Mind-Body Therapies for Anxiety, Depression a Critical Part of Comprehensive Cancer Care

Posted on September 6, 2023September 6, 2023 by mpn_admin

August 30, 2023

The recent publication of a guideline recommending mindfulness-based interventions highlight how important it is as a tactic to address symptoms of anxiety and depression in patients with cancer.

Mind-body therapies have been shown — and are recommended in guidelines — to decrease symptoms of anxiety and depression in patients with cancer who may be at any part of the care continuum, an expert said.

With this whole-person system of care, patients can use techniques including mindfulness-based stress reduction, cognitive therapy, meditation and others to address depression and anxiety symptoms. Now that mindfulness-based interventions are now recommended in a guideline prepared by the Society for Integrative Oncology (SIO) and American Society of Clinical Oncology (ASCO) as a way to treat anxiety and depression during cancer treatment, this may allow more cancer centers to offer this as part of their multidisciplinary care.

CURE® spoke with Linda E. Carlson, Enbridge Research Chair in Psychosocial Oncology and professor in the department of oncology at Cumming School of Medicine at the University of Calgary in Canada, to learn more about the ASCO/SIO guideline that she and an expert committee prepared, why they are important for patients and how patients with cancer can advocate for themselves to obtain care related to integrative oncology.

CURE®: Why are these guidelines so important?

Carlson: We know that patients suffer high levels of anxiety and depression, quite commonly around the time of diagnosis, but also going forward through transitions in care, the end of care, trying to get back into regular life. And so anxiety and depression symptoms can haunt people for a very long time.

At the same time, there’s no really good pharmacological treatments, … and many people prefer to go non-pharmacological, more natural routes.

The integrative therapies, the mind-body therapies that are in this guideline are proven. You can see through the evidence they help decrease symptoms of anxiety and depression. And so they’re non-pharmacological alternatives for patients to help cope with these difficult symptoms.

What exactly is integrative oncology?

The definition of integrative oncology … is this idea that it’s incorporating a whole-person system of care that incorporates conventional treatments, as well as complementary therapies where appropriate to help manage symptoms throughout the continuum, from prevention through lifestyle interventions, things like exercise and nutrition, right through treatment with modalities like the mind-body therapies, natural health products, and into survivorship and even end of life.

The idea is that it’s consistent with the person’s beliefs and values. It takes these complementary therapies that have an evidence base to them, applies them throughout the whole cancer journey to improve treatment tolerance and symptom reduction.

Is integrative oncology meant for all patients regardless of disease, stage and other factors?

Absolutely. The evidence base is a bit lacking for some of the rarer forms of cancer. A lot of the research has been done on women with breast cancer. So there’s definitely some holes in the evidence that have limited the kinds of recommendations that could go into the guideline, because the guideline’s based on very strict criteria, randomized-controlled trials, etc. There have been many studies done with more diverse groups of patients, but not enough to get some of those things in the guideline.

Another side note is that just because a complementary therapy may not be included in the guideline, it doesn’t mean that it isn’t helpful or it doesn’t work. It just means there hasn’t been enough research to date. So for example, things like energy therapies or massage may still have potential, but just didn’t make it into the guideline because there hasn’t been the research done yet.

The strongest recommendation was given to mindfulness-based interventions like stress reduction, meditation and mindful movement. Can you go into more detail about what those are?

We use mindfulness-based interventions as an umbrella term to talk about, usually adaptations that stem from the mindfulness-based stress reduction program that was developed by Jon Kabat-Zinn back in the 1970s.

Mindfulness-based stress reduction has been around for about 40 years, but there’s many different takes on it, different adaptations. So there’s some that are specific for people with cancer, like mindfulness-based cancer recovery, or mindfulness-based stress reduction for breast cancer, there’s mindfulness-based cognitive therapy. But what these all have in common is they’re usually group programs, they usually meet once a week over a period of six to eight weeks.

And people are taught mindfulness meditation techniques. So usually, they practice at home for 20 minutes a day or so of meditation on the breath, on the body. And mindfulness is really this idea of bringing awareness into the present moment, non-judgmentally with kindness, self-compassion with openness. And so the meditation is training people on how to do that in a systematic way. Because often our minds are trained to be out of the present moment. We’re either reliving the past and saying, “Why me? If only this or that.” We have regrets, we get depressed or we’re worrying about the future. The mind’s going off to what if this? What if that? How am I going to cope, all the terrible things that could happen, the pressures. And so, we worry and get anxious.

Depression, regret, worry, anxiety, it’s all caused by the past and future focus. But mindfulness training is more about living in the moment. It’s easy to say, it’s a simple idea, but it’s not easy to do. So the mindfulness based intervention trains people in that capacity to be in the present moment, through sitting meditation, body scan, different kinds of awareness practices, everyday mindfulness.

Usually, they have the form of mindfulness meditation practice. And they also have mindful movement, or yoga, incorporated in them. And that is around bringing awareness into the body, learning to identify when there’s stress or tension, identifying our triggers of stress, we even get into the stories we tell ourselves and the interpretations we make and how that elevates stress. There are many components to a mindfulness-based intervention. But we do know that the studies, many of them have consistently shown that they really help people cope with anxiety and depression.

There has always been some thought that any form of mindfulness would be beneficial for patients with cancer. But why was it so important to put these into a formalized guideline?

The way the medical system works is that the guidelines drive treatment decisions, and they drive insurance reimbursement. So while many people have experienced these therapies and know they’re helpful, until we have it formalized with a recommendation from a trusted body like ASCO, like SIO, that’s the first step in really making it standard of care. In fact, it makes it almost compulsory that for cancer centers to be credited as comprehensive cancer centers, they need to include these types of therapies.

The recommendations around mindfulness-based interventions, the language is “should;” people with cancer should have access, not “may,” which is the less strong language. But they should be part of comprehensive cancer care because we know they’re helpful, and they’re less harmful than other pharmacological approaches and more useful, they’re more effective.

There’s no reason why we shouldn’t take advantage of these relatively low-cost interventions with very few side effects, little harm and make those available to everybody. Everybody who’s suffering from anxiety and depression can benefit. So this is a really important institutional step in moving more towards that idea of having them really part of standard of care.

If a patient thinks that this would be a good fit for their care, how should they bring it up to their cancer team?

