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Treatment Algorithms for Philadelphia-Negative ALL

Insights From: Max S. Topp, MD, University Hospital of Wuerzburg
Published: Sunday, Jan 27, 2019



Transcript: 

Max S. Topp, MD: Within Europe, we try to re-treat all our patients on cooperative study protocols. So at our center, at least, it’s very rare that a patient doesn’t go on to study protocol. So, saying that, the study protocol is obviously fixed and leaves less space for maneuvering between A and B. And there are certain rules that are very clearly set on what to do if this and that happens. One very good example is that we have elaborate liver-testing protocol or demographic factors, which deem which dose we’re going to be using for asparaginase in these patients. But that’s fixed within the protocol, which is great that we have that. We use this guidance to really give the patient the ideal therapy in that situation.

I think for patients between 18 and 55 years old, the rules are fairly straightforward regarding what to do with them or when to adapt to the comorbidities. And the majority of patients in that age group are reasonably fit. It’s obviously when you have patients coming in with very severe infections due to leukemia or if they have a very unfortunate performance status due to comorbidities. But that’s actually, I would say, in about only 10% to 15% of patients, where you have to take a slow start and try to overcome those challenges that are caused by leukemia once you put the patient into remission.

The more complicated patients to treat are actually 55 and older. Obviously, patients in that age group come in very different flavors. Some of them have had a very healthy lifestyle and no comorbidities, and you may be inclined to treat them more aggressively. But we have shown in our studies that those patients, despite having a good performance status, are still biologically 60 and can’t withstand pediatric-based protocols as good as someone who is 10 years younger.

And then you have patients who have a lot of comorbidities and are 65, 70 years old, and it’s pretty obvious that to treat those patients with aggressive protocols is a huge challenge. The infectious disease death rate rises in those patients. Although we always try to treat them in study protocols or in treatment guidelines, often you see a patient who can’t get to that point where you can adequately give therapy. And you also know that the prognosis of those patients is actually quite poor when compared with the younger patients, because at 2 years, about 20% or 25% will be still leukemia free.

Whereas in the young patients we were talking about—particularly in the IR [intermediate-risk] group, which is 18 to 30 years old—cure rates are in the ballpark of about 75% to 80%. So it’s a very different way of actually approaching this patient. So you would personally feel sometimes that when it’s very difficult to get therapy in, you would be inclined to reduce therapy to leave away elements that might be toxic to the patient. Because only 1 out of 5 will potentially be cured in that situation. So that is, to me, particularly the biggest challenge.

And then once you get in the age group of 70 and 75, it becomes even more complicated. Because obviously there are many patients in that age group with certain comorbidities who make cure almost impossible. And there are a few patients who are able, even at 75, to go all the way, including an allotransplantation. So algorithms that have been published to assess physical fitness have become actually very important; and mental fitness too, because the protocol is a challenge for most patients. It is a long protocol, 2 or 3 years treatment. And they need a very good support team to get through that system.

ALL [acute lymphoblastic leukemia] is always treated with a cocktail of chemotherapy agents and steroids. So the majority of elderly patients will see something that is just a dose reduction of what you would do in the pediatric situation. So they will all get vincristine but reduce the dose. They all will get dexamethasone or some other steroid. All of them will get some anthracycline. Everyone will get, at some point, cyclophosphamide or cytarabine. And hopefully we can, in some sets of patients, also get asparaginase, which is a very important drug for ALL, plus methotrexate.

For all these substances, you start at a dose reduction. Hence the cure rates can’t be the same, because you’re reducing greatly what we know works. And then you learn as you’re doing things. You see someone getting methotrexate, although dose reduced, and they get renal impairment. So the second time you can’t expose any more methotrexate to the patient, or they will have a higher rate of toxicity. With PNP [peripheral neuropathy] problems in the fingertips, we start reducing the vincristine. That is all linked to age, and you identify patients where you have your limits.

And then you have information. “OK, you’re not responding very well.” You may put them into remission, but we know they are MRD [minimal residual disease] positive. For those patients, if they have seen this cocktail, and at the end of the day, they are MRD positive—particularly the elderly patient population, where there’s a higher rate of MRD positivity despite the cocktail—we know what’s going to happen. They’re going to be relapsing sooner or later, despite continuing on the therapy in that context. It’s a real dilemma that we face.

