Future of Therapy and Final Thoughts on Myelofibrosis


Moshe Talpaz, MD: Myelofibrosis has been known for many years. It’s an orphan disease in the following sense: We didn’t have any therapy. We were frustrated. I’m referring to the physician community. It was very frustrating because these patients suffered terribly. It’s one of the worst diseases when you see the patient as far as their outcome—their weight loss, the general deterioration, the huge spleen. And we didn’t have any tools to help them.

So there is no question that the development of the JAK2 [Janus kinase 2] inhibitors helped change the scenario of the disease outlook. Patients live better and maybe also longer. But primarily, I want to emphasize that they live better. The quality of life for many years is much better. The spleen getting smaller and not painful is a big thing. The lack of night sweats, the gaining of energy, the gaining of weight—all of those are extremely positive. But what we have accomplished is that we just postpone the inevitable. The patients eventually go back to the symptoms and progression once the drug stops to work.

We are in a period in which a lot of new drugs are being developed for the management of myelofibrosis, so it’s an exciting period. We have a lot of things to test, ranging from JAK2 inhibitors to what we refer to as BET [bromodomain and extraterminal] inhibitors and hedgehog inhibitors. And I would not dwell on it because all of those are experimental drugs, and I’m testing many of those.

I also expect to see gain in knowledge of the molecular biology of the disease. That’s perhaps more critical than the development of drugs. I would like to see the development of specific drugs that are based on what drives the disease, so we can deal with the more basic fundamental phenomena of this disease; how it progresses, how it progresses to leukemia, what are the genes that are involved, how we can affect them. This was a good theoretical discussion 30 years ago, but now it’s very practical because we have tools to do it and to test it, and that’s being done.

Doctors tend to look at a disease therapy and say the glass is half full or half empty. In that context, I would say, in the context of myelofibrosis, I would relate to it as the glass is half empty, which means to me that we need to develop a lot of things that we have not developed so far. We have developed a few things. We changed a little bit the outlook of the disease, but there is a lot to be done. We do not eradicate the disease in any case with conventional treatment. We can occasionally do it with bone marrow transplantation, but the trade-off is very costly because many patients don’t do it and don’t make it. They succumb to the treatment. It’s not an optimal treatment. It’s a toxic and dangerous treatment. So we are not at the point that treatments totally change the trajectory of the disease. We’re able to suppress the mutations and bring back the normal bone marrow hematopoiesis and restore it. We are not there yet. So the need is great for a new group of drugs or a combination of drugs that will start to systematically alter the outlook of the disease, and in that respect we are very early in that development.

There are several issues to discuss when it comes to myelofibrosis. There are issues that are relevant to the academic experimentalist and basic investigator in which we feel that our knowledge of the mechanism and biology of myelofibrosis is not adequate and clearly doesn’t match, let’s say, its cousin disease like CML [chronic myelocytic leukemia]. So we cannot yet alter dramatically the course of the disease because we don’t have the tools that research should provide us and will provide us over the years. But then there is the bigger issue for the community physician, the dissemination of the existing knowledge. The community doctors regretfully don’t see this disease very often. Hematologists in the community may see a case of myelofibrosis once a year or not even that.

I strongly advise that they consult with the academic physicians as far as how to manage these patients. What is the place of old agents like hydroxyurea? Is there a place for those still? And when should we use JAK2 inhibitors? JAK2 inhibitors are still a relatively new concept, but because of their dramatic effect, at least on the quality of life of the patients, the doctors need to be aware of it and know how to use it because the dosage matters. It should be a big difference between using 5 mg of ruxolitinib twice daily to 25 mg twice daily—it does make a heck of a difference. So acquiring knowledge in how to use the existing drugs is extremely important. Add to it the need to know how to diagnose this condition and to know…the prognostic outlook of the patients is of extreme importance as well. And I strongly emphasize the need for collaboration between the practitioner in the community and the academic physicians in order to deal with this condition better than the way we do.

Ruben Mesa, MD, FACP: There is much for treating clinicians to be hopeful for that I would summarize as it relates to myelofibrosis. First, we’re having a much better understanding of the disease and the impact of new molecular mutations and helping refine that prognosis. I think that for individuals having that, particularly in the young individuals that may still be of a transplantable age, it has become the standard of care for us to conduct that molecular typing and have it inform a more robust prognostic approach.

Second, a takeaway is the important consideration of stem cell transplant in potential candidates, and that is a discussion that is important to have…with a transplant colleague if you yourself are not a transplanter, as well as with the patient.

Third, we have much better therapies than we’ve had in the past. Ruxolitinib is an effective therapy and is clearly the standard of care as it relates to myelofibrosis. I’d be very hopeful that soon we will have an additional JAK inhibitor that will be commercially available for you to consider for a patient. That might be fedratinib, that might be pacritinib, that might be something else. But I think it is highly likely that those drugs that have safety and efficacy from phase 3 trials will be utilized.

Finally, I would say that there are many exciting things in the pipeline, combinations with JAK inhibitor. Whether that’s with ruxolitinib or one of the alternative JAK inhibitors. There are additional pathways that were reported at this annual American Society of Hematology Meeting that show activity, whether that’s in PI3 [phosphoinositide 3] kinase, whether that’s in telomere inhibition with middle STAT [signal transducers and activators of transcription], whether that’s in combination with a hypomethylating agent.

Finally, I would say that the emerging revolution in immuno-oncology, I think, will evolve to hit myeloid malignancy. There is much refinement that continues to occur, but I have little doubt that in the future—whether that is trying to utilize aspects of checkpoint inhibition alone or in combination, or even cellular-based therapies—these will end up having an important impact for our patients.

John Mascarenhas, MD: So I think for the community oncologist, treating myelofibrosis is challenging. It’s easier in many ways for someone like myself or the other speakers on this panel because we see many of them and we have resources at our disposal, whether it’s clinical trials or transplantation options.

So for the physician in the community who is seeing many different types of patients and seeing myelofibrosis patients, my recommendation would be to carefully analyze the patient’s current clinical status and goals of care, to weigh the potential for transplantation, and to refer early for evaluation for transplantation. And when using ruxolitinib, in my opinion, you should start with low-dose titrate and up the dose carefully by blood counts, to set expectations. I think the patient has to realize that ruxolitinib—although it’s an effective agent and has clearly advanced this field—is not an agent that’s going to induce a complete response and and is not curative, and that there’s really very little benefit, for example, for the clinician or the patient to do serial JAK2 V617F monitoring. We don’t expect that to be a molecular response. So I think setting expectations and goals is important for the physician and the patient.

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