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Philadelphia Chromosome-Positive ALL: Upfront Approaches

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: Friday, Feb 09, 2018



Transcript: 

Mark R. Litzow, MD: MRD, of course, refers to minimal residual disease assessment, and we’re going to get into an extensive discussion about that later in our discussion here today. Let’s turn and talk a little bit about induction therapy. Typically for induction therapy, we divide our patients into whether they’re BCR-ABL–positive, if they have a Philadelphia chromosome or not. If they do not, then we approach those patients differently. I’d like to make a few comments about how we approach Philadelphia-chromosome–positive, or BCR-ABL–positive, acute lymphoblastic leukemia.

I think the game changer in the treatment of this subtype of ALL has been the tyrosine kinase inhibitors that were first developed for chronic myeloid leukemia and are now an established therapy for Philadelphia-chromosome–positive ALL. Certainly, imatinib has been the first agent that was tested in this subset of patients, but most of the tyrosine kinase inhibitors have now been tested in one form or another.
Our pediatric colleagues have relied primarily on the use of imatinib, and some of their studies have suggested that if a pediatric patient with Ph-positive ALL achieved MRD negativity becomes BCR-ABL–negative, they don’t appear to need a transplant and their outcomes are similar to what’s seen with either a matched related or unrelated donor. I think we still don’t know that with certainty in our adult patients, and it’s something that we should discuss.

The initial approach to treating these patients was to add a tyrosine kinase inhibitor to our established chemotherapy regimens, and that’s still what many of us do. The Italians have taken an interesting approach in relying on a tyrosine kinase inhibitor with corticosteroids along with some CNS prophylaxis. They use that as a sole therapy in elderly, but even in younger patients, and have shown that they can achieve a high rate of compete hematologic response with lower levels of complete molecular response. I know their initial studies were with dasatinib, and they had a complete molecular remission around 20%. There’s a new study from their group that was presented at this year’s ASH meeting, where they’ve added ponatinib to corticosteroids and they’re showing even better responses: complete hematologic responses over 90% and molecular responses approaching 40%. So, it’s really a very exciting time in the treatment of this poor-prognosis ALL.

Aaron C. Logan, MD, PhD: Speaking of ponatinib, MD Anderson had shown some very compelling data adding ponatinib to hyper-CVAD with 1-year survival upwards of 70% or 75%. Of course, we’ll need to see longer term outcome data from that study. Hopefully we’ll see it done in a multi-institutional setting, because with the hyper-CVAD dasatinib study, we did see some later relapses. But ponatinib seems to have particularly robust activity in ALL, which is great for this patient population. If we can add it to backbones like hyper-CVAD and other regimens, and get outcomes that rival those that we see in children, then perhaps we don’t need to transplant the Ph-positive population any more.

Bijal D. Shah, MD: Right. You bring up some very compelling points. I’d like you to comment on the Alliance trial that’s coming. I think we’ll be testing this approach. If I understand correctly, it’s going to be a low-dose chemo versus a steroid/vincristine combination plus Sprycel [dasatinib] versus chemotherapy, I think a hyper-CVAD backbone, with Sprycel to formally test. Do we need the high-dose induction chemotherapy? If we see a positive result, should we extrapolate that to ponatinib? Are we at that stage where we can say that with each generation of TKIs, we need to be ready to push it forward. This is particularly relevant as ABL001 is now making its foray into the clinical trial space.

Mark R. Litzow, MD: Anthony, what’s your perspective on this question?

Anthony S. Stein, MD: The goal of treatment is to get a complete molecular response. When you combine either dasatinib or ponatinib with steroids alone, you’re only getting a complete molecular response, at most, in 45% of patients. So, most of those patients are going to relapse in the future. Even if your goal is to take them to a transplant, most patients will do better if they come in molecularly negative prior to the transplant. I still don’t buy into the concept of using steroids and a TK inhibitor alone, and will often even add a little bit of chemotherapy to the regimen.

Aaron C. Logan, MD, PhD: Some of the patients in whom you might consider steroids with a TKI alone would be patients who may not be fit for transplant. That calculus about by getting them to MRD negativity, specifically for improving outcomes and transplant, may not be quite as relevant. Certainly, in those patients you want to have the best progression-free survival of your initial therapy, because that’s really what they’re relying on without a consolidative transplant.

Anthony S. Stein, MD: For an elderly patient, I have no problem giving them steroids and a TK inhibitor, because they’re able to tolerate the treatment. You can get them into at least a hematological remission, and you can prolong their survival.