I would advise patients to get a copy of those guidelines and put them on the desk the next time they go to see the oncologist and say, “How come we don’t have these programs at our cancer center? Why do I have to go to the community and seek this out and pay out of my pocket? Why isn’t this covered by my insurance?” I think we need the patients to stand up and advocate. And they can use (this guideline) as a tool, a very strong tool to help them do that.

This transcription has been edited for clarity and conciseness.

Patients with MPNs ‘Don’t Know What They Don’t Know’

Posted on August 28, 2023August 28, 2023 by mpn_admin

Aug 28, 2023

Alex Biese

For patients with myeloproliferative neoplasms (MPNs) — blood cancers that cause the bone marrow to overproduce red or white blood cells or platelets — being able to engage in educated and productive conversations with their care team can be crucial.

“There are so many variables in cancer from not only the diagnoses, but ‘how do we treat it?’ to what the prognosis is, and that’s always evolving (so) that it’s hard for providers to keep up with that, let alone patients,” said Charina Toste, a nurse practitioner specializing in oncology and hematology at OptumCare Cancer Care and a professor at Chamberlain College of Nursing, both located in Las Vegas, Nevada.

When it comes to the vast category of MPNS (which includes a range of diseases such as myelofibrosis, essential thrombocythemia, and polycythemia vera) patients don’t know what they don’t know.

“(Patients) don’t always know, what is the treatment that’s out there? What are the clinical trials that are out there? Oh, and then let’s talk about symptom management, how is my life going to change? How is this going to affect me? How is this going to affect my family? These are questions patients don’t even know to ask. And they trust their health care provider to have the three or four hours it takes to educate them at an appointment that usually is only 15 to 30 minutes.”

Toste spoke with CUREⓇ about the importance of education for patients with MPNs in order to empower themselves to have informed conversations with their care team.

CUREⓇ: In general, why is it so important for patients to educate themselves, and be prepared to have informed conversations with their care team as they’re going through their cancer journey?

pull quote: "I think it's important to at least have a solid basis of information about your disease, your cancer diagnosis, so you know what to ask."

Patients with myeloproliferative neoplams should learn about their disease to ensure that they know what questions to ask, a nurse practitioner said.

Toste: I think because with any type of diagnosis, there’s kind of the shock factor. And once you get over the shock factor, it’s a different language that patients are learning, it’s a different lifestyle that they’re learning, they have to learn to adjust their entire life for it. And many patients don’t know what to ask because they don’t know what they don’t know.

So, I think it’s important to at least have a solid basis of information about your disease, your cancer diagnosis, so you know what to ask. There are so many variables in cancer, from not only the diagnoses, but how we treat it to what the prognosis is, and that’s always evolving (so) that it’s hard for providers to keep up with that, let alone patients.

What sorts of questions should patients be prioritizing, especially if they are early on in the experience?

‘What is their current diagnoses?’ specifically, so that they understand their diagnoses. Quite honestly, they hear the words and they don’t understand what those words mean; if they see myeloproliferative neoplasms, that’s all they might look up and not know their specific diagnoses (or) that there are different types underneath there.

As we well know, there are so many different hematological malignancies. And when you say the word leukemia, there are 200 different types of leukemia. So, you have to know exactly what you have. And what does that mean to you? What does that mean, as far as prognosis? What can I expect now? And what can I expect in the future? So they can adjust their life.

Because if anything, after a world pandemic has happened, we realize we can’t always predict the future and we have to enjoy what we have to the best (of our) abilities. So, does this mean I have to quit my job? Does this mean I need to adjust my family lifestyle? Should I move to where I have family and support? Will I be OK here on my own? I think those are the questions that they need to ask: how is it going to impact them personally now and in the future so they can prepare?

What are some specific challenges or roadblocks related to MPNs that make it a particularly disease type for patients to inform themselves on?

Not always but usually, most of these diagnoses are based in an elderly population. So, with the myelofibrosis and the polycythemia vera, you’re usually looking around the 60s or 70s age group. And for a lot of these patients, they don’t always have the best support, so they don’t always know how to go to Dr. Google and look everything up. They don’t always know what the latest clinical trials are, they don’t always know how to ask those questions. And they aren’t always surrounded by family members, their children are grown, they have their own lives. So, they don’t always have that support that others would have. Sometimes they’re on their own, and they don’t have transportation. They’re wondering about the basics: economics, transportation, those kinds of things. So that’s how it affects them. And those can be some of the obstacles going forward for these patients in obtaining information. And then (for) some of these patients, some are working, some aren’t some are active and family, some aren’t. Some are socially active.

And I also think in an elderly population, what are some of the symptoms, when you look at a patient and they go, ‘Well, yes, I’m tired. Yes, I have bone pain, but I’m 80. How do I know that this is disease related?’ So, I think those are also some of the obstacles. Whereas if you’re 20 or 30 years old, and you’re saying, ‘Wow, I have a lot of bone pain, I have a lot of fatigue, I have memory loss,’ that’s going to seem unusual at that age versus if you’re older, a lot of times you just take it as the age and the sands of time moving forward. First, is this actual disease might be progressing.

Say there is a patient who is kind of between doctor visits and is looking to inform themselves further, what are some resources that are out there for patients to turn to if they’ve got weeks or months to go before they see their provider for the next time?

Sometimes I always feel there’s not enough. I know there are associations that they can look up and reach out to. I know there are support groups, there are Facebook support group pages. Sometimes, though, you have to worry about the accuracy of information. I know there are pharmaceutical companies out there that also provide information about their medications, or sometimes just disease-related treatments and information. So, that’s out there.

But honestly, it’s (about) going to the journals of medicine or magazines or things like that to get more neutral, objective information, honestly, because you don’t know and I hear so many times as provider, ‘Well, I read this on the Internet,’ and I thought, ‘Oh, wow, that was a big waste of time.’ And it really skews what (information) they have. Or they get information from (people who) say, ‘Oh, well, in healthcare, I know this.’ Well, it’s not our healthcare system. They might have followed health care systems overseas. So different societies and different cultures have different decisions when it comes to treatment plans and pathways. So sometimes, I think it’s very challenging for them to find accurate information, even in today’s society.

