SHAMMO: I always [go for bone marrow testing] because MF is one of those entities [for which] you must demonstrate fibrosis by doing a bone marrow biopsy.
Certainly you need to exclude other entities that might present as MF, in order to access next generation sequencing [NGS] can give you very important prognostic characteristics. You can get results from peripheral blood, but it is an extremely important diagnostic and prognostic tool.
KOKO: I tend to use a combination of the criteria along with the bone marrow diagnosis. I rely on hematopathology to read the bone marrow biopsy sample, which gives me information as to whether [the disease] are fibrosis or atypical megakaryocytes.
Often the differential diagnosis could be essential thrombocythemia, especially in the patient who is not the sickest.
KASSEM: After getting a JAK2– positive or negative result, one of the things you would want to understand, or rule out, is whether it is primary or secondary myelofibrosis. That being said, a bone marrow biopsy helps define a particular percentage [of patients], but it’s not something we often see in many cases.
However, one of the diagnostic criteria is [determining] a dynamic international prognostic scoring system [DIPSS] score to define the risk classification, if you really think about myelofibrosis. Otherwise, I would also consider it part of the [myelodysplastic syndrome (MDS)] conversion.
SHAMMO: You’re right, because MDS with fibrosis is one of the differential diagnoses, at least from a pathological point of view, and you’re also right in wanting to do IPSS risk stratification. However, this is done once the diagnosis of myelofibrosis is made.
For example, let’s say you didn’t find a driver mutation, but if you found JAK2 it would make the treatment easier. But what if it’s one of those triple negatives [cases]? If so, is it easy to make this diagnosis of MF? Sometimes it can be difficult if you want to make sure there are 2 or 3 [or more areas of] fibrosis.
You also want to rule out other entities, like chronic myeloid leukemia, MDS, fibrosis, or maybe other entities with neurotensin or myeloproliferative syndrome [MPS] overlaps. You also want to demonstrate the clonal nature of the myeloproliferative neoplasms you are dealing with by showing JAK2 or another clonal hematopoiesis.
Ten percent of patients with myelofibrosis [MF] don’t have which could be problematic. Certainly you can look at megakaryocyte morphology, and if [the patient has] dysplasia, then of course you are guided by cytogenetics, because that too can be very useful.
Flejsierowicz: In our system, we usually ask [testing for] specific mutations, but they also come in panel form. Then our strong hematology person always remind [us about] solicit the NGS on new cases. There is so much [that is targetable to treat at this moment], but maybe I will ask a little more about the evolution of the disease.
Kalakota: [Our practice is pretty similar.] I usually order a JAK2 test, then it will cascade to MPL or CALR mutations, so it usually happens sequentially from there. Then, once the diagnosis is confirmed, I’ll order high-risk mutations for further analysis, but that’s a separate test.
SHAMMO: I’m glad to see that no one uses any formal risk assessment tools. Everybody [should] use some form of risk assessment, as this is a disease [in which] allogenic [transplantation] and sub-transplantation is useful and is a curative therapy. So it’s very important, and even from a prognostic point of view, it’s important to have an idea of where a patient might go because the disease is characterized by heterogeneity.
Flejsierowicz: I’m just going to speak for myself, a person who is not an FM specialist, but I happen to practice in a downtown hospital, where everything goes through the door. I have encountered several cases during my 16 year career with this practice and to my surprise 2 of those patients who were classified as high risk were then [aged] in their sixties.
They were offered a transplant and they refused. Despite what cytogenetics says, these patients are still here, still alive. They may be struggling with cytopenia at their [first line of treatment], but in my experience, these high-risk patients did not transform or progress.
[Again in my] limited experience, I have noticed that some patients who would be [classified as] intermediate risk ended up having a lot of cytopenias. These are the patients I was most worried about, and in fact, they progressed faster than cytogenetics would tell me.
SHAMMO: I think when people talk about risk, it’s exactly that: risk. I could take 100 patients who may be at increased risk, but maybe your patient is the one who [actually doesn’t have that increased risk]. [Calculating risk is] good from a statistical point of view, but it may not apply to some patients. This comment on transplant is absolutely nothing new to me as I have had the same experience with my own patients.
