowvingians. Great job. At this point, it’s time for the Mavericks, for Dr Park and the rest of his crowd to really give it to the Marrowvingians. This is the time to ask them questions, ask them to defend the data, and make sure they did a great job. Go at it.

Anthony Mato, MD, MSCE: I’ll ask a question. I’m not that familiar with the ALL [acute lymphoblastic leukemia] literature, but to the first presenter, it seems like it’s completely acceptable to change the standard of care without doing a randomized trial, which isn’t something we’re used to in our world. But based on the inotuzumab data—you can direct the answer to me and to Dr Kantarjian—do you think that regimen should be considered a standard of care anywhere in the absence of a randomized study?

Nikesh Shah, MD: That’s an excellent question. That’s tough. We always like to see randomized data. Things do get approved in phase 2 studies with very promising data, or if they’re changing the treatment paradigm. The challenging thing is that since the publication of the inotuzumab–mini-CVD [reduced-dose cyclophosphamide, vincristine, and dexamethasone] trial in 2018, there have been so many more advances in the frontline setting. Dr Thompson is going to talk about frontline blinatumomab [Blincyto] pretty soon, and both blinatumomab and CAR [chimeric antigen receptor] T-cell therapy in the relapsed setting. It’s tough. It’s tough to sell frontline inotuzumab in the context of hepatotoxicity and VOD [veno-occlusive disease]. It wasn’t covered in this paper, but subsequent lowering of the inotuzumab dose even more reduced the VOD, but that’s still something you’re going to be worried about as well.

Anthony Mato, MD, MSCE: As a follow-up, because I’m learning this for the first time, I’ve never seen a paper that didn’t conclude that the regimen was safe and effective. It seems like you have to say that, at least if you want to publish. If you don’t want it published, then maybe those papers exist….

Bijal D. Shah, MD: I’ve written 3 of them, so I can attest to that.

Anthony Mato, MD, MSCE: Everybody knows that. But the rate of VOD was 10%, and most of those people died, so do you conclude that this regimen is safe and effective? That’s the first question. The other thing that I was a little curious about is that it seemed like so many of these patients dropped off to go to allogeneic transplant. How does that muddy the interpretation of these data?

Nikesh Shah, MD: Absolutely. For the first question, in the way the trial was initially written, I’d say it wasn’t safe from the VOD standpoint, hence the multiple amendments they made. The initial amendment was to lower the inotuzumab dosing, which did decrease the rate of VOD, as they reported. Then following the advent of blinatumomab, they further lowered the inotuzumab dose and added consolidation or maintenance Blincyto. That wasn’t reported. That second amendment wasn’t reported in this trial, but there are ongoing data, and some were reported at ASH [American Society of Hematology annual meeting] that reported no VOD with the much lower inotuzumab dosing. I’m sorry, I forgot your second question.

Anthony Mato, MD, MSCE: Me too. We’ll go to somebody else.

Nikesh Shah, MD: Oh, you were asking in reference to allo-transplant afterward. This trial only had 3 or 4 patients go on to get an allo-transplant, if I’m not mistaken. I don’t think there was a big proportion of patients on this trial who went on to get an allo-transplant, because they were older patients and most of them weren’t eligible.

Jae Park, MD: The third part of the talk is an attempt to see the utilization of the pediatric asparaginase-based induction or consolidation chemotherapy for ALL. It’s interesting to see the uptick from the CALGB or intergroup studies, and then the rate goes back down to where it was before. What do you make of that from the standpoint of the California data? What do you believe, reading the paper, what are the barriers of using it? Why do you believe the rate went down?

Reem Akel, MD: Most of the patients who we saw getting these pediatric regimens were on the trial, so they were obviously being accrued to this trial. Once that trial closed off, we saw the number come down. The reason I think a lot of people don’t use the pediatric-inspired regimens is that they come with a lot of toxicity, particularly due to the asparaginase, and they’re very regimented. Patients have to be able to go through the whole treatment, and it can be very tough. There could be social barriers where they can’t make it to all these cycles that they have to go through. Then, of course, the toxicities from the different phases of the cycle. Those are some of the biggest barriers. Compared with the adult regimens, it might be harder to use the pediatric regimens. But we saw in this study that most of these patients were being accrued as part of the trial. That’s all I have to say. Does that answer your question?

Jae Park, MD: It was more of your take and then the authors’ take from the paper as well. I wonder, too, because we always question. Despite all this wealth of data for the pediatric asparaginase-based regimen, we still don’t have a standard established, mainly because we don’t have a randomized trial. That’s probably what we need to do. It’s very hard to do in rare diseases like this, and the intergroup hasn’t taken on that aspect, so I’m trying to see what else is needed to convince one way vs another.

There’s a notion that it’s very cumbersome to use, but hyper-CVAD [cyclophosphamide, vincristine, doxorubicin, dexamethasone], even with a mini-CVD, inotuzumab, is a very toxic regimen there too. If you don’t know how to monitor these patients after hyper-CVAD, the same toxicity can occur. I’m curious to see. It was my attempt to get your thoughts from what you have seen in the first year and what the barriers are in using it. I think the randomized trials will be necessary to establish them. Short of that, we’ll continue to have this conversation for years to come, which is the frustrating part.

Reem Akel, MD: Yes, exactly. Most of what we know is based on historical comparators, retrospective studies. We don’t have a large multicenter, randomized clinical trial comparing one regimen to the other in terms of the outcomes, overall survival, PFS [progression-free survival], and so on. It would be nice to have that, so we’ll hope for that.