Charina Toste Discusses the Educational Obstacles Patients With MPNs Face

Posted on August 28, 2023August 28, 2023 by mpn_admin

Aug 25, 2023

Charina Toste, DNP, APRN-C, AOCNP, MSN, BSN, RN

As with any disease type, it is crucial that patients with myeloproliferative neoplasms (MPNs) are able to engage in educated and productive conversations with their care team. Yet, according to Charina Toste, DNP, APRN-C, AOCNP, MSN, BSN, RN, sometimes patients do not know where to begin or which questions they should ask.

“[Patients] don’t always know what treatments [are] out there. What are the clinical trials that are out there? [There’s also] symptom management [questions], how is [their] life going to change? How is this going to affect [them]? How is this going to affect [their] family?” said Toste, who is a nurse practitioner specializing in oncology and hematology at OptumCare Cancer Care and a professor at Chamberlain College of Nursing, both located in Las Vegas, Nevada.

“These are questions patients don’t even know to ask. And they trust their health care provider to have the 3 or 4 hours it takes to educate them at an appointment that usually is only 15 to 30 minutes.”

Further, when it comes to the vast category of MPNs—which includes a range of diseases including myelofibrosis, essential thrombocythemia, and polycythemia vera—patients oftentimes do not know what they do not know.

“There are so many variables in cancer from not only the diagnoses, but how do we treat it and what is the prognosis. That’s always evolving. It’s hard for providers to keep up with that, let alone patients,” she said.

In an interview with Oncology Nursing News, Toste addressed some of the hurdles patients may face when educating themselves about MPNs. She noted, for example, that many patients are in their 60s or 70s and do not always have the best support systems. Therefore, these patients do not always know how to use Google to conduct research. This makes it difficult for them to learn more about clinical trials and clinical trial availability.

Further, patients who lack social support sometimes struggle with simple aspects of treatment, including transportation to and from their appointment. According to Toste, this can all have a significant effect on the patient.

“Those can be obstacles going forward for these patients in obtaining information,” Toste said.

Scientists create a tool to identify individuals at risk of developing different myeloid leukemias

Posted on August 28, 2023August 28, 2023 by mpn_admin

August 24, 2023

by Wellcome-MRC Cambridge Stem Cell Institute

Scientists have created a new test for identifying people at risk of developing acute myeloid leukemia and related cancers, years before they do. The new platform, “MN-predict,” will allow doctors and scientists to identify those at risk and to design new treatments to prevent them from developing these potentially lethal cancers.

The study is published in Nature Genetics.

Researchers at the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), the University of Cambridge’s Department of Haematology, and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) analyzed data from more than 400,000 individuals participating in the United Kingdom Biobank.

Using this data, the scientists have created “MN-predict,” a platform for predicting the risk of developing blood cancers such as acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms over a 10–15-year period.

This test, now available in NHS clinics, requires patients to provide a blood sample from which DNA is extracted for limited sequencing, alongside basic blood cell counts. With this information, MN-predict identifies those at high risk of any of these cancers and can be used in specialist clinics for leukemia prevention.

Professor George Vassiliou, senior author of the study said, “We all know that prevention is better than cure, but it is not easy to prevent diseases like leukemia without knowing who is at risk. MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukemia prevention programs.”

The myeloid neoplasms are a group of related cancers encompassing acute myeloid leukemia, myelodysplastic syndromes and myeloproliferative neoplasms. Treatments for these cancers have improved in the last few years, but most cases remain incurable.

In the last few years, scientists discovered that these cancers develop over decades through the accumulation of DNA mutations in blood stem cells, the cells responsible for normal blood formation. These mutations encourage these stem cells to grow faster than normal and, as more mutations accumulate, they can progress towards leukemia.

Thankfully, while mutations that promote cell growth are common, leukemia develops only in a small minority of cases. Identifying these cases early on helps efforts to prevent the cancers from developing.

Dr. Muxin Gu, first author of the paper, said, “We hope that MN-predict will help clinicians to identify people at risk of myeloid cancers and use novel treatment to prevent the cancers from developing.”

Dr. Pedro M. Quiros, joint senior author of the study, said, “Despite some recent advances in their treatment, these cancers remain lethal to many sufferers. We hope that our efforts will help advance prevention in favor of treating the full-blown disease.”

Symptom Assessments, Guidelines Inform Nurses Whether They Are ‘Moving in the Right Direction’ in MPN Treatment

Posted on August 23, 2023August 23, 2023 by mpn_admin

Aug 22, 2023

Darlene Dobkowski, MA

Although patients with myeloproliferative neoplasms (MPN) often experience many symptoms either related to the disease or from treatment itself, nurses can help patients navigate symptom management and help seek relief, one expert said.

Oncology Nursing News® spoke with Tetyana Furmanets, CRNP, MSN, an oncology nurse practitioner at Penn Medicine Abramson Cancer Center in Philadelphia, to learn more about how nurses can advise patients with MPN on symptom relief and tools available for nurses to gauge treatment responses.

Oncology Nursing News: What are some of the symptoms associated with MPN and what are some ways nurses can help patients manage them?

Furmanets: MPN comes with a lot of symptoms, the most prominent one being probably fatigue. A lot of patients report debilitating, generalized fatigue. That is probably one of the hardest ones to manage as well because there’s no specific targeted agent for that. I recommend [that] our patients continue to exercise as much as possible while listening to their body, going on daily walks while taking time to rest at home. Certain medications that patients are taking for MPN might help with the symptoms of fatigue.

Some of the other symptoms that we see with myeloproliferative neoplasms are itching. That’s one of the big ones. Specifically, patients report severe itching after they take a shower. Our recommendation is either lowering the temperature of the water before taking a shower or using topicals. There is one lotion—which is over the counter—that we use a lot, Sarna cream, which is very helpful for our patients. We recommend applying that after taking a shower while their skin is still wet.

There are some side effects of the myeloproliferative neoplasms that are very tricky to deal with. Some of them may be fevers, which you can take Tylenol, but there comes a point of the disease process where Tylenol is just not helping with it. So promote fluids, hydration. Sometimes that can be very helpful with symptoms of fevers as well as bone pain, which we see a lot with this patient population as well.

Some of the more vague symptoms that we see is difficulty with concentration, which is a little hard to get out of the patients to talk more about, but when you ask them about it, they’re like, ‘I definitely started noticing I’m having more issues with that.’ This one is a little harder to treat. But I feel like going for those walks and trying to like breaks, take rest and listen to your body and don’t push it too hard, have been definitely helpful.

