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Overview on Management of 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: Tuesday, Dec 29, 2015


Transcript:

Bijal Shah, MD:
The treatment of acute lymphoblastic leukemia (ALL) has been revolutionized over the past few years, and I think it’s wonderful to see. We’re starting to recognize now that there are subsets of ALL that need to be treated radically differently than others. The first that comes to most people’s minds is the Philadelphia-positive subset. At this point, if we talked about not integrating a tyrosine kinase inhibitor, be it imatinib, dasatinib, nilotinib, or ponatinib, people would look at us as though we were crazy. Why wouldn’t you do this? These agents are known to considerably add to therapeutic benefit.

Speaking further, we now understand, from a prospective trial presented at the ASH 2015 meeting, that rituximab is highly &autoplay=1in those patients with CD20-positive disease. I absolutely think that as we begin to define more and more molecular subsets, be it the Philadelphia-like or the MLL translocated subset, that we’re going to define therapeutics that are especially beneficial for these patients, and with that, move the survival forward.

That brings me to the not-so-enthusiastic part of the historical perspective of ALL, and that is we are still batting about 40% long term in terms of what we expect as it relates to overall survival in acute lymphoblastic leukemias. We haven’t really beat that benchmark, as we’ve gone from the Larson to the Linker to the ECOG 2993 to the hyper-CVAD regimens. We’re still at that same place. Now, the hope is, as we integrate rituximab and other novel therapeutics into this space, we’ll do better.

I think that the management of the adolescents and young adults is one that deserves special mention. There are certainly data to suggest that we may be able to improve outcomes in that space by intensifying chemotherapy and by including asparaginase from the beginning of treatment. I hope that that notion pans out over time. I know that there are data from the MD Anderson group where they tried to compare their outcomes, in this case with the augmented BFM versus the hyper-CVADi regimen. They didn’t see much of a difference. There was about a 50% long-term event-free and overall survival benefit, which is about what we were getting in the CALGB 10403 study.

Where I’m going with this is that we really need to come up with good Cooperative Group studies where we’re randomizing patients across these intensive regimens and asking who’s the winner. I think that blindly adopting one strategy and saying this is what we’re going to go with may not be the best approach as we move forward into the next decade. This is what was essentially occurring within the context of the Children’s Oncology Group and the Pediatric Oncology Groups. They decided on their backbone and then you could see, incrementally, how they built on that backbone using things like minimal residual disease (MRD) monitoring, or technologies like MRD, to risk stratify their patients.

Raoul Tibes, MD, PhD: The question I'm often asked, is, what is the progress in the treatment of patients with lymphoblastic leukemia? Here, we have to distinguish between pediatric patients and adult patients. Fortunately, the outcomes in pediatric patients have improved over the last several years and decades. Later, we'll talk about some of the improvements in those patients using CAR T-cells.

In adult patients with acute lymphoblastic leukemias, progress has been made in several areas. One is the discovery of cytogenetic and molecular risk stratification, and I will talk to that effect a little later. A big improvement over the last several years was the use of pediatric-inspired cytotoxic regimens in the treatment of younger adults with ALL. Pediatric patients have historically done better than adult patients, including young adult patients.

Several groups, including large Cooperative Group trials, have now tested the more intensive pediatric-inspired regimen in young adults. Younger is often defined as above the age of 16 to 18, up to the age of 40, and I can talk later to that effect about the cutoff for younger or all adults patients. Those pediatric-inspired protocols have shown that adult patients actually can improve their complete remission rates, as well as the outcomes of long-term overall survival and relapse-free survival. So, that's one improvement in the treatment of ALL.

Another area where improvements have been made and we continue to incorporate it into clinical practice is MRD monitoring. Yet another area of improvement over the last several years is the development of very specific monoclonal antibodies, and there are several different approaches being used. For example, there are bispecific antibodies, like blinatumomab, which was recently approved for relapsed ALL. There are also antibody-drug conjugates that are in clinical development, as well as CAR T-cell treatment protocols that are also being developed.

