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Experts Share Primary Myelofibrosis Research Updates

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Published on July 6, 2021

Current Myelofibrosis Research, Clinical Trials, and Treatments

In this live Answers Now program, host and MPN patient advocate Ruth Fein is joined by two renowned myelofibrosis experts, John Mascarenhas, MD, from Mount Sinai, and Angela Fleischman, MD, PhD, from UC Irvine Health. Follow along as they discuss the latest research updates, clinical trial findings, and current treatment options for primary myelofibrosis.

Support for this series has been provided by AbbVie, Inc. Patient Power maintains complete editorial control and is solely responsible for program content.

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Transcript | Experts Share Primary Myelofibrosis Research Updates

Ruth Fein: Hi everyone. Thanks for joining us. This is the first in a new series on myelofibrosis. One of the [myeloproliferative] neoplasm diseases, which we call MPNs. I'm Ruth Fein, I'm a health and science writer and a patient advocate for Patient Power. We're here today with two of the top specialists in the field, and we want to talk to each of them about what updates they have since ASH, the American Society for Hematology, which was virtually of course, back in December. So, we want to update people if there's new things to talk about, and certainly just for anybody who missed what's happening out there, or if you're new to Patient Power. So, thanks for joining us.

I have to say, as someone who's had an MPN of one kind or another for more than 25 years, this is an extraordinary time for MPN research and new treatment options, not to mention a great time for hope. Our guests today are experts who are contributing to that hope every single day. So before I introduce them a quick thanks to our sponsor, AbbVie, for their support, and as with all Patient Power programs, they have no editorial control over our content.

Our guests today are the esteemed Dr. John Mascarenhas, Chair of the Leukemia Disease Management Team at Mount Sinai in New York, who has led multiple early and late phase clinical trials, evaluating innovative approaches to the treatment of MPNs.

And Dr. Angela Fleischman, Associate Professor of Medicine at the University of California, Irvine. She's an MD and a PhD who focuses on translational research. Her primary research goal is to identify what drives disease initiation in MPNs, and to use this knowledge to develop therapies, to treat or prevent this group of blood disorders. So, thanks so much to you both for joining us today.

Dr. Fleischman: Thank you for having us.

Dr. Mascarenhas: Yes, thank you.

What Are the Latest Updates on Primary Myelofibrosis Research and Treatment?

Ruth Fein: It's my pleasure. It's been a while, so let's just get started. I'd love to start with a, we can call it an update or just catch us up on what did happen in ASH. What's happening with some of the research and clinical trials that we heard about then, which of course was six months ago. The good, the bad, the encouraging, even what we’re disappointed about, and we'll start with what was presented at ASH. And then later we'll move on to any new investigations that are ongoing now or new in the pipeline.

So I don't usually like to start with the open-ended questions, but in this case, let's launch the conversation there. Dr. Mascarenhas, you published a paper just last month that did truly an amazing job of laying out what's happening currently in MPN research. And today we're talking specifically about myelofibrosis, but before we get into too many specifics, let's put MF research into perspective for our audience.

So the first line of treatment is often JAK inhibitors like ruxolitinib (Jakafi), right, that's Jakafi or fedratinib (Inrebic). And these drugs often dramatically improve many of the symptoms of myelofibrosis, the classic constitutional symptoms like fatigue and bone pain and brain fog, which I get all the time, and headaches, et cetera. So, reducing these symptoms significantly improves their quality of life, obviously, but as you write in your recent paper, and that was in the journal Cells, many, if not, most patients will discontinue ruxolitinib because of either adverse effects or eventually because of disease progression. So, you say, quote, as a result, current therapeutic development in MF is focused on targets outside the signaling pathway. And you also say that combination drug therapies are likely to continue as the major theme in research and treatment. So, talk us through this, and I know it's a lot, but what do we know more about than either we did at ASH, or just a continuation of what we heard at ASH, that's about these sort of JAK workarounds, if we can call them that.

