Dr. Ruben Mesa, from the MPN Education Foundation, discusses various treatment options for myeloproliferative neoplasms, and highlights how advances in research can help patients with the disease and beyond.
BY Kristie L. Kahl and Dr. Ruben Mesa
PUBLISHED July 01, 2020
Kristie L. Kahl: What are the current standards of care for treating the various myeloproliferative neoplasms?
Dr. Ruben Mesa: So it is very disease-specific. First, with essential thrombocythemia, pretty much all patients we consider a low dose aspirin except perhaps with some exceptions to try to decrease the risks of blood clots for these individuals. And then if individuals need medicines to control their counts and normalize those counts, particularly the high platelet count, we consider the oral medication of hydroxyurea which is a pill to try to control those counts. We might consider injections with pegylated interferon to help to normalize those. And then we might consider a plated lowering medicine called (Agrylin [anagrelide]) that helps to lower those. So for the ET, all of those medicines that are broadly used and available. There are some others but those are the main ones that are helping to decrease and normalize the platelets, decrease that risk of blood clots or bleeding in addition to the aspirin.
Now, for patients with polycythemia vera, it's similar but with a couple important nuances. First, most patients get aspirin to try to decrease the risk of blood clots or bleeding, but very importantly, in addition, in polycythemia vera, the red blood cell count is elevated and because of that we try to control that so that the hematocrit is less than 45%. The hematocrit is the percent of blood by volume that are red blood cells. So we should to have that be less than 45%. Now, like patients with ET, we then have medicines that we'll use to control the counts in some individuals: higher risk, not doing well with phlebotomy alone, difficult symptoms, a range of different reasons. We might still use hydroxyurea or interferon as we discussed similar like patients with ET, but importantly we have an additional option: a second-line therapy which is (Jakafi [ruxolitinib]) or a JAK inhibitor. And that can help to lower the counts but also improve enlargement of the spleen and symptoms. So ruxolitinib is most commonly for individuals that have more difficult polycythemia vera.
Finally, we have patients with myelofibrosis. This is the most difficult of the three MPNs. Our initial decision is whether we do something quite dramatic like a bone marrow transplant, which can potentially cure the disease; however, it's a very involved therapy and for that we use it in very specific sort of scenarios: younger patients, difficult disease, etc. For the majority of patients, we start as our first treatment with a JAK inhibitor, which now includes ruxolitinib but also recently approved (Inrebic [fedratinib]) – both JAK inhibitors that improve the screen, improve the symptoms, potentially help to prolong life, may have an impact in helping to delay disease progression. The patients started with the JAK inhibitor ruxolitinib first, if they don't have an adequate response, we may then consider going to fedtartinib or vice versa. So those are the main treatments and I'm sure we'll discuss in a moment some of the treatments that might be coming in the future.
Kristie L. Kahl: Are there any particular common side-effects that patients should be aware of from any of these treatments?
Dr. Ruben Mesa: Although aspirin sounds very benign, there can be risk of bleeding, nosebleeds and others, and your health care provider should be made aware. Individuals with phlebotomy, it's like giving blood but it can cause soreness in the arm and it causes iron deficiency which can lead to fatigue or other difficulties, again things to monitor for your doctor. Hydroxyurea might cause risk of skin cancers, mouth sores and leg ulcers, the things for us to be mindful of. Interferon sometimes can cause a drop in the counts, cause mood changes such as depression or hypothyroidism. Anagrelide can cause palpitations, diarrhea or an upset stomach. Ruxolitinib can drop the blood counts as the others can, and has a rare risk of infections like shingles or others, headaches, things of that nature and might slightly increase the risk of skin cancers. Fedratinib, we monitor for thiamine deficiency. a type of vitamin that if it's deficient in individuals it might cause confusion or some changes of that nature. It can drop the blood counts, it can cause anemia like the ruxolitinib dropping the platelets, and it really can cause some GI side effects. This sounds like a huge list of things, but again for the majority of individuals they don't have these things when they take these medicines but these are things that we watch for and again something that your doctor both should describe for you but things to be mindful if you start any of these particular medications.
Kristie L. Kahl: Can you discuss some of the exciting trials that are going on and maybe any that you might be involved in at the moment?
Dr. Ruben Mesa: There are many exciting things going on and we'll take it disease by disease. So, first with essential thrombocythemia, there's both trials that are looking at very long-acting interferons, one called pegylated interferon versus anagrelide as second-line therapy for patients with ET. We're excited about that study. Interferons are being used, but have not been FDA approved yet for ET, so we’re excited about that part.
Additionally, we have a trial at my center and there's a national study going on with a drug from a company called Imago Pharmaceuticals that works against the cells in the bone marrow, the megakaryocytes, that we’re excited about.
For polycythemia vera, there are some drugs trying to help individuals by acting like hepcidin, which is a molecule in the blood, but to act like a phlebotomy. There's a drug from a company called Protagonist that is ongoing with that. There's other experimental drugs both with pegylated interferon that's trying to become approved in the US as it is in Europe. And there's other agents that are being tested such as MDM2 inhibitors that work against some of the biology of the disease.
