JAK inhibitors represent a key weapon in the myelofibrosis arsenal when it comes to managing symptoms associated with the disease, according to Raajit K. Rampal, MD, PhD, who added that although challenges remain with regard to defining disease progression and determining when treatment should be initiated in certain patients, novel agents in the pipeline may help to further improve outcomes.

“The management of myelofibrosis is not necessarily black and white. There are shades of grey in terms of trying to figure out who needs treatment, when they need it, and what they should receive. There is some nuance there, but the good news is that we have options,” Rampal said. “It is important to know that several promising agents are under Investigation, including many agents in late-stage trials. We are in a far better place than we were 5 years ago. Hopefully, these drugs will get approved, and most importantly, [improve] outcomes for our patients.”

, Rampal, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, discussed symptom management in patients with myelofibrosis, defining disease progression, and key considerations for starting or delaying treatment.

: What are some strategies used to manage symptoms associated with myelofibrosis?

: To treat symptoms in patients with myelofibrosis, we often use therapies such as JAK inhibitors. Of course, this depends on the symptoms. Principally, we are talking about symptoms that many patients experience, such as fatigue, night sweats, fevers, early satiety, and abdominal discomfort. In multiple studies, JAK inhibitors have been shown to have an important impact on that symptom burden. Oftentimes, that is our major intervention to try to alleviate those symptoms [for patients].

What are some of the characteristics of disease progression in patients? What are the different ways to define this?

I am not sure that we necessarily have a uniform definition for disease progression. However, we do know that [progression] encompasses certain things. When breaking it down, [the first thing to consider are] the symptoms, and patient-reported symptoms are a component of this. For example, if patients have been stable on [treatment with a] JAK inhibitor and suddenly they are experience recurrence of their initial symptoms, or potentially even new symptoms, then that can be consistent with symptomatic disease progression.

When we consider this on a hematologic level, what are the things that would indicate to us that we have a problem? If we have a patient who has been stable on therapy, and now their platelet count is starting to fall, or their hemoglobin is starting to fall, they need transfusions and they had not previously been transfusion dependent, and they have been on their JAK inhibitor for 6 months or more—those are all the things that would be worrisome to us. That is a sign that the bone marrow is not functioning as well as it used to.

Other things that we worry about from a blood perspective, is, for example, if we start to see an increasing number of circulating blasts; that is also potentially an indicator of progression to an accelerated phase, or even beyond that. Scans sometimes help us. If a patient has had a clinically stable spleen or liver size, and upon exam [we see] it is a little bit larger, and then we radiographically confirm that there has been an increase in size, then that is also consistent with progression.

What factors do you consider when deciding when to begin or hold off on treatment in a patient with myelofibrosis?

[The decision] is a little bit more straightforward in a patient who has not been previously treated. However, if there is evidence that a patient’s disease is progressing or accelerating, is it a black or white decision in terms of when to start treatment? No. It depends on what the symptom burden is, or what the disease findings are. Obviously, if a patient has a spleen that is enlarging, and that is causing them symptoms, then that is a reason to start to treat them. If a patient reports that they are mildly more fatigued than usual, but their blood counts are stable, they otherwise feel well, and [the symptoms are] not impacting their quality of life, then that may be a reason not to treat [them right away]. It really depends on the degree of symptoms. However, in some cases, it is very clear when it is time to treat someone.

Regarding patients who are on active treatment, [this situation was historically] more difficult. For example, if we had someone who was on ruxolitinib [Jakafi] and doing fine, and then suddenly their symptoms and disease started to progress, a few years ago, we would have very few options [to offer them] aside from clinical trials or taking the patient to transplant. The advent of fedratinib [Inrebic] as a potential second-line therapy has changed things. We know we have a second-line option that we can go to that has a reasonable chance of improving symptoms and spleen size. Regardless, we must always be vigilant regarding evidence of disease progression—whether someone is on treatment or they have not yet started treatment. In either case, there are things that we can do to intervene and help them.

How do you choose among the options that are now available? What is factored into this decision?

It is challenging. We are glad to have these options, but is there a clear-cut reason to use 1 drug over the other? In most cases, the answer is no. [However,] there are some select cases where we can think differently. For example, the dosing of ruxolitinib is based on platelet [counts], and we lower the dose if the platelets are lower, particularly if patients have platelet counts of 50,000 to 100,000. With fedratinib, that is not the case. We can use the same dose, regardless of the platelet count, as long as it is above 50,000. In select patients, it may make more sense to use a drug like fedratinib in those who have platelet counts of less than 100,000 because we can use the full dose of the drug. However, in patients with a higher platelet count, it might not make so much of a difference.

[Additionally,] it is important to discuss the potential adverse effects [AEs] with patients. We do see more gastrointestinal AEs with fedratinib, relatively speaking. Discussing potential AEs with the patients is always an important part of that conversation.

Articles

Raajit K. Rampal, MD, PhD, discusses symptom management in patients with myelofibrosis, defining disease progression, and key considerations for starting or delaying treatment. 

