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Relapsed/Refractory ALL: Evaluating Novel Agents

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: Tuesday, Mar 27, 2018



Transcript: 

Ryan D. Cassaday, MD: Now that blinatumomab is approved for Ph-positive ALL, it’s certainly a consideration as well. There is only now the very inkling of data to suggest that we can maybe combine TKIs with blinatumomab. I’m not quite sure I’m there yet. People around the table may disagree with me there. But similar to the story in Ph-negative ALL, generally, in my experience, blinatumomab works really well for people with low-burden disease. It doesn’t work particularly well in people with high-burden disease. So, I might try a TKI plus/minus chemotherapy to get a little bit of disease control, then maybe come in on the back end with blinatumomab. If they’re a transplant candidate, I’d use it as a bridge. If they’re not, I’d maybe just try to string things along for as long as I can.

Mark R. Litzow, MD: I think the studies that have been done have borne out your experience that the response rate is higher in patients for whom they used a cutoff of 50% blasts. If you have less than 50%, there’s a greater likelihood that you’re going to respond to blinatumomab.

Bijal D. Shah, MD: I want to extend that though, and I would extend that concept to extramedullary relapse. We do see that more commonly in the relapsed/refractory space, where they may have large nodal deposits or even just other extramedullary sites of involvement. I’ve had very limited success with blinatumomab in that setting, and that may be a situation where during the 2-week break, I’ll integrate something like Marqibo (vincristine) or—in the case of Ph-positive ALL, if they weren't getting it concurrently with a TKI—integrate a TKI.

Aaron C. Logan, MD, PhD: There was recently a publication that speaks to the lack of strong activity of blinatumomab in the setting of extramedullary disease. It’s likely an immune microenvironment issue. But I’ve definitely had patients as well with extramedullary disease who had responses in their peripheral blood and their marrow, but the tumor mass in the retroperitoneum, or wherever it was, is still hot on the PET scan when you look again. That’s particularly problematic. That might be a scenario where inotuzumab might be favorable. We don’t have a lot of data for extramedullary disease on inotuzumab. All of us are going to learn this through our clinical experience, but I’m certainly compelled to try it for those patients with extramedullary disease.

Anthony S. Stein, MD: But my sense was that you might cytoreduce the patient to reduce the extramedullary disease, and you can either use inotuzumab with chemotherapy or chemotherapy alone. And then, once that has been reduced, then you can come in with the blinatumomab.

Aaron C. Logan, MD, PhD: Come in with the blinatumomab and then transplant them. Give them everything.

Bijal D. Shah, MD: The challenge for me though with cytoreduction: As we step up the intensity, we really do run into a lot of problems with infection, at least at our site. That has been somewhat dose limiting, which is why for us, I’m trying to figure out Marqibo combinations. How do I de-intensify things just to help control that extramedullary relapse, and then very quickly follow with blinatumomab?

Anthony S. Stein, MD: Often, you can just use a CVP [cyclophosphamide, vincristine, prednisolone]-like regimen.

Aaron C. Logan, MD, PhD: It’s possible.

Anthony S. Stein, MD: Or Marqibo, or any of those agents.

Aaron C. Logan, MD, PhD: I think what we see is that with chemotherapy, the response rates are about 20%. That was actually the CR rate for Marqibo that got it approved. So, the answer at the end of the day is going to be how we combine these things to achieve the best response in the relapsed/refractory patient, and I think Marqibo is great because it’s well tolerated. But you definitely have to add something to it if you want to have good responses in the majority of patients.

Bijal D. Shah, MD: This is just to manage the extramedullary disease, and what I tell my patients is that we poke holes in the tumor, in the masses, so that the blinatumomab can do what it needs to do.

Anthony S. Stein, MD: Another option that hasn’t been done is when you use blinatumomab for the large-cell lymphoma, the dose of blinatumomab is much higher, where you get benefit, and it’s given for a longer duration.

Aaron C. Logan, MD, PhD: If your medical center allows you to.

Anthony S. Stein, MD: That’s correct, but maybe eventually—I don’t know if it will ever be done—for patients with extramedullary disease, we will manage those patients like you manage lymphoma patients.

