Pacritinib and Azacitidine Clinical Trial for CMML
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Unlocking New Treatment Strategies for Chronic Myelomonocytic Leukemia: Pacritinib and Azacitidine in Clinical Trial

Unlocking New Treatment Strategies for Chronic Myelomonocytic Leukemia: Pacritinib and Azacitidine in Clinical Trial image

Unlocking New Treatment Strategies for Chronic Myelomonocytic Leukemia: Pacritinib and Azacitidine in Clinical Trial


Jan 10, 2025 / 10:00AM EST
HealthTree Podcast for CMML
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Full Transcript

Mary Arnett (00:12)

Welcome to today's episode of Health Tree Podcast for CMML, a show that connects patients with researchers. I'm your host, Mary Arnett. Today we're going to be talking about two things. First, the basics of CMML, and then second, some exciting new research being done that patients have a chance to be a part of. Our guest today is Dr. Douglas Tremblay. Dr. Tremblay is a hematologist out of Mount Sinai in New York specializing in hematologic malignancies, particularly myelodysplastic myeloproliferative overlap syndromes, including CMML as well as MPNs and AML. Dr. Tremblay has been an incredible source of information for our AML and MDS communities in the past, and we are excited to bring his knowledge and expertise to our CMML community today.

 

Mary Arnett (00:57)

Dr. Tremblay, we are so pleased to have you here with us today on our show I'm excited that we were able to get this scheduled and that you're willing to come spend some time with us to talk about your exciting research.

 

Douglas Tremblay (01:07)

Mary, thank you so much, and thank you so much to Health Tree for having me on and especially for highlighting this disease, which while rare is really important and there's a lot of new exciting research that's being done. So I'm really happy to have this very timely conversation.

 

Mary Arnett (01:23)

Today we're going be talking about your research into chronic myelomonasitic leukemia or CMML. So first I'd to get a little bit of background information that will help us to set the scene for what CMML is and what the treatment landscape currently looks like. And then we'll dive into your research and what you're seeing if that works for you.

 

Douglas Tremblay (01:43)

Sounds great. Thank you, Mary.

 

Mary Arnett (01:46)

So first let's start with basics. What is chronic myelomonocytic leukemia and what can make it a tough disease to treat?

 

Douglas Tremblay (01:53)

Great, so chronic myelomonocytic leukemia or CMML is a type of chronic blood cancer and it is very closely related to other blood cancers that we see and treat. So for instance, many people with CMML may have been told they have a disease called myelodysplastic syndrome or MDS, which is a type of chronic leukemia where the bone marrow doesn't work well to produce blood counts.

 

What makes CMML unique is that not only is there an issue with the bone marrow where it's not making enough blood cells, but there's also an overproduction of a very specific type of blood cells called monocytes. So whenever you get your blood report, there's different types of white blood cells. In CMML, there is an increase in the amount of these monocytes. And specifically, not just the amount of them, but also the percentage of the overall white blood cells. So CMML is one of these diseases that exists in a spectrum between where the bone marrow is not making enough red blood cells, white blood cells or platelets, and where it's making too many of some of these cells like monocytes. And so for that reason, we call it one of these diseases called MDS slash myelopulphid neoplasm overlap syndromes, because it kind of exists between both of these. And it used to be considered a type of MDS, but it has very unique clinical features. And people who have CMML may have symptoms and findings that are much different than patients with myelodysplastic syndrome, which is more common. Not just the white blood cells with the monocyte predominance, but also increase spleen size or fatigue and fevers and night sweats and itching and other sort of constitutional symptoms that are classically not associated with mild dysplastic syndrome. So why it's such a hard disease to treat is that it has only really been recognized as a disease for about two decades now. And before that, it was not really considered to be its own disease. And because of its rarity, it is something that has been understudied until recently. And a lot of the treatments that are developed for CMML have actually just been borrowed from other diseases and haven't been specifically analyzed for CMML. So patients with CMML, they may be getting treatments that are designed for patients who have a different disease like mild dysplastic syndrome or a myeloproliferative neoplasm. And because of that, you're not really getting tailored treatment for this specific disease and the specific problems that are associated with the disease.

