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MRD-Positive ALL: Personal Approaches to Treatment

Panelists: Mark R. Litzow, MD, Mayo Clinic; Ryan D. Cassaday, MD, University of Washington School of Medicine; Aaron C. Logan, MD, PhD, University of California San Francisco Medical Sciences Building; Bijal D. Shah, MD, Moffitt Cancer Center; Anthony S. Stein, MD, Hematologic Malignancies and Stem Cell Transplantation Institute
Published: Monday, Mar 19, 2018



Transcript: 

Ryan D. Cassaday, MD: Since blinatumomab has been available, I’ve had 1 patient who had chemotherapy refractory disease, I gave them blinatumomab, and they did not go to transplant. That was after a very lengthy discussion about the risks and the benefits, and the patient ultimately decided they didn’t want to do a transplant. I’m curious, has anybody else here done that so far?

Aaron C. Logan, MD, PhD: Yes.

Anthony S. Stein, MD: If you probably have a fully matched sibling donor or unrelated donor and the patient is fully fit and young, you may go to transplant. For somebody who doesn’t have a fully matched donor, that sort of patient, you may just continue with blinatumomab and see what their long-term outcome is.

Aaron C. Logan, MD, PhD: The decision to go to transplant is not always simply based on availability of a donor and the medical scenario. We find that the social support for that patient is critically important. There are patients who we cannot transplant because they lack adequate social support. That exact scenario has happened. I wanted to allograft a patient, but it just wasn’t going to work socially; 5 cycles of blinatumomab and 2 years later, they’re still in remission. Those data, those anecdotal experiences that recapitulate the BLAST study data, are very compelling, but we need a larger experience to ever sit back and say, “OK, we’re done.” It feels very uncomfortable to leave those patients without additional therapy of some kind.

Mark R. Litzow, MD: Ryan, would you ever use inotuzumab in this setting?

Ryan D. Cassaday, MD: I would consider it. I think while blinatumomab tends to be—at least in my practice—well tolerated, particularly in patients with low-burden disease, and though it’s highly active, not all patients are going to be willing to use blinatumomab or it’s just feasibly not possible. For example, where I practice, we have a catchment area that includes Alaska, Montana, and places like this. Blinatumomab is not something that they’re comfortable using in these smaller communities that don’t see a lot of these patients. So, it’s a bit of an extrapolation, but that’s chemotherapy-refractory disease. We know from the INNOVATE study published in the New England Journal of Medicine that inotuzumab is superior to standard-of-care salvage chemotherapy. You could argue that in that scenario, inotuzumab is probably going to be more effective at eliminating the residual disease.

Aaron C. Logan, MD, PhD: It’s a bit of a jump though, right? Because there are no data for treating MRD with inotuzumab.

Ryan D. Cassaday, MD: That is true.

Aaron C. Logan, MD, PhD: Inotuzumab is technically not an immunotherapy. It’s chemotherapy. You’re delivering it in a specified way, getting more chemotherapy into the cells, and I think that’s why it has better activity than salvage chemotherapy. But I don’t think we have any data to guide us to use inotuzumab in the MRD setting.

Ryan D. Cassaday, MD: For someone who has B-cell ALL but can’t get blinatumomab, in that scenario, I’m curious: What would you do?

Aaron C. Logan, MD, PhD: I’d lose sleep over it. Maybe I would give them inotuzumab because there are no other great options.

Ryan D. Cassaday, MD: Right.

Aaron C. Logan, MD, PhD: Sometimes I will do high-dose methotrexate, or in the past I have. If they haven’t had PEG-asparaginase before, because maybe they were treated on a hyper-CVAD regimen, I’m definitely going to get some PEG-asparaginase into that patient before they go to transplant.

