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Induction and Post-Induction Therapy for Adult ALL

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


Transcript:

Bijal D. Shah, MD:
Risk stratification in acute lymphoblastic leukemia (ALL) is absolutely the next most important thing we can do to improve outcomes. Now, risk stratification involves, I think, fundamentally two components. The first is moving beyond things like white blood cell count or LDH and moving towards both a better characterization of the patient at presentation, so, looking more specifically at comorbidities, looking at the performance status, looking at those features which we think are going to show this is not an individual who will tolerate the intensity of the therapy that we’re outlining.

The second component is looking at the disease itself, so, the macroenvironment to the microenvironment, asking what is the genetics of this leukemia? Is it Philadelphia-positive? Is it a Philadelphia-like ALL? Are there other high- risk genomic translocations that will predict for inferior outcome? The last component is using that information and coupling it to minimal residual disease assessments. Asking, after we approach this patient with molecularly targeted or molecularly-based therapy, then moving forward to say, did we achieve the outcome we set out to achieve. And, if we didn’t, developing a platform for either adding additional agents, changing agents, or intensifying therapy in some way, shape, or form, for example, allogeneic transplant.

Raoul Tibes, MD, PhD: One question that comes up often is, what is the upper age limit for adult patients treated with pediatric-inspired regimen? Many trials are including an upper age limit. The most recent large CALGB trial included an age limit of 40, or below the age of 40. However, I can tell you from our experience in our institution, sometimes, we even go higher to the age of 50. Why is this important? Because the pediatric-inspired regimens have different drugs, less myelosuppressive drugs, and importantly, they incorporate asparaginase in the treatment for adult ALL patients. Why is this important? Because the addition of asparaginase in the treatment of ALL protocols has shown, over the years and over many trials, that it improves the outcome for patients with ALL.

 A question that comes up is, who are the patients who are fit or unfit for more intensive regimens? As I mentioned earlier, several of the clinical enrolled patients up to the age of 40. I would say some of the academic institutions go past the age of 40 in incorporating asparaginase or pediatric regimens for very fit patients. Fitness, however, is a relative term. As everybody is getting older, many patients are in better shape when they come to us. There are formal comorbidity scores that we can use to try to get an idea how fit patients are. However, those scores are sometimes cumbersome to calculate, and I think a general assessment based on a physician’s experience or comorbidities of patients should not necessarily prevent one from treating patients with the appropriate more intensive therapy, including asparaginase.

 I would like to mention that I think asparaginase is an essential part in the treatment of adult patients with ALL. There are several good regimens that have been developed for adult patients that do not include asparaginase. However, with the recent several trials we have seen, with the addition of asparaginase in the management of adult patients with ALL, I think we have to incorporate it in our treatment regimen upfront for most of the patients. The dosage can be adjusted in adult patients, based on their comorbidities, based on medical concerns, and based on organ function.

One side effect that is notable for asparaginase is hypersensitivity reactions. There are several formulations of asparaginase. E. coli-derived asparaginase was the original asparaginase and needs to be given more frequently, and has a higher incidence of hypersensitivity reactions. The new formulation, pegylated asparaginase, has been developed and it’s approved for the treatment of ALL. And hypersensitivity reactions are remarkable, reduced down to a range of 10-15%, as opposed to, previously, up to the range of 30%. I think it’s important to know there are two different hypersensitivity reactions. There’s an immediate hypersensitivity reaction related to the application infusion of asparaginase, which is manifested by fevers, by chills, pruritis, and even hypotension, which can be managed with stopping the infusion if it’s intravenous infusion, and giving the appropriate supportive medicines including steroids, epinephrine, and fluid support.

A second form of hypersensitivity is mediated through or from antibodies against asparaginase, essentially. This has a two-fold implication. First, sometimes we see these antibody mediated hypersensitivity reactions after the initial induction, of course, because it takes some time to produce those antibodies. Another implication is for the treatment response. They are so-called silent antibodies. It means not all antibodies will inhibit the effect of asparaginase. Some antibodies, some patients do not develop clinically significant transfusion reactions. However, the antibodies are still able to reduce the activity of asparaginase, which then would reduce the activity. There are assays to measure the asparaginase level and we’re aiming to maintain a level of asparaginase in the blood of above 100 IU per liter. That is important. Antibodies are not yet routinely measured. So what I would say is, it’s important to keep those hypersensitivity reactions in mind, for the clinical care of the patients immediately, as well as potentially for the outcome of patients, giving them the appropriate asparaginase dose and keeping the level over time.

Another question that sometimes comes up is, what is the right dose of asparaginase or Peg-asparaginase to give? In some of the regimens, for example, the augmented hyper-CVAD and some of the other regimens, we use a dose of 2500 units/m2. But I can tell you from experience that sometimes we go down to 2,000 units/m2 or even 1500 units/m2. I mentioned earlier that, ideally, we would have serial measurements of the asparaginase level because that’s a good reflection of the continued activity of asparaginase in the blood. Hopefully, at some point, we will do this routinely, in all of our patients. It is often done in clinical trials to show what the right dosages are and to compare the outcomes. So, to close, I want to emphasize that with asparaginase, age is not necessarily a contraindication, but just the opposite, if adult patients receive it. Pegylated asparaginase has less hypersensitivity reaction and is generally well tolerated. It also has less other side effects like transaminitis, hypertriglyceridemia, as well as pancreatitis. These are some of the other feared consequences or side effects.