 

Mary Arnett (04:53)

You mentioned, that there's not a lot of options available for these patients and I understand with it being a rare disease. Can you tell us a little bit about what the treatment landscape overall does look like? what options do patients have currently and then what gaps is your research going to try to help fill?

 

Douglas Tremblay (05:07)

Great. So the current treatment landscape for CMML, like I mentioned, is borrowed from other diseases. And in general, the treatment of a CMML all depends on how aggressive the CMML is. Some patients with CMML might not need any treatment at all, while other patients with CMML are at a very high risk of their disease progressing to acute leukemia or dying from their CMML and require rather urgent treatment. So we do a lot of things when I first meet a patient with CMML to try to understand, is this someone who is going to just live with CMML for years and years and years, and it's just gonna be something that they have, but nothing that we need to treat? Or is this someone who needs treatment right away? And so we look at different mutations, different factors in their blood, as well as if they need things like blood transfusions and how high the white blood cell count is to see, understand, how aggressive the disease is. But how it's currently treated is that if someone is high risk, meaning their disease is likely to progress and cause real problems and issues, then the best treatment is really a bone marrow transplant because that is the only cure for the disease is a bone marrow transplant. But if you're older or if you have a lot of other medical problems, a bone marrow transplant is dangerous. fact, it's so dangerous that I wouldn't recommend it to a patient because they're more likely to die from the transplant rather than from the CMML. And in general, because CMML is a disease that affects older people, that this many individuals, in fact, most individuals are probably not eligible for a transplant because it is so dangerous. So people who are not eligible for a transplant, there are many different treatment options, but I will say none of them are really that effective at controlling the disease, preventing the disease from progressing, and ultimately making people live longer and happier lives who have this disease. So some of those treatments include things like hypomethylating agents, are drugs which affect the expression of different genes to try to improve the overall clone and amount of leukemia and also improve things like blood counts to make red blood cells higher so you don't need blood transfusions or make white blood cells lower in certain cases. But hypomethine agents aren't extremely effective in this disease. They do help many people, their response rates are very unsatisfactory. There's other medications that are given to try to improve anemia like drugs like erythropodes and stimulating agents, injections to kind of trick your body into making more red blood cells, but many patients aren't eligible for those drugs because your body doesn't have enough, has a problem with that hormone and it can't really respond well enough to it. So many patients are left without any real treatment options and the disease kind of progresses. And so what the kind of future is looking for is trying to understand different biologic features of CMML that we have drugs for that we can try to treat and combine together to really effectively treat CMML with many other diseases in oncology, the real success and the real paradigm shifts in treatment haven't been from one specific drug, but a combination of multiple drugs. Most leukemias, for instance, one drug doesn't really do the trick and multiple drugs are needed to kind of exploit different vulnerabilities in the leukemia. So the story is very similar with CMML too, where one drug might not be enough and that multiple drugs together might be needed to really make a big impact on the disease.

 

Mary Arnett (08:55)

Thank you for giving us that background, helping us understand the complexities that exist within treating CMML and for helping us understand some of those trickier spots that patients may find themselves in. So let's get into your study specifically. Can you give us an introduction or a description of your study?