However, there still remains an unmet need in the treatment of adult patients with ALL. This unmet need is incorporating MRD monitoring systematically into routine clinical practice. Many adult patients with ALL, unfortunately, do relapse and we need to develop consolidation strategies, which could consist of hematopoietic stem cell transplantation, allogeneic stem cell transplantation, or addressing MRD treatment in patients who achieve complete remission.
                                                                                                                                                                                                                                                                                                                 Transcript Edited for Clarity
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Transcript:

Bijal Shah, MD:
The treatment of acute lymphoblastic leukemia (ALL) has been revolutionized over the past few years, and I think it’s wonderful to see. We’re starting to recognize now that there are subsets of ALL that need to be treated radically differently than others. The first that comes to most people’s minds is the Philadelphia-positive subset. At this point, if we talked about not integrating a tyrosine kinase inhibitor, be it imatinib, dasatinib, nilotinib, or ponatinib, people would look at us as though we were crazy. Why wouldn’t you do this? These agents are known to considerably add to therapeutic benefit.

Speaking further, we now understand, from a prospective trial presented at the ASH 2015 meeting, that rituximab is highly &autoplay=1in those patients with CD20-positive disease. I absolutely think that as we begin to define more and more molecular subsets, be it the Philadelphia-like or the MLL translocated subset, that we’re going to define therapeutics that are especially beneficial for these patients, and with that, move the survival forward.

That brings me to the not-so-enthusiastic part of the historical perspective of ALL, and that is we are still batting about 40% long term in terms of what we expect as it relates to overall survival in acute lymphoblastic leukemias. We haven’t really beat that benchmark, as we’ve gone from the Larson to the Linker to the ECOG 2993 to the hyper-CVAD regimens. We’re still at that same place. Now, the hope is, as we integrate rituximab and other novel therapeutics into this space, we’ll do better.

I think that the management of the adolescents and young adults is one that deserves special mention. There are certainly data to suggest that we may be able to improve outcomes in that space by intensifying chemotherapy and by including asparaginase from the beginning of treatment. I hope that that notion pans out over time. I know that there are data from the MD Anderson group where they tried to compare their outcomes, in this case with the augmented BFM versus the hyper-CVADi regimen. They didn’t see much of a difference. There was about a 50% long-term event-free and overall survival benefit, which is about what we were getting in the CALGB 10403 study.

Where I’m going with this is that we really need to come up with good Cooperative Group studies where we’re randomizing patients across these intensive regimens and asking who’s the winner. I think that blindly adopting one strategy and saying this is what we’re going to go with may not be the best approach as we move forward into the next decade. This is what was essentially occurring within the context of the Children’s Oncology Group and the Pediatric Oncology Groups. They decided on their backbone and then you could see, incrementally, how they built on that backbone using things like minimal residual disease (MRD) monitoring, or technologies like MRD, to risk stratify their patients.

Raoul Tibes, MD, PhD: The question I'm often asked, is, what is the progress in the treatment of patients with lymphoblastic leukemia? Here, we have to distinguish between pediatric patients and adult patients. Fortunately, the outcomes in pediatric patients have improved over the last several years and decades. Later, we'll talk about some of the improvements in those patients using CAR T-cells.

In adult patients with acute lymphoblastic leukemias, progress has been made in several areas. One is the discovery of cytogenetic and molecular risk stratification, and I will talk to that effect a little later. A big improvement over the last several years was the use of pediatric-inspired cytotoxic regimens in the treatment of younger adults with ALL. Pediatric patients have historically done better than adult patients, including young adult patients.

Several groups, including large Cooperative Group trials, have now tested the more intensive pediatric-inspired regimen in young adults. Younger is often defined as above the age of 16 to 18, up to the age of 40, and I can talk later to that effect about the cutoff for younger or all adults patients. Those pediatric-inspired protocols have shown that adult patients actually can improve their complete remission rates, as well as the outcomes of long-term overall survival and relapse-free survival. So, that's one improvement in the treatment of ALL.

Another area where improvements have been made and we continue to incorporate it into clinical practice is MRD monitoring. Yet another area of improvement over the last several years is the development of very specific monoclonal antibodies, and there are several different approaches being used. For example, there are bispecific antibodies, like blinatumomab, which was recently approved for relapsed ALL. There are also antibody-drug conjugates that are in clinical development, as well as CAR T-cell treatment protocols that are also being developed.

However, there still remains an unmet need in the treatment of adult patients with ALL. This unmet need is incorporating MRD monitoring systematically into routine clinical practice. Many adult patients with ALL, unfortunately, do relapse and we need to develop consolidation strategies, which could consist of hematopoietic stem cell transplantation, allogeneic stem cell transplantation, or addressing MRD treatment in patients who achieve complete remission.
                                                                                                                                                                                                                                                                                                                 Transcript Edited for Clarity
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