Pathophysiology of Myelofibrosis


The role of signaling pathways, mutations, and alterations in the development of myelofibrosis (MF), and characteristics that distinguish primary MF from secondary MF.

John Mascarenhas, MD: Welcome to this Cancer Networkä presentation “Advances in the Treatment of Myelofibrosis.” I am your host, John Mascarenhas. I am the director of the Adult Leukemia Program and leader of clinical investigation within the Myeloproliferative Disorders Program at Mount Sinai in New York. Joining me today are Aaron Gerds, Raajit Rampal, and Srdan Verstovsek. I'll ask each of you to introduce yourselves and I'll start with Aaron.

Aaron T. Gerds, MD: Hi, thank you very much. My name is Aaron Gerds and I am an associate professor of medicine at Cleveland Clinic in Cleveland, Ohio.

John Mascarenhas, MD: Thanks for joining us, Aaron, how about Raajit?

Raajit K. Rampal, MD, PhD: Hi, I'm Raajit Rampal. I'm an associate member at the Memorial Sloan Kettering Cancer Center in New York.

John Mascarenhas, MD: Thanks, Raajit. Srdan?

Srdan Verstovsek, MD, PhD: Hello, everybody. I'm Srdan Verstovsek from The University of Texas MD Anderson Cancer Center in Houston, Texas.

John Mascarenhas, MD: Welcome, Srdan. I'm happy to have 3 of my closest colleagues and friends in the field here today. We're going to discuss challenges and advances in the treatment of patients with myelofibrosis. We'll review 2 patient cases and involve our audience by using an interactive online platform to answer several polling questions that will then be discussed by our panelists. Let's begin.

Our first topic is myelofibrosis biology and disease landscape. The first question is: What is myelofibrosis, how is it diagnosed, and what are the differences between primary and secondary myelofibrosis? I'll start with you, Aaron. Can you explain in clearest terms, what is MF and how do you distinguish between primary and secondary MF?

Aaron T. Gerds, MD: Myelofibrosis, first and foremost, is a type of cancer. I think a lot of folks sometimes forget that and call it a disease or disorder. Certainly, mutations and clonality have occurred in the bone marrow, leading to uncontrolled growth of cells. The hallmark and what's in the name there, is scar tissue in the bone marrow, myelofibrosis. That is the common pathologic finding that we see in the bone marrow. Some mutations occur in the JAK/STAT [Janus kinase/signal transducer and activator of transcription]signaling pathway that lead to this proliferation and growth, and the ultimate laying down of scar tissue in the marrow. Over time, that scar tissue can lead to dysfunction in the hematopoietic process, and you see low blood counts in patients. There's this whole concept of primary versus secondary myelofibrosis. Those words are a little tricky; primary myelofibrosis refers to a disease of bone marrow cancer and secondary myelofibrosis can mean either inflammatory scar tissue in the bone marrow. This differs from a rheumatological disorder, which can also indicate myelofibrosis that has evolved out of a preexisting polycythemia vera or essential thrombocythemia.

John Mascarenhas, MD: Raajit, can you give me some examples of non-MPN [myeloproliferative neoplasm] secondary myelofibrosis? In what other settings could you see a myelofibrotic marrow?

Raajit K. Rampal, MD, PhD: It's an interesting question. Fibrosis in the marrow is in many cases, nonspecific. Can you see it in other myeloid diseases? The answer is yes. Rarely do you see it in MDS [myelodysplastic syndromes]. There's a rare MDS subtype known as MDS with fibrosis, but beyond hematologic cancers, you can certainly see it in autoimmune conditions. There is an entity known as autoimmune myelofibrosis, as we've just discussed, which can be associated with things like lupus, for example, or other rheumatologic conditions. Fibrosis can also be seen for other inflammatory infectious processes that may be more systemic. It is certainly not exclusive to primary myelofibrosis.

John Mascarenhas, MD: Can you give the audience a sense of how signaling pathways mutations and genetic and epigenetic alterations may contribute to the pathophysiology of myelofibrosis?