 

Douglas Tremblay (09:15)

Great, so my study is a trial that's called Pekritinib plus Azacytidine in chronic myelomonasitic leukemia. And how this really arose is that there is good evidence that a class of drug called JAK inhibitors can really make the amount of monocytes go down and improve the symptoms of patients who have CMML and improve the spleen size and shrink the spleen size and may be really effective in certain patients, but the response rates again are not too good. There's other types of JAK inhibitors that might even be better for CMML. So for instance, a drug called Pocritinib, which is the topic of this trial, is a medication that's a JAK inhibitor that can have some of the effects where it can reduce the amount of monocytes and affect that. But it also has different targets where it can reduce inflammation in this pathway called NF-kappa-beta or reduce the amount of monocyte development by targeting kinase called CSF1R. And it also can allow for the bone marrow to get more iron by modulating a hepcidin expression, iron regulation, to make it so that red blood cell amounts improve as well. there's really good studies from the laboratory that look at treating cells that are CMML cells from patients or from different models. and giving them procritinib and it really seems effective when it's done in the laboratory. But we know that it's not 100 % effective and that other laboratory studies combining it with azacytidine, a hypomethylating agent, produce even better results when done together, kind of synergizing together instead of one agent or the other. So the idea behind this trial is to take what we've learned in the laboratory and translate it into the clinic to say, if we combine this really specifically well-suited Jack inhibitor procritinib plus the standard treatment of azacytidine, does that really produce better responses and ultimately make patients live longer with the drug than one or the other alone? So this is really trying to explore the combination in patients who have chronic myelomaniacid leukemia to see if it's safe, is it effective? and does it need to be studied in larger studies in the future? So that's really the kind of rationale behind this study.

 

Mary Arnett (11:45)

I think you explained HMAs earlier. Can you explain JAK inhibitors a little bit more?

 

Douglas Tremblay (11:51)

So, JAK inhibitors are pills that are taken that inhibit this pathway called JAK-STAT, which is a really important inflammatory pathway. So, JAK inhibitors are used in many diseases like myelofibrosis in our space and graft versus hosties after transplant, but also in a lot of rheumatologic conditions where there's a lot of inflammation. And because CMML is such an inflammatory disease, there's a lot of these pathways that produce things called cytokines, which create inflammation in the body, it's important for a therapeutic purpose to try to reduce that amount of inflammation with these drugs called Jack inhibitors. But also the way that monocytes are overproduced in CMML very much is dependent on that Jack-Stab pathway. So if you can shut off that kind of motor that's going in the CMMLs stem cells that's producing too many of these monocytes, you can really reduce the amount of monocytes and improves many of the features of disease. So there have been other studies with JAK inhibitors, specifically ruxolitinib, that have shown real benefits in patients, but it hasn't really been as satisfactory as you would like to really make a meaningful contribution in terms of delaying disease progression and preventing people from progressing to leukemia and making patients live longer. And so we need to do better by not only tailoring the type of JAK inhibitor with pocretinib, but also combining it with hypomethylating agents to really synergize and improve on those outcomes.

 

Mary Arnett (13:31)

Thank you for explaining that. For patients who are interested in this, is the study enrolling? Where is it in terms of the life cycle of a clinical trial?

 

Douglas Tremblay (13:43)

Great, so the trial is enrolling now and we're really looking for patients who are motivated to be treated for this very rare disease that can receive this treatment and hopefully get benefit from it as well too. Not every patient, just like with every clinical trial, is eligible for treatment. Really there's very specific characteristics and criteria that have to be met to be enrolled. And for this disease too, it has to be a certain risk disease, certain organ function, and some other things. But we're actively looking for patients because while this is a disease that has been described now for decades, there is still a lack of recognition from many hematologists and many even specialists that this is a really disease that needs to be treated differently than other mild dysplastic syndromes. And so we're actively looking for patients who are interested in really participating and partnering with us because we think that this could really be a major benefit for the patients themselves, but also a way to learn more about CMML to help other patients with this really debilitating and understudy disease.

 

Mary Arnett (14:56)

You mentioned that there's a lot of exclusion criteria, there's potential, not every patient is right for every trial. Can you talk about maybe some of the biggest inclusions or exclusions for this study?