Dr. Mascarenhas: So, I think it's absolutely correct that JAK inhibitors were really the first step forward in treating myelofibrosis patients. And they do a phenomenal job at improving spleen and symptom burden, which is not an insignificant aspect of the disease and an important therapeutic goal. Unfortunately, JAK inhibitors as a class, they do not induce histopathologic remissions in the bone marrow or molecular emissions, and therefore they really don't hold promise as they stand right now in reliably changing or altering the natural course of the disease, because myelofibrosis is both chronic and could be progressive, and it does it in different ways in different patients. So, with all the good benefits of ruxolitinib and fedratinib, there's still unmet needs and room for improvement. And I think at ASH we saw a lot of that work that's been ongoing for a number of years now to build upon the JAK inhibitor theme, because we know the JAK-STAT signaling pathway is central to the disease process, but is unlikely alone, at least with the current tools we have, to be sufficient to really get the kind of responses that Dr. Fleischman and I want for our patients, which are not simply improving patients' wellbeing, that's important, but extending life with a good quality of life and reducing the anxiety associated with the disease about wondering when the next thing will occur, the shoe will drop.

So, what we saw at ASH was a continuation of this theme of building upon JAK inhibitor benefits by adding drugs on. So, in some cases, adding drugs on to salvage responses to patients who are losing a response, or never enjoy an optimal response in terms of spleen and symptom. So, drugs like navitoclax, which is a Bcl-2 inhibitor, is a very interesting drug.

And the other thing I'll stop and say right from the beginning is what I'm very proud about in this field, and what we're doing today, is all of the stuff that's being done is really mechanism and laboratory-based. None of the stuff that is being looked at, none of the patients that are being put on trials, are being given drugs for the sake of just trying out a drug. They're all rational in design and have preclinical evidence to support its use, and navitoclax is such an example. We know that Bcl-2, Bcl-xL are important in the pathogenesis of the disease, and this is what this drug inhibits. Pre-clinical data actually from my mentor, Ron Hoffman, a decade ago showed this activity in this space of MF. And what the AbbVie folks did with the investigators that ran that study was they added navitoclax to patients who were getting a stable dose of Rux at their optimal dose, who are not enjoying the full benefit of the treatment in terms of spleen or symptom burden relief.

And what that study showed was you can add on, and regain, and capture excellent responses, in probably about a third of the patients with this combination. It provides evidence and strategies for helping prolong or improve responses where responses may not be robust to JAK inhibitors. There are other examples of that, like parsaclisib is a PI3 kinase inhibitor, also rational. Incyte ran that study with a number of investigators that showed you can add that drug on to ruxolitinib and again, salvage spleen and symptom response to this in a proportion of patients. And then a trial called Constellation’s MANIFEST study was a study looking both at salvage, adding on to ruxolitinib, but also as monotherapy for patients who failed to come off ruxolitinib and then a cohort, which was probably the more interesting of the three cohorts, which was the upfront.

So in patients who had never received a JAK inhibitor, combining the two drugs upfront, and seeing if the responses would appear to be better than single agent. And across the board with that drug called pelabresib or CPI-0610, there was clear clinical activity in spleen, symptom, even anemia responses. And I should say both in navitoclax and in the CPI-0610 study, the MANIFEST study, there were a good proportion of patients who had reduction in bone marrow fibrosis, which is a biomarker of disease activity. Although I will point out, and I'm interested to hear what Angela thinks about this, it's an exploratory endpoint and it's an interesting endpoint, but it's an endpoint itself that doesn't necessarily translate neatly to patients enjoying clinical benefits. So that has yet to come.

But I would say my general impression of what I saw at ASH, as it relates to JAK inhibitor-based therapy, was really exciting, exciting enough that we are now taking the field into the next generation of trials and hopefully approaches in the commercial space, much like our colleagues in lymphoma and myeloma that use combinations of therapies to improve upon the responses and durations of response. We've been late to the game in myelofibrosis and in that strategy of combination therapy strategies, and this was really an ASH that was full of combination therapy strategies that all looked very good. But none of them have proven that they are superior than what we currently do. And that is why this year we see a whole host of randomized Phase III studies that are looking to prove a point, that combining these drugs with ruxolitinib either upfront, or second line with a placebo controlled arm, can demonstrate in a prospective rigorous fashion that there is actual benefit in terms of spleen symptom, anemia, and bone marrow fibrosis reduction, as well as perhaps even reduction in meeting the real burden with these drugs.

