When to Treat?
Last Updated: Thursday, October 21, 2021
Lindsey Kalhagen, MMS, PA-C, of Northwestern Medicine, and Lindsey Lyle, MS, PA-C, of University of Colorado, discuss important factors involved in knowing when to treat myelofibrosis, including understanding monitoring, markers of disease progression, and the appropriate urgency to treat.
Meet the faculty
University of Colorado
Lindsey Lyle, MS, PA-C, is a physician assistant in the UCHealth Blood Disorders and Cell Therapies Center at University of Colorado, working with patients undergoing treatment for blood cancers and non-cancer–related blood disorders. She also specializes in clinical trial patient care.
Lindsey Kalhagen, MMS, PA-C, is a physician assistant in the Northwestern Medicine Center for Bleeding and Clotting Disorders at Northwestern Medicine in Chicago, working with patients with myeloproliferative neoplasms, bleeding and clotting disorders, and other nonmalignant blood diseases..
When we're talking about when to treat myelofibrosis (MF), I find that it's so important to understand the monitoring process. It’s an ongoing process that involves both labs and symptoms for patients, and we now have so many different risk stratification tools that we use not only to help determine prognosis, but also to help us guide management both at the time of diagnosis and continuously throughout the disease course.
I'm curious, in your practice, which risk stratification tools do you use the most and when?
We use the DIPSS and DIPSS Plus scoring systems.1,2 In clinical trials, the International Prognostic Scoring System (IPSS) was used more often, but now, as we've gained more information about different disease characteristics that make people higher risk or lower risk, the DIPSS really comes into play. Particularly looking at chromosome abnormalities with the DIPSS Plus, in addition to higher points being associated with anemia—now platelets less than 100 being involved—I think that these are really important clinical features of myelofibrosis that do make some patients higher risk. You can use the DIPSS at an up-front diagnosis, but also as the disease evolves. So a patient may have one DIPSS score at initial presentation in the clinic and then 2 or 3 years down the road have a different score, which speaks to the usefulness of that prognostic scoring system.
Yes, certainly. Patients oftentimes ask us some years down the road, "What is my life expectancy?” or “What is my prognosis at this point?" So I also like using the DIPSS to be able to give them a real-time indicator for their disease and prognosis based on current labs.
Symptoms are also important when thinking about monitoring. So many patients with myelofibrosis have some degree of splenomegaly, and obviously it varies as far as symptom burden and how much it's affecting quality of life day to day in terms of pain, early satiety, or weight loss.
Anemia is another important component of MF that we think about from a symptom burden perspective; it varies from patient-to-patient in terms of how significant it is and how much it’s impacting quality of life, based on age and underlying comorbidities. Our patients who have underlying cardiovascular disease may not be able to handle as significant a degree of anemia as someone who is otherwise healthy outside of myelofibrosis, for example.
What other symptoms do you focus on with ongoing patient monitoring?
Recently I've had a number of patients with pretty bad bone pain that’s been quite debilitating, so that's something that I'm paying more attention to in my patients. Fatigue—whether it's related to anemia, worsening of anemia, or just the disease itself or likely a combination—is also a huge symptom that we monitor very closely. Some of these other symptoms, like weight loss, we need to pay attention to because they’re really important from an overall well-being perspective.
As we're assessing a patient’s symptoms and continuing to assess their labs and overall clinical status, we also need to take into account whether the patient is transplant eligible, and then decide how to use that information. Are we using the prognostic scoring systems to estimate when our patients may be potentially nearing the end of their life, or are we using this for some other reason, such as to pursue a transplant or higher intensity therapy to improve overall outcomes? Symptoms can really play a role in this as well from a monitoring perspective. If we are noticing that our patients are becoming worse and worse from a performance status perspective, then transplant unfortunately becomes less of a viable option.
I often find that patients may downplay their symptoms, and their care partners or family members who are with them actually are able to provide a more accurate description of what's going on at home. Do you feel like you experience the same thing?
Absolutely. I'm such an advocate for patients having family members or other members of their support system accompany them to clinic visits, in part for this reason. Patients often see things very differently, especially when it comes to fatigue or eating or other activities of daily living. Maybe they're getting by, but right now they're not doing the things that they used to enjoy doing. In the MPN and MF world, there's been a significant increase in focus over the past 5 to 10 years on some of these other symptoms like fatigue, concentration, night sweats, and bone pain, as well as making sure we’re addressing all of the patient's symptoms from a disease perspective and not focusing only on the labs.
In your practice, do you use the MPN-SAF? We definitely use it with our patients on clinical trials, but I would say that we're not as consistent with using this as a formal tool with other patients.
That would be true for me also. I consistently ask all of the MPN-SAF questions from a symptom standpoint as far as how patients are doing, but not in a formalized questionnaire. And I think our patients are oftentimes so well educated about myelofibrosis and associated symptoms that they're able to bring up some of these symptoms to us or tell us what has changed over time. But personally, I also don't necessarily use a standardized form every visit.
