Roundtable Discussion: Exploring Bone Marrow Biopsies, Prognostication, and Treatment in Myelofibrosis

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During a Targeted Oncology case-based roundtable event, Srdan Verstovsek, MD, PhD, discussed the procedure of prognosis, biopsy, and treatment of a 68-year-old woman with myelofibrosis.

Srdan Verstovsek, MD, PhD

United Energy Resources, Inc, Professor of Medicine

Director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX

Srdan Verstovsek, MD, PhD

United Energy Resources, Inc, Professor of Medicine

Director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms

Department of Leukemia

The University of Texas MD Anderson Cancer Center

Houston, TX

VERSTOVSEK: I cannot think of the possibility of not doing bone marrow biopsy in patients, but maybe in those in whom it is very early in the process or those presenting with high platelets alone, and you think maybe it is essential thrombocythemia [ET], or early-stage myelofibrosis, and for practical purposes maybe there is no need for a biopsy. Then, one might wonder about the thrombotic risk and whether you need to lower the platelets first.

Otherwise, I always do a bone marrow biopsy to see what is happening there and make sure there is no other disease causing the clinical findings.

DRUCK: I once had a patient many years ago who seemed to have myelofibrosis, but the biopsy ultimately showed an infiltrating lymphoma. I always do a biopsy.

VERSTOVSEK: Even when you do the biopsy, fibers on their own are not the only finding. Like in your case, one must eliminate any other possibilities; patients with MDS [myelodysplastic syndrome] have fibers; patients with PV [polycythemia vera] may have some fibers too. At the beginning, about 20% of them have grade 2 fibrosis.

In your practice, do you rely on a hematopathologist to make a diagnosis? Do you use the diagnostic criteria for myelofibrosis? What are the challenges in making the diagnosis?

ALAM: Yes. Sometimes you can have a high suspicion even from the clinical features and the cytopenia.

VERSTOVSEK: Are you the one to call the shots or [is it] the hematopathologist?

ALAM: It is a combination, mostly.

VERSTOVSEK: I think that is the best way. For our institution, we meet once a week and review all the cases to make sure we are correct. Some of you are in smaller practices and perhaps away from the academic center. How does it work when you need to send out the sample?

VARADI: I came from a European school but basically my boss was the hematopathologist. We looked at every case, made the diagnosis, and [ran] the show. In the United States, it is a little different, but I think the treating physician must make the diagnosis by looking at the bone marrow, collecting the cytogenetics, and nowadays the molecular biology data, and we can put them in the computer and use the criteria or the classification in making the diagnosis.

VERSTOVSEK: That is good. Many times, we depend on each other from a distance if you do not have a hematopathologist next door. So that is good to understand that you collect all this information and you make a diagnosis.

VERSTOVSEK: How extensive does the testing need to be to make a differential diagnosis? For example, if you do not have a JAK2 mutation, do you differentiate further by other testing including next-generation sequencing [NGS]?

BRAUNSTEIN: [At NYU Langone Health], we have an in-house panel that has 400-plus genes. So, we send that for NGS and they report it with different tiers of reliability. I think it is helpful to get a sense of their prognosis but sometimes it can be difficult to interpret.

VERSTOVSEK: So you are at a place where you can do the 400 genes. We do 82 genes here. How about the colleagues in a practice that requires sending a sample off for extended genetic testing?

HOFFMAN: We send the bone marrows to 1 of 2 academic centers with hematopathology and, depending on what the results are, they make a recommendation of what needs to be done, but we do not routinely do NGS testing. We wait for the bone marrow to come back. Most of the patients are older as well and usually have had symptoms for some time and the physical examination also gives a hint of how significant the disease is.

VERSTOVSEK: You do the bone marrow biopsies routinely?

HOFFMAN: Yes. Sometimes we do both sides to see what is going on, particularly if on one side it is hard to get any sort of marrow out—because occasionally you will just get fibrosis.

