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Emerging Therapeutic Alternatives in 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: Friday, Apr 29, 2016


Transcript:

Raoul Tibes, MD, PhD:
Another antibody that has shown clinical responses in the treatment of ALL is inotuzumab, targeting CD22. Inotuzumab is an antibody drug conjugate. Single-agent data were reported and published over the last couple of years, and there were quite some good response rates seen, up to 30% to 40% complete remission rates in patients with ALL. At this year’s ASH, there was a study presented adding inotuzumab to mini–hyper-CVAD in patients above the age of 60—so the older ALL patient population where we really need therapies. So, essentially, most of the dosages of the anthracycline or vincristine were cut in half by 50%. Methotrexate and ara-C was reduced, and inotuzumab was added. Ninety-seven percent of the patients achieved a complete remission. Importantly, every patient who achieved a CR also achieved MRD-negativity, our hallmark for depths of response. At 2 years, the overall survival rate was high, in the range of 70%, and the relapse-free survival rate was 87%. I think those are quite good numbers for this patient population.

Now, we are learning to incorporate those new antibodies targeting CD19, CD20, or CD22 in our chemotherapeutic regimen: how to sequence, when to use it, develop new therapies, and, at some point, also possibly combining those drugs together. So, I do think it’s very exciting to see that we have several antibodies, or novel approaches, tying ALL-specific antigens that all yield good response and remission rates, can convert CR rates into MRD-negative states, and clearly help patients improve their outcome and treat adult patients with ALL.

Stefan Faderl, MD: What is the role of novel signaling pathways and targeted therapy in ALL? I think we are learning a very good lesson, from the BCR-ABL–like ALL. A lot of those BCR-ABL–like acute lymphoblastic leukemia cells have mutations in cytokine receptors or tyrosine kinases, which opens up the field for treatment of targeted drugs that address those abnormalities. I mentioned before the activity of dasatinib, or imatinib, or ruxolitinib, or some other kinase inhibitors in ALL, which is something you would not traditionally think about, because ALL always has been a very chemotherapy-heavy disease. There are also some preclinical data, partly from the ASH meeting in 2015, that show that combinations of those targeted drugs—for instance, drugs targeting the JAK2 pathway and mTOR pathway—have activity in BCR-ABL–like ALL models.

If the extent is more molecule type inhibitors, you may also think about drugs that target MLL rearrangements and DOTL1 inhibitors, and that are in clinical trials currently. Even in some T-cell subtypes, it’s a more newly described subtype, the early T-cell precursor ALL. Regardless of how it’s defined, it now seems to show responses to targeted drugs addressing signaling pathways, such as JAK2 or combinations of JAK2 and BCL2 antagonists even. So, I think this is a rapidly expanding field, and there are already clinical trials in progress starting to combine JAK2 inhibitors, for instance, with chemotherapy. It’s a very interesting area.

Another big area is immunotherapy. That’s not necessarily what you would refer to as small molecules, but it’s a very interesting and active field. We talked about blinatumomab. I mentioned several times CAR T-cell programs, but there is a lot of activity in that area, as well. It’s a little bit harder in T-cell ALL. NOTCH1 was brought up: it’s rearranged or mutated in about 50% of patients with T-cell ALL. Drugs have been developed and brought into clinical trials, gamma-secretase inhibitors to try NOTCH1 as a target. It didn’t work out very well in initial studies, partly because of the toxicity of gamma-secretase inhibitors, partly because of the more moderate clinical activity. But there are also attempts in trying to combine those drugs and maybe even with other targeted molecules. So, the area of small molecule inhibitors is really a treatment area in ALL that I think we’ll see much more of, and that may become very important indeed.

Bijal D. Shah, MD: We’re finally in a position where we can start talking about an improvement in survival for adults with ALL. I don’t think I can speak more powerfully than that. The technologies, be they blinatumomab, be they inotuzumab, be they CAR T-cells, we now have the opportunity to approach ALL in a way that’s radically different and a way that’s less dependent on things like DNA damage response, and ultimately obtain better outcomes. What we’re seeing with these novel compounds also allows us to decrease the intensity of therapy relative to high-dose chemotherapy. If you look at where we’ve shown improvements in ALL, and you focus on those patients over age 65, I don’t think anyone would be surprised to say that this is a group of patients who have seen very, very little improvement over time. We can now arguably improve their outcomes. I was just talking to a colleague of mine from Emory University who treated an 87 year-old with blinatumomab, safely. This patient is in a remission from his leukemia. That’s the take-home message: we now have therapeutic alternatives to high-dose chemotherapy.