Aaron C. Logan, MD, PhD: Exactly.

Bijal D. Shah, MD: The challenge, of course, will be the CNS events that develop as we bump up the dose. I do think we have to be cognizant that as we push to 104 micrograms, we really are going to see more CNS toxicity. I think I saw seizures as the limiting grade 3 toxicity on the phase I studies.

Ryan D. Cassaday, MD: Just to round off the discussion, let’s not leave out our unfortunate patients with T-cell ALL where the options have not been quite evolving over the last few years. Really, nelarabine and liposomal vincristine, at least to my knowledge, are the 2 drugs that are uniquely approved in that situation. My experience with nelarabine has been hit or miss, to say the least. I’ve seen some patients develop pretty significant neurologic toxicity from it, but I’ve also seen some really impressive results. But it’s mostly anecdotes, and that is not a therapy that I would think is a standalone. It really is a bridge to transplant if we can get them into remission.

Bijal D. Shah, MD: For the very high-risk T-cell ALLs, I haven’t seen much activity at all with nelarabine. I’ve been really pushing a lot of asparaginase. We’re a hyper-CVAD center, so most of these patients didn’t get it with their induction. But even in some who started with a COG (Children’s Oncology Group) regimen, some of the young adults who make their way from our children’s hospital down the road, I try to use an asparaginase-intense regimen like a VXLD (vincristine, dexamethasone, pegylated L-asparaginase, doxorubicin) backbone. I like the Velcade (bortezomib)/VXLD combination. I’ve gotten some good responses with that. It’s toxic. I don’t want to mince words. Certainly, neuropathy is no small matter with the regimen. I think the TACL (Therapeutic Advances in Childhood Leukemia & Lymphoma) group is now working on a revised regimen using Kyprolis (carfilzomib) in place of the Velcade, and we may see some very interesting data emerge from that ongoing study. I think venetoclax is showing some interesting responses, at least preclinically in the early T-cell space, so hopefully that’s an agent that moves forward. Certainly, it’s moved forward for a lot of other indications.

Transcript Edited for Clarity

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Transcript: 

Ryan D. Cassaday, MD: Now that blinatumomab is approved for Ph-positive ALL, it’s certainly a consideration as well. There is only now the very inkling of data to suggest that we can maybe combine TKIs with blinatumomab. I’m not quite sure I’m there yet. People around the table may disagree with me there. But similar to the story in Ph-negative ALL, generally, in my experience, blinatumomab works really well for people with low-burden disease. It doesn’t work particularly well in people with high-burden disease. So, I might try a TKI plus/minus chemotherapy to get a little bit of disease control, then maybe come in on the back end with blinatumomab. If they’re a transplant candidate, I’d use it as a bridge. If they’re not, I’d maybe just try to string things along for as long as I can.

Mark R. Litzow, MD: I think the studies that have been done have borne out your experience that the response rate is higher in patients for whom they used a cutoff of 50% blasts. If you have less than 50%, there’s a greater likelihood that you’re going to respond to blinatumomab.

Bijal D. Shah, MD: I want to extend that though, and I would extend that concept to extramedullary relapse. We do see that more commonly in the relapsed/refractory space, where they may have large nodal deposits or even just other extramedullary sites of involvement. I’ve had very limited success with blinatumomab in that setting, and that may be a situation where during the 2-week break, I’ll integrate something like Marqibo (vincristine) or—in the case of Ph-positive ALL, if they weren't getting it concurrently with a TKI—integrate a TKI.

Aaron C. Logan, MD, PhD: There was recently a publication that speaks to the lack of strong activity of blinatumomab in the setting of extramedullary disease. It’s likely an immune microenvironment issue. But I’ve definitely had patients as well with extramedullary disease who had responses in their peripheral blood and their marrow, but the tumor mass in the retroperitoneum, or wherever it was, is still hot on the PET scan when you look again. That’s particularly problematic. That might be a scenario where inotuzumab might be favorable. We don’t have a lot of data for extramedullary disease on inotuzumab. All of us are going to learn this through our clinical experience, but I’m certainly compelled to try it for those patients with extramedullary disease.

