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Considering Induction Regimens for ALL

Panelists: Ryan D. Cassaday, MD, University of Washington School of Medicine; Mark R. Litzow, MD, Mayo Clinic; Jae Park, MD, Memorial Sloan Kettering Cancer Center; Rachel E. Rau, MD, Baylor College of Medicine
Published: Friday, Jan 31, 2020



Transcript:

Mark R. Litzow, MD: That’s a nice segue into talking about therapy and induction therapy. Rachel, maybe you can start us off and talk about what the optimal approach in induction therapy is for acute lymphoblastic leukemia [ALL] and what factors you take into account in your treatment planning.

Rachel E. Rau, MD: I suspect that our induction therapy may be different than many adult regimens, but in general for pediatrics, we employ a standard induction therapy that consists of either vincristine, pegaspargase, intrathecal [IT] methotrexate, and steroids—either prednisone or dexamethasone—plus or minus anthracycline. And for the Children’s Oncology Group, we reserve the anthracycline use in induction for patients with National Cancer Institute [NCI] high-risk disease in infants because we know they are harder to get to a minimal residual disease [MRD]-negative remission at that the end of that month of induction.

Additionally, we know that patients with increased leukemic burden with cerebrospinal fluid [CSF] at diagnosis require additional central nervous system [CNS]-directed therapies, so we administer extra IT treatments throughout induction to clear the CSF disease.

Mark R. Litzow, MD: And Ryan, what have we learned from our pediatric colleagues about how to treat some of our younger patients with ALL?

Ryan D. Cassaday, MD: A lot, in my opinion. While I think there is still certainly some healthy and appropriate controversy on this topic, I think many of us who treat adult ALL have transitioned toward using pediatric inspired regimens for young adults. The age range that we use to define that is a bit of a moving target. Again, as an adult oncologist, I see primarily patients above 18 years old. I typically think of young adult ALL as being under 40 years old. The C10403 Intergroup study was just published this year, and that was the upper age range that they used in their trial, for a regimen modeled virtually identically off a high-risk pediatric ALL regimen. And I think that the results from that study were certainly encouraging and many have taken that on as an approach for pH-negative young adult ALL.

Mark R. Litzow, MD: I think what we’ve learned from our pediatric colleagues is that they use much more of the non-myelosuppressive drugs that I talked about: vincristine, pegaspargase, steroids. And I think we’ve incorporated that into some of these young adult regimens. I think there are a lot of factors that can play into the outcomes of these patients, but I think use of those agents in higher doses and with more intensity has been a big difference in that category.

Ryan D. Cassaday, MD: I would add though they are not for the faint of heart in terms of administering these treatments. There is a pretty steep learning curve to learn how to administer these regimens safely and effectively, so it’s definitely something to make sure that you feel comfortable with before embarking upon such a treatment.

Mark R. Litzow, MD: Yes, and a 35-year-old patient is still not a 10 year old.

Ryan D. Cassaday, MD: Correct.

Mark R. Litzow, MD: And there’s more toxicity, which has been my experience as well. Rachel, will you talk a little bit about the Philadelphia-like ALL and how you and your pediatric colleagues are addressing that?

Rachel E. Rau, MD: I think it’s an exciting area where we can really move the needle for some patients, certainly we’re hoping in the same way we’ve done Ph-positive patients with imatinib or dasatinib.

So we’re studying this in the Children’s Oncology Group, and other consortiums around the world are also asking the same questions. We have an arm of our past NCI high-risk trial where they’re incorporating dasatinib for the ABL class fusions that are identified as Ph-like. Additionally, we have another trial run by Sarah Tasian, MD. It’s an industry sponsored trial with Incyte, where they’re using ruxolitinib for patients with JAK-activating Ph-like lesions.

We don’t yet know if this will really improve outcomes. Step one was to determine if it was tolerable to do. We were quite confident that the introduction of imatinib or dasatinib for the ABL-class fusions would be tolerated as it was in our Ph-positive patients, but ruxolitinib was an unknown. It had never been incorporated into the intensive chemotherapy backbone that we give our pediatric patients. Thus far, that trial has shown that it is tolerable.

Jae Park, MD: Do you think it’s actually too late to be added by the consolidation? Because most of these Ph-like patients will be MRD positive at the end of induction one and two, so do you think we actually get there too late?

Rachel E. Rau, MD: It’s an excellent question, and I think incorporating imatinib or dasatinib during induction, by day 14, certainly has shown to be tolerated and probably more effective at clearing MRD and Ph positive. So ultimately that may be the goal to move that into upfront therapy. But again, we were in really early stages and incorporating ruxolitinib into our chemotherapy backbone. So I think starting post-induction made a lot of sense for the study design.