Probably the greatest number of trials are in myelofibrosis. There truly are dozens and currently won't list those all. That's in part because these are our sickest patients so the need is the greatest and the hope is that again as we find things being effective in myelofibrosis we may then be able to advance them in to help patients with ET or polycythemia vera.
First, there's other JAK2 inhibitors which I’m involved with both studies trying to get both momelotinib approved, which can help both the anemia as well as spleen and symptoms and that's in an ongoing study for individuals that have anemia and have failed ruxolitinib. Similarly, there is pacritinib that is for patients with low platelets in myelofibrosis but can also improve screen and symptoms.
Then there are combinations with ruxolitinib with agents such as thalidomide to help improve anemia with navitoclax from AbbVie as a combination to be effective. There's combinations with the BET inhibitor from Constellation Pharmaceuticals that has shown very interesting activity both as front-line and combination or subsequently. CPI-0610 might have a deeper set of responses for spleen symptoms improving scarring in the bone marrow, anemia and things of that nature.
There are trials for people that are off ruxolitinib altogether. We have one from Avid200, an agent from Forbius, through the MPN Research Consortium, of which I'm an investigator. As well as that drug I had mentioned from Imago, 7289, that is being looked at for individuals with myelofibrosis. So, that's just even just a partial list but many things either as second line-for people that have failed ruxolitinib or adding on to JAK inhibitors for individuals that have had an inadequate response.
There is even cadence to try to help further improve the anemia drug called luspatercept that just got approved in myelodysplastic syndrome and hemoglobinopathies might be helpful alone or in combination for myelofibrosis.
Kristie L. Kahl: Why is it important and why should patients be getting involved in clinical trials?
Dr. Ruben Mesa: Clinical trials are how we make advances. Clinical trials are how we improve therapy. To try to demystify clinical trials, what clinical trials are is just a very structured way of treating individuals and us learning whether the treatment is better or not. Currently they're hearing a lot about clinical trials because of the cOVID pandemic, whether there's trials to see is a vaccine effective or not, is it safe or not, is a therapy for someone who has a common infection effective or not, whether that's hydroxychloroquine or Remdesivir. We only learn about these things and answer these things because of clinical trials.
In MPNS, the situation is exactly the same. The therapies that we have, hydroxyurea, anagrelide, pegylated interferon, ruxolitinib, fedratinib, we only have them because we had clinical trials and people received those on clinical trials before they got approved. The key of the clinical trials is realizing it's a structured way for us to treat you as a therapy, see if it's effective, see if you're having side effects.
What it is not is a permanent obligation, meaning the patient is always in control. If you're on a clinical trial, if you take one tablet and you don't want to be on the clinical trial again you could say “I don't want to take it anymore.” If you sign the consent form and decide you don't want to take the medicine even before you've taken a single tablet, fine. It’s not it's not a contract. It is a structured way for you to try a therapy.
Many times it's the only way to be able to try a therapy before it is approved and that's because if we know for certain that the therapy is safe and effective and everyone should get it, then it should be approved. Before then, we're hopeful that it's helpful and the people that are on the trial might indeed be better off because they were able to receive that therapy. But that's the only way to receive that therapy, if for nothing else because the FDA wants to be sure that people are being closely monitored for side effects. So everything having to do with the clinical trials is really done under the principles of being sure that people will participate with them or are fully informed and are kept as safe as possible
Kristie L. Kahl: What would you say is the best way for patients to learn more about clinical trials and if they're eligible for one?
Dr. Ruben Mesa: Patients can learn about potential clinical trials through clinicaltrials.gov, that is the main website run by the National Institutes of Health, but it really helps to share all the information regarding the trials that are out there. Whether a trial is appropriate for their situation and whether they're eligible is clearly a discussion between them and their health care provider. Clinical trials do tend to be very specific in terms of which patients, but also very much which specific phase of disease or features of the disease are key for the individuals on this study for us to be able to learn from that trial. So sometimes there is a trial available for a patient in a specific situation, sometimes there is not and that's okay. Sometimes being eligible for a trial is because your disease is being a bigger problem. If everything is perfectly stable and they're doing very well maybe there is a trial in terms of a survey study or donating blood so that research can be done. But a trial in terms of a new treatment is usually in the setting of there being an unmet need, meaning the disease is not being controlled as well as we would like.
Kristie L. Kahl: what would you say patients with this disease have the most to look forward to?
Dr. Ruben Mesa: Well, I think they have a tremendous amount to look forward to. We've made tremendous progress. There is unbelievable teamwork going on around the world now to better understand why people develop these diseases, why they progress and how to better treat them, as well as how to improve their symptoms, their quality of life and avoid progression. So, a lot to look forward to.
The research impacts patients in that it is not only done in MPN patients. We may learn advances in therapy are being used in other diseases of the blood or other cancers that may indeed have an important impact for them. And likewise, things we learn in MPN patients may help others. At the current time, one or more of the MPN drugs, ruxolitinib as an example, do have an impact on the COVID infection. In fact, ruxolitinib helps to decrease the inflammation in the pneumonia that COVID patients develop and was able to get people to come off the ventilators earlier. So again, an example of a drug approved for myelofibrosis helping a much broader group of people for different reasons. So that is really a two-way street: MPN advances help others but advances in other diseases clearly have the potential to help MPN patients.