And I think that's key, it's important. Without that data we can't draw any firm conclusions, and I would encourage the patient community, if capable, to participate in those studies. Those are important studies. And they're safe studies because the reality is you either get standard of care plus a sugar pill, so you're never gypped in terms of treatments, or you get standard of care plus an experimental drug, which may or may not be more active than a sugar pill, and that's the question.

So I would say it's really a great time to participate in these clinical trials and to move the field forward. And I firmly believe that these trials will significantly increase our knowledge base and our treatment for myelofibrosis. And so that's all I'll say about the JAK inhibitor combination. And we can talk about Imetelstat (GRN163L) and other drugs as well at some point.

Ruth Fein: Sure. Thanks. Let me just interject for a second. Many people who have watched our webinars along the way know that I'm on one of those trials. At the Constellation trial, I'm about 16 months in, and I'm one of those fortunate people that my doctor's calling me a poster child, because we have seen an actually significant reduction in my bone marrow fibrosis. So, I too am right up there with you encouraging people to explore clinical trials or to see what they're eligible for.

Dr. Fleischman, I'd like to move on to you. So, what's going on in your research world, again, that you're excited about, whether it's an update or just ongoing work since ASH in December?

How Have Combination Therapies and JAK Inhibitors Improved?

Dr. Fleischman: Thanks for the question. I think Dr. Mascarenhas did a very comprehensive discussion about clinical trials, in particular JAK combinations. I think it's really demonstrating that we're moving forward and expanding the endpoints that we deem important in myelofibrosis clinical trials. It's hard for us to imagine, at this point in time, an era when we didn't have the availability of JAK inhibitors, because it's been over a decade now. The availability of JAK inhibitors really changed the landscape of myelofibrosis, but now we're thinking we can do better. It's clear that reduction in spleen size and improvement in symptoms is critical for MF patients, but now we're moving on to the next level to identify additional primary endpoints for trials to drive home what's really important in myelofibrosis: making people live longer. The question about the importance of fibrosis is a very good one. Whether you know what the true importance of fibrosis is, is a little unclear. Is it actually driving disease or is it a marker of disease severity?

But I think that including things like fibrosis, JAK2 allele burden are important things to measure. From my perspective, and in terms of my own personal research, I really think that where we can improve upon in the next years and decades is the prevention of myelofibrosis. We have PV and ET patients who are living with their PV and ET for years, decades, and then move on to progress to myelofibrosis. So, I see that it's, that’s a wonderful opportunity to try to prevent myelofibrosis rather than wait until the person gets myelofibrosis and then treat it. So, I think that the blocking of progression from ET or PV to myelofibrosis is an area where we could really improve upon, and where I think that some significant strides will be made in the next years to decades.

Will We Eventually Move Away from the “Watch and Wait” Approach?

Ruth Fein: So, if I could follow up with you on that, I think progression is fascinating and what we should be talking about, I agree. When it comes to ET and PV, do you think that the little bit we are learning about progression is changing clinical practice? Do you think the wait and see mode — I mean, I had ET for almost 15 years before I did anything other than take an aspirin and I was symptomatic. Do you think that what we know now is changing that wait and see approach at all? Or do you see it changing?

Dr. Fleischman: I sure hope so. Potentially with the re-invigoration of interferon for PV for lower non-myelofibrosis patients may reinvigorate this drive to prevent myelofibrosis, so I'm hopeful about that. One would hope that additional agents besides interferons will be evaluated for their ability to prevent progression from ET or PV to myelofibrosis. But I think we're learning more and more about the basic biology of myeloproliferative neoplasms, and why people go from PV or ET to myelofibrosis, so it helps us identify targets.

There was another very interesting, and now we're even moving way back, like way, way before even PV or ET. There were two very interesting oral presentations at ASH about the question of... I'm sure every MPN patient asks, when did I get my mutation? Like, how long have I been sitting around with these JAK2 mutant cells in my body? And the answer is for decades. There were two papers or oral presentations who in parallel found that patients have their JAK2 mutant cells, 20, 30 years before their diagnosis. And in some patients, they developed it in their mother's womb, or like right after birth. So that really highlights that there's a lot of years where we could potentially intervene before people actually have any sort of abnormalities.

What Can You Tell Us About Interferon Treatment?

