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- [00:02]
Dr. Laura Michaels
Welcome to the American Society of Hematology Conversations with Blood Authors Podcast. This episode is hosted by Dr. Laura Michaels. She discusses increased prevalence of clonal hematopoiesis in children with sickle cell disease with Dr. Alexander Beck. She also discusses with Dr. Jorge Cortez. His article on asiminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4 first trial.
- [00:31]
Podcast Host
I'm so pleased to welcome Dr. Jorge Cortez, the Cancer Center Director for the Medical College of Georgia, whose paper on asimitib is in the most recent issue of blood. Dr. Cortez Many of our listeners may not realize why another treatment option would be required in cml. Perhaps you could just discuss a little bit of the clinical rationale of adding another agent to the armamentarium and why this one is different from the other TKIs that are available.
- [01:04]
Dr. Jorge Cortez
We have wonderful therapy for CML, but I think that there's still a lot of room for improvement. For one, the majority of patients have to continue taking the medication for the rest of their life and more and more patients want to be able to stop therapy. That's a reality only for about 25 30% of patients. So a minority and the ones who need to continue taking therapy have these low grade chronic toxicities that affect their quality of life. So improving the quality of life is another need. No longer is survival a major need because already with imatinib patients get their normal life expectancy. But I think that other elements can be improved and should be improved. And that was the rationale, that's been the rationale for several years of trying to improve on what we had so far. Asimity being very potent. It had shown already high efficacy in patients with prior Therapies with mutation T315I and with a different mechanism of action that's very unique for abo. Without other kinases it has the potential for minimizing toxicity, perhaps improving efficacy, perhaps both. And that was the rationale for bringing it to the frontline therapy and the
- [02:23]
Podcast Host
key endpoints in a study for newly diagnosed chronic phase CML ability to get into molecular remission what were the other important endpoints that you were looking at, especially with the longer term follow up that's presented in this submission in this manuscript.
- [02:43]
Dr. Jorge Cortez
We wanted to see if the major molecular response would improve any further from the initial look, et cetera, but we wanted to start getting a better idea about the deeper molecular responses, which are the ones that can lead to a treatment discontinuation. But also we wanted to see the tolerability. The tolerability early on looked great, but it was only one year. So as I said, you know, patients along therapy start having low grade toxicities and other problems. So very, very important to see how the tolerability. Is there any new adverse events that we hadn't seen? Cardiovascular toxicities, those kind of things that are critical for the long term therapy of patients.
- [03:30]
Podcast Host
In patients that had either disease progression or inadequate response in the group that was treated with asiminib versus the group that was treated either with imatinib or in the second generation tkis, was there differences in the reasons for those disease progression or inadequate response based on the cohorts?
- [03:54]
Dr. Jorge Cortez
That was a very interesting observation. Yes. We saw that the patients that had resistance to asiminib, but largely they were because of mutations and very specifically that myristoid pocket mutations. Now that's important because those mutations in principle would respond to any other tyrosine kynos in factors they don't affect those inhibitors. For the patients that were treated with the conventional TKIs, where the Rimatinib or second generation, we had more resistance, but there was a mix. Some patients had no mutations, many patients had no mutations and others had the typical mutations that we see in those patients, the P loop mutations and those kind of mutations. There was a bit more of a mix of the reasons and the ones with no mutations are sometimes a problem because then we don't really understand what the mechanism of resistance is when there's no detectable mutation.
- [04:49]
Podcast Host
Does a mutation in the myristoil pocket, does that transfer in any way to resistance to a second generation TKI or vice versa?
- [05:00]
Dr. Jorge Cortez
No, not really. Patients that develop a myristoid pocket mutation in vitro, those mutations respond to any of the conventional TKIs, whether imatinib, second generation or even ponatinib. And in the clinic we've seen that. And that's what we're doing for patients who develop resistance after a simnib due to a myristo pocket mutation.
- [05:24]
Podcast Host
Fascinating. So it sounds like based on the article, next steps is to look and see what percentage in each group studied could move on to treatment. Free remission.
- [05:34]
Dr. Jorge Cortez
Exactly. That's going to take a little longer. You know, we need to get the deep molecular responses to be durable for a couple of years and then stop therapy and make sure that they maintain it. So right now we're focusing on these earlier surrogates of that. But that's the ultimate goal. Absolutely.
- [05:53]
Podcast Host
That's great. Dr. Corjas, thank you so much for this work and for all that you've done to promote options for people with CML.
- [06:01]
Dr. Jorge Cortez
My pleasure. Thank you.
- [06:03]
Podcast Host
I'm so pleased to welcome Dr. Alexander Bick. He's an associate professor of medicine at Vanderbilt University Medical school, and he is the director of the division of genetic medicine. The paper that he's going to talk about is a fascinating study looking at clonal hematopoiesis in individuals with sickle cell disease. Dr. Bick, I really found this to be quite interesting. Can you describe the rationale? I always think about clonal hematopoiesis as something that happens in the later decades of life. What prompted you to look at it in sickle cell disease, especially in the younger populations that you identified?