MO: In our center, we always do a bone marrow biopsy. We will request to check the BCR-ABL and the CALR and the MPL genes, the special gene mutations, and not just the JAK2 mutation.

VERSTOVSEK: So you do the BCR-ABL first. It makes sense [because it could be] masquerading acute myeloblastic leukemia [AML], and then you look for JAK2, MPL, and CALR driver mutations. Is there anybody else who does not do the NGS?

DRUCK: It has reached that point now. In the old days, I used to bring the bone marrow over to the pathologist and review it together. Now we are in different hospitals, so we send it over through the hospital. The hospital then sends it off to Paradigm. Paradigm then decides what is going on, and whether the initial chromosome genetic testing like JAK2, etc, is negative. Sometimes they will decide to do the NGS, but it is all out of our hands. It is 3 levels away with the private companies. That is the way it has been for the last couple of years.

VERSTOVSEK: It sounds like an algorithm that you go through. Somebody is directing what test to be done based on the needs and then, of course, the cost.

DRUCK: That is why Paradigm makes sure that they do it, because they charge for it.

VERSTOVSEK: I see. For those who do NGS, is it for diagnostic purposes or more for prognostication?

DRUCK: Diagnosis.

ALAM: It can be both.

VERSTOVSEK: This is an interesting part of the whole field of MPNs [myeloproliferative neoplasms]. We were looking for examples here at The University of Texas MD Anderson Cancer Center and we found that of the patients who come through the door with myelofibrosis, 15% do not have myelofibrosis. It is not that easy because you must combine things… and that is why I am asking how extensive the testing is so that I can get the sense of whether it is directed by the cost rather than the real need.

VERSTOVSEK: I think [picking a risk-assessment tool] is in part affected by what kind of testing you have, because different prognosis scoring systems require different information including cytogenetics and extensive molecular testing.

It seems to me that extensive testing sometimes is not available from what we have discussed. How strict are you in making sure that you prognosticate correctly? If you are prognosticating, do you see the correlation between the prognosis scoring system of choice and the outcome of the patients? What is the purpose of prognosticating?

SUAREZ LONDONO: At New York University, we have a strong bone marrow transplant team, so when we see a patient who is relatively young, has no big comorbidities, and they are high risk, we tend to send them for transplant evaluation. So, it is for one to think about, even if the patient is not symptomatic, what the end goal of that patient is going to be.

VERSTOVSEK: So, prognostication is the No. 1 reason. I was participating not too long ago in an advisory board where most of the participants said that they prognosticate to be able to prescribe a different JAK inhibitor. Is this something that is common? Is there anybody required to prognosticate to prescribe any of the JAK inhibitors?

VARADI: I think maybe in the future. I do not believe that is so today when we have only a few approved JAK inhibitors. If there will be another 2 or 3 different agents approved, in that case, yes.

VERSTOVSEK: I assume most of us prognosticate for the purpose of referring to transplant or for discussion of outcome with the patient. These are the 2 most common ones. Does anyone prognosticate for transformation to AML? It looks like this is not a reason to prognosticate.

VERSTOVSEK: What is the trigger to initiate therapy for a patient with myelofibrosis? I understand that you do not see too many of these patients. That is normal, but what is the No. 1 reason to treat the patient? Is it prognostic scoring system? I guess, probably not. Is it something else?

ALAM: Severity of patients’ symptoms.

VERSTOVSEK: Any reason other than symptoms? How do you assess the symptoms? Is it by using a questionnaire or an electronic gadget that you may have in your office?

I have seen a lot of different things but mostly it is by asking questions. The National Comprehensive Cancer Network [NCCN] guidelines suggest a questionnaire called MPN-10.1 Availability does not mean that [individuals] use it right away. I understand the difficulty, in my own clinic, when it is a paper it is not easy to always get it into the medical records.