Raajit K. Rampal, MD, PhD: We know that the hallmark of MPN pathogenesis are activations in the JAK/STAT pathway, which is a pathway that is involved in both inflammation and hematopoiesis. The disease is principally driven by unregulated JAK/STAT signaling. That being said, a number of other mutations can occur in the disease as well, and it’s very clear to us now from both patient data and laboratory data that those mutations can alter the biology of the disease, and in many cases, advance it or cause it to be more aggressive. In addition to that, other pathways are activated by the JAK/STAT pathway, which we certainly think plays a role in the pathogenesis of the disease, and are currently targets of inhibitors in clinical trials.

John Mascarenhas, MD: Can we take a minute to discuss the inflammatory consequences of these activated pathways?

Raajit K. Rampal, MD, PhD: The inflammatory pathways are a major component. We think of the disease biology and we know that a number of inflammatory cytokines are markedly elevated in this disease. There is emerging biology about their role in disease pathogenesis. We know that some of the mediators of this such as the NF-kappaB [nuclear factor kappa B (NF-κB)]pathway plays a key role in the disease pathogenesis, and are also targets for currently studied drugs.

John Mascarenhas, MD: Srdan, we use the word biomarkers a lot in oncology and hematology, but in reference to myelofibrosis, what are the biomarkers of interest? When do you test them? How do they help you in terms of prognosis or even therapeutic implications?

Srdan Verstovsek, MD, PhD: The prognostication in myelofibrosis has become complicated because we have identified multiple biomarkers. Some 15 years ago, we started with the biomarkers that would be easy to understand, that would be the number of white blood cells, or do you have a blast in the blood, or a clinical finding of a big screen sometimes in some studies or symptoms or age.We will be combining those in what I consider now, a simple prognosis. Since then, we have identified multiple other biomarkers, like what we were saying just a minute ago, different driver mutations activate this JAK/STAT pathway, so JAK2 mutation, […or other] mutations, or presence of none of the 3 so-called triple-negative have an influence on the outcome or mutations in some other genes, which we can test for by NGS [next-generation sequencing] panels in academic centers. They contribute as well. Abnormalities in chromosomes that carry genes, sometimes even the level, or the allele burden of the mutation, what is the number of cells that are influenced or affected by the disease? Like a JAK allele burden, how many cells are affected by the JAK2, matters. There is a variety of prognosis calling systems. Where we are going is the individualized approach. Which prognosis calling systems will be used for which patient, and why is it needed to determine whether a patient goes for a transplant? Perhaps in the future to identify targets for particular therapies, or perhaps there will be therapies that will be more prone to help some other patients with specific genetic profiles.

John Mascarenhas, MD: It sounds like you employ, at least from a molecular standpoint, next-generation sequencing as a biomarker when you first meet patients, but are you doing tests like NGS in a serial fashion? When do you repeat the testing?

Srdan Verstovsek, MD, PhD: We do automatically repeat the testing when there is a clinical progression. There is a loss of control over the disease sign and symptoms, for example, with JAK inhibitors, when there is a progression in blood so people go into the accelerator blastic phase. Ideally, one would test patients periodically, even when they're stable, to predict a progression by the acquisition of certain molecular abnormalities or cytogenetic abnormalities, but that is not a standard practice and not really feasible to do. This is not being done because there is really not much you can do. You only do something when things change clinically. If information is applicable to influence the management, then it is justifiable enough to be tested.

Transcript edited for clarity.

Related Videos
A panel of 5 experts on colorectal cancer
A panel of 5 experts on colorectal cancer
A panel of 5 experts on colorectal cancer
Arvind N. Dasari, MD, MS, an expert on colorectal cancer
Stacey Cohen, MD, an expert on colorectal cancer
Arvind N. Dasari, MD, MS, an expert on colorectal cancer
A panel of 5 experts on colorectal cancer
Aparna Parikh, MD, an expert on colorectal cancer
Stacey Cohen, MD, an expert on colorectal cancer
Carey Anders, MD, an expert on breast cancer
Related Content