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Up-front Approaches to Treating Ph-Negative 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: Monday, Feb 19, 2018



Transcript: 

Mark R. Litzow, MD: Aaron, can you talk about your approach to Ph-negative patients and how that whole area is evolving?

Aaron C. Logan, MD, PhD: Absolutely. As Ryan mentioned earlier, one of our best prognosticators for outcome is the age of the patient. We really have to take that into account when we decide how we’re going to treat someone. For the under-age-40 group, I think it’s very well established now that we should try, if at all possible, to use a pediatric inspired regimen. And hopefully, it’s going to be on a clinical trial. The first consideration for a patient of any age should be a clinical trial. We haven’t yet established a golden standard. But if you don’t have a clinical trial opened for your young adult up to age 40, you should be using an AYA (adolescents and young adults) protocol. An example would be the Intergroup 10403 study that has shown very compelling outcomes in patients up to age 39. There are other similar pediatric inspired regimens that can be utilized in this setting, or the intensification of other backbones. I would not typically wish to see a patient in this age group treated with hyper-CVAD, because I don’t think it’s the best therapy for that age group.

Now in the more elderly patients who can’t tolerate chemotherapy, as we just mentioned, you have very limited options. You typically might consider corticosteroids with perhaps some vincristine. For the fit elderly patients, I think a very viable option is to do the mini–hyper-CVAD, which many patients will tolerate. And then for everyone between ages 40 and 60, hopefully you’ve got a clinical trial for that population to see, can we push pediatric-like therapies into a slightly older age group? Or is there some other method to get those patients into a deep remission?

I think at most institutions, everyone has their favorite recipe or protocol. It’s hard to break those habits, for better or worse. I think the field is still learning how to treat patients in the different age groups. But I think we’ve all agreed that we need to intensify for every patient who can tolerate intensive therapy.

Now, what we do know, even in these pediatric inspired regimens, is there are patients who are going to have a higher likelihood of failing to achieve their MRD-negative remission, and those would, for instance, be the Ph-like population. Our center, as well as probably everyone who represents a center here today, has probably gotten to the point where we’re doing up-front molecular profiling of our patients so we can identify these lesions. I think we all probably get referrals from outside centers where that’s not being done, and then we lack that vital information. So, I think one of the lessons today would be that it’s important to enable molecular profiling for patients at time of diagnosis to facilitate downstream decision making.

Bijal D. Shah, MD: I have the dubious task of pushing back against every member of the group as it relates to this transition to intensified pediatric regimens. I don’t agree. In fact, I’ve not seen any data to tell me that an intensified pediatric regimen is superior to hyper-CVAD. It’s not to say that intensified pediatric therapies are the wrong approach. Certainly, if a patient can tolerate the asparaginase-based regimen, I have no ill will towards anyone who gives a pediatric regimen.

But I think we need to be very careful with a lack of randomized data to say that any particular approach is superior to another. In fact, most of the comparisons we have as they relate to pediatric therapy are retrospective or historical comparisons, and that makes it very, very challenging. This is not to say that I don’t use pediatric-inspired therapy; this is not to say that I don’t use hyper-CVAD, because I use a little bit of both.

For me, what I found is that I try and tailor it to the patient. The real key about intensified pediatric therapies is they require a lot of compliance, a lot of outpatient follow-up. And without question, there are some of my adolescent and young adult patients who cannot manage that. If I can bring them in the hospital every 3 weeks, it’s much easier to get them through the regimen, ensure compliance, and get the best possible outcome I can.

Aaron C. Logan, MD, PhD: I think one of the important lessons from 10403 was that there wasn’t a center difference. It didn’t matter whether it was a pediatric center or an adult center. If you followed the protocol and got your patients to comply, the outcomes were the same. Because that was one of the questions: Is it actually how you treat your patient, because of your background and training? And I think that 10403 finally showed us importantly that adult doctors can give a pediatric-inspired regimen and make sure it’s punctual and on time and the patients comply. So, I think it can be done. I agree that there are patients, particularly as they approach 40 and above, where they have commitments in their life that make it very difficult to comply with some of those regimens.

Bijal D. Shah, MD: I’ll extend that a step further, just to be the advocate, because I know where most of the members of the committee stand. I think it’s different when you’re on a study. When you’re getting 10403 on a study and you have a research nurse who can keep you on task to help you manage the methotrexate, to help you manage the 6 MP (6-mercaptopurine) and the asparaginase and so on, I think it makes it a little bit easier. When you’re doing it off of protocol and your pharmacist calls you at 3 in the afternoon in the middle of a busy clinic and says, “What do I do with this patient’s Capizzi methotrexate,” it can be a little bit daunting to turn to page—I can’t remember now—in the protocol.

Ryan D. Cassaday, MD: Fifty-something, I think.

