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.
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.
In an interview with OncLive®, 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.
Pemmaraju: 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.
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?
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.
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 CALR, JAK2, and MPL. It appears that in many scoring systems, if [a patient] has a CALR mutation by itself, they appear to do markedly better than their counterparts who have JAK2 or MPL 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 ASXL1 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.