Ruth Fein: Yeah. I saw that about in vitro identification. It’s amazing. You know, interferon is something that I wanted to ask you about. Dr. Mascarenhas, let me go back to you for a minute. On interferon, I keep getting asked the question constantly, when are we going to have this new version of interferon? Is there any update on that? That's once a month, as opposed to once a week, if I have that right?
Dr. Mascarenhas: Yep. So, the currently available interferon alpha-2a, which is Pegasys, is a Roche compound, has been available for quite some time. Many patients have taken that, and that's usually weekly dosing. Over the years a different model pegylated form of interferon alpha-2b called ropeginterferon, or Besremi, was developed mostly outside of this country in Europe and in Asia, and is now approved for PV patients in Europe. This drug is now with the FDA being evaluated for approval here. There's an anticipation that it may be approved in third quarter of this year, which would be really nice because it would give patients with MPNs, particularly PV patients where the data is probably the most rich, an opportunity for a commercially available drug that's FDA approved. As many patients probably realize and have experienced, it's not so easy to get a drug off label, particularly an expensive drug that doesn't have an indication for that disease. So, this will validate the utility of interferon and the availability and access to it in the United States. So, there's a lot of excitement about the potential for that. It is dosed less frequently. It's not been compared head-to-head to Pegasys, so it's unclear if the toxicity profiles are definitely different, but the pharmacokinetics, the way the drug is distributed in the blood, and the fact that it can be dosed less frequently would suggest maybe a more tolerable form of the drug.

Ruth Fein: Right. And I know that it's much more first line of treatment in Europe as opposed to here, so it'll be interesting to see what happens. But thanks for that update.

How Can JAK Inhibitors Be Further Improved?

Ruth Fein: Going back to some of the things that you were talking about before, we were talking about JAK inhibitors, approximately 10-20%, if I'm correct, of patients with MF are ineligible for ruxolitinib or fedratinib because of thrombocytopenia or transfusion dependency, or probably other things as well. What can you tell us about that, that direction, the other research areas, and Dr. Mascarenhas, if I can stay with you right now, what else are we looking at?

Dr. Mascarenhas: So that's been an unmet need for quite some time. So ruxolitinib was approved in 2011, and then in August of 2019 fedratinib was approved, but both drugs really are appropriate for patients with platelet counts greater than 50,000. That's where the bulk of the data sits. A drug called pacritinib has been under evaluation for many years now. It actually has very robust Phase III data and ongoing Phase III data that would suggest that you can deliver this drug, which is a less myelosuppressive form of a JAK2 inhibitor, and also inhibits IRAK1, which may be relevant to the biology of myelofibrosis, and deliver at effective doses, spleen and symptom benefit with less myelosuppression, less lowering of the red count and platelet count. So, for those patients with less than 50,000, which I would consider an urgent unmet need, which our current repertoire of drugs don't really cover, it really is an important addition to the armamentarium. And I'm hopeful that that drug will finally reach approval and make it out to the commercial space for those patients in the community that are in need with low platelets.

And I would even be as bold to suggest it's not relegated to simply those patients with a platelet count of 49,000 or less, but it would include patients to 75,000 or 100,000. And that is quite good. So, it really offers an opportunity to treat patients with soft platelet counts, you can say, that may not be able to enjoy the best benefit of titrating up the dose with ruxolitinib or fedratinib, and I think that's really important. That would also include patients upfront or even second line after failure of their current JAK inhibitor.

How Would You Define Myeloproliferative Neoplasms (MPNs)?

Ruth Fein: Right. An important area that people are looking to. So, Dr. Fleischman, I've heard you call MPNs a chronic leukemia, and we all know that we go see our doctors and it's always in the leukemia clinics. So, we know there's some connection, but can you explain that? Why that label's accurate and without getting too deep in the weeds but explain that for us.

Dr. Fleischman: Okay. So, I guess it depends on what you define as a leukemia. A leukemia is an overproduction of blood cells. I guess one could say that an MPN could be characterized as a chronic “leukemia.” It could also be characterized that there's a chronic… there’s an expansion of mutant cells. I think that our understanding of the spectrum from totally normal blood to an acute leukemia is more of a spectrum, because once the JAK2 mutation was identified... Previously the MPNs were a myeloproliferative disorder, not a neoplasm. But once a JAK2 mutation was identified, then when we think of a cancer, we think of cells that have a mutation, and those cells expand. And then with a JAK2 mutation, that fits that definition of what we say is a cancer.

