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Approaching Treatment for Relapsed/Refractory ALL

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: Wednesday, Mar 21, 2018



Transcript: 

Mark R. Litzow, MD: Let’s turn now to the challenge of treating relapsed and refractory ALL. Anthony, give us your perspective on what the goals of therapy are in the relapsed/refractory setting and how you approach the patient in terms of trying to deal with that situation.

Anthony S. Stein, MD: The goals of treating a relapsed/refractory patient depend on the age of the patient. The general goal is to try and get the patient into remission or an MRD-negative state, and then proceed to transplant as that’s the only current curative therapy for these patients.

Bijal D. Shah, MD: How often do you consider a second allotransplant?

Anthony S. Stein, MD: For City of Hope to consider doing a second transplant, it has to be more than 6 months following a patient’s first transplant. They have to preferably be in remission, or just have very minimal disease present, and they have to fulfill all the organ criteria to be able to go through a transplant. Transplant-related mortality doing a second transplant is maybe a little bit higher than the first transplant, but it’s generally manageable.

Aaron C. Logan, MD: My opinion is that second transplants, particularly within the first year, should hopefully be on protocol. I send my patients like that to Anthony, because they have the total marrow and lymphoid irradiation clinical trial that looks to be very compelling in terms of disease control. Those patients do have an exceptionally high risk of relapse after a second allotransplant, but they also have increased risks of toxicity such as VOD, and the treatment-related mortality really goes up in that scenario.

Bijal D. Shah, MD: The reason I ask is for those very high-risk subsets. We have a gaping hole. We transplant them, and we know they’re still at very high risk of relapse. Most of our current protocols won’t allow those patients to come on. If it’s CAR T-cell therapy, if they’re still receiving their immunosuppressive medications, or if there’s any ongoing GvH (graft-versus-host disease), this is a big exclusion. This is the problem across multiple protocols.

Anthony S. Stein, MD: I think there are some clinical trials now that are, for very high-risk patients, considering giving blinatumomab as maintenance therapy following a transplant to see if that will prevent relapse.

Bijal D. Shah, MD: I’ve certainly tried giving it to patients who were still receiving their TAC (tacrolimus) and their RAPA (sirolimus), which is what we use as our GvH prophylaxis without much success.

Aaron C. Logan, MD: You have to taper first. Blinatumomab is technically inert without T cells. It’s a protein. It’s not going to kill cells directly. You need to have the T-cell activity. If they’re on a calcineurin inhibitor or other T-cell active immune suppressants or high-dose steroids, then it’s just not going to work.

Ryan D. Cassaday, MD: I think in terms of post-transplant maintenance. I think as is often the case in any maintenance therapy in hematologic malignancies, one must ask, is it better to use it as maintenance or as rescue or salvage therapy at the time of relapse? We know in large cell lymphoma that if you get rituximab maintenance, it really doesn’t improve outcomes if you’re giving rituximab as part of your frontline therapy. There are a lot of people who don’t necessarily believe in rituximab maintenance or other circumstances where we do actually have data to say it has improved progression-free survival, such as when you’re talking about blinatumomab where it’s not trivial to give and it’s fairly expensive. It’s a challenging topic. Certainly, it’s an important study question that needs to be addressed, and it’s a good thing that that study is ongoing. But it’s not something I would do as part of routine practice, even in someone who I thought was at very high risk of relapse.

Mark R. Litzow, MD: You bring up good points, because we do need to think about the patients who relapse without having had a transplant and certainly those who relapse after a transplant. Unfortunately, that’s still a familiar scenario. Ryan, what’s your approach to how you would treat a patient? Let’s say they haven’t had a transplant, you’re treating them for their Ph-positive ALL, and either you find that they’re not a candidate for a transplant or you haven’t got there yet, and now they’ve relapsed.

Ryan D. Cassaday, MD: The first thing I do at that time, and we brought this up before, if a patient with Ph-positive ALL has relapsed—assuming that they got a TKI as part of their initial therapy, which I certainly hope would be the case—I would at that point do BCR-ABL kinase domain mutation testing to see if there was a mutation that may have predicted the failure of whatever TKI they were on before. If a mutation is present, I would take the experience from the CML literature and use that to guide choices. If it was a patient who had imatinib frontline, but there’s no mutation, I might try dasatinib. If it was dasatinib that they got first-line, and they relapsed and there’s no mutation, I might try nilotinib. But of course, if they have a T315I mutation, that pretty much limits us to ponatinib. If it’s a patient who is relatively young and fit, and I’m going to try to get them to transplant and try to get them to the deepest remission possible, I’ll usually not rely solely on a TKI in that setting. I’ll usually combine it with some chemotherapy. There are not a whole lot of data that support that, but it’s certainly reasonable extrapolation to know, “We can give these drugs safely with hyper-CVAD in the frontline setting. We could certainly do it in the relapsed setting.”


Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: Let’s turn now to the challenge of treating relapsed and refractory ALL. Anthony, give us your perspective on what the goals of therapy are in the relapsed/refractory setting and how you approach the patient in terms of trying to deal with that situation.

Anthony S. Stein, MD: The goals of treating a relapsed/refractory patient depend on the age of the patient. The general goal is to try and get the patient into remission or an MRD-negative state, and then proceed to transplant as that’s the only current curative therapy for these patients.

Bijal D. Shah, MD: How often do you consider a second allotransplant?

Anthony S. Stein, MD: For City of Hope to consider doing a second transplant, it has to be more than 6 months following a patient’s first transplant. They have to preferably be in remission, or just have very minimal disease present, and they have to fulfill all the organ criteria to be able to go through a transplant. Transplant-related mortality doing a second transplant is maybe a little bit higher than the first transplant, but it’s generally manageable.

Aaron C. Logan, MD: My opinion is that second transplants, particularly within the first year, should hopefully be on protocol. I send my patients like that to Anthony, because they have the total marrow and lymphoid irradiation clinical trial that looks to be very compelling in terms of disease control. Those patients do have an exceptionally high risk of relapse after a second allotransplant, but they also have increased risks of toxicity such as VOD, and the treatment-related mortality really goes up in that scenario.

Bijal D. Shah, MD: The reason I ask is for those very high-risk subsets. We have a gaping hole. We transplant them, and we know they’re still at very high risk of relapse. Most of our current protocols won’t allow those patients to come on. If it’s CAR T-cell therapy, if they’re still receiving their immunosuppressive medications, or if there’s any ongoing GvH (graft-versus-host disease), this is a big exclusion. This is the problem across multiple protocols.

Anthony S. Stein, MD: I think there are some clinical trials now that are, for very high-risk patients, considering giving blinatumomab as maintenance therapy following a transplant to see if that will prevent relapse.

Bijal D. Shah, MD: I’ve certainly tried giving it to patients who were still receiving their TAC (tacrolimus) and their RAPA (sirolimus), which is what we use as our GvH prophylaxis without much success.

Aaron C. Logan, MD: You have to taper first. Blinatumomab is technically inert without T cells. It’s a protein. It’s not going to kill cells directly. You need to have the T-cell activity. If they’re on a calcineurin inhibitor or other T-cell active immune suppressants or high-dose steroids, then it’s just not going to work.

Ryan D. Cassaday, MD: I think in terms of post-transplant maintenance. I think as is often the case in any maintenance therapy in hematologic malignancies, one must ask, is it better to use it as maintenance or as rescue or salvage therapy at the time of relapse? We know in large cell lymphoma that if you get rituximab maintenance, it really doesn’t improve outcomes if you’re giving rituximab as part of your frontline therapy. There are a lot of people who don’t necessarily believe in rituximab maintenance or other circumstances where we do actually have data to say it has improved progression-free survival, such as when you’re talking about blinatumomab where it’s not trivial to give and it’s fairly expensive. It’s a challenging topic. Certainly, it’s an important study question that needs to be addressed, and it’s a good thing that that study is ongoing. But it’s not something I would do as part of routine practice, even in someone who I thought was at very high risk of relapse.

Mark R. Litzow, MD: You bring up good points, because we do need to think about the patients who relapse without having had a transplant and certainly those who relapse after a transplant. Unfortunately, that’s still a familiar scenario. Ryan, what’s your approach to how you would treat a patient? Let’s say they haven’t had a transplant, you’re treating them for their Ph-positive ALL, and either you find that they’re not a candidate for a transplant or you haven’t got there yet, and now they’ve relapsed.

Ryan D. Cassaday, MD: The first thing I do at that time, and we brought this up before, if a patient with Ph-positive ALL has relapsed—assuming that they got a TKI as part of their initial therapy, which I certainly hope would be the case—I would at that point do BCR-ABL kinase domain mutation testing to see if there was a mutation that may have predicted the failure of whatever TKI they were on before. If a mutation is present, I would take the experience from the CML literature and use that to guide choices. If it was a patient who had imatinib frontline, but there’s no mutation, I might try dasatinib. If it was dasatinib that they got first-line, and they relapsed and there’s no mutation, I might try nilotinib. But of course, if they have a T315I mutation, that pretty much limits us to ponatinib. If it’s a patient who is relatively young and fit, and I’m going to try to get them to transplant and try to get them to the deepest remission possible, I’ll usually not rely solely on a TKI in that setting. I’ll usually combine it with some chemotherapy. There are not a whole lot of data that support that, but it’s certainly reasonable extrapolation to know, “We can give these drugs safely with hyper-CVAD in the frontline setting. We could certainly do it in the relapsed setting.”


Transcript Edited for Clarity 
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