How often do you see your patients? I imagine it varies.
Yes, it depends on where patients are in their disease as well as their therapy. Certainly for patients who have been newly or recently diagnosed, particularly those who are symptomatic or are starting treatment, we probably see them every 2 to 4 weeks initially and then maybe not quite as often going forward. But I would say that we see most of our active MF patients at least every 1 to 3 months, but it varies patient to patient. What about you?
I would agree. Certainly patients on clinical trials have more frequent mandated follow-ups based on the trial requirements. But outside of that, it’s a broad spectrum. You can have a patient with myelofibrosis who is on a stable dose of a JAK inhibitor, perhaps, outside of the context of a clinical trial who may only need to be seen every couple of months because they're very stable for now. But then, of course, we have other patients who need frequent transfusions and therefore need to be seen more often. So I would agree with you: It's variable, and certainly very patient dependent.
We also have many patients who, even if we're not seeing them in the office every 1 to 2 months, are often getting labs done between visits, which is also an important part of our monitoring process. We're watching for their current blast status and whether they’re having a progressive increase in blasts or a worsening anemia or leukocytosis or if their platelets are dropping. So sometimes our monitoring changes. For example, if we're also seeing unfavorable changes in labs over time, that suggests that we need to be following them a bit more carefully and brings up the conversation of potential disease progression.
Certainly, for me, labs are important, and as you mentioned, if it's someone who either has new transfusion requirements or increasing transfusion requirements due to worsening anemia, that's concerning for me from a disease progression perspective. In addition, as we mentioned, an increase in blasts or a significant rise in blasts causes concern about the potential for leukemic transformation. What other factors do you typically consider markers of disease progression?
In addition to those that you mentioned, which are really critical for us to be following closely, progressive splenomegaly is a marker of disease progression. Perhaps a patient has had an initial reduction in their spleen size, and then it starts to grow and become a problem from a symptomatic perspective.
We also have those patients who may have just never really responded to the up-front treatment. It's fairly rare, but it does happen in some cases. Also, something that we don't think about as much as disease progression is that perhaps the lack of an optimal response is occurring due to the inability to push the dose of their up-front treatment due to cytopenias. This is another thing that I think of when I think of progression because maybe it's not progression in every single element, but perhaps their spleen is growing and causing problems as a result.
Additionally, if patients had symptoms that had improved on their current treatment but that they start to develop again—like night sweats, fatigue, bone pain—I would certainly wonder if their disease is progressing or if there are potentially other causes for these symptoms. Then I would re-evaluate the patient as a whole. Leukocytosis, as we mentioned, can certainly be present at diagnosis, but is it getting worse? Is their hemoglobin dropping? They could be more thrombocytopenic, but also is their white blood cell count increasing—irrespective of the presence or increase in peripheral blasts? I'd watch for this as well.
All of these factors, not only at the time of diagnosis but also as we're continuing to monitor patients, help guide us on how urgently or aggressively we need to treat a patient and also help us monitor for disease progression. We know that for our high-risk patient population, if they're eligible, transplant is curative and the best treatment for them. Unfortunately, a lot of the patients we see are ineligible for transplant because they have significant comorbidities, or sometimes age makes it more difficult for patients to potentially be transplant candidates. So we try to find clinical trials that these patients could participate in or treatments that would be best for them depending on their primary symptoms, with our goals being to help improve their quality of life if we know that transplant is not going to be possible.
Absolutely. When thinking about urgency to treat, I'm always brought back to the oath that we take in medicine, to first do no harm. So looking at this patient in front of us, do we have available options that will potentially help from a symptom perspective, from a disease control perspective, and where are we going? What are the goals of therapy? And potentially, in some rare cases of low-risk myelofibrosis, potentially the answer is to observe—watch and wait. The NCCN guidelines have recently been updated to reflect the currently FDA-approved treatment options for myelofibrosis and can be a great resource.3
The other thing to consider is a patient who has had some other major event from a comorbidity standpoint. In these situations, we may need to hold off on therapy. But aligning your treatment goals with the patient's goals needs to be the focus of the conversation when deciding on treatment and the urgency to treat, in addition to how aggressive you are and what treatment you choose.
There’s also a group of patients that fall into the low- to intermediate-risk category, where they're not necessarily at a point of warranting transplant, but they may certainly be symptomatic. And we need to guide their treatment to address their primary symptoms, whether from significant anemia or splenomegaly, especially since outside of transplant we don't have a lot of strong data on which treatment can improve overall survival. So we decide on symptom-directed therapy, which is also guided by labs.
Yes, absolutely. Getting a good, comprehensive look at your patient prior to starting therapy is really key.
- Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29:392-397.
- Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). 2010;115:1703-1708.
- NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative Neoplasms. Version 2.2021. Published August 18, 2021. Accessed September 27, 2021. https://www.nccn.org/professionals/physician_gls/pdf/mpn.pdf