Nuanced Approaches Needed to Adequately Manage Symptoms, Guide Care in Myelofibrosis 

Patients with myelofibrosis can present with a variety of symptoms, and awareness of these effects is crucial to inform novel treatment strategies that will provide patients with the best possible outcome, irrespective of risk status, according to Naveen Pemmaraju, MD.

“Symptoms are part of the myeloproliferative neoplasm [MPN]. They are common and they can be quantified on the MPN total symptom score,” Pemmaraju said. “They can be followed over time in clinical trials to see whether drugs are alleviating or leading to total disease modification.”

Moreover, Pemmaraju added that there are many ways for a patient to experience disease progression. As such, research efforts need to focus on what it means to progress and how to standardize and quantify this across clinical trials.

, Pemmaraju, an associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses approaches to adequately manage symptoms experienced by patients with myelofibrosis, challenges faced with defining disease progression, and strategies for when to initiate or delay treatment.

: What are some strategies used for managing symptoms associated with myelofibrosis?

: The symptoms, or symptom burden, [observed with] MPNs are really part of the main presentation and main part of the disease; this is very important that potentially contrasts with [what is seen in] some of the other acute leukemia states. Symptom burden in MPNs is oftentimes thought of as subjective. However, my friend and colleague, Ruben Mesa, MD, of the Mays Cancer Center at UT Health San Antonio MD Anderson Cancer Center, and his group, pioneered a way to make [what was considered] subjective into objective.

What I mean by that is that it is a little bit of a disparate-sounding group of symptoms that our patients experience to someone who is not in the field. [For example], symptoms in myelofibrosis can be as varied as bone pain and early satiety, which means getting full too fast, possibly in the setting of splenomegaly. Some patients can have neuropathy, fevers, weight loss, sweats, and fatigue. In fact, fatigue is probably the most common [symptom that we are seeing] in 2021.

These symptoms seem like a wide variety of seemingly random effects], but they are not; they are all due to the underlying disease process, the cytokine storm that the myelofibrosis can cause. Importantly, these symptoms can also occur in patients with polycythemia vera and essential thrombocytopenia, suggesting that earlier, or more chronic disease states can also experience them.

What are some of the characteristics of disease progression in this population? What are some of the different ways in which you define progression in practice?

Defining disease progression and modification in 2021 and beyond is going to be one of the most important questions that we can answer. The difficulty [faced in] the field of myelofibrosis is that we cannot agree yet on what that is, and part of that is because the disease itself is so heterogeneous; it is a complex disease. I consider disease progression in different buckets or categories, and there are several.

For example, a patient may progress due to blood counts becoming very low, or needing more transfusion, [so they go to a] transfusion-dependent state from an independent one. A second way to progress may be uncontrollable splenomegaly, despite [treatment with a] JAK inhibitor or another therapy. Another way to progress may be an increase in the blasts to accelerated phase. Yet still another one may be uncontrollable symptom burden, and so on and so forth.

We have 5 or 6 buckets, or categories, of what would be considered disease progression. They can happen in isolation, they can happen together, or they can happen dynamically over time. Some patients can experience this early on [in their treatment journey], and others [experience it] markedly later. The concept is twofold. One is that JAK inhibitor monotherapy may not control the disease in everyone; that is what we are starting to learn. Two, a slew of phase 2 or phase 3 clinical trials are actively [exploring] adding back, or adding on, a second agent.

The take home point is, in myelofibrosis, there are many ways to progress, and those ways may not always be the same for every patient. They also may differ from clinical trial to clinical trial. As such, we all need to start thinking about what it means to progress and what is means to modify that. How do we standardize and quantify that across clinical trials?

In terms of making the decision to begin treatment for a patient with myelofibrosis, what are some of the factors you consider to inform your approach?

Much of this can be what is called the ‘art of medicine,’ meaning that some of this you may not be able to look up in a textbook. Now that I have been in the field for a while, we know what we are looking for. [When it comes to] profound fatigue, or constitutional symptoms, sometimes the patient may not appreciate or notice [it as a symptom]. For example, some may think [what they are experiencing] is part of normal aging, or [that they are] just tired from [too much] activity. Sometimes the caregiver and the providing team can help the patient identify [these symptoms for what they are]. Another concept here is looking at blood counts. [With] increasing transfusions, or increasing blasts, the blood counts can tell us a lot. Then of course, the spleen size [is also telling].

The concept here is that when it is time to start therapy, regardless of the setting, this is a big decision; it is one of those that may not always be clear cut. The guidance there is to look at the whole patient, to look at everything that they are going through, the symptoms, the spleen, the lab counts, the blasts, the transfusion needs, and then put it all together. I would urge at this point that the best option for most of our patients is a clinical trial—even in the frontline setting. We are seeing that now in the field where we have over 10 ongoing phase 3 trials. Many of them are randomized and many of them are offering an attempt to get a definitive answer. We will know the results of those in the next couple years. It is a difficult disease to explain and to understand, but certainly, there are things we look for in the clinic, and this varies from patient to patient.

