What Advanced Practitioners Need to Know about Myelofibrosis
Part 1: Diagnosing and Assessing Myelofibrosis
Julie Huynh-Lu, PA, Lindsey Lyle, PA-C, and Maureen Thyne, PA, start this Roundtable series with a primer on myelofibrosis, the pathophysiology, diagnostic criteria, how these patients present, and determining their risk.
MD Anderson Cancer Center
Weill Cornell Medicine
Julie Huynh-Lu: Welcome to JADPRO's Roundtable discussion on myelofibrosis. My name is Julie Huynh-Lu. I am a physician assistant at the University of Texas MD Anderson Cancer Center in Houston, Texas. And joining me today are two of my colleagues, Lindsay and Maureen. Lindsay, I'll let you introduce yourself.
Lindsay Lyle: Thank you so much, Julie. My name is Lindsay Lyle. I am a physician assistant living in Denver, and really happy to be going through this with you and Maureen today. Thanks for having me.
Maureen Thyne: And hi, I'm Maureen Thyne. I'm also a physician assistant. I work at Weill Cornell Medical Center in New York City, and just thrilled to be joining my two esteemed colleagues. Thanks so much.
Julie Huynh-Lu: Thank you guys, Lindsay, Maureen, for joining me today. For this first part of the Roundtable series, I thought we would start off just by discussing myelofibrosis at its bare bones, the pathophysiology, diagnostic criteria, how these patients present, and of course, determining their risk.
So, the first part I'm sure you guys are well versed in is the JAK/STAT pathway. It's a signaling pathway that's involved in hematopoiesis, inflammation, and immune function. The JAK2 mediates cytokine signaling for red blood cells and platelets. It involves recruiting STATs to cytokine receptors, activation, localization of STATs to nucleus, and leads to modulation of gene expression, and inflammatory cytokines like interleukin-2 receptor alpha and interleukin-6 induces hepcidin via mRNA transcription via this pathway.
This is important given the new treatment landscape that has come out, particularly with pacritinib and momelotinib more recently approved for myelofibrosis patients, and also interleukin-1 and the toll-like receptors in IRAK signaling as well as mitosome activates the nuclear factor kappa B. It's upregulated and is also a source of inflammatory cytokines, which we all know plays a huge part in myelofibrosis and the reason why our patients present the way they do. It feeds into this JAK/STAT signaling through cytokine receptor engagement.
And I briefly mentioned hepcidin earlier, but the gene that is involved with this is the ACVR1, which mediates the SMAD2/3 signaling that contributes to upregulation of hepcidin production, and of course, iron-restricted erythropoiesis. So hepcidin technically inhibits iron release and levels are elevated in primary and secondary myelofibrosis, hepcidin levels that is. And again, this is important because of the recent approval of momelotinib, which is a JAK1 and JAK2 inhibitor, but also an ACVR1 inhibitor. So therefore, it actually inhibits the hepcidin and allows additional iron to be released and can technically help patients who have anemia with myelofibrosis.
I'll pass this on to Lindsay. How do we diagnose these patients? These patients can present so differently from each other, whether they're prefibrotic or overt fibrotic. So if you could just touch on the criteria for that.
Lindsay Lyle: Yes, absolutely. And also, just to echo what you were saying, I think that especially in this disease state when we are approaching patients and perhaps what they may look like phenotypically, it's really important to understand this basic pathophysiology, which is becoming less basic beyond the JAK/STAT pathway. But really just learning so much about how this contributes to what our patients are experiencing from a symptom perspective, from a spleen perspective, and also really helps us see the whole picture. So I'm glad that we started with that because I think it really sets the stage, especially for this disease state, to really understand that.
And then really going into the diagnostic criteria, it's really important to differentiate between a prefibrotic versus an overt myelofibrotic patient. And this is maybe not spoken about quite as often when advanced practitioners are learning about myelofibrosis, but it's quite important to distinguish, as there is a survival difference, and in a presentation, may look more like a patient with ET, essential thrombocythemia.
