Myelofibrosis: Molecular Pathways and Prognostic Factors

EP: 1.Overview of Myelofibrosis Types and Presentations

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EP: 2.Myelofibrosis: Molecular Pathways and Prognostic Factors

EP: 3.Approved Therapies for Myelofibrosis

EP: 4.Potential Role of Momelotinib in Myelofibrosis

EP: 5.Treatment Sequencing Considerations in Myelofibrosis

EP: 6.Emerging Research in Myelofibrosis Treatment

EP: 7.Closing Remarks on the Future Treatment Landscape of Myelofibrosis

Transcript:

Aaron Gerds, MD, MS: In myelofibrosis, the key deranged pathway is the JAK [Janus kinase]-STAT [signal transducer and activator of transcription] pathway, and that is central to the pathobiology of the disease. Whether there is a JAK mutation, a JAK2 mutation, a calreticulin mutation, or an MPL mutation driving disease, it all leads to constituent activation of this pathway leading to downstream effects like elevated cytokine levels and proliferation in cell survival. JAK2 mutations are obviously right in the pathway. MPL mutations, that’s the TPO [thrombopoietin] receptor, so it’s upstream of JAK-STAT. Even more upstream from that is calreticulin mutations, which is an oddball because calreticulin is an endoplasmic reticulum chaperone protein. When it becomes mutated, it leaves the ER [endoplasmic reticulum], floats up over to the MPL receptor or the TPO receptor MPL, and activates it. Thus, again, increasing JAK-STAT signaling. All 3 classic driver mutations do the same thing.

Of course, there are other key pathways dysregulated within myelofibrosis. We often talk about pro-fibrotic pathways, such as TGF [transforming growth factor] and NF-kappaB [nuclear factor kappa-light-chain-enhancer of activated B cells]. We know that targeting other pathways can improve clinical features of the disease, such as targeting ACVR1 or ALK, also known as ALK2, which is a key regulator of hepcidin to potentially improve anemia. We can also target pathways that include the mTOR pathways that ultimately involve different proteins like BET. The ultimate point here is that this disease is not a one-hit-wonder. It is not like CML [chronic myeloid leukemia], where there’s a singular mutation leading to a singular abnormal protein and an easily targeted disease that can be ameliorated, if you will, with a single pill. We really need to attack this disease in multiple ways in order to affect a deep change and really significantly change disease course.

The typical prognosis for a patient with myelofibrosis is quite variable, and we use a number of different models to predict who has a more or less aggressive disease. The classic model that’s been around for some time is the DIPPS [The Dynamic International Prognostic Scoring System] score, but we often like to incorporate molecular markers into that as well. We know that molecular marker mutations in high-risk genes, such as ASXL1, U2AF1, and others, can predict a more aggressive disease course. Symptom burden can also factor into prognosis, specifically when we talk about blood counts. We know that anemia and thrombocytopenia are strong predictors for inferior survival. Often, too, more symptomatic patients have a worse prognosis; particularly those with the classic constitutional symptoms of fevers, night sweats, and 10% weight loss over 6 months have a worse prognosis.

Lastly, response to therapy can predict survival as well. We know that patients who have splenic volume reductions on a JAK inhibitor have better survival rates than those who do not. Certainly, prognosis is driven in large by what we can determine molecularly is deranged in the disease as well as the clinical presentation of the individual patient.

Transcript edited for clarity.