The other big one we see with myeloproliferative neoplasms is getting full after a few bites of food. A lot of patients are not able to finish full meals because of their spleen size. They have some discomfort associated with their spleen. That comes hand in hand along with fatigue and is probably one of the biggest symptoms we see in this patient population. Again, some of the treatments help with reducing the spleen size. When patients do experience that, they’re so grateful and they feel amazing. They’re like, ‘I could finally finish a full plate and I’m able to sleep on that side.’ So that’s very encouraging.

Unfortunately, sometimes patients don’t respond that well to treatment, so they’ll experience some of that left-sided abdominal pain. We work with nutritionists a lot for those patients; we encourage them to [try] some small, frequent meals that are high-protein, high-calorie content, so that even though they’re not getting a lot of food in at one time, they are still getting their adequate nutrition and their caloric amount during the day.

We work a lot with our palliative care team to help with the pain management aspects when we get to severe cases of myelofibrosis. Pain medication might help with that, as well [as] avoiding sleeping on that side, avoiding certain types of activity or exercise to avoid more trauma to the spleen.

Are there tools that nurses can use to educate their patients about the side effects?

I utilize NCCN guidelines a lot during the treatment phase. We use an MPN treatment symptom assessment during our visits. It’s a questionnaire; patients score [their symptoms] on a scale from zero to 10, zero being no symptoms at all and 10 being the worst imaginable. It lists all of the most common symptoms, fatigue, pain, itching, abdominal pain. It is very helpful as far as determining where the patients are on the scale of the severity.

It might be beneficial if the nurses utilize it and give it to the provider, something to compare it to because a lot of times when you ask the patients, how are you feeling and they’re telling you they feel fine. And when you give them the questionnaire it’s like everything’s like nine or 10 out of 10, so you have to dig a little deeper with those questions.

It is a very tricky disease to manage because everybody’s so different as far as that goes. But we have been utilizing that symptom assessment form a lot and have been helpful to determine if we’re moving in the right direction or making any progress, if we are addressing those symptoms at all.

What’s the most important thing for nurses to keep in mind when caring for patients with MPN who are experiencing symptoms?

Unfortunately, a lot of treatments don’t work overnight. It takes weeks to a month to fully kick in. It can be very frustrating for our patients. We have a lot of patients who are coming in and reporting that they just started this medication, they’re still not feeling too great, and they get a little discouraged. Reinforce that it might take some time for the medication to kick in.

Research Reveals Potential Achille’s Heel in Treatment-Resistant MPN

Posted on August 23, 2023August 23, 2023 by mpn_admin

Research By: Mohammad Azam, PhD

Post Date: August 21, 2023

Cincinnati Children’s experts show, in mice, that targeting DUSP1 eradicates JAK2 mutated MPN

Myeloproliferative neoplasms (MPNs) are malignant bone marrow diseases that cause dangerous overproduction of red blood cells, white blood cells, and/or platelets. These conditions mostly strike adults around age 60 but can occur at any age. Some of these patients ultimately develop acute myeloid leukemia (AML).

Based on successes achieved in treating chronic myeloid leukemia (CML) with a class of drugs called ABL tyrosine kinase inhibitors (TKI), cancer researchers had high hopes that a similar class of drugs called JAK2 inhibitors would be a breakthrough for treating MPNs. However, clinical studies have found that JAK2 inhibitors are ineffective.

Now, a study recently published in the journal Leukemia reports achieving curative response in mice when they selectively knock-out a negative regulator of MAPK signaling: DUSP1. This highly complex study took a team of scientists at three institutions seven years to complete. The work was led by senior author Mohammad Azam, PhD, Divisions of Cancer Pathology and Experimental Hematology and Cancer Biology.

“This study, for the first time, provides mechanistic understanding why JAK2 inhibitors are ineffective in vivo and how JAK2^V617F signaling suppresses P53 function required for MPN transformation and progression,” Azam says. “Selective targeting of DUSP1 opens up a completely novel therapeutic approach and a potentially curative treatment outcome in MPNs.”

OVERCOMING DEAD ENDS

Inspired by the clinical efficacy of TKI therapy for treating CML, a race began to identify similar molecular drivers in MPN that could be targeted for intervention.

Scientists initially found mutations of interest within three genes JAK2, MPL, and CALR. Further study of mouse genetic models revealed that all the mutations produced a common outcome: elevated and persistent JAK-STAT and MAPK signaling. This provided a strong rationale for developing small molecule inhibitors to target JAK2 kinase activity.

Numerous JAK inhibitors have been assessed in MPN and myelofibrosis (MF), another rare, chronic blood cancer. So far, three JAK2 inhibitors are approved by the FDA to treat MPN and MF while almost a dozen JAK inhibitors are currently undergoing pre-clinical and clinical assessment for potentially treating conditions such as arthritis, psoriasis, inflammation, graft-versus-host disease (GVHD), and autoimmune disorders.

However–unlike the success of TKI therapy in CML–JAK2 inhibitors do not induce remission. Instead, they simply slow cell division. Similarly, inhibitors targeting the MAPK pathway by blocking MEK1/2 or ERK1/2 either alone or in combination with JAK2 inhibitors failed to induce remission.

“Even the most potent kinase inhibitors failed to kill MPN cells in vivo,” Azam says.

It became clear that other mechanisms must be involved in preventing the effectiveness of JAK2 inhibitors. In prior studies, Azam’s lab had explored another mouse model of MPN that involved a different cancer cell growth factor called BCR-ABL kinase. That work revealed that growth-factor signaling in the context of oncogenic signaling induces the expression of c-FOS and DUSP1 that causes resistance to TKI treatment.

Inflammatory cytokine signaling is one of the cardinal features of MPN, with about 60 different cytokines induced in the context of these conditions. Azam reasoned that inflammatory cytokine signaling drives TKI persistence in JAK2 targeted MPNs.

ZEROING IN ON DUSP1

In addition to Azam, the research team on this project included first author Meenu Kesarwani, PhD, Division of Pathology; H. Leighton Grimes, PhD, director of the Cancer Pathology Program; and six other members of the pathology division at Cincinnati Children’s. Experts from the Medical College of Wisconsin and the Memorial Sloan-Kettering Cancer Center also contributed.

The team worked for seven years to conduct numerous experiments to tease apart the reasons for the persistent cellular resistance to JAK2 inhibitors in MPN. The co-authors conducted an extensive set of genetic analyses that revealed deregulation of 19 genes in TKI resistant cells. Ultimately, the team focused on DUSP1 because this gene appears to dampen the MAPK signaling that suppresses the P53 apoptotic pathway.