Transcript Edited for Clarity 

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Transcript: 

Mark R. Litzow, MD: MRD, of course, refers to minimal residual disease assessment, and we’re going to get into an extensive discussion about that later in our discussion here today. Let’s turn and talk a little bit about induction therapy. Typically for induction therapy, we divide our patients into whether they’re BCR-ABL–positive, if they have a Philadelphia chromosome or not. If they do not, then we approach those patients differently. I’d like to make a few comments about how we approach Philadelphia-chromosome–positive, or BCR-ABL–positive, acute lymphoblastic leukemia.

I think the game changer in the treatment of this subtype of ALL has been the tyrosine kinase inhibitors that were first developed for chronic myeloid leukemia and are now an established therapy for Philadelphia-chromosome–positive ALL. Certainly, imatinib has been the first agent that was tested in this subset of patients, but most of the tyrosine kinase inhibitors have now been tested in one form or another.
Our pediatric colleagues have relied primarily on the use of imatinib, and some of their studies have suggested that if a pediatric patient with Ph-positive ALL achieved MRD negativity becomes BCR-ABL–negative, they don’t appear to need a transplant and their outcomes are similar to what’s seen with either a matched related or unrelated donor. I think we still don’t know that with certainty in our adult patients, and it’s something that we should discuss.

The initial approach to treating these patients was to add a tyrosine kinase inhibitor to our established chemotherapy regimens, and that’s still what many of us do. The Italians have taken an interesting approach in relying on a tyrosine kinase inhibitor with corticosteroids along with some CNS prophylaxis. They use that as a sole therapy in elderly, but even in younger patients, and have shown that they can achieve a high rate of compete hematologic response with lower levels of complete molecular response. I know their initial studies were with dasatinib, and they had a complete molecular remission around 20%. There’s a new study from their group that was presented at this year’s ASH meeting, where they’ve added ponatinib to corticosteroids and they’re showing even better responses: complete hematologic responses over 90% and molecular responses approaching 40%. So, it’s really a very exciting time in the treatment of this poor-prognosis ALL.

Aaron C. Logan, MD, PhD: Speaking of ponatinib, MD Anderson had shown some very compelling data adding ponatinib to hyper-CVAD with 1-year survival upwards of 70% or 75%. Of course, we’ll need to see longer term outcome data from that study. Hopefully we’ll see it done in a multi-institutional setting, because with the hyper-CVAD dasatinib study, we did see some later relapses. But ponatinib seems to have particularly robust activity in ALL, which is great for this patient population. If we can add it to backbones like hyper-CVAD and other regimens, and get outcomes that rival those that we see in children, then perhaps we don’t need to transplant the Ph-positive population any more.

Bijal D. Shah, MD: Right. You bring up some very compelling points. I’d like you to comment on the Alliance trial that’s coming. I think we’ll be testing this approach. If I understand correctly, it’s going to be a low-dose chemo versus a steroid/vincristine combination plus Sprycel [dasatinib] versus chemotherapy, I think a hyper-CVAD backbone, with Sprycel to formally test. Do we need the high-dose induction chemotherapy? If we see a positive result, should we extrapolate that to ponatinib? Are we at that stage where we can say that with each generation of TKIs, we need to be ready to push it forward. This is particularly relevant as ABL001 is now making its foray into the clinical trial space.

Mark R. Litzow, MD: Anthony, what’s your perspective on this question?

Anthony S. Stein, MD: The goal of treatment is to get a complete molecular response. When you combine either dasatinib or ponatinib with steroids alone, you’re only getting a complete molecular response, at most, in 45% of patients. So, most of those patients are going to relapse in the future. Even if your goal is to take them to a transplant, most patients will do better if they come in molecularly negative prior to the transplant. I still don’t buy into the concept of using steroids and a TK inhibitor alone, and will often even add a little bit of chemotherapy to the regimen.

Aaron C. Logan, MD, PhD: Some of the patients in whom you might consider steroids with a TKI alone would be patients who may not be fit for transplant. That calculus about by getting them to MRD negativity, specifically for improving outcomes and transplant, may not be quite as relevant. Certainly, in those patients you want to have the best progression-free survival of your initial therapy, because that’s really what they’re relying on without a consolidative transplant.

Anthony S. Stein, MD: For an elderly patient, I have no problem giving them steroids and a TK inhibitor, because they’re able to tolerate the treatment. You can get them into at least a hematological remission, and you can prolong their survival.

Transcript Edited for Clarity 
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