Anthony S. Stein, MD: But my sense was that you might cytoreduce the patient to reduce the extramedullary disease, and you can either use inotuzumab with chemotherapy or chemotherapy alone. And then, once that has been reduced, then you can come in with the blinatumomab.

Aaron C. Logan, MD, PhD: Come in with the blinatumomab and then transplant them. Give them everything.

Bijal D. Shah, MD: The challenge for me though with cytoreduction: As we step up the intensity, we really do run into a lot of problems with infection, at least at our site. That has been somewhat dose limiting, which is why for us, I’m trying to figure out Marqibo combinations. How do I de-intensify things just to help control that extramedullary relapse, and then very quickly follow with blinatumomab?

Anthony S. Stein, MD: Often, you can just use a CVP [cyclophosphamide, vincristine, prednisolone]-like regimen.

Aaron C. Logan, MD, PhD: It’s possible.

Anthony S. Stein, MD: Or Marqibo, or any of those agents.

Aaron C. Logan, MD, PhD: I think what we see is that with chemotherapy, the response rates are about 20%. That was actually the CR rate for Marqibo that got it approved. So, the answer at the end of the day is going to be how we combine these things to achieve the best response in the relapsed/refractory patient, and I think Marqibo is great because it’s well tolerated. But you definitely have to add something to it if you want to have good responses in the majority of patients.

Bijal D. Shah, MD: This is just to manage the extramedullary disease, and what I tell my patients is that we poke holes in the tumor, in the masses, so that the blinatumomab can do what it needs to do.

Anthony S. Stein, MD: Another option that hasn’t been done is when you use blinatumomab for the large-cell lymphoma, the dose of blinatumomab is much higher, where you get benefit, and it’s given for a longer duration.

Aaron C. Logan, MD, PhD: If your medical center allows you to.

Anthony S. Stein, MD: That’s correct, but maybe eventually—I don’t know if it will ever be done—for patients with extramedullary disease, we will manage those patients like you manage lymphoma patients.

Aaron C. Logan, MD, PhD: Exactly.

Bijal D. Shah, MD: The challenge, of course, will be the CNS events that develop as we bump up the dose. I do think we have to be cognizant that as we push to 104 micrograms, we really are going to see more CNS toxicity. I think I saw seizures as the limiting grade 3 toxicity on the phase I studies.

Ryan D. Cassaday, MD: Just to round off the discussion, let’s not leave out our unfortunate patients with T-cell ALL where the options have not been quite evolving over the last few years. Really, nelarabine and liposomal vincristine, at least to my knowledge, are the 2 drugs that are uniquely approved in that situation. My experience with nelarabine has been hit or miss, to say the least. I’ve seen some patients develop pretty significant neurologic toxicity from it, but I’ve also seen some really impressive results. But it’s mostly anecdotes, and that is not a therapy that I would think is a standalone. It really is a bridge to transplant if we can get them into remission.

Bijal D. Shah, MD: For the very high-risk T-cell ALLs, I haven’t seen much activity at all with nelarabine. I’ve been really pushing a lot of asparaginase. We’re a hyper-CVAD center, so most of these patients didn’t get it with their induction. But even in some who started with a COG (Children’s Oncology Group) regimen, some of the young adults who make their way from our children’s hospital down the road, I try to use an asparaginase-intense regimen like a VXLD (vincristine, dexamethasone, pegylated L-asparaginase, doxorubicin) backbone. I like the Velcade (bortezomib)/VXLD combination. I’ve gotten some good responses with that. It’s toxic. I don’t want to mince words. Certainly, neuropathy is no small matter with the regimen. I think the TACL (Therapeutic Advances in Childhood Leukemia & Lymphoma) group is now working on a revised regimen using Kyprolis (carfilzomib) in place of the Velcade, and we may see some very interesting data emerge from that ongoing study. I think venetoclax is showing some interesting responses, at least preclinically in the early T-cell space, so hopefully that’s an agent that moves forward. Certainly, it’s moved forward for a lot of other indications.

Transcript Edited for Clarity
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