Are there any specific factors that would prompt you to hold off on starting treatment in a patient?

There is a sizable portion of our patients, fortunately, who have low-risk disease. There are scoring systems, the International Prognostic Scoring System [IPSS] is the first and most famous at diagnosis; it has 5 clinical factors which are easily obtained, and they include age, white blood cell count, hemoglobin or anemia, circulating blasts, and symptoms. If [a patient] scores a 0 on those 5, then [they are] considered [to be] low risk. We tend to measure that patient’s survival in terms of decades. It is good to know that a patient can have myelofibrosis but not [always have] intermediate- or high-risk [disease]. A second factor with the newer scoring systems is the incorporation of cytogenetic and molecular data.

We now know that there are certain karyotypes, or cytogenetic profiles, that are not bad and possibly considered good risk to have. It’s the same thing with molecular drivers like 

. It appears that in many scoring systems, if [a patient] has a 

 mutation by itself, they appear to do markedly better than their counterparts who have 

 mutations with an intermediate prognosis and those who are triple negative. We believe patients [with triple-negative disease] may have the worst outcomes, because possibly they have another driver mutation outside of the big 3.

The final issue is this concept of early-intervention clinical trials; that [concept] is still in its infancy stages. However, for a patient who has early- or intermediate-risk [disease], but…possibly has a big spleen, an 

 mutation, or they have some other high-risk feature, can they then be put forward for clinical trials with new therapies, such as JAK inhibitors early on? [Can] clinical trials, or early stem cell transplant protocols [be put in place] for [those] high-risk patients? That is a whole other area that needs to be looked at.

The concept here is that not all low-risk patients are low risk. There is heterogeneity—even in those patients. Yes, there are patients who can be observed safely early in the disease. There are factors, such as cytogenetics, molecular drivers, and other factors, where you can tease out who is the low of the lowest risk, and who is the highest in the low-risk category. However, suffice it to say that this is an important area of research in the next few years.

Naveen Pemmaraju, MD, discusses approaches to adequately manage symptoms experienced by patients with myelofibrosis, challenges faced with defining disease progression, and strategies for when to initiate or delay treatment. 

Spotlighting Symptom Management Strategies, Factors to Inform Treatment Decisions in Myelofibrosis

Naveen Pemmaraju, MD, an associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discusses the characteristics of disease progression in patients with myelofibrosis.

Defining disease progression and modification is one of the most important unanswered questions for this patient population, according to Pemmaraju. Due to the heterogeneity and complexity of the disease, progression has been difficult to define, Pemmaraju says. Currently, disease progression is thought to have several characteristics, including decreased blood count, going into a transfusion-dependent state, having uncontrollable splenomegaly despite treatment with a JAK inhibitor, an increase in the bone marrow blast to accelerator blast phase, or uncontrollable symptom burden, Pemmaraju explains.

These progression events can happen in isolation, simultaneously, or dynamically over time, Pemmaraju notes. Additionally, some patients may experience progression early on, while others can experience it markedly later on in their treatment journey, Pemmaraju concludes.

Videos

Naveen Pemmaraju, MD, discusses the characteristics of disease progression in patients with myelofibrosis.

Dr. Pemmaraju on Characteristics of Disease Progression in Myelofibrosis

Michael J. Mauro, MD, the leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center, discusses managing symptom burden in patients with myelofibrosis.

The management of symptom burden in patients with myelofibrosis often starts with symptom assessment, according to Mauro. Standard tools are utilized in clinical trials and have been validated and added to the National Comprehensive Cancer Network treatment guidelines; these tools can aid in identifying some of the symptoms that patients may experience, Mauro says. These tools are helpful, as certain symptoms experienced by patients with myelofibrosis can be difficult to discern from other chronic illnesses, Mauro notes. 

Taking inventory of symptoms is the first step in disease management, followed by prioritization and determining which symptoms are the most bothersome for patients, according to Mauro; this can be a part of a broader discussion with the patient when determining treatment goals, Mauro notes. Lastly, it is important to look at all available therapy options to decide which will be the most beneficial strategy for each patient, Mauro concludes.

Michael J. Mauro, MD, discusses managing symptom burden in patients with myelofibrosis. 


Dr. Mauro on Managing Symptom Burden in Myelofibrosis

This publication spans multiple updates regarding systemic treatment for patients with myelofibrosis, as well as expert insights in video format covering how they approach their patients with newly available agents. 

Therapeutic Updates in Myelofibrosis | Supplements and Featured Publications

Nuanced Approaches Needed to Adequately Manage Symptoms, Guide Care in Myelofibrosis

Spotlighting Symptom Management Strategies, Factors to Inform Treatment Decisions in Myelofibrosis

Dr. Pemmaraju on Characteristics of Disease Progression in Myelofibrosis

Dr. Mauro on Managing Symptom Burden in Myelofibrosis