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Using Blinatumomab in Acute Lymphoblastic Leukemia

Insights From:Stefan Faderl, MD, John Theurer Cancer Center; Raoul Tibes, MD, PhD, Mayo Clinic; Bijal D. Shah, MD, Moffitt Cancer Center
Published: Friday, Apr 15, 2016


Transcript:

Bijal D. Shah, MD:
Blinatumomab is a bispecific engaging antibody. What we’re trying to do is bind both CD19 on the leukemic blasts and CD3 on the T-cells. The consequence of binding CD3 is to activate the T-cell and to do so in the context of the B-cell. In so doing, the thought processes will both expand those T-cells and potentially even generate an antigen-based response against the leukemia. What do I mean by that? Although we’re not specifically engaging and activating T-cells, there is the possibility that we may be activating T-cells that would otherwise have recognized antigen in the context of MHC and because of other host immunosuppressive functions as the leukemia progresses would have been inhibited, it has the chance to grow and translate into a memory T-cell response.

This is incredibly important as we start to think about the role of blinatumomab as more than just an induction agent to drive CRs, but as a means of generating long-lived CRs. I think about blinatumomab in this context more as it relates to a consolidation. How do I keep a patient in remission? Strategically we also know that blinatumomab may work less well in patients with high burden disease, but if we can get them to a low level disease, using the blinatumomab as a consolidation therapy may give us the advantage of both efficacy and durability and that’s important.

Raoul Tibes, MD, PhD: Blinatumomab is an active but also potent drug, so patients are usually admitted for up to the first 9 days in the hospital. It’s an intravenous continuous infusion. It’s started at a low dose for the first several days, and then if it’s well tolerated, the dose is increased. We give steroid pre-medications at first prior to starting the infusion and in dose step increase. You need to re-dose the patient with steroids. I think it’s also important to teach your medical team, your pharmacists, and your infusion nurses, never to flush or push the line because the infusion rate is so low and so minimal, that any flushing will deliver a tremendous amount of the antibody at one point. It has not happened or I’ve not heard about it, but it’s important because it’s a different concept and a different drug; we’re learning how to use it.

You start slow, you observe the patient for the first 7days in the hospital. You have a dose increase at day 8, you observe the patient, and then usually on day 9, the patient goes home. It’s important that if transfusion side effects, or allergic reactions, or [other] reactions occur. We have to stop the infusion, wait for recovery of the side effects, reduce the dose slowly, start over again at the low dose, and delay the increase for up to a week before you dose re-escalate the patient. And patients who have grade 4 side effects are usually discontinued permanently.

Bijal D. Shah, MD: I’d like to speak to the safety of blinatumomab in acute lymphoblastic leukemias. We now recognize that there are two primary toxicities we’re going to see in this space. The first is cytokine release phenomena. Those are going to come on within the first 7 to 10 days. Those are going to be accompanied typically by low blood pressure, fever, and potentially organ dysfunction, meaning renal failure and so on if the hypotension gets severe. All that being said, we have found as we’ve transitioned to cytoreductive therapy or even dexamethasone-based therapy to reduce disease burden prior to the blinatumomab, dexamethasone therapy at the time of starting blinatumomab and at the time of dose escalation one week later that we’ve been able to significantly reduce the onset of cytokine release phenomena. Of the dozen or so patients we treated at Moffitt Cancer Center, I can tell you from experience now, the worst that we have seen has been fever. We’ve actually not had to send anyone to our ICU or adopt any more intensive therapies.

It may be possible that the neurologic side effects are also a sequalae of this cytokine release phenomenon. We know that they tend to come on around the same time as a cytokine release syndrome. We know that they also tend to respond to therapies like dexamethasone. Again, so far in our hands, we have not seen that emerge. It’s not to say that it is not a significant side effect and one that needs to be monitored for, but so far we’ve been fortunate in that regard with the use of dexamethasone to both reduce burden prior to the blinatumomab and at the time of onset and the time of dose escalation, as illustrated in the manuscript published in Lancet Oncology.

I want to speak specifically to its efficacy in the Philadelphia chromosome-positive space because this is a very important observation that we didn’t have prior to the ASH 2015 meeting. We now know that blinatumomab can be effective in this space with upwards of 40% of patients showing responses to the blinatumomab agent. This is critically important for our patients who become tyrosine kinase inhibitor-refractory and for the first time provides us with a therapeutic alternative.

