The disease process in myelofibrosis may start with the acquisition of a mutation within the stem cell population and end with the development of acute myeloid leukemia, with most patients falling somewhere along this continuum. The ultimate goal of therapy is disease modification such that patients can live longer with a better quality of life.

The ultimate goal of therapy in patients with myelofibrosis is disease modification. Right now, we do a reasonable job of addressing symptoms, and there are some data suggesting that we may be prolonging some patients’ lives (eg, those who convert from being transfusion dependent to being transfusion independent). But the drugs that we utilize right now, unfortunately, are not curative of disease, and they may have a limited degree of efficacy in terms of both the extent of efficacy and the length of time that they are effective.

Looking forward, there are a couple of different ways that we will likely be approaching the treatment of these patients. One is to try to continuously improve and innovate with newer JAK inhibitor therapies, and the other is to add additional agents that target a different pathway to current JAK inhibitor therapy. These approaches are being investigated, both preclinically and clinically, in an effort to evaluate whether they provide additional spleen benefit or a greater improvement in symptom reduction. Ultimately, what we would like to see is that the new regimens have a survival benefit. We want our patients to live longer and better, and that is where I think a lot of our research efforts are focused at the moment.

Our goal in disease management should be to get patients to a point where they can live without the burden of disease, and we still have a way to go before we achieve that goal. I am fairly bullish on the ability of JAK inhibitors to improve overall survival. It was difficult to determine the effect of JAK inhibitors on survival in the COMFORT studies because of the crossover designs and the patients’ advanced disease, but it appears that overall survival is improved. Thus, I do think that we are modifying the disease, and perhaps we are even more successful when treating patients earlier and for longer periods. We may not be preventing patients from progressing to leukemia if they were destined to do so or preventing them from having progressive myelofibrosis, but effective therapy may slow that progression, and patients may have a higher quality of life for a longer period than they would have had otherwise.

An important clinical question for continued investigation is: How we can identify patients who would benefit from being treated earlier? While we do not want to put patients with very low-risk myelofibrosis or all patients with polycythemia vera or essential thrombocythemia on JAK inhibitor therapy, it would be useful to identify the patients who have a signal driver mutation with other modifying genetic risk factors early in their disease process. We might have a chance to initiate early treatment in these patients with existing drugs and perhaps eliminate measurable disease.

There is also a very strong wellspring of research investigating the role of bone marrow dysfunction, inflammation, and damage-associated molecular patterns, and how the signaling of inflammation emanating from these somatic lesions leads to clinical phenotypes (eg, fibrosis) in the bone marrow. Utilizing drugs that can impact these targets are likely going to be most successful early on in the disease process. Trying to change the focus from treating people who have life-ending diseases to identifying and treating people earlier, and preventing disease progression, is really a whole different approach for oncologists. It will be interesting to see how we can find ways to better identify patients who are at high risk earlier and then identify therapies that can be used earlier in these patients, who are less affected by the ravages of this progressive neoplasm.

The disease process in myelofibrosis is a continuum. At the earliest origins, it probably starts with the acquisition of a mutation within the stem cell population that we would call clonal hematopoiesis of indeterminate potential (CHIP) that does not initially appear to have any clear clinical consequence. But over time, and probably due to the acquisition of other events and epigenetic alterations, a clonal proliferation of blood cells develops that does have an increasing impact on the development of overt hematologic disease, as well as an increased inflammatory thrombotic potential and risk of cardiovascular disease. This gives you a glimpse of how long and complicated the disease process may actually be and illustrates how it is all on a continuum, with the end of that continuum resulting in the development of acute myeloid leukemia. Unfortunately, we probably intervene late in a lot of these patients, but, if we had therapies that could reliably fundamentally alter the natural course and behavior of the CHIP clone, we could meaningfully intervene before patients develop these overt diseases and cardiovascular complications.

I think that the future course will be to continue dissecting out the pathways that are relevant to the disease, while recognizing that those pathways will probably vary for different patients. This will include utilizing combinations of therapies to attack different nodes in those pathways, ideally to shut down the malignant clone and disarm the microenvironment that supports that clone. Novel immunologic approaches may also have potential, and we are excited to see whether vaccination strategies and mutant CALR antibody approaches, which have demonstrated promise in preclinical models, will have a clinical impact that is meaningful. So, the field is moving in different directions, and, ultimately, we are moving toward a personalized approach in which the ideal treatment for an individual patient will depend on both the patient’s disease state and their molecular profile.