 

Douglas Tremblay (15:08)

Yeah, so the big thing that is important about this study is that we really want to see if this combination works together right away. So if you've received a JAK inhibitor before, or if you've received a hypomethylene agent for more than a cycle, then those patients are generally not included in the trial because we really want to see if giving them upfront is going to help the disease and if someone's received the medications, one of them or the other one, it changes the biology of the disease and it makes it so that it's hard to figure out if that's really helping or not. There's also features about how much adequate organ function with their kidneys and liver and some specifics related to the heart features and EKG findings. many patients, the weak specifically designed the trial so that many patients could be included as many as possible. And we are actively looking to expand the amount of patients who can really be enrolled in this by maybe even including other MDS, MPN, overlap syndromes that are similar to CMML, but may also benefit from the disease too. So CMML is a really complicated disease to treat. So it's really important to be at a center that really specializes in this. And because of that, I think it is important it is helpful to even just reach out and see if this is something that could be eligible or interested in doing.

 

Mary Arnett (16:36)

Where is the study? Where can patients join? Specific centers, international, just the US? What does that look like?

 

Douglas Tremblay (16:44)

So right now it's just at Mount Sinai in New York, although we are planning to expand to several other centers around the United States to provide this treatment option for more patients, those who don't live in the New York tri-state area or aren't able to travel here for the trial. So we are looking to expand in the future, but right now it's just at Mount Sinai.

 

Mary Arnett (17:07)

For a patient who is on the trial, what does that look like? what does the treatment and follow-up schedule look like? And what kind of tests would patients expect to be done throughout that treatment?

 

Douglas Tremblay (17:22)

Yeah, so that's a really important question because enrolling and participating in a clinical trial is a little bit different than just seeing your doctor every three months or getting injections. There's a lot more tests involved with it. But we also specifically designed this study so that it wouldn't be too onerous for people who maybe don't live nearby or are coming from out of state. So initially, a bone marrow biopsy needs to be done to say what is the disease like before we start the treatment? And then the azacytidine, which is given, is once a day for seven days, which is very standard dosing for it. And the procretinib is a pill that's given twice a day. Initially, for the first month, it's seeing almost once a week just to make sure everything's going well. But then after that, it's really about once a month being seen, although that azacytidine needs to be given for once a month for a straight. But it can be possible to be seen not that frequently, maybe once a month to after the initial month, first month of treatment to then kind of go back to regular life and continue getting the study drugs. But initially that's that bone marrow biopsy and then that first month about once a week being seen with the treatment for the first week.

 

There's other bone marrow biopsies that need to be done just to see if the drugs are working so far and different assessments that we do in asking that symptoms and forms to fill out. But so far, patients have told us at least that it's not an overly burdensome involvement and that most people enjoy taking part of it because we have an excellent research team here who really focuses on patients and tries to really cater to any sort of needs that they have.

 

Mary Arnett (19:11)

We understand the background of CMML, the goals, the overall goals of the study, what the study would look like for a patient to be on. What kinds of things are you seeing in the research so far? Any trends, anything like that?

 

Douglas Tremblay (19:26)

You know, it's really early days, so it's really too hard to say exactly what's gonna be shown here. I've been very encouraged and optimistic from what we've seen so far, but obviously we need more patients to be enrolled before we can really say exactly what's happened.

 

I think that the rationale for the trial is extremely strong from a scientific perspective, but it also makes a lot of sense because you're attacking the inflammation as well as the stem cell and the bone marrow at the same time. So I think that there's a lot of reasons to think that this really is going to be a big improvement on current standard therapy. But of course, it's a clinical trial and we have to really do the trial to understand what those benefits are.

 

Mary Arnett (20:11)

What does the timeline for the study look like? How long are you going to be recruiting for? When could patients start hearing about results?

 

Douglas Tremblay (20:20)

You know, it really depends on how many patients come onto the study and what the rate of that is. And we hope to kind of expand this to other centers to accelerate that process. With that said, we're hoping to get preliminary information in the next few years so that we can present this and see what the preliminary information is. But there's still many opportunities for patients to be involved in this trial or other trials that we have open and exploring in CMML and other MDS/MPN, overlap syndromes to try to help those patients as well. So I think that we're at the very early stages of this trial, but we have many opportunities, not just for this trial, but for other ways to get involved in participating clinical research and participate in trials.