I don’t know if the transplanter frightened the patients by talking about risks and benefits. Even as you dig through the data, there’s plenty of room for improvement, but [undoubtedly] it is the only curative option we have. However, it may also be related to the philosophy of some elderly patients that they prefer to focus on the quality of life rather than the word. to cure.
SHAMMO: [At the time of] diagnostic, [we] assess their risk using one of the risk models. It is the recommendation of [National Comprehensive Cancer Network].1 For example, if you have mutation enhanced IPSS [MIPSS] score, MIPSS70 or MIPSS70+, [and] you have IPSS+, then you can use MYSEC [Myelofibrosis Secondary to PV and ET] prognostic model in the secondary setting. So now you have a risk stratification between low risk and high risk, based on the score.
Kalakota: For [a patient whom] I followed [most recently], I use the symptom management tool. Using the 10 symptoms listed, including fatigue, bone pain, cytopenias, and weight loss, I kind of rate these symptoms as a trigger for when to start treatment.
SHAMMO: So you go with the symptoms, but what about the timing? Is there a time to start this? For example, do you complete the symptom assessment form when the patient tells you something specific, such as symptoms related to splenomegaly? Is it weight loss, night sweats? What particular trigger could you get? Or do you fill out the symptom assessment form each time they come to see you at the clinic?
Flejsierowicz: roughly I [follow that], and then everything is symptom-driven. In addition, if there is progression of anemia, [and] the spleen enlarges, they complain of premature satiety and they cannot go about their daily activities. So this is where I always try to find where the window really is. Should I wait until they are very sick? Or do I intervene before they get very sick? It’s a fight; It’s always like that.
SHAMMO: How important is it to start treatment early? Or, how should we think about starting treatment early? Or should we even [change their treatment], Moreover? Any idea on this from the rest of the group?
KOKO: [I think this question] is something to debate. If the patient is asymptomatic, I don’t know what the benefit of initiating treatment would be. I’ve waited until a patient is symptomatic unless they have severe cytopenia, but if they’re asymptomatic, I don’t initiate any treatment.
SHAMMO: can someone [else] weigh on the [decision when a patient is] asymptomatic, or early vs late [treatment]?
KOKO: When you say “early”, what I did was start therapy earlier when symptoms presented, not necessarily late.
SHAMMO: The question when it comes to [initiating therapy] early is kind of a trick. I don’t mean to say it’s a tricky question, obviously, but the question is, in terms of their symptoms, how closely have we looked at those symptoms? How? ‘Or’ What [closely] have we assessed these patients? [I ask this because] Sometimes these conditions tend to be chronic, so patients can learn to live with them. [The patient may] gradually decrease their level of physical activity without even noticing it, and if they become slightly or gradually more anemic, they may not even notice that they are becoming increasingly tired or fatigued.
[Furthermore, if] their spleen is [gradually] getting bigger and bigger, they may not even report symptoms. So it’s very tricky, and I agree with you. I don’t claim to know the correct answer, but I’m just saying that I think what you said about cytopenia resonates with me. If we’re using drugs that tend to cause cytopenia, then I think, from a practical point of view, there’s probably no reason to wait for the patient to develop bad cytopenia. Then you’re going to start taking drugs that will make them have even more cytopenias, and then you might have problems with that. Nevertheless, it is a point of debate. There are no start or end tries [treatment initiation], but I think it’s a matter of debate and certainly [to be determined on] case by case.
So what about participating in clinical trials? Have you had the chance to consider patients for clinical trials?
Flejsierowicz: Well, that’s ideally what we should be doing, so I’m always watching and making sure I don’t miss anything, although there aren’t many trials our patients are eligible for or going on in my firm. Often patients ask [whether a trial is available], and nothing has been recently, at least [at my practice]. Few people are willing to travel, [although] Chicago is around the corner. Again, I’m only talking [of] my practice, in which most of the patients are inner-city patients, and they can’t afford to travel to a larger center or [to be seen] apart from [Medicaid system].
SHAMMO: It’s difficult to enroll patients in clinical trials, in general, in the United States. However, that’s no reason to stop [trying to get them on trials]. Of course I’m biased, but I think we all have to look at this as an opportunity to improve these [options] that we already have.
1.NCCN. Clinical practice guidelines in oncology. Myeloproliferative tumors, version 1.2021. Accessed December 10, 2021. https://bit.ly/31QFMCD