- [06:42]
Dr. Alexander Bick
Her investigation really came from demand from the clinical community that, as you know, for many years, patients with sickle cell disease have not had that many treatment options. But recently, in the last five years or so, there's been really a considerable interest in curative therapy for sickle cell disease that could take the form of hematopoietic stem cell transplant, or it could take the form of autologous gene therapy. But unfortunately, early in one of the gene therapy programs, several individuals developed myelodysplastic syndrome and AML after getting gene therapy. And around the same time, there was also some really interesting work looking at patients who had gone on to get AML after curative therapy in the form of stem cell transplant. And so there is this question of how is it possible that these individuals who had sickle cell disease were developing or effectively secondary leukemias? And some pioneering work in this area found that several individuals had TP53 mutations before they received their stem cell transplant. And that that clone, that pre cancer, was what progressed and developed into secondary leukemia. And so the clinical community who was working on this was really keen to know, is this something about those individuals just having bad luck, or is there something different or unusual about patients with sickle cell disease being predisposed to these secondary leukemias? And so I had the privilege of being at Vanderbilt with Dr. Michael DeBaun, who's a very prominent investigator in the sickle cell community. He said, alex, we really should work together on this. You have studied clonal hematopoiesis. I have partnerships across the sickle cell field and access to really incredible cohorts. Why don't we put some of your assays together with our cohorts and see whether sickle cell patients have increased risk of developing clonal hematopoiesis, this pre myeloid blood cancer.
- [08:57]
Podcast Host
So one of the theories or the hypotheses that I read in the work was that the chronic inflammation might predispose the marrow niche to clonal hematopoiesis. And yet what she found was that actually there seems to be a decline in the VAF levels rather than an incline. Is that right? And what does that say about inflammation and chronic clonal hematopoiesis?
- [09:24]
Dr. Alexander Bick
We were pretty surprised to find that even in the pediatric population, patients with sickle cell disease have an appreciable amount of clonal hematopoiesis, which is not something that we see in patients without sickle cell disease. Perhaps 10% of kids with sickle cell disease had measurable clonal metapoiesis. And so that was strange and puzzling. And the question is sort of why we think of sickle cell disease as a red cell disorder. We think of clonal heapoiesis as a stem cell disorder. And so how are these things coming together? And I think part of the study is we don't know. We observed that the clonal hematopoiesis in these kids looked different than what we see in adults with clonal hematopoiesis. So in general in adults, the clones grow and expand. And in these kids, in the samples that we had multiple time points, often the clones actually shrunk. And so that makes us wonder what is different about the bone marrow microenvironment in sickle cell disease. And we and others are actively trying to answer that question.
- [10:32]
Podcast Host
You had a cohort of children that didn't have sickle cell disease. Correct. Do their allelic burdens go down over time?
- [10:42]
Dr. Alexander Bick
That's a great question. We are still working on finding the multi time point samples. It's really hard actually to find enough samples that have multiple time points. Coming soon, I hope to have more of an answer to that question.
- [10:56]
Podcast Host
I thought the other thing that was so just fascinating was that even in the cohort of 0 to 6, so these newborns, they have clonal hematopoiesis which they haven't had time to accumulate. The problems that you think would give you clonal hematopoies. It's really interesting.
- [11:15]
Dr. Alexander Bick
I think one of the avenues that we're investigating further is trying to understand where does the mutation actually arise? Is the mutation actually arising in the long term hematopoietic stem cell? Perhaps the mutation is occurring in a stem cell that's not a long term stem cell or a multipotent progenitor. And perhaps patients with sickle cell disease just are having more of these clonal expansions just because of the burden of producing more red blood cells. But again, I think red going to learn a lot more in the coming years through deeper characterization of these cohorts.
- [11:53]
Podcast Host
A second hypothesis that you investigated was whether hydroxyurea in your population affected clonal hematopoiesis. Did your team have sufficiently long follow up to have certainty on this finding?
- [12:07]
Dr. Alexander Bick
Hydroxyurea has been thought to potentially be genotoxic. Another concern from sickle cell clinicians that we've worked with with the majority of contemporary sickle cell patients have been exposed to hydroxyurea. One of the things that we were able to take advantage of was an old randomized control trial that actually randomized patients to with and without hydroxyurea. That gave us sort of added confidence that we weren't seeing hydroxyurea as driving clonal hematopoiesis, which would really be conundrum for clinicians treating patients who might go on to need curative therapy. And so fortunately we did not see any association between hydroxyurea and clonal hematopoiesis. There are new tools now for measuring clones in different ways that we're trying to bring to bear on this question.
- [13:02]
Podcast Host
I want to thank you so much for this really fascinating study. It generated a lot of thought for me and lot of things I want to read about. So I appreciate your work. Dr. Bick. Thank you and your team.
- [13:14]
Dr. Alexander Bick
Thank you for having me.
- [13:19]
Dr. Laura Michaels
Thank you for listening to this episode of Conversations with Blood Authors. To read the articles, visit bloodjournal.org this episode is copyrighted by the American Society of Hematology.