However, we know now that even a big percentage, like 20 to 25% of normal older adults will have mutant cells in their blood. And JAK2 is the fifth most common one of those. That scenario is called clonal hematopoiesis of indeterminate potential (CHIP). So, there are plenty of people out there who are walking around with no knowledge of having mutant cells in their blood, also no knowledge of having JAK2 mutant cells in their blood. They're just walking around totally oblivious. You know, where do you put the line from? I think that the lines are blurring, to tell you the truth.

Ruth Fein: I'm really happy to hear that. One of the things that, to me, what we're talking about is a chronic cancer, which is of course a very different concept than an acute cancer. Right? I think that that's an important distinction, and I think that changing the conversation around that is really important. So let me just follow up with you on that.

When you talk to patients, they don't hear much after that big C-word or in this case leukemia words. So how do you handle that?
Dr. Fleischman: You know, we have to put a label on every disease, or a doctor has to put a label on things to sort of describe the patient's situation. But I think that MPNs are a very unique type of “cancer.” And I usually explain why they're called a cancer and how they're different than what we usually think of cancers, like a breast cancer or a lung cancer. It's a very different scenario. And with a diagnosis of cancer, you hate to say you should take… there's a silver lining in everything, but then that opens up support services like from the Leukemia & Lymphoma Society. So, there are some benefits to having a disease that is characterized as a cancer in terms of support services for patients. So, I try to have a very positive spin on it in terms of the availability of very special resources for this patient population that they wouldn't have otherwise, if their disease wasn't labeled as a cancer.

Ruth Fein: Right. Perfect. And not to mention research dollars that have come in…

Dr. Fleischman: That's true.

Ruth Fein: .... and just because it was finally diagnosed as a cancer, but we can call them all kinds of things. We can call it lots of things and just make that explanation so that patients hear the full explanation. Again, it's difficult after you hear that cancer word.

New and Ongoing Clinical Trials for Myelofibrosis

Ruth Fein: Dr. Mascarenhas, back to you. We only have a few minutes left, but we had a progress report, a great thorough one, on what's happening with some of the clinical trials that we heard about late last year. But just quickly, are there any new trials that have either begun since then, or they're in the pipeline that you want to mention?

Dr. Mascarenhas: I think one trial worth mentioning, which deviates from the JAK inhibitor-based combination strategies is a trial evaluating a drug called Imetelstat, and there's a trial called IMpactMF, and it's a randomized Phase III study for patients who have failed ruxolitinib and come off the drug and are in need of treatment. This is an infusional drug that's given every three weeks. And in Phase II's testing, would suggest that it has the potential to prolong survival, which becomes a very different discussion than what we have been talking about in terms of palliation of symptoms and spleen. It is a drug that affects the malignant hematopoietic stem cell, preferentially through inhibiting an enzyme called telomerase, which is up regulated in a constitutive fashion in these malignant cells. So it gives you a window of opportunity to poison this protein and thereby limit the ability of these malignant stem cells to survive and propagate and provide progeny in the body.

And with that prospect, a drug like that, at least in Phase II testing, has been shown to affect multiple aspects of disease biology in myelofibrosis, including reduction of JAK2 allele burden, reduction in bone marrow fibrosis, and it seems to hit the target that it's intended to do. So, we have figured out from what are called biomarkers or correlative laboratory data points that help us understand perhaps which patients may be best suited for a drug like that. And that's another concept that I think is worth three seconds on. Which is, going forward I think you're going to see, and I hate using the term cause it sounds cliche, but you're going to see more of a personalized approach to a lot of the therapies based on either molecular mutation patterns or even cytokine patterns or other biologic markers that may help us direct and say, "Well, you're more likely to enjoy benefit from this drug and less likely to enjoy benefit from this drug."

So it may turn out to be that the therapies will be tailored around the patient and their characteristics, rather than one size fits all. Imetelstat may be one of those therapies where certain biomarkers like short telomeres or high telomerase activity may predict for better response with drugs like that. But the randomized Phase III study I think is very exciting for two reasons. For one, I'm a believer, I do think that the drug has activity and has the potential to improve survival, which is a concern for patients who fail ruxolitinib. And there are a number of studies, unfortunately, that show us that survival can be compromised in that setting. So, a drug that can improve that survival would be very important. This is a randomized Phase III study where the primary endpoint is overall survival, and that in itself is quite unique and speaks volumes about where we're going with this research endeavor in which it's not simply focused on spleen and symptom, which are not unimportant, but also in other important things like living longer.