So you go by the questions then. How important is participation of your nurse or the physician assistant and nurse practitioner in assessing the quality of life of the patient? Is this a team effort or do you rely on what you see and discuss?

HOFFMAN: Our nurse practitioners are equal members and partners in our firm and have active patient control and intervention, even prescribing as well. In our state, they can prescribe everything in Schedule II and anything else along with the physician’s support. They play an important role in the symptomatology, and we find there are patients who are more honest with them.

They do not like to tell the physicians that things are not working or get mad at them because they are afraid that we will not show up at 2 in the morning, but they will certainly tell the nurses the truth because they are much more friendly and gentle in their questioning and are willing to sit and talk. In the pre–COVID-19 time, they spent a lot more time with the patients than we did.

VERSTOVSEK: That is a very good observation. What about the role of the spouses when they are present? I hear that is quite important.

BLOKH: Yes. I do a lot of telehealth and especially if I have older patients, a lot of them here in Brooklyn will have home attendants. I rely on the home attendant as well. Usually, I interview the home attendant to ask questions about how the patient is doing. There is usually no midlevel provider with me. I just ask them directly over the telephone. I do not use any formal scores or survey.

DRUCK: These are rare diseases and, in the beginning, complicated in terms of trying to navigate what is wrong with patients, and the symptoms, and the family members, and they are not getting any injectable drug. The nurses are not involved because basically, I am deciding about whether to treat and what is going on. Furthermore, it is the patient-doctor relationship that is going to extend over the next couple of years.

These patients are going to be alive with the disease for the next 5 to 10 years and that initial time one spends with them creates a therapeutic relationship that is far more important than whether I miss knowing if their itching is better or worse. That is how I see it.

HOFFMAN: When you have a male patient, [for example]—and it is not just in myelofibrosis—they do not tell you much and I am right there with them, but their wife might remind him of things of this nature. Sometimes you get mad at them, but we have to work it out together.

We have all been physicians. I do not think there are too many [individuals] who are new to the art of the medicine and the art of marriage, perhaps, in dealing with the symptomatology and then trying to convert that into a physical need for treatment and how to get a patient better so that their quality of life is as good as their quantity of life. Maximize it as best as possible.

I agree that the patient-doctor relationship is great, but I know our nurse practitioners play an important role, particularly in family support because they can do that. They are educated to deal with symptomatology and quality-of-life issues a lot better.

VERSTOVSEK: Some of you might have a physician assistant or nurse practitioners. Does anybody else have a team that extends beyond yourself to others who may help in management?

TANG: I do not have a team. I do not have a nurse practitioner, so it is mainly me making the decisions.

VERSTOVSEK: So, if the decision is made, how does the burden of symptoms influence when you start treatment? Do you say, “Oh, you are not sick enough. You need to wait more.” My perspective is that we wait for too long.

KIM: When the patient becomes symptomatic, like presenting with an enlarging spleen or worsening cytopenia, I think those are good indications to start a conversation about therapy. But these drugs carry adverse events [AEs]. Sometimes one wonders [whether] they are choosing therapy too early. You must consider the quality of life as well.

VERSTOVSEK: So, multiple factors come into play when you decide to treat or not treat.

MALIK: Treatment is not curative. We are only doing symptom palliation, so unless there is a very strong reason or the patient is very symptomatic, I personally wait. Symptoms could be anything. It could be either a big splenomegaly causing an issue, cytopenia that becomes an issue, or it could just be a decrease in the performance status. I think for minor symptoms, we can probably sit on it and when the patient is markedly symptomatic then treat them, especially because we do not have many agents to use here. We have only 1 or 2 shots at it.

VARADI: I think for myelofibrosis, with the JAK inhibitor for lot of patients, after a while they see quite a dramatic symptom improvement. Sometimes you can consider starting earlier treatment even if they are asymptomatic.

VERSTOVSEK: It looks like it is a judgment call, right? You are looking at the palliation, the degree of symptoms, possible AEs, the size of the spleen, and many factors come together.