Transcript Edited for Clarity

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Transcript:

Mark R. Litzow, MD: That’s a nice segue into talking about therapy and induction therapy. Rachel, maybe you can start us off and talk about what the optimal approach in induction therapy is for acute lymphoblastic leukemia [ALL] and what factors you take into account in your treatment planning.

Rachel E. Rau, MD: I suspect that our induction therapy may be different than many adult regimens, but in general for pediatrics, we employ a standard induction therapy that consists of either vincristine, pegaspargase, intrathecal [IT] methotrexate, and steroids—either prednisone or dexamethasone—plus or minus anthracycline. And for the Children’s Oncology Group, we reserve the anthracycline use in induction for patients with National Cancer Institute [NCI] high-risk disease in infants because we know they are harder to get to a minimal residual disease [MRD]-negative remission at that the end of that month of induction.

Additionally, we know that patients with increased leukemic burden with cerebrospinal fluid [CSF] at diagnosis require additional central nervous system [CNS]-directed therapies, so we administer extra IT treatments throughout induction to clear the CSF disease.

Mark R. Litzow, MD: And Ryan, what have we learned from our pediatric colleagues about how to treat some of our younger patients with ALL?

Ryan D. Cassaday, MD: A lot, in my opinion. While I think there is still certainly some healthy and appropriate controversy on this topic, I think many of us who treat adult ALL have transitioned toward using pediatric inspired regimens for young adults. The age range that we use to define that is a bit of a moving target. Again, as an adult oncologist, I see primarily patients above 18 years old. I typically think of young adult ALL as being under 40 years old. The C10403 Intergroup study was just published this year, and that was the upper age range that they used in their trial, for a regimen modeled virtually identically off a high-risk pediatric ALL regimen. And I think that the results from that study were certainly encouraging and many have taken that on as an approach for pH-negative young adult ALL.

Mark R. Litzow, MD: I think what we’ve learned from our pediatric colleagues is that they use much more of the non-myelosuppressive drugs that I talked about: vincristine, pegaspargase, steroids. And I think we’ve incorporated that into some of these young adult regimens. I think there are a lot of factors that can play into the outcomes of these patients, but I think use of those agents in higher doses and with more intensity has been a big difference in that category.

Ryan D. Cassaday, MD: I would add though they are not for the faint of heart in terms of administering these treatments. There is a pretty steep learning curve to learn how to administer these regimens safely and effectively, so it’s definitely something to make sure that you feel comfortable with before embarking upon such a treatment.

Mark R. Litzow, MD: Yes, and a 35-year-old patient is still not a 10 year old.

Ryan D. Cassaday, MD: Correct.

Mark R. Litzow, MD: And there’s more toxicity, which has been my experience as well. Rachel, will you talk a little bit about the Philadelphia-like ALL and how you and your pediatric colleagues are addressing that?

Rachel E. Rau, MD: I think it’s an exciting area where we can really move the needle for some patients, certainly we’re hoping in the same way we’ve done Ph-positive patients with imatinib or dasatinib.

So we’re studying this in the Children’s Oncology Group, and other consortiums around the world are also asking the same questions. We have an arm of our past NCI high-risk trial where they’re incorporating dasatinib for the ABL class fusions that are identified as Ph-like. Additionally, we have another trial run by Sarah Tasian, MD. It’s an industry sponsored trial with Incyte, where they’re using ruxolitinib for patients with JAK-activating Ph-like lesions.

We don’t yet know if this will really improve outcomes. Step one was to determine if it was tolerable to do. We were quite confident that the introduction of imatinib or dasatinib for the ABL-class fusions would be tolerated as it was in our Ph-positive patients, but ruxolitinib was an unknown. It had never been incorporated into the intensive chemotherapy backbone that we give our pediatric patients. Thus far, that trial has shown that it is tolerable.

Jae Park, MD: Do you think it’s actually too late to be added by the consolidation? Because most of these Ph-like patients will be MRD positive at the end of induction one and two, so do you think we actually get there too late?

Rachel E. Rau, MD: It’s an excellent question, and I think incorporating imatinib or dasatinib during induction, by day 14, certainly has shown to be tolerated and probably more effective at clearing MRD and Ph positive. So ultimately that may be the goal to move that into upfront therapy. But again, we were in really early stages and incorporating ruxolitinib into our chemotherapy backbone. So I think starting post-induction made a lot of sense for the study design.

Transcript Edited for Clarity
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