So bone marrow biopsy, critical for diagnosis, okay? And then our pathology colleagues are going to be really, really helpful in teasing out does this look like in a patient with ET? Does this look like a pre-fibrotic myelofibrosis patient? And so for this pre-fibrotic MF patient, they'll have megakaryocytic proliferation without reticulin fibrosis > grade 1, accompanied by an increased cellularity of the bone marrow. There'll be granulocytic proliferation and often decreased erythropoiesis.
It's important when we are making a diagnosis of myelofibrosis that we are eliminating the possibility of this being another myeloid disorder or otherwise. So being sure that this does not fall under the criteria of CML, of course, with Philadelphia chromosome. Also want to be sure that doesn't fit the criteria for PV and then ET, in addition to MDFs or other myeloid neoplasms.
So the genetics would be the same between a prefibrotic myelofibrosis patient and a patient with overt myelofibrosis. And we know that JAK2, CALR, or NPL are three main drivers of this disease process, going back to that pathophysiology that you talked about. So one of these should be present to help aid in diagnosis, or in the absence of one of these mutations, there should be a presence of another clonal marker, an absence of minor reactive reticulin fibrosis in the bone marrow. So this isn't just ... there are other disorders, non-malignant disorders that can cause some scarring the marrows, cause some fibrosis. So we really need to have this clonal marker that tells us this is a clonal process.
And then looking into the minor criteria, these are more clinical features. This includes anemia not contributed to another comorbid condition, white blood cells > 11, palpable spleen, and an LDH that's elevated above the upper limit of normal for whatever your lab is.
So that's the pre-fibrotic MF. And then really going into overt myelofibrosis, the criteria are almost very similar, except for that the patient would have megakaryocytic proliferation and atypia, accompanied by either reticulin or collagen fibrosis, grade 2 or 3. So that's really where the difference lies.
And then the minor criteria is very similar with one addition, and that is that of leukoerythroblastosis, so peripheral blasts in the blood that we are detecting. So I think this really gives us an initial idea of how these patients may present clinically, but I'm going to let Maureen talk about what these patients actually look like in the clinic.
Maureen Thyne: Yes, I mean, you guys took care of all the really hard parts, so thank you so much. I'm much more comfortable taking on what the patients look like. Thank you. But no, it's actually not any easier. It's just that the patients come in and they look actually quite diverse. As you guys certainly can appreciate, just as Lindsay talked about how the criteria are quite diverse, so are the patients.
They can come in and sometimes we separate them or we come up with some ways to separate them. We can first off describe them as having either primary or secondary myelofibrosis. And what that means is that either they could be diagnosed with myelofibrosis straight off the bat, that is, their first diagnosis, or they could have had an antecedent disease, like polycythemia vera or essential thrombocythemia, and then develop myelofibrosis after the fact.
Their bone marrow becomes essentially spent after having had PV or ET for some number of years, and they start to develop fibrosis in the marrow and they come up with these criteria that Lindsay just described, and we diagnose them with secondary myelofibrosis. So the criteria are still the same, what Lindsay described, but they have this second disease.
The way that the patients are treated are exactly the same, and we'll get into treatment in a little bit, but we can describe them as having either primary or secondary disease. Primary myelofibrosis patients tend to be a little bit more cytopenic. So at their presentation, their blood counts might be a little bit lower. They might present with a little bit more anemia, a little bit more thrombocytopenia.
A second way to describe these patients might be to call them either proliferative or non-proliferative. The proliferative patients tend to show a little bit more preserved counts. They might even have dichotomous counts, is the way I describe my patients. They might have some of their blood counts as being low and some might be high. They might come in with a white blood cell count that's elevated, but have thrombocytopenia, for example. These patients tend to have higher JAK2 allele burden or JAK2 variant allele frequency, but they tend to have all of the same mutations that were described earlier, so we're still diagnosing them exactly the same way.
Patients who are cytopenic or myelodepleted tend to have all the lower counts. Again, just as that is indicative by the name, these patients have anemia, thrombocytopenia, they tend to have a lower JAK2 burden, and tend to have accumulated more mutations in addition to their JAK2.