NOVEL APPROACH FOR MPN THERAPY

Importantly, their work revealed that mice lacking DUSP1 exhibit normal growth and reproduction, thus supporting the notion that a treatment targeting this gene’s function would have minimal side effects. When mice without the DUSP1 gene were further tested, the team gained crucial insight into the cell signaling mechanisms that help MPNs resist JAK2 inhibitors.

“In essence, inflammatory cytokine and JAK2^V617F signaling converge to induce the expression of DUSP1, which prevents the function of P53.” (See figure)

P53 is often referred to as the “guardian of the genome” due to its role in regulating diverse external or internal stresses, such as DNA damage, activation of oncogenes, nutrient deprivation, and hypoxia. Importantly, it plays a critical role in deciding the cell fate, cell death or division arrest for DNA repair. Consequently, it plays a significant role in treatment outcomes to chemotherapy as most resistant patients harbor P53 inactivating mutations.

NEXT STEPS

While the genes and signaling pathways involved in the mouse research also appear to exist in humans, much more research is needed to determine whether a selective eradication of DUSP1 can be achieved to cure JAK2-induced MPN, Azam says.

Meanwhile, co-authors say the new discoveries about how to control growth factor signaling in MPN cells may also lead to improved treatments for other forms of cancer.

Double funding success to improve detection and risk classification of myeloproliferative neoplasms (MPNs)

Posted on August 23, 2023August 23, 2023 by mpn_admin

August 21, 2023

Blood Cancer UK and Cancer Research UK recognise the need and impact of artificial intelligence approaches developed by Professor Daniel Royston and Professor Jens Rittscher for early detection and assessment of these blood cancers.

Cancer Research UK and Blood Cancer UK have awarded funding to a multidisciplinary team from the University of Oxford. These awards will help to advance the AI-based methods and predict the progression of myeloproliferative neoplasms (MPNs) more accurately.

MPNs are a group of closely related disorders of the bone marrow affecting around 5000 people every year in the UK. Patients with MPNs are at higher risk of developing leukaemia, especially those with a subtype called myelofibrosis (the most severe) where this develops in >10% of patients.

Because the treatment strategy varies depending on the MPN subtype, accurate assessment of MPN type at diagnosis is crucial for optimal treatment selection. In addition to mutational and blood count analysis, morphological analysis of a bone marrow biopsy is a key component for classification. Unfortunately, this is highly subjective, reliant on qualitative observations and there is great variability even when it is done by expert haematopathologists.

There is unmet clinical need for a more accurate method for diagnosing MPN from a bone marrow biopsy. The team, led by Professor Daniel Royston (Radcliffe Department of Medicine and Oxford University Hospitals NHS Foundation Trust) and Professor Jens Rittscher (Institute of Biomedical Engineering and Big Data Institute), have already developed artificial intelligence approaches to help pathologists extract quantitative data from scanned images of bone marrow biopsies. These algorithms will enable more accurate and reliable classification of MPN type.

With the new funding, the team now wish to refine and validate these methods with the aim of integrating them into existing NHS pathology workflows to bring about earlier diagnosis of MPNs in the clinic. Importantly, this work will include input from patient representatives from the Oxford Blood Group. They will give feedback on the visualisation tools designed to help patients better understand what’s happening in their bone marrow and the progress of their disease.

Better diagnostics and management of MPN disease are key priorities for our patients. Receiving this funding from Cancer Research UK and Blood Cancer UK will allow us to make significant progress towards our aim of applying our AI-based tool for more accurately diagnosing MPN type in the clinic so that patients can benefit. – Professor Daniel Royston (Radcliffe Department of Medicine and Oxford University Hospitals NHS Foundation Trust), research lead.

Evolving Drug Classes Expand Treatment Options Across Hematologic Malignancies

Posted on August 23, 2023August 23, 2023 by mpn_admin

August 18, 2023

Ashling Wahner

Individualized myelofibrosis treatment begins with correctly identifying a patient’s disease subtype and considering their symptoms, from which accurate decisions regarding the use of JAK inhibitors vs radiation vs hypomethylating agents (HMAs) can lead to spleen and symptom burden reductions, according to Raajit K. Rampal, MD, PhD.

During an OncLive^® State of the Science Summit™ on hematologic malignancies, Rampal and colleagues highlighted the role of JAK inhibitors in myelofibrosis; considerations for CAR T-cell therapy in follicular lymphoma (FL); efficacy and safety findings with asciminib (Scemblix) in chronic myeloid leukemia (CML); the future of BTK inhibitors in mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL); unmet needs in diffuse large B-cell lymphoma (DLBCL); and research on the horizon in lower-risk myelodysplastic syndrome (MDS).

Rampal, who chaired the event, is the director of the Myeloproliferative Neoplasms Program and an associate attending physician at Memorial Sloan Kettering Cancer Center in New York, New York.

Rampal was joined by his colleagues:

Alexander P. Boardman, MD, assistant attending physician, Memorial Sloan Kettering Cancer Center
Michael J. Mauro, MD, leader, Myeloproliferative Neoplasm Program, Leukemia Service, Memorial Sloan Kettering Cancer Center
Prioty Islam, MD, MSc, assistant attending physician, Memorial Sloan Kettering Cancer Center
Jennifer K. Lue, MD, clinical director, Lymphoma Service, Memorial Sloan Kettering Cancer Center
Jan Philipp Bewersdorf, MD, hematology/oncology fellow, Memorial Sloan Kettering Cancer Center

Below, Rampal, Boardman, Mauro, Islam, Lue, and Bewersdorf summarize the main messages from their presentations.

Current and Emerging Treatments in Myelofibrosis

Rampal: [Myelofibrosis] treatment depends on the issue. This is 1 of the major principles in treating [patients with] myelofibrosis. It’s not a monolithic entity. This disease has different manifestations, and we need to treat the manifestation that is causing the patient the major issue. [When] some patients [present with myelofibrosis], anemia is the major [symptom] they’re [experiencing], not spleen [issues]––nothing else, just anemia. For those patients, a JAK inhibitor may not necessarily be the right choice, but [treatments such as] erythropoiesis-stimulating agents [ESAs], danazol, corticosteroids, or even immunomodulatory agents may be an appropriate first-line choice.