Bijal D. Shah, MD: I’m glad you hit on that, because I think it ties in nicely to the concept of T-cell ALL. We’ve been very focused on B-cell ALL. Actually, that is exactly what I do: I’ll add asparaginase to the hyper-CVAD backbone, based off the augmented hyper-CVAD study that was published a few years back, as a way of trying to mitigate that MRD. We initially were using nelarabine on the hyper-CVAD backbone and particularly in those higher risk early thymic precursor ALLs, we weren’t seeing the activity that we wanted. In contrast, with the asparaginase, we’re seeing a little bit more in the way of responses and durable responses. The goal is still allogenic transplant for me.
This is the hard part about inotuzumab: How do I get them to the allotransplant? We’re talking about first remission now, the goal of first remission. How do I get them to the allotransplant, because I know they’re chemotherapy refractory? I’ve had to use an agent to get them there. How long am I going to wait after inotuzumab to take them to the allotransplant? Is it really just the double alkylators that are going to be the risk? Or if I give them a TBI (total body irradiation)-based or even BU/FLU (busulfan/fludarabine)-based allotransplant, what risks am I exposing that patient to?

Aaron C. Logan, MD, PhD: The MD Anderson data regarding inotuzumab and VOD (veno-occlusive disease) suggest it’s not just these double alkylators at the time of conditioning, but it’s also age over 55, any abnormality in the bilirubin at the initiation of conditioning, and the number of exposures to inotuzumab. So, if we were put into that scenario where we have to bridge our MRD-positive patient to transplant, hopefully we would use a minimal amount of inotuzumab to achieve that MRD-negative status.
We don’t know in the absence of any prospective data whether that’s actually going to augment the outcome of the transplant. But in the very least, if you can minimize exposure to inotuzumab going to the transplant, hopefully we can mitigate some of those risks of VOD. One of the things I’ve heard, that as a transplanter makes me a little bit frustrated, is some people say, “Well, you don’t have to worry about VOD anymore because defibrotide has been approved.” That’s just simply not true. The fatality rate for VOD, even with defibrotide, is still 30% to 40%. Transplanters hate VOD. That is something I lose sleep over. If I have a patient and it looks like they're developing VOD, I’m really, really worried about that patient even if I have them on defibrotide.
We don’t yet know whether defibrotide can mitigate the risk of VOD that is caused by calicheamicin conjugate prior to transplant or whether it could, for instance, be used prophylactically. These are really interesting questions that I think we can address. For instance, is there something we can do during inotuzumab therapy to mitigate subsequent risk of VOD? These are really important questions that we need to answer.

Transcript Edited for Clarity 

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Transcript: 

Ryan D. Cassaday, MD: Since blinatumomab has been available, I’ve had 1 patient who had chemotherapy refractory disease, I gave them blinatumomab, and they did not go to transplant. That was after a very lengthy discussion about the risks and the benefits, and the patient ultimately decided they didn’t want to do a transplant. I’m curious, has anybody else here done that so far?

Aaron C. Logan, MD, PhD: Yes.

Anthony S. Stein, MD: If you probably have a fully matched sibling donor or unrelated donor and the patient is fully fit and young, you may go to transplant. For somebody who doesn’t have a fully matched donor, that sort of patient, you may just continue with blinatumomab and see what their long-term outcome is.

Aaron C. Logan, MD, PhD: The decision to go to transplant is not always simply based on availability of a donor and the medical scenario. We find that the social support for that patient is critically important. There are patients who we cannot transplant because they lack adequate social support. That exact scenario has happened. I wanted to allograft a patient, but it just wasn’t going to work socially; 5 cycles of blinatumomab and 2 years later, they’re still in remission. Those data, those anecdotal experiences that recapitulate the BLAST study data, are very compelling, but we need a larger experience to ever sit back and say, “OK, we’re done.” It feels very uncomfortable to leave those patients without additional therapy of some kind.

Mark R. Litzow, MD: Ryan, would you ever use inotuzumab in this setting?

Ryan D. Cassaday, MD: I would consider it. I think while blinatumomab tends to be—at least in my practice—well tolerated, particularly in patients with low-burden disease, and though it’s highly active, not all patients are going to be willing to use blinatumomab or it’s just feasibly not possible. For example, where I practice, we have a catchment area that includes Alaska, Montana, and places like this. Blinatumomab is not something that they’re comfortable using in these smaller communities that don’t see a lot of these patients. So, it’s a bit of an extrapolation, but that’s chemotherapy-refractory disease. We know from the INNOVATE study published in the New England Journal of Medicine that inotuzumab is superior to standard-of-care salvage chemotherapy. You could argue that in that scenario, inotuzumab is probably going to be more effective at eliminating the residual disease.