It will be interesting to see how other agents in this space, like inotuzumab, will ultimately influence both the response rate and provide another means for providing durable remissions for these patients.

It’s very exciting from my perspective to see how inotuzumab will also influence outcomes in the Philadelphia chromosome-positive space. I want to transition from there to the Philadelphia chromosome-negative space where blinatumomab has already had published data showing a high level of efficacy and durability. I think the problem that we’re going to have with blinatumomab moving forward is understanding who is the best patient for this therapy and how do we get them there.

And by that I mean when should we use this? Should we really try to use this agent in the context of consolidation, as I mentioned, after chemotherapy to try and really whittle down the disease in the bone marrow? Should we begin thinking about blinatumomab in the context of CAR T-cell therapy? And what I mean specifically is for those patients who progress after CAR T, can we use a bi-specific engaging molecule to rescue that CAR T vector and to allow for remissions to occur in that space? Can we use blinatumomab after inotuzumab? Inotuzumab also has high efficacy rates. But, can we use the blinatumomab compound to drive the durability of that response over time? I think that there’s a lot of exciting things that are coming with this particular molecular, information that’s already been presented both at this ASH 2015 meeting as well as in publication. But I think the real future of blinatumomab is a very exciting one moving forward.

We’ve treated a dozen patients with blinatumomab off study. So far, from a safety perspective, the biggest problem we’ve run into is not the cytokine release phenomena or even the neurologic sequalae of that T-cell expansion. It’s actually been infection. We’re treating patients who are heavily pretreated with multiply relapsed disease and while the blinatumomab is more selectively targeting those malignant B-cells, we are going to see neutropenia develop, we are going to see infections develop in that space. For us, that has actually been the more challenging aspect as it relates to this molecule.

We will hospitalize all of our patients with blinatumomab and monitor them closely over the first 10 days. Now, we won’t necessarily keep them in the hospital beyond 10 days if they’re neutropenic. On the other hand, should they have a fever, should they have any other signs or symptoms of infection, most of those patients are remaining in the hospital until they recover their counts.

Transcript Edited for Clarity
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Transcript:

Bijal D. Shah, MD:
Blinatumomab is a bispecific engaging antibody. What we’re trying to do is bind both CD19 on the leukemic blasts and CD3 on the T-cells. The consequence of binding CD3 is to activate the T-cell and to do so in the context of the B-cell. In so doing, the thought processes will both expand those T-cells and potentially even generate an antigen-based response against the leukemia. What do I mean by that? Although we’re not specifically engaging and activating T-cells, there is the possibility that we may be activating T-cells that would otherwise have recognized antigen in the context of MHC and because of other host immunosuppressive functions as the leukemia progresses would have been inhibited, it has the chance to grow and translate into a memory T-cell response.

This is incredibly important as we start to think about the role of blinatumomab as more than just an induction agent to drive CRs, but as a means of generating long-lived CRs. I think about blinatumomab in this context more as it relates to a consolidation. How do I keep a patient in remission? Strategically we also know that blinatumomab may work less well in patients with high burden disease, but if we can get them to a low level disease, using the blinatumomab as a consolidation therapy may give us the advantage of both efficacy and durability and that’s important.

Raoul Tibes, MD, PhD: Blinatumomab is an active but also potent drug, so patients are usually admitted for up to the first 9 days in the hospital. It’s an intravenous continuous infusion. It’s started at a low dose for the first several days, and then if it’s well tolerated, the dose is increased. We give steroid pre-medications at first prior to starting the infusion and in dose step increase. You need to re-dose the patient with steroids. I think it’s also important to teach your medical team, your pharmacists, and your infusion nurses, never to flush or push the line because the infusion rate is so low and so minimal, that any flushing will deliver a tremendous amount of the antibody at one point. It has not happened or I’ve not heard about it, but it’s important because it’s a different concept and a different drug; we’re learning how to use it.