However, for patients with symptomatic splenomegaly or constitutional symptoms, JAK inhibitors have made their mark. Compared with [treatments such as] hydroxyurea, JAK inhibitors have superior efficacy, reducing both spleen size and symptom burden. We have 3 FDA-approved [JAK inhibitors] currently.

For other manifestations of this disease, there are other [treatments] we can use. For patients with extramedullary hematopoiesis in the lungs or bones, radiation is appropriate. For patients who are early in their disease, sometimes pegylated interferon can be useful; some data support that. When patients progress to accelerated or blast-phase disease, HMAs are the backbone of therapy, usually in combination with other agents.

CAR T-Cell Therapy in FL

Boardman: CAR T-cell therapy is clearly active in relapsed/refractory FL, with high response rates, and is effective in patients with high-risk disease. Current data suggest that these remissions are durable but given [that FL is] an indolent lymphoma, we need more time to [confirm these data]. Adverse effects [AEs] [including] cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome are common and must be considered when weighing treatment options for patients, especially those who may be frailer. Lastly, the optimal timing of CAR T-cell therapy vs bispecific antibodies and other targeted agents will require further study.

Current and Novel TKIs in CML

Mauro: We might think of ponatinib [Iclusig] being favored [over asciminib] in patients with primary resistance [and] high transcript levels. For patients with compound mutations and pan cytopenias, neither drug may be successful. These can be challenges. Patients with a mixture of intolerance and resistance who have perhaps more preserved response or at least more residual response from prior therapy exposure may have a better AE experience and better long-term outcomes with asciminib, at least speculatively.

The T315I [mutation] is up for grabs. [Either ponatinib or asciminib may effectively target this mutation] because [both drugs seem to have activity there], and we don’t have concerns about the differences in dosing [between] asciminib [and ponatinib].

Looking into the future, other drugs are under further study. Olverembatinib, which is approved In China, is the drug that is closest to ponatinib and is in trials in the United States [US] now. [Regarding] other agents, we have some trials at Memorial Sloan Kettering Cancer Center. The [phase 1] ELVN-001 trial [NCT05304377] is open, [investigating an] ATP-competitive inhibitor that’s probably [similar to] ponatinib in its activity but may be much safer. Some other second-line allosteric inhibitors, such as TERN-701, [will also be investigated in clinical trials].

[The evolution of TKIs in CML is] a good story. A growing number of patients with CML are surviving CML, so survivorship is another effort and project at Memorial Sloan Kettering Cancer Center. The number of patients living with CML in the US will probably be 10 times what it used to be by the middle of the century. Asciminib will be a big help, [because] it offers better safety [than other TKIs]. We’ll see how other trials look.

BTK Inhibitors in CLL and MCL

Islam: BTK inhibition with small-molecule–targeted drugs has transformed the way we treat [patients with] B-cell malignancies over the past decade, ever since the advent of ibrutinib [Imbruvica] in the early 2010s. Newer-generation BTK inhibitors continue to improve safety and efficacy and are now even trying to overcome the resistance mechanisms we’ve seen with covalent BTK inhibitors. These drugs are being studied as monotherapies and have promising efficacy as single agents. [They] are also being combined with already-approved and emerging therapies. This has been a paradigm shift in both CLL and MCL, away from combination chemoimmunotherapy and more intensive therapies like autologous stem cell transplantation, potentially. There’s much to come, and many exciting data will be published in the next couple of years.

Updates in DLBCL Management

Lue: POLA-R-CHP [rituximab (Rituxan), cyclophosphamide, doxorubicin, polatuzumab vedotin-piiq (Polivy), and prednisone], has become the standard of care [(SOC) for patients with DLBCL with an] International Prognostic Index [score of] 2 and activated B-cell biology. We still believe dose-adjusted R-EPOCH [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] or more intensive therapies for high-grade B-cell lymphoma or double-hit or triple-hit lymphoma should be the SOC. The role of central nervous system prophylaxis in DLBCL is controversial. [We may] need to develop ways to identify truly high-risk patients, [such as through] novel assays like cell-free DNA to find subclone populations. Long-term follow-up for CD19-targeting CAR T-cell therapies [demonstrated] an overall survival benefit in refractory patients, and bispecific antibodies are having significant efficacy in the relapsed/refractory setting, although patients who relapse after bispecific antibodies and CD19-targeting agents [have] an unmet need.

Updates in Lower-Risk MDS Management

Bewersdorf: The treatment landscape for anemia in lower-risk MDS is finally moving. The [phase 3] COMMANDS trial [NCT03682536] showed luspatercept-aamt [Reblozyl] to be superior to ESA in patients with lower-risk MDS. In the second-line setting, imetelstat seems to be an effective option in ESA-refractory patients, independent of their [disease’s] molecular subtype.

At this point, [the role of] roxadustat is unclear. We’ll see what the final presentation of the [phase 3] MATTERHORN trial [NCT03263091] yields. There are still many open questions in the field. How do we sequence luspatercept and imetelstat? What do intriguing data [regarding] allele fraction reduction [show about roxadustat] as a disease-modifying effect? There’s more work to be done, but finally [we’re seeing] some progress.

Advocacy, Education of Individuals With Myeloproliferative Neoplasms Are Important to Support Patient Outcomes

Posted on August 14, 2023August 14, 2023 by mpn_admin

Aug 10, 2023

Erin Hunter, Assistant Editor

Patients with hematologic myeloproliferative neoplasms (MPNs)—a group of rare blood diseases that include primary myelofibrosis, essential thrombocythemia (ET), and polycythemia vera (PV)—should be more active in their treatment plan, according to experts in oncology pharmacy who participated in a Pharmacy Times clinical forum in Chicago, Illinois, in June 2023. “Our role as pharmacists is to give [patients] as much information as we possibly can, then encourage them to move forward with advocating for themselves,” said Krystal Preston, PharmD, BCPS, a senior clinical oncology pharmacist at CVS Health and a clinical pharmacist at the University of Chicago Medicine.

Patients who are serious about taking an active role in their treatment could inspire health care providers to collaborate more, both with them and with other members of the care team, according to discussion leader Zahra Mahmoudjafari, PharmD, MBA, BCOP, FHOPA, clinical pharmacy manager of hematology, blood and marrow transplant, and cellular therapy at the University of Kansas Health System in Mission.