Transcript Edited for Clarity

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Transcript: 

Max S. Topp, MD: Within Europe, we try to re-treat all our patients on cooperative study protocols. So at our center, at least, it’s very rare that a patient doesn’t go on to study protocol. So, saying that, the study protocol is obviously fixed and leaves less space for maneuvering between A and B. And there are certain rules that are very clearly set on what to do if this and that happens. One very good example is that we have elaborate liver-testing protocol or demographic factors, which deem which dose we’re going to be using for asparaginase in these patients. But that’s fixed within the protocol, which is great that we have that. We use this guidance to really give the patient the ideal therapy in that situation.

I think for patients between 18 and 55 years old, the rules are fairly straightforward regarding what to do with them or when to adapt to the comorbidities. And the majority of patients in that age group are reasonably fit. It’s obviously when you have patients coming in with very severe infections due to leukemia or if they have a very unfortunate performance status due to comorbidities. But that’s actually, I would say, in about only 10% to 15% of patients, where you have to take a slow start and try to overcome those challenges that are caused by leukemia once you put the patient into remission.

The more complicated patients to treat are actually 55 and older. Obviously, patients in that age group come in very different flavors. Some of them have had a very healthy lifestyle and no comorbidities, and you may be inclined to treat them more aggressively. But we have shown in our studies that those patients, despite having a good performance status, are still biologically 60 and can’t withstand pediatric-based protocols as good as someone who is 10 years younger.

And then you have patients who have a lot of comorbidities and are 65, 70 years old, and it’s pretty obvious that to treat those patients with aggressive protocols is a huge challenge. The infectious disease death rate rises in those patients. Although we always try to treat them in study protocols or in treatment guidelines, often you see a patient who can’t get to that point where you can adequately give therapy. And you also know that the prognosis of those patients is actually quite poor when compared with the younger patients, because at 2 years, about 20% or 25% will be still leukemia free.

Whereas in the young patients we were talking about—particularly in the IR [intermediate-risk] group, which is 18 to 30 years old—cure rates are in the ballpark of about 75% to 80%. So it’s a very different way of actually approaching this patient. So you would personally feel sometimes that when it’s very difficult to get therapy in, you would be inclined to reduce therapy to leave away elements that might be toxic to the patient. Because only 1 out of 5 will potentially be cured in that situation. So that is, to me, particularly the biggest challenge.

And then once you get in the age group of 70 and 75, it becomes even more complicated. Because obviously there are many patients in that age group with certain comorbidities who make cure almost impossible. And there are a few patients who are able, even at 75, to go all the way, including an allotransplantation. So algorithms that have been published to assess physical fitness have become actually very important; and mental fitness too, because the protocol is a challenge for most patients. It is a long protocol, 2 or 3 years treatment. And they need a very good support team to get through that system.

ALL [acute lymphoblastic leukemia] is always treated with a cocktail of chemotherapy agents and steroids. So the majority of elderly patients will see something that is just a dose reduction of what you would do in the pediatric situation. So they will all get vincristine but reduce the dose. They all will get dexamethasone or some other steroid. All of them will get some anthracycline. Everyone will get, at some point, cyclophosphamide or cytarabine. And hopefully we can, in some sets of patients, also get asparaginase, which is a very important drug for ALL, plus methotrexate.

For all these substances, you start at a dose reduction. Hence the cure rates can’t be the same, because you’re reducing greatly what we know works. And then you learn as you’re doing things. You see someone getting methotrexate, although dose reduced, and they get renal impairment. So the second time you can’t expose any more methotrexate to the patient, or they will have a higher rate of toxicity. With PNP [peripheral neuropathy] problems in the fingertips, we start reducing the vincristine. That is all linked to age, and you identify patients where you have your limits.

And then you have information. “OK, you’re not responding very well.” You may put them into remission, but we know they are MRD [minimal residual disease] positive. For those patients, if they have seen this cocktail, and at the end of the day, they are MRD positive—particularly the elderly patient population, where there’s a higher rate of MRD positivity despite the cocktail—we know what’s going to happen. They’re going to be relapsing sooner or later, despite continuing on the therapy in that context. It’s a real dilemma that we face.

Transcript Edited for Clarity
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