Anthony Mato, MD, MSCE: Can I also ask you a question about the modified BFM-90 protocol? One number that jumped out at me was when you mentioned that the fungal infection rate was something like 30%, a ridiculously high number. Can you comment on what supportive care was used at that center in India and whether you think the same types of outcomes would be seen here in the United States with that same regimen?

Reem Akel, MD: They used some fungal prophylaxis for some of these patients, but it was a very well annotated paper, and they even mentioned the numbers of the candidal infections and exactly what type of infections they saw in these patients. It was interesting to see that. But it could be very particular to the region in India, and if this were to be done here in the United States, we may not necessarily see these same numbers just because of the region they’re from. It’s hard to say, but with just this 1 study, we can’t tell for sure whether this is a common adverse effect with this regimen. We’d like to see it in different settings as well to confirm.

Jae Park, MD: Maybe one last [question]. Do we have time?

Steven Frommeyer: What are your questions?

Jae Park, MD: For any of the 3 of you, what data do you think you’ll need to convince you to use either the hyper-CVAD–based regimen or the pediatric-based regimen? What data do you think you need to see in the absence of randomized trial data that will move you one way vs another? From what you have read from the papers and then others that we’re going to present, what do you think is needed there?

Nikesh Shah, MD: I can start to answer. It’s tough in the context of not having great randomized data. I alluded to this in regard to the initial hyper-CVAD trial from 2000. The young patients still did pretty well with hyper-CVAD, the patients who were younger than 30. Since then, we’ve had other retrospective or meta-analyses that have come out in favor of pediatric-based regimens. But cross-trial comparisons are hard because the populations are very different. If we try to make that because that’s the best we have, to answer 1 of your prior questions, some of the challenge of the pediatric regimens is the toxicity, but also maybe the lack of familiarity in non-hyperspecialized centers. If people are used to doing hyper-CVAD for Burkitt lymphoma, for example, they may not be as comfortable with the pediatric-based regimen. I hope that somewhat answers your question.

Jae Park, MD: There are no right answers here.

Nikesh Shah, MD: It’s challenging without randomized data, but I don’t think it’s necessarily a huge disservice for people to get hyper-CVAD if the institution or provider is more comfortable with that, rather than giving a pediatric-based protocol for the first time and not knowing the regimen details or the toxicity and how to handle that.

Jae Park, MD: Just to press on that, though, it may be a disservice to the patient if the outcome is better for the pediatric vs hyper-CVAD. I’m not saying that it is in the absence of randomized trial data.

Nikesh Shah, MD: Absolutely. I agree.

Jae Park, MD: Familiarity with it doesn’t mean that it’s an acceptable standard if there’s a better therapy out there.

Nikesh Shah, MD: Absolutely. I agree with you

Anthony Mato, MD, MSCE: I could ask a question about blinatumomab unless somebody else has a question. Do you have one?

Meghan Thompson, MD: Yes. If we have time, I was going to ask about the role of minimal residual disease [MRD], which we’ve seen time and time again is arguably the most important test for these patients with ALL. The papers we discussed have all used different methods to detect MRD. We’ve talked about the NGS [next-generation sequencing] method, which is quite sensitive. The other paper used RT-PCR [reverse transcription polymerase chain reaction], and there’s also flow cytometry. Taking those 2 papers together, and for the group, do you think that the field needs to come up with a standard approach of which assay to use, which method to use, and the timing of that testing? If you were to design a study moving forward, which methodology would you use, thinking that hopefully this would be implemented in clinical practice?

Somedeb Ball, MD: Thank you for that question. There are different ways you can look at it. First, I showed you the data and background that when they put together all the studies’ data, it didn’t matter what tests they used for MRD, whether it was RT-PCR or NGS. Any form of MRD presence was an independent predictor across groups. NGS is more sensitive, but does 10-6 mean a lot more than 10-3? I’m not sure. I don’t think we have enough data to justify that.

But on the other hand, to answer your question about designing a trial, if I’m designing a trial today, I’d like to be as contemporary as possible. Looking at the standard practice patterns, we have widely adopted NGS testing. I’d design a trial based on NGS because it has the highest sensitivity. It’s being more validated, and now we have data, even peripheral blood and bone marrow concordance. Overall, if I’m designing a study right now, I’d use NGS. I’d prefer NGS over RT-PCR. But if we end up in a community center where we don’t have NGS, RT-PCR is still a good test. We saw that if we measure the MRD, even RT-PCR can still guide us in treatment decision-making in the form of incorporation of blinatumomab, because that trial was based on RT-PCR. There’s no outright answer, but that’s how I look at it.

Anthony Mato, MD, MSCE: Can I ask a follow-up about blinatumomab in terms of treatment decision-making based on MRD? If you have a patient who’s young and is Ph [Philadelphia chromosome]–negative who’s in complete remission but is MRD positive, and the ultimate intent is to take them to allo-transplant and they have a donor available, based on the data that you presented, do you think they should receive blinatumomab to induce MRD-undetectable disease prior to transplant? Can you discuss the pros and cons of that approach?

Somedeb Ball, MD: Yes. Thank you for that question as well. It’s very interesting that you bring this up. In transplant studies, it has been seen that the presence of MRD before transplant is a predictor of poor outcome post-transplant as well. In the study that we discussed, blinatumomab was used as a consolidation, and turning them MRD-negative and proceeding to transplant improved the outcome. The study unfortunately wasn’t designed to answer the question that’s still lingering of how much impact the consolidated transplant itself had on the outcome instead of blinatumomab coupled with transplant. I don’t think we know for sure, but we have good enough data to say that if MRD is negative before going into any consolidated therapy, then the overall outcome is better. I’d probably feel more comfortable getting rid of that MRD with some form of consolidated therapy before going into transplant.

Transcript edited for clarity.

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