Bijal D. Shah, MD: Exactly. Say this is what we’re going to do. And so, really all I want to emphasize is that I don’t think there’s a 1-size fits all solution. I think that’s fundamentally what you’re also saying as you talk about elderly ALL, as you talk about trying to account for the biology of ALL in some of our treatment decision making and some of the trials that will be coming to address those features. The first thing I think we have to do is get away from the 1-size-fits-all approach. If we continue to do that, I think we’re just going to find ourselves beating our heads against that wall.

Aaron C. Logan, MD, PhD: I think when we think we’ve finally figured it out, we’ll be moving the new agents to the frontline and it’ll be even more murky.

Bijal D. Shah, MD: Yes.

Anthony S. Stein, MD: There was a study where they looked at patients between the ages of 16 and 20, where patients were treated either on a pediatric protocol versus an adult protocol, and patients who got a pediatric protocol had a much better outcome than if you they were treated on an adult protocol.

Bijal D. Shah, MD: I don’t remember that specific study, but I will come back to the hyper-CVAD versus BFM (Berlin-Frankfurt-Munster) study, which—recognizing again that it’s an historical comparison—was patients who were treated with a pretty well-defined timeframe. I can’t remember the specific years of inclusion, but a modern period. And the outcomes were indistinguishable, both MRD acquisition as well as long-term survival.

I think a large part of that is what the Dutch have already shown, that for these very high-risk subgroups—the Ph-like disease, which tends to dominate probably a third or so of our young-adult population—the addition of asparaginase doesn’t clearly influence that outcome.

Ryan D. Cassaday, MD: I would just add a couple of things about this, at least in my practice. While I appreciate Bijal’s points about hyper-CVAD—to tailor it is a good idea, if you can—one thing that I find more compelling about using the pediatric regimens in this patient population is that we can leverage all of the incredible knowledge and experience that pediatricians have obtained over the years of using MRD to really risk stratify patients. We don’t have very good data with hyper-CVAD to use MRD to understand who are really the best responders and who aren’t. That’s a pretty well-established understanding, at least in the pediatric literature. It is an extrapolation to take it from an 8-year-old to a 28-year-old, but at least it gives us something to work off of. That’s one of the reasons that I tend to prefer the pediatric regimens in this age group, to be able to take advantage of MRD. But I also have to admit that I had the luxury of being able to use1 of the Children’s Oncology Group reference labs as my own clinical flow cytometry. So, when I’m doing the bone marrow testing, it’s that level of quality.

Mark R. Litzow, MD: Well, thank you, Bijal, for giving us that perspective. That’s an important point.

Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: Aaron, can you talk about your approach to Ph-negative patients and how that whole area is evolving?

Aaron C. Logan, MD, PhD: Absolutely. As Ryan mentioned earlier, one of our best prognosticators for outcome is the age of the patient. We really have to take that into account when we decide how we’re going to treat someone. For the under-age-40 group, I think it’s very well established now that we should try, if at all possible, to use a pediatric inspired regimen. And hopefully, it’s going to be on a clinical trial. The first consideration for a patient of any age should be a clinical trial. We haven’t yet established a golden standard. But if you don’t have a clinical trial opened for your young adult up to age 40, you should be using an AYA (adolescents and young adults) protocol. An example would be the Intergroup 10403 study that has shown very compelling outcomes in patients up to age 39. There are other similar pediatric inspired regimens that can be utilized in this setting, or the intensification of other backbones. I would not typically wish to see a patient in this age group treated with hyper-CVAD, because I don’t think it’s the best therapy for that age group.

Now in the more elderly patients who can’t tolerate chemotherapy, as we just mentioned, you have very limited options. You typically might consider corticosteroids with perhaps some vincristine. For the fit elderly patients, I think a very viable option is to do the mini–hyper-CVAD, which many patients will tolerate. And then for everyone between ages 40 and 60, hopefully you’ve got a clinical trial for that population to see, can we push pediatric-like therapies into a slightly older age group? Or is there some other method to get those patients into a deep remission?

I think at most institutions, everyone has their favorite recipe or protocol. It’s hard to break those habits, for better or worse. I think the field is still learning how to treat patients in the different age groups. But I think we’ve all agreed that we need to intensify for every patient who can tolerate intensive therapy.

Now, what we do know, even in these pediatric inspired regimens, is there are patients who are going to have a higher likelihood of failing to achieve their MRD-negative remission, and those would, for instance, be the Ph-like population. Our center, as well as probably everyone who represents a center here today, has probably gotten to the point where we’re doing up-front molecular profiling of our patients so we can identify these lesions. I think we all probably get referrals from outside centers where that’s not being done, and then we lack that vital information. So, I think one of the lessons today would be that it’s important to enable molecular profiling for patients at time of diagnosis to facilitate downstream decision making.