Transcript Edited for Clarity
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Transcript:

Raoul Tibes, MD, PhD:
Another antibody that has shown clinical responses in the treatment of ALL is inotuzumab, targeting CD22. Inotuzumab is an antibody drug conjugate. Single-agent data were reported and published over the last couple of years, and there were quite some good response rates seen, up to 30% to 40% complete remission rates in patients with ALL. At this year’s ASH, there was a study presented adding inotuzumab to mini–hyper-CVAD in patients above the age of 60—so the older ALL patient population where we really need therapies. So, essentially, most of the dosages of the anthracycline or vincristine were cut in half by 50%. Methotrexate and ara-C was reduced, and inotuzumab was added. Ninety-seven percent of the patients achieved a complete remission. Importantly, every patient who achieved a CR also achieved MRD-negativity, our hallmark for depths of response. At 2 years, the overall survival rate was high, in the range of 70%, and the relapse-free survival rate was 87%. I think those are quite good numbers for this patient population.

Now, we are learning to incorporate those new antibodies targeting CD19, CD20, or CD22 in our chemotherapeutic regimen: how to sequence, when to use it, develop new therapies, and, at some point, also possibly combining those drugs together. So, I do think it’s very exciting to see that we have several antibodies, or novel approaches, tying ALL-specific antigens that all yield good response and remission rates, can convert CR rates into MRD-negative states, and clearly help patients improve their outcome and treat adult patients with ALL.

Stefan Faderl, MD: What is the role of novel signaling pathways and targeted therapy in ALL? I think we are learning a very good lesson, from the BCR-ABL–like ALL. A lot of those BCR-ABL–like acute lymphoblastic leukemia cells have mutations in cytokine receptors or tyrosine kinases, which opens up the field for treatment of targeted drugs that address those abnormalities. I mentioned before the activity of dasatinib, or imatinib, or ruxolitinib, or some other kinase inhibitors in ALL, which is something you would not traditionally think about, because ALL always has been a very chemotherapy-heavy disease. There are also some preclinical data, partly from the ASH meeting in 2015, that show that combinations of those targeted drugs—for instance, drugs targeting the JAK2 pathway and mTOR pathway—have activity in BCR-ABL–like ALL models.

If the extent is more molecule type inhibitors, you may also think about drugs that target MLL rearrangements and DOTL1 inhibitors, and that are in clinical trials currently. Even in some T-cell subtypes, it’s a more newly described subtype, the early T-cell precursor ALL. Regardless of how it’s defined, it now seems to show responses to targeted drugs addressing signaling pathways, such as JAK2 or combinations of JAK2 and BCL2 antagonists even. So, I think this is a rapidly expanding field, and there are already clinical trials in progress starting to combine JAK2 inhibitors, for instance, with chemotherapy. It’s a very interesting area.

Another big area is immunotherapy. That’s not necessarily what you would refer to as small molecules, but it’s a very interesting and active field. We talked about blinatumomab. I mentioned several times CAR T-cell programs, but there is a lot of activity in that area, as well. It’s a little bit harder in T-cell ALL. NOTCH1 was brought up: it’s rearranged or mutated in about 50% of patients with T-cell ALL. Drugs have been developed and brought into clinical trials, gamma-secretase inhibitors to try NOTCH1 as a target. It didn’t work out very well in initial studies, partly because of the toxicity of gamma-secretase inhibitors, partly because of the more moderate clinical activity. But there are also attempts in trying to combine those drugs and maybe even with other targeted molecules. So, the area of small molecule inhibitors is really a treatment area in ALL that I think we’ll see much more of, and that may become very important indeed.

Bijal D. Shah, MD: We’re finally in a position where we can start talking about an improvement in survival for adults with ALL. I don’t think I can speak more powerfully than that. The technologies, be they blinatumomab, be they inotuzumab, be they CAR T-cells, we now have the opportunity to approach ALL in a way that’s radically different and a way that’s less dependent on things like DNA damage response, and ultimately obtain better outcomes. What we’re seeing with these novel compounds also allows us to decrease the intensity of therapy relative to high-dose chemotherapy. If you look at where we’ve shown improvements in ALL, and you focus on those patients over age 65, I don’t think anyone would be surprised to say that this is a group of patients who have seen very, very little improvement over time. We can now arguably improve their outcomes. I was just talking to a colleague of mine from Emory University who treated an 87 year-old with blinatumomab, safely. This patient is in a remission from his leukemia. That’s the take-home message: we now have therapeutic alternatives to high-dose chemotherapy.

Transcript Edited for Clarity
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