Transcript Edited for Clarity
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Transcript:

Bijal D. Shah, MD:
Risk stratification in acute lymphoblastic leukemia (ALL) is absolutely the next most important thing we can do to improve outcomes. Now, risk stratification involves, I think, fundamentally two components. The first is moving beyond things like white blood cell count or LDH and moving towards both a better characterization of the patient at presentation, so, looking more specifically at comorbidities, looking at the performance status, looking at those features which we think are going to show this is not an individual who will tolerate the intensity of the therapy that we’re outlining.

The second component is looking at the disease itself, so, the macroenvironment to the microenvironment, asking what is the genetics of this leukemia? Is it Philadelphia-positive? Is it a Philadelphia-like ALL? Are there other high- risk genomic translocations that will predict for inferior outcome? The last component is using that information and coupling it to minimal residual disease assessments. Asking, after we approach this patient with molecularly targeted or molecularly-based therapy, then moving forward to say, did we achieve the outcome we set out to achieve. And, if we didn’t, developing a platform for either adding additional agents, changing agents, or intensifying therapy in some way, shape, or form, for example, allogeneic transplant.

Raoul Tibes, MD, PhD: One question that comes up often is, what is the upper age limit for adult patients treated with pediatric-inspired regimen? Many trials are including an upper age limit. The most recent large CALGB trial included an age limit of 40, or below the age of 40. However, I can tell you from our experience in our institution, sometimes, we even go higher to the age of 50. Why is this important? Because the pediatric-inspired regimens have different drugs, less myelosuppressive drugs, and importantly, they incorporate asparaginase in the treatment for adult ALL patients. Why is this important? Because the addition of asparaginase in the treatment of ALL protocols has shown, over the years and over many trials, that it improves the outcome for patients with ALL.

 A question that comes up is, who are the patients who are fit or unfit for more intensive regimens? As I mentioned earlier, several of the clinical enrolled patients up to the age of 40. I would say some of the academic institutions go past the age of 40 in incorporating asparaginase or pediatric regimens for very fit patients. Fitness, however, is a relative term. As everybody is getting older, many patients are in better shape when they come to us. There are formal comorbidity scores that we can use to try to get an idea how fit patients are. However, those scores are sometimes cumbersome to calculate, and I think a general assessment based on a physician’s experience or comorbidities of patients should not necessarily prevent one from treating patients with the appropriate more intensive therapy, including asparaginase.

 I would like to mention that I think asparaginase is an essential part in the treatment of adult patients with ALL. There are several good regimens that have been developed for adult patients that do not include asparaginase. However, with the recent several trials we have seen, with the addition of asparaginase in the management of adult patients with ALL, I think we have to incorporate it in our treatment regimen upfront for most of the patients. The dosage can be adjusted in adult patients, based on their comorbidities, based on medical concerns, and based on organ function.

One side effect that is notable for asparaginase is hypersensitivity reactions. There are several formulations of asparaginase. E. coli-derived asparaginase was the original asparaginase and needs to be given more frequently, and has a higher incidence of hypersensitivity reactions. The new formulation, pegylated asparaginase, has been developed and it’s approved for the treatment of ALL. And hypersensitivity reactions are remarkable, reduced down to a range of 10-15%, as opposed to, previously, up to the range of 30%. I think it’s important to know there are two different hypersensitivity reactions. There’s an immediate hypersensitivity reaction related to the application infusion of asparaginase, which is manifested by fevers, by chills, pruritis, and even hypotension, which can be managed with stopping the infusion if it’s intravenous infusion, and giving the appropriate supportive medicines including steroids, epinephrine, and fluid support.

A second form of hypersensitivity is mediated through or from antibodies against asparaginase, essentially. This has a two-fold implication. First, sometimes we see these antibody mediated hypersensitivity reactions after the initial induction, of course, because it takes some time to produce those antibodies. Another implication is for the treatment response. They are so-called silent antibodies. It means not all antibodies will inhibit the effect of asparaginase. Some antibodies, some patients do not develop clinically significant transfusion reactions. However, the antibodies are still able to reduce the activity of asparaginase, which then would reduce the activity. There are assays to measure the asparaginase level and we’re aiming to maintain a level of asparaginase in the blood of above 100 IU per liter. That is important. Antibodies are not yet routinely measured. So what I would say is, it’s important to keep those hypersensitivity reactions in mind, for the clinical care of the patients immediately, as well as potentially for the outcome of patients, giving them the appropriate asparaginase dose and keeping the level over time.

Another question that sometimes comes up is, what is the right dose of asparaginase or Peg-asparaginase to give? In some of the regimens, for example, the augmented hyper-CVAD and some of the other regimens, we use a dose of 2500 units/m2. But I can tell you from experience that sometimes we go down to 2,000 units/m2 or even 1500 units/m2. I mentioned earlier that, ideally, we would have serial measurements of the asparaginase level because that’s a good reflection of the continued activity of asparaginase in the blood. Hopefully, at some point, we will do this routinely, in all of our patients. It is often done in clinical trials to show what the right dosages are and to compare the outcomes. So, to close, I want to emphasize that with asparaginase, age is not necessarily a contraindication, but just the opposite, if adult patients receive it. Pegylated asparaginase has less hypersensitivity reaction and is generally well tolerated. It also has less other side effects like transaminitis, hypertriglyceridemia, as well as pancreatitis. These are some of the other feared consequences or side effects.

Transcript Edited for Clarity
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