VERSTOVSEK: This is a patient [who just received a diagnosis] with a palpable spleen, anemia, and thrombocytopenia. Sometimes transplant can help them right away and that is fine. It looks like ruxolitinib [Jakafi] is the preferred choice because fedratinib [Inrebic] was also listed there as a choice for initial therapy.

In the NCCN guidelines, for the high-risk patients, [it is recommended to] look at the platelet number and use a JAK inhibitor like ruxolitinib and fedratinib for [individuals] who have platelets above [or equal to] 50 × 103/μL. This is reflective even for patients who are transplant candidates; we start therapy with JAK inhibitors early to improve their condition and control their quality of life.1

DRUCK: For second line, I have never even heard of [fedratinib]. This is the first time I have read about it, but more importantly I have had cases where I added hydroxyurea [Hydrea] to the ruxolitinib and manipulated the 2 drugs together in the second-line setting to try and get the laboratory parameters better and try to get through. It never occurred to me that I could go to another JAK inhibitor. I do not see the point of that, quite frankly, and the only alternative seems to be adding hydroxyurea to ruxolitinib. That is how I approach it.

VERSTOVSEK: How often do you combine other agents with ruxolitinib in the beginning? Anybody adding anemia drugs or hypomethylating agents?

VARADI: Yes. I add hypomethylation drugs like decitabine [Dacogen] and erythropoietin-stimulating agents mainly at the beginning when the anemia is getting more prominent with the ruxolitinib.

VERSTOVSEK: We try to combine things quite often to control the situation better. We do not want to give up too early, whatever we do, because there are not too many choices.

MURAKHOVSKAYA: I use a combination of ruxolitinib with hydroxyurea in patients with highly proliferative myelofibrosis that was not controlled with a maximum dose of ruxolitinib. I have used a combination of azacitidine [Vidaza] and ruxolitinib in patients with high-risk myelofibrosis and MDS overlap. That has been my experience but cytopenia is generally an issue unless you have a very cellular patient.

VERSTOVSEK: That reflects what we do here. Any other combinations by anybody else that we did not mention? I am open to learn because I would like to boost or maintain the responses, but we are limited in choices.

ALAM: As other physicians have said, I have used a combination of hypomethylating agents and hydroxyurea.

VERSTOVSEK: [When using ruxolitinib], what affects your choice of how you treat the patients more? Is it the platelet number or the red blood cell count?

SUAREZ LONDONO: I think the platelets. I have seen severe thrombocytopenia where you have platelets drop below 50,000 very quickly. So, I think it’s platelets.

MODI: Both are equally important. If a patient is transfusion-dependent despite using the erythropoietin-stimulating agent, then the thrombocytopenia is also a consideration.

VERSTOVSEK: You do not have a strong feeling, basically. It is one or the other, and it depends but they usually follow each other. That is probably right. When the counts are low, they are low. We have some guidelines on what to do with patients with low platelets and I guess we will follow it, but with anemia, I guess you can transfuse the patients or add anemia drugs.

How does age or frailty factor in? Does it factor in?

HOFFMAN: What we do is we take the disease away and ask ourselves, “How long do you think the patient is going to live if they did not have myelofibrosis or any other disease that we are treating, whether it be breast cancer or lung cancer?” Then we decide on aggressiveness or supportive care. I think fragility does make a difference, particularly in assisted-living facilities, nursing homes, things of that nature, and other comorbid conditions that bring significant quality-of-life issues. Age itself is not an issue. Whether you are 50, 70, or 90 years old, if you are healthy and a tennis player just doing your activities of normal daily living with performance status of 0 to 1, we will consider treating them as you would anybody else. But fragility and comorbid conditions play a major role as well as mental status and the ability to give written and witnessed informed consent.


1. NCCN. Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms, version 1.2022. Accessed March 1, 2022.

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