Aaron C. Logan, MD, PhD: It’s a bit of a jump though, right? Because there are no data for treating MRD with inotuzumab.

Ryan D. Cassaday, MD: That is true.

Aaron C. Logan, MD, PhD: Inotuzumab is technically not an immunotherapy. It’s chemotherapy. You’re delivering it in a specified way, getting more chemotherapy into the cells, and I think that’s why it has better activity than salvage chemotherapy. But I don’t think we have any data to guide us to use inotuzumab in the MRD setting.

Ryan D. Cassaday, MD: For someone who has B-cell ALL but can’t get blinatumomab, in that scenario, I’m curious: What would you do?

Aaron C. Logan, MD, PhD: I’d lose sleep over it. Maybe I would give them inotuzumab because there are no other great options.

Ryan D. Cassaday, MD: Right.

Aaron C. Logan, MD, PhD: Sometimes I will do high-dose methotrexate, or in the past I have. If they haven’t had PEG-asparaginase before, because maybe they were treated on a hyper-CVAD regimen, I’m definitely going to get some PEG-asparaginase into that patient before they go to transplant.

Bijal D. Shah, MD: I’m glad you hit on that, because I think it ties in nicely to the concept of T-cell ALL. We’ve been very focused on B-cell ALL. Actually, that is exactly what I do: I’ll add asparaginase to the hyper-CVAD backbone, based off the augmented hyper-CVAD study that was published a few years back, as a way of trying to mitigate that MRD. We initially were using nelarabine on the hyper-CVAD backbone and particularly in those higher risk early thymic precursor ALLs, we weren’t seeing the activity that we wanted. In contrast, with the asparaginase, we’re seeing a little bit more in the way of responses and durable responses. The goal is still allogenic transplant for me.
This is the hard part about inotuzumab: How do I get them to the allotransplant? We’re talking about first remission now, the goal of first remission. How do I get them to the allotransplant, because I know they’re chemotherapy refractory? I’ve had to use an agent to get them there. How long am I going to wait after inotuzumab to take them to the allotransplant? Is it really just the double alkylators that are going to be the risk? Or if I give them a TBI (total body irradiation)-based or even BU/FLU (busulfan/fludarabine)-based allotransplant, what risks am I exposing that patient to?

Aaron C. Logan, MD, PhD: The MD Anderson data regarding inotuzumab and VOD (veno-occlusive disease) suggest it’s not just these double alkylators at the time of conditioning, but it’s also age over 55, any abnormality in the bilirubin at the initiation of conditioning, and the number of exposures to inotuzumab. So, if we were put into that scenario where we have to bridge our MRD-positive patient to transplant, hopefully we would use a minimal amount of inotuzumab to achieve that MRD-negative status.
We don’t know in the absence of any prospective data whether that’s actually going to augment the outcome of the transplant. But in the very least, if you can minimize exposure to inotuzumab going to the transplant, hopefully we can mitigate some of those risks of VOD. One of the things I’ve heard, that as a transplanter makes me a little bit frustrated, is some people say, “Well, you don’t have to worry about VOD anymore because defibrotide has been approved.” That’s just simply not true. The fatality rate for VOD, even with defibrotide, is still 30% to 40%. Transplanters hate VOD. That is something I lose sleep over. If I have a patient and it looks like they're developing VOD, I’m really, really worried about that patient even if I have them on defibrotide.
We don’t yet know whether defibrotide can mitigate the risk of VOD that is caused by calicheamicin conjugate prior to transplant or whether it could, for instance, be used prophylactically. These are really interesting questions that I think we can address. For instance, is there something we can do during inotuzumab therapy to mitigate subsequent risk of VOD? These are really important questions that we need to answer.

Transcript Edited for Clarity 
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