Subtypes of MPNs, ET, and PV typically transform into myelofibrosis, which can subsequently turn into acute myelocytic leukemia (AML). At least 20% of MPNs may transform into AML; therefore, the goal for treatment is to prevent this from occurring, Mahmoudjafari explained.

With more than 90% of patients with PV having a JAK2 mutation, “it is probably, by far, the mutation that we have the most actionable ability to do something about,” Mahmoudjafari said. She noted that there are 3 FDA-approved Janus kinase (JAK) inhibitors for MPN—ruxolitinib (Opzelura; Incyte), fedratinib (Inrebic; Bristol Myers Squibb), and pacritinib (Vonjo; CTI BioPharma Corp)—which were approved based on results from the COMFORT-I (NCT00952289), JAKARTA (NCT01437787), and PERSIST-2 (NCT02055781) pivotal trials, respectively.

Ruxolitinib and fedratinib are primarily for patients with intermediate- or high-risk myelofibrosis, including intermediate-2 risk and primary and post-PV/ET myelofibrosis, Mahmoudjafari explained. Pacritinib is indicated for patients with a platelet count below 50,000; all 3 JAK inhibitors have expected adverse event (AE) profiles, which include thrombocytopenia, anemia, bruising, dizziness, headache, and diarrhea.

Although the only true potentially curative treatment for myelofibrosis is transplant, there is a 30% mortality risk associated with it, Mahmoudjafari said. Further, patient adherence remains a predominant issue in patient care, according to Connor Roth, PharmD, BCOP, hematology/oncology pharmacy specialist with Franciscan Alliance, Inc in Chicago, Illinois. Whether due to dosing schedule, toxicities, cost, or all these reasons, people remain forgetful, Roth said. It is much harder to contact patients with a reminder via phone call because “nobody picks up [a call from] a phone number they don’t know,” Roth added.

Tammy McClellan, PharmD, a clinical oncology pharmacist at Riverside Healthcare in Kankakee, Illinois, said one of the greatest unmet needs she is seeing is timely access to medications. The faster a patient can get on a proper treatment regimen, the better they can prevent a blood-clotting event.

Insurance is another barrier to access; however, pharmacists understand how to work within the system and are best positioned to advocate for patients, according to Roth. Location is equally important for access to medications because patients living close to a city can access treatment centers and pharmacies more easily than those in a rural setting. Patients in cities also have better access to clinical trials, Preston said.

McClellan noted that an unmet patient need is effective communication with care providers. She said patients frequently mention that their provider does not listen to their input often enough.

McClellan said a solution may be individualized patient care. Further, Latha Radhakrishnan, PharmD, BCOP, BCPS, a clinical oncology pharmacist and an assistant professor in the College of Pharmacy at the University of Illinois at Chicago, noted that pharmacists and providers can foster improved individualized care through better organized collaboration with the patient and care team. This can make it easier to manage AEs and drug-drug interactions because treatment can be exceedingly difficult, according to Mahmoudjafari. Therefore, improving AE management can improve patient quality of life. “[Symptoms can be] enough to drive these patients absolutely insane,” McClellan added.

Additionally, financial burden is a significant issue for many patients. For this reason, some clinics have financial navigators who work with pharmacists and patients to coordinate benefits, co-pays, and prior authorization. Other institutions may assign these tasks to specialty pharmacists, who typically have experience with patient assistance programs that help older adults or individuals with limited resources to access affordable medications via grants, foundational support, or other means. Ideally, insurance or patient assistance would be connected to the patient’s electronic medical record, according to Roth. The panelists also emphasized patient education. “I really try to explain to [patients], in layman’s terms, what’s going on and just listen to what their issues are,” Preston said.

The panelists said that a best practice is to provide as much information about the disease state and treatment as possible. Because many patients do not understand their disease state, improving their understanding can provide the patient with more control, which can lead them to feeling better able to express concerns and be their own advocate.

“You can’t make the assumption that the patient already knows [everything],” Mahmoudjafari said. This is especially important because oncologists or other providers may be struggling to keep up with a complicated, changing treatment and guidelines landscape.

“Guidelines are dividing, and there’s so many things to know [about the drugs],” Roth said. “Pharmacists can be the ones to extend the hands of the physicians and be a patient advocate when [the patient] doesn’t always have one.”

Reference

American Society for Clinical Oncology. Pharmacy Times Clinical forum. 2023 American Society of Clinical Oncology Annual Meeting; June 2-6, 2023; Chicago, IL. Accessed July 13, 2023. https://conferences.asco.org/am/attend

Survival Expectation After Thrombosis and Overt-Myelofibrosis in Essential Thrombocythemia and Prefibrotic Myelofibrosis: A Multistate Model Approach

Posted on August 14, 2023August 14, 2023 by mpn_admin

July 28, 2023

Alessandra Carabbio, Alessandro Maria Vannucchi, Elisa Rumi, Valerio De Stefano, Alessandro Rambaldi, Giuseppe Carli, Heinz Gisslinger, Francesco Passamonti, Juergen Thiele, Naseema Gangat, and Tiziano Barbui

Ample evidence has been provided that accurate discrimination between essential thrombocythemia (ET) and early prefibrotic primary myelofibrosis (pre-PMF) has an impact not only on presenting laboratory data but also on complications, like thrombosis, progression to overt myelofibrosis (MF), transformation to blast phase (BP), and overall survival [1,2,3,4,5,6,7,8]. However, studies estimating the epidemiology of these critical events in the two entities have mainly focused on one isolated outcome at a time, without considering the entire spectrum of multiple intermediate disease states, possibly affecting probabilities and risk factors of the outcome of interest. This situation calls for a multistate model approach, a technique that allows a more in-depth insight into intermediate factors likely influencing the progressive transitioning from one status to another.

The aim of the present investigation was to estimate the probabilities that intermediate-state passages, including thrombosis, overt MF, and BP, impact the final absorbing state (death) in ET versus pre-PMF. To this purpose, retrospective data from two multicenter and well-documented studies [1, 9] were used: (i) ET patients (n = 791) from a multicenter international study of 891 cases, selected for the availability of complete disease history [1] and (ii) pre-PMF patients (n = 382) from four different Italian centers [9]. Both studies were approved by all institutional review boards or ethical committees of participating centers.