Bijal D. Shah, MD: I have the dubious task of pushing back against every member of the group as it relates to this transition to intensified pediatric regimens. I don’t agree. In fact, I’ve not seen any data to tell me that an intensified pediatric regimen is superior to hyper-CVAD. It’s not to say that intensified pediatric therapies are the wrong approach. Certainly, if a patient can tolerate the asparaginase-based regimen, I have no ill will towards anyone who gives a pediatric regimen.

But I think we need to be very careful with a lack of randomized data to say that any particular approach is superior to another. In fact, most of the comparisons we have as they relate to pediatric therapy are retrospective or historical comparisons, and that makes it very, very challenging. This is not to say that I don’t use pediatric-inspired therapy; this is not to say that I don’t use hyper-CVAD, because I use a little bit of both.

For me, what I found is that I try and tailor it to the patient. The real key about intensified pediatric therapies is they require a lot of compliance, a lot of outpatient follow-up. And without question, there are some of my adolescent and young adult patients who cannot manage that. If I can bring them in the hospital every 3 weeks, it’s much easier to get them through the regimen, ensure compliance, and get the best possible outcome I can.

Aaron C. Logan, MD, PhD: I think one of the important lessons from 10403 was that there wasn’t a center difference. It didn’t matter whether it was a pediatric center or an adult center. If you followed the protocol and got your patients to comply, the outcomes were the same. Because that was one of the questions: Is it actually how you treat your patient, because of your background and training? And I think that 10403 finally showed us importantly that adult doctors can give a pediatric-inspired regimen and make sure it’s punctual and on time and the patients comply. So, I think it can be done. I agree that there are patients, particularly as they approach 40 and above, where they have commitments in their life that make it very difficult to comply with some of those regimens.

Bijal D. Shah, MD: I’ll extend that a step further, just to be the advocate, because I know where most of the members of the committee stand. I think it’s different when you’re on a study. When you’re getting 10403 on a study and you have a research nurse who can keep you on task to help you manage the methotrexate, to help you manage the 6 MP (6-mercaptopurine) and the asparaginase and so on, I think it makes it a little bit easier. When you’re doing it off of protocol and your pharmacist calls you at 3 in the afternoon in the middle of a busy clinic and says, “What do I do with this patient’s Capizzi methotrexate,” it can be a little bit daunting to turn to page—I can’t remember now—in the protocol.

Ryan D. Cassaday, MD: Fifty-something, I think.

Bijal D. Shah, MD: Exactly. Say this is what we’re going to do. And so, really all I want to emphasize is that I don’t think there’s a 1-size fits all solution. I think that’s fundamentally what you’re also saying as you talk about elderly ALL, as you talk about trying to account for the biology of ALL in some of our treatment decision making and some of the trials that will be coming to address those features. The first thing I think we have to do is get away from the 1-size-fits-all approach. If we continue to do that, I think we’re just going to find ourselves beating our heads against that wall.

Aaron C. Logan, MD, PhD: I think when we think we’ve finally figured it out, we’ll be moving the new agents to the frontline and it’ll be even more murky.

Bijal D. Shah, MD: Yes.

Anthony S. Stein, MD: There was a study where they looked at patients between the ages of 16 and 20, where patients were treated either on a pediatric protocol versus an adult protocol, and patients who got a pediatric protocol had a much better outcome than if you they were treated on an adult protocol.

Bijal D. Shah, MD: I don’t remember that specific study, but I will come back to the hyper-CVAD versus BFM (Berlin-Frankfurt-Munster) study, which—recognizing again that it’s an historical comparison—was patients who were treated with a pretty well-defined timeframe. I can’t remember the specific years of inclusion, but a modern period. And the outcomes were indistinguishable, both MRD acquisition as well as long-term survival.

I think a large part of that is what the Dutch have already shown, that for these very high-risk subgroups—the Ph-like disease, which tends to dominate probably a third or so of our young-adult population—the addition of asparaginase doesn’t clearly influence that outcome.

Ryan D. Cassaday, MD: I would just add a couple of things about this, at least in my practice. While I appreciate Bijal’s points about hyper-CVAD—to tailor it is a good idea, if you can—one thing that I find more compelling about using the pediatric regimens in this patient population is that we can leverage all of the incredible knowledge and experience that pediatricians have obtained over the years of using MRD to really risk stratify patients. We don’t have very good data with hyper-CVAD to use MRD to understand who are really the best responders and who aren’t. That’s a pretty well-established understanding, at least in the pediatric literature. It is an extrapolation to take it from an 8-year-old to a 28-year-old, but at least it gives us something to work off of. That’s one of the reasons that I tend to prefer the pediatric regimens in this age group, to be able to take advantage of MRD. But I also have to admit that I had the luxury of being able to use1 of the Children’s Oncology Group reference labs as my own clinical flow cytometry. So, when I’m doing the bone marrow testing, it’s that level of quality.

Mark R. Litzow, MD: Well, thank you, Bijal, for giving us that perspective. That’s an important point.

Transcript Edited for Clarity 
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