 

Mary Arnett (21:07)

This is an exciting time for patients with CMML to be able to get involved in something early and be able to be a part of some research that could really make a difference for the way that CMML is treated. And like you mentioned earlier, really make a difference for other CMML patients and their potential for standard of care treatment.

 

Douglas Tremblay (21:25)

Yeah, absolutely. I think that one of the best parts about my job is interacting with patients in the patient communities and seeing how the advocacy from patient groups to really get involved and really take hold of their own health care has really been nothing short of amazing. So I think that CMML is just getting started in terms of a lot of the specialized attention and organization from a patient level perspective. And I think an amazing way to get involved is to consider clinical research and clinical trials as a way to get the next frontier of treatments available and to give back to the CMML patient community so that we can hopefully really improve the lives of patients with this rare leukemia.

 

Mary Arnett (22:13)

What does next steps look like for someone maybe who's listening today and is interested in getting involved in this trial from kind of a logistical standpoint? Where do they go? What do they do?

 

Douglas Tremblay (22:24)

You know, I'm very happy to entertain any emails or phone calls at all, and hopefully we can share my information in the episode notes, and you can email me directly at douglas.tremblay.mssm.edu, and I'm happy to facilitate evaluations or anything else I can do to sort of help a patient who's going through this disease in any way. So, reaching out to me directly is something that I would highly encourage. And we have an amazing research staff here too who can help facilitate if a visit makes sense and about everything else to support patients. But I'm a big proponent of personally being involved in patients' care, even if it's someone who may not end up seeing me, but at least helping out from someone who has experience treating this specific disease because it is so rare. And many oncologists and hematologists may not have a lot of experience treating patients with CMML. So they can reach out to me directly or call my office and we can arrange to coordinate if they would like to come in and be evaluated and participate.

 

Mary Arnett (23:34)

Exciting! I will definitely make sure that we get that information shared in the description of this episode so for anyone interested who is listening that they can reach out and ask questions and see if this trial might be right for them.

 

Douglas Tremblay (23:49)

Thanks, yeah, exactly. I really think that trying to be proactive and trying to understand if this trial or other trials or other sort of opportunities makes sense because it is such a specialized disease that requires specialized care.

 

Mary Arnett (24:08)

Is there anything else about this trial or about the direction of CMML research that you want to share today?

 

Douglas Tremblay (24:14)

Yeah, I think that the direction of CMML research is something that I've personally been very optimistic about where a few years ago there was no real interest in this, not just from doctors, but also pharmaceutical companies and that people weren't too excited to develop treatments in this. I think in the last five, 10 years, there's been a real shift now where there's increasing recognition of the disease, increasing research into this disease, increased research funding for the disease and a real understanding that there needs to be tailored therapies specific for CMML. And because of that, there's been multiple new clinical trials and studies to try to really focus in and study this and try new treatments and find the next great therapy for CMML. And I'm just excited to be a part of that and to kind of move the field forward.

 

Mary Arnett (25:09)

Yeah, it definitely sounds like an exciting time in the research for this disease and an exciting time for patients as well who are watching and seeing more develop for their own condition. So thank you so much for joining us today and for sharing this information, sharing your knowledge. We're grateful for the generosity of your time and willingness to share your expertise. We're excited to see what comes and we'd love to have you on again in the future when there's some results to talk about and put that out for our community as well.

 

Douglas Tremblay (25:40)

Absolutely, yeah, that would be wonderful. Thank you so much, Mary, and thank you so much, HealthTree, for really highlighting this disease.

 

Mary Arnett (25:47)

Thanks for listening to the Health Tree Podcast for CMML. Join us next time to learn more about what's happening in CMML research and what it means for you. Have a wonderful day.

 

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