At the time of diagnosis, treatment-naïve ET and pre-PMF patients revealed different hematologic and clinical characteristics (Table S1). A parametric Markov multistate model [10] was applied to analyze data on survival considering intermediate states that are part of the natural history of ET and pre-PMF. The model included five states with ten possible transitions (Fig. S1): all patients begin in the initial state of diagnosis (ET, panel A, n = 791 or pre-PMF, panel B, n = 382) and then they could transit through the occurrence of an incident thrombotic event (Table S2) and/or the evolution to overt MF and/or BP (transient states) before death (absorbing state).

In ET, transition-1 from diagnosis to thrombosis included 101/791 patients (12.7%), but this status was transient in 21/101 patients that moved to death (21%) after a median time of 4.0 years (IQR: 1.6–6.4), 3/101 (6%) and in 1/101 (2%) to MF and BP, after a median time of 4.7 and 5.2 years, respectively. Remarkable was that in pre-PMF, the direct transition to thrombosis was found in 13.9%, a figure not different from ET (i.e., 12.7%). Conversely, pre-PMF substantially differed from ET for a higher rate of direct transition to overt MF or BP, that was 13 and 4% vs. 4 and 0.6%, respectively.

After 10 years, the state occupation probability of being event-free was 70 and 50% in ET and pre-PMF, respectively, and progressively decreased, particularly in pre-PMF (Fig. S2), due to earlier mortality, particularly for a greater probability of hematological evolutions. This trend was even more evident for death; regardless of the pathways through hematological evolutions, deaths were double in pre-PMF than ET, reaching 30, 60, and 80% vs. 15, 30, and 60% at 5, 10, and 20 years, respectively.

Probabilities to direct transition to thrombosis (n = 101 in ET and n = 53 in pre-PMF) and overt MF (n = 29 in ET and n = 51 in pre-PMF) are compared in Fig. 1. The trend of experiencing thrombosis directly after ET diagnosis showed to increase in the first 10 years (10%) and to decline subsequently (less than 5% at 30 years). On the contrary, in the first decade after diagnosis (<5%), the same probability grew slowly in pre-PMF while subsequently rose up to crossing the ET trend (8% after 30 years). Instead, the direct transitions from pre-PMF to overt-MF had an opposite trend: in the first 10 years, it reached a peak of 11%, while in ET, the trend was less pronounced, reaching a probability not exceeding 2.3% in the same period post-diagnosis.

**Fig. 1: Direct transition probabilities to thrombosis and evolution in overt MF.**

Concerning survival, most of the deaths in ET and pre-PMF occurred directly from diagnosis (Fig. 2). The intermediate events that most influenced death were thrombosis (25.3%) in ET and BP (23.8%) in pre-PMF. In comparison with ET, the probability of direct transition from diagnosis to death in patients with pre-PMF increased linearly over time (Fig. 2) and was twofold higher, reaching values of 15, 30, and 60% at 5, 10, and 20 years, respectively. Of note, the probability of death in ET patients with an intermediate thrombosis state maintained a fourfold higher value over time than the ones without thrombosis. As expected, the probabilities of death in MF or BP status were higher and occurred faster, and not substantially different in ET or pre-PMF.

**Fig. 2: Transition probabilities to death in ET and pre-PMF.**

The present multistate analysis, provides new insights for a better understanding of ET and pre-PMF disease processes. For example, in pre-PMF, the probability of thrombosis in the first decade was lower (<5%) due to a strong competitor represented by the evolution in MF (up to 11%). Consequently, occupation of thrombosis state in the first decade was lower in pre-PMF than in ET patients but became comparable in the last decades of observation (13 and 14% in ET and pre-PMF, respectively), supporting our previous cumulative estimates obtained with conventional methodology [1]. This notion might have practical implications to differentiate treatments during the course of the two entities by preferring antithrombotic prophylaxis according to IPSET thrombosis in ET that kept its discriminatory power also in this multiple competing adjustment analysis. In pre-PMF, therapy of first choice might be directed to prevent myelofibrosis evolution, provided agents able to do that are positively evaluated in appropriate clinical trials.

Regarding BP evolution, we highlight that the direct transition from the diagnosis was predominant in ET (n = 6/7, 86%), and it was modestly influenced by the pathway through thrombosis (n = 1/7, 14%). Unfortunately, we could not provide sufficient information on the role of cytoreductive therapy in these transitions due to the unreliable timing of drug administration.

Mortality prediction in ET was the topic addressed in a previous study [12]. On the basis of the hazard ratio estimates from Cox regression models, the IPSET-survival model was constructed, and 867 ET patients were allocated into three risk categories with significantly different survival [12]. In the present analysis, in a selected group of patients (n = 791) from the same database, we re-evaluated the risk factors of death considering the possible influence of the intermediate states that occurred before death, and confirmed the performance of the IPSET-survival scoring system for the prediction of direct mortality. However, we also found that the effect on mortality exerted by the intermediate thrombosis state was not negligible (accounting for 25% of deaths) and fourfold higher than in patients without incident thrombosis. Whether the reduction of vascular complications may impact survival remains to be demonstrated in appropriate prospective studies. Furthermore, we found two additional independent predictors of mortality in thrombosis-mediated transition, namely platelet count >1000 × 10⁹/L (HR = 5.74, 95% CI = 1.79–18.40, p = 0.003), in line with a previous observation [13], and the incident arterial vs. venous thrombosis (HR = 4.43, 95% CI = 1.04–18.91, p = 0.044).

Limitations of this study concern its retrospective design and a possible bias related to the reporting accuracy of events, in terms of completeness and timing. In addition, since in these databases, the administration times of the cytoreductive drugs (hydroxyurea in absolute prevalence) were not well specified, we could not reliably evaluate the influence of the pharmacological cytoreduction on the post-diagnosis events. Furthermore, given that current results were obtained in the same ET database used for IPSET scores, a possible “self” confirmation bias could not be excluded. However, our aim was not to confirm the overall performance of the two scores, but to evaluate whether the transition from one state to another could have affected the overall survival or the cumulative incidence of thrombosis in a different way.

Strengths of the study are the relatively large number of patients for rare diseases such as ET and pre-PMF and the clinical and hematological diagnostic accuracy of the two entities and outcomes.

In conclusion, this multistate analysis provides novel information on the temporal probability of intermediate critical events occurring in ET and pre-PMF, and their impact on mortality. This knowledge might inform clinical practice and could also make more feasible the design of clinical trials.