You start slow, you observe the patient for the first 7days in the hospital. You have a dose increase at day 8, you observe the patient, and then usually on day 9, the patient goes home. It’s important that if transfusion side effects, or allergic reactions, or [other] reactions occur. We have to stop the infusion, wait for recovery of the side effects, reduce the dose slowly, start over again at the low dose, and delay the increase for up to a week before you dose re-escalate the patient. And patients who have grade 4 side effects are usually discontinued permanently.

Bijal D. Shah, MD: I’d like to speak to the safety of blinatumomab in acute lymphoblastic leukemias. We now recognize that there are two primary toxicities we’re going to see in this space. The first is cytokine release phenomena. Those are going to come on within the first 7 to 10 days. Those are going to be accompanied typically by low blood pressure, fever, and potentially organ dysfunction, meaning renal failure and so on if the hypotension gets severe. All that being said, we have found as we’ve transitioned to cytoreductive therapy or even dexamethasone-based therapy to reduce disease burden prior to the blinatumomab, dexamethasone therapy at the time of starting blinatumomab and at the time of dose escalation one week later that we’ve been able to significantly reduce the onset of cytokine release phenomena. Of the dozen or so patients we treated at Moffitt Cancer Center, I can tell you from experience now, the worst that we have seen has been fever. We’ve actually not had to send anyone to our ICU or adopt any more intensive therapies.

It may be possible that the neurologic side effects are also a sequalae of this cytokine release phenomenon. We know that they tend to come on around the same time as a cytokine release syndrome. We know that they also tend to respond to therapies like dexamethasone. Again, so far in our hands, we have not seen that emerge. It’s not to say that it is not a significant side effect and one that needs to be monitored for, but so far we’ve been fortunate in that regard with the use of dexamethasone to both reduce burden prior to the blinatumomab and at the time of onset and the time of dose escalation, as illustrated in the manuscript published in Lancet Oncology.

I want to speak specifically to its efficacy in the Philadelphia chromosome-positive space because this is a very important observation that we didn’t have prior to the ASH 2015 meeting. We now know that blinatumomab can be effective in this space with upwards of 40% of patients showing responses to the blinatumomab agent. This is critically important for our patients who become tyrosine kinase inhibitor-refractory and for the first time provides us with a therapeutic alternative.

It will be interesting to see how other agents in this space, like inotuzumab, will ultimately influence both the response rate and provide another means for providing durable remissions for these patients.

It’s very exciting from my perspective to see how inotuzumab will also influence outcomes in the Philadelphia chromosome-positive space. I want to transition from there to the Philadelphia chromosome-negative space where blinatumomab has already had published data showing a high level of efficacy and durability. I think the problem that we’re going to have with blinatumomab moving forward is understanding who is the best patient for this therapy and how do we get them there.

And by that I mean when should we use this? Should we really try to use this agent in the context of consolidation, as I mentioned, after chemotherapy to try and really whittle down the disease in the bone marrow? Should we begin thinking about blinatumomab in the context of CAR T-cell therapy? And what I mean specifically is for those patients who progress after CAR T, can we use a bi-specific engaging molecule to rescue that CAR T vector and to allow for remissions to occur in that space? Can we use blinatumomab after inotuzumab? Inotuzumab also has high efficacy rates. But, can we use the blinatumomab compound to drive the durability of that response over time? I think that there’s a lot of exciting things that are coming with this particular molecular, information that’s already been presented both at this ASH 2015 meeting as well as in publication. But I think the real future of blinatumomab is a very exciting one moving forward.

We’ve treated a dozen patients with blinatumomab off study. So far, from a safety perspective, the biggest problem we’ve run into is not the cytokine release phenomena or even the neurologic sequalae of that T-cell expansion. It’s actually been infection. We’re treating patients who are heavily pretreated with multiply relapsed disease and while the blinatumomab is more selectively targeting those malignant B-cells, we are going to see neutropenia develop, we are going to see infections develop in that space. For us, that has actually been the more challenging aspect as it relates to this molecule.

We will hospitalize all of our patients with blinatumomab and monitor them closely over the first 10 days. Now, we won’t necessarily keep them in the hospital beyond 10 days if they’re neutropenic. On the other hand, should they have a fever, should they have any other signs or symptoms of infection, most of those patients are remaining in the hospital until they recover their counts.

Transcript Edited for Clarity
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