Patients with myelofibrosis, regardless of whether they present as primary myelofibrosis or secondary myelofibrosis, regardless of whether they are proliferative or cytopenic, have a heterogeneous collection of symptoms. Sometimes they could present with constitutional symptoms such as night sweats or fevers. They might have splenomegaly at presentation. The majority of patients have anemia either at the time of diagnosis or develop it over the course of their disease. They might have thrombotic or hemorrhagic events during the course of their disease. It really becomes a question of how we monitor our patients. I don't know if you guys want to get into that now or you want to save that for later in our discussion, but we are going to talk about that on this video.
There are certain assessment forms we can use with our patients to discuss with them and over the course of their disease time, how they interpret their symptoms. And it's important sometimes with respect to splenomegaly, not only to be assessing the patient on a physical exam, but sometimes through imaging, like ultrasound or CAT scan to get a more formal size of the spleen.
So now that we've talked more about some of the way that our patients present, maybe we should hear more about how we assess our patients in a formal manner. Julie, do you want to talk to us about some of those prognostic scoring systems?
Julie Huynh-Lu: Thank you, Maureen. Yes. You actually set up perfectly because when we're talking about symptoms, some may not consider that as a risk factor for patients in their prognosis. However, specifically in NPNs there's quite a few actually risk assessments that we can use. There's IPSS, there's DIPSS, there's DIPSS-plus, MIPSS70-plus, and of course now MYSEC-PM for secondary myelofibrosis.
So just to go through a few of these. DIPSS plus takes into consideration of course patients' age, if they're over 65, if they have a proliferative disease in terms of their white blood cell count, so they have a leukocytosis of over 25, if they're anemic, where the hemoglobin is < 10, and if their peripheral blasts are > 1%. And of course these constitutional symptoms that they may have, and we'll see this more when we talk about the total symptom score, but their karyotype, if they're transfusion-dependent, and of course if they have any thrombocytopenia where their platelets are less than a hundred.
Now MIPSS70 also looks at kind of the same categories, but they tease out a little bit more. So rather than just looking at anemia where their hemoglobin is < 10, there is what we call severe and moderate anemia. So now they're saying is their hemoglobin < 8 for severe, or are they somewhere in between 8 and 10, which is moderate anemia? And this kind of gives ... you grade them using this risk assessment scoring. Again with the leukocytosis, if their white blood cell count is over 25, if they're thrombocytopenic, platelets < 100, and peripheral blood blasts where instead of 1%, now we're looking at is it ≥ 2%? Of course, their bone marrow fibrosis grade ≥ 2. Again, constitutional symptoms, this is coming back up again. And the absence of CALR type 1-like mutation.
So we know that patients who have myelofibrosis with a CALR type 1 actually have a better prognosis than those who do not have, barring that they're triple negative. I know that's another something, but if they have the CALR type 1, then that's a good mutation for them to have.
If they have any high risk mutations such as a ASXL1, EZH2, SRSF2, IDH1, IDH2, U2, AF-1, those all we take into consideration, which now that we have this technology to test these patients for this 81 gene panel, it's just such a wonderful way to be able to determine if these patients are at high risk, intermediate, or low risk, and that kind of drives our discussion in terms of their treatment. It also looks at unfavorable karyotype or high-risk karyotype.
The other risk assessment I wanted to talk about was the MYSEC-PM. Now, this is for patients who have EP or PV that have now transformed into myelofibrosis. The risk assessment qualifications on this is a little bit different. So here they're looking at hemoglobin < 11, platelets < 150, peripheral blasts ≥ 3%, and absence of CALR mutation, and then constitutional symptoms. And I really think this is because patients who have a primary myelofibrosis tend to be more cytopenic. And in secondary patients, that's not really the case. So this is essentially why the hemoglobin and platelet levels are a little bit different.
And our biggest concern, of course, is patients who have myelofibrosis that are considered high risk that can transform into acute myeloid leukemia. And that will, again, trigger different type of treatment conversation with them.
So this brings us to the end of this discussion. I'd like to thank Lindsay Lyle, Maureen Thyne for taking time out of their busy days to talk with me. For more information and to view our other discussions on myelofibrosis, please visit JADPRO online at JADPRO.com. Thank you so much, and have a great day.