Ruth Fein: Yeah. Can you just repeat the name of that drug again? I don't know that we got it.

Dr. Mascarenhas: Sure. That's called Imetelstat, I-M-E-T-E-L-S-T-A-T.

Ruth Fein: Right, thanks. One of the benefits of these webinars is that, not that that particular drug is available, but the study might be still open. And we certainly like people to know what they can talk to their doctors about and find out more about, whether it's now or later. So, thank you for that insight.

What Should Patients Know About Living with MPNs Today?

Ruth Fein: As we start to wrap up, I'd like to thank both of you, our special guests today, and to our sponsor AbbVie. But first I'd like to end with a few words from each of you, digging sort of back into how we changed the conversation and progressed the conversation about MPNs. So, just in a few short words, what can you tell a patient today, probably a patient with ET or PV, about the possible and of course feared progression to myelofibrosis. What can you tell them today that you might not have been able to say five years ago, or certainly not 10 years ago?

Dr. Mascarenhas: Okay. Let me take a stab at it. So, I've been doing this for approximately 15 years, and I can say with confidence that it has changed dramatically over that 15 years in terms of our insights into the molecular biology and underpinnings of these diseases and the evaluation of treatments and where we're going in the field, where we are looking at this very differently than we did before.

I think it is important, as Angela pointed out, it is important in some ways that this is recognized as a cancer, because it focuses the needed attention to address it in a much more aggressive fashion, in a much more upfront fashion, rather than waiting for things to get worse and trying to salvage a worse situation. So, I'm optimistic that with a lot of the advances that are made by Angela, for example, and folks in the laboratory that better understand the mechanisms that go wrong in these cells that help exploit, for therapeutic purposes, drugs that can go into the clinic and make a difference in people is really tangible today. You can feel it, and there's so much energy within the research community and synergy within the clinical community and the patient engagement is at its all-time highest. So, I'm really optimistic that we've got all the working parts together and it will only result in continued progress for patients.

Ruth Fein: Great. Thanks for those wise words of wisdom. Dr. Fleischman, what would you add that you might say to an ET or PV patient today that you couldn't have said five years ago or even 10 years ago?

Dr. Fleischman: I'll just echo that I think that what I can really tell patients now is that I know a lot more about their disease in terms of their personal disease. There was a time before I was practicing where you didn't even know whether somebody had a JAK2 mutation. I do remember a time when either somebody was JAK2 positive or JAK2 negative, and we learned about calreticulin, so there's been a lot more knowledge about somebody's disease. And now at the present time, it's much more common to have a full NGS profile on somebody, so knowing all of their mutations.

So I think we're starting with — each person's MPN is very different. We lump them all together, but everybody has, honestly, a unique disease. And we can learn more about what type of person, this MPN person is sitting in front of me, and predicting what their clinical course is, and trying to identify appropriate treatments for them to reach their specific goals. And I also want to point out that each person has different goals, and all MF patients are very unique. And I think it's important for them to identify what they feel is important for them in terms of their therapeutic goals, whether it's reduction, "I don't want to sit around having transfusions all the time,” or “I want my spleen to be smaller." But I think it's such a unique disease that each person has unique items that they really should target, and I think that should be an integral discussion between the patient and the physician, what their goals are and the best approach to reach those goals.

Ruth Fein: Thanks again, two very special guests, and to our sponsor, AbbVie. To our audience, remember to discuss with your doctor new information that you learned through our Answers Now series and through other reliable sources. It could help you with your own healthcare decisions and ultimately improve your care.

So I have one more exciting announcement today. Patient Power is piloting a new clinical trial finder tool, and the information on how to use this new tool is in the MPN newsletter sent out by Patient Power, which we hope you're already receiving. If you aren't, please sign up at The information is also on the Patient Power Facebook page, and you can always follow Patient Power on Instagram and on Twitter. That's all from here in beautiful sunny, upstate New York today. Take care, be well. And remember that knowledge can be the best medicine of all.

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