Understanding the Variability of a Rare Blood Cancer

An expert discusses two primary unmet needs in myelofibrosis, current treatments and new approaches to this complex disease.

More focus is needed on the development of new drugs that treat low blood counts and new therapies that eradicate the disruption to bone marrow in patients with myelofibrosis, according to an expert at Dana-Farber Cancer Institute.

In a recent interview with CURE®, Dr. Ann Mullally, an associate professor of medicine at Harvard Medical School and a physician-scientist at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, discussed this rare blood cancer, who is at higher risk and some indicators of the disease. She also noted some unmet medical needs in treating myelofibrosis, as well as some exciting developments on the horizon.

CURE®: When people think about types of cancer, myelofibrosis isn’t often one that comes to mind. Can you explain what it is and who is at higher risk?

Mullally: Myelofibrosis is a type of blood cancer that is uncommon. Like all cancers, it’s associated with aging, so it’s most common in people in their 60s, 70s and older. Sometimes, however, younger patients can get it.

It’s primarily a problem in the bone marrow. The bone marrow is the factory that makes blood for the body. All the cells in our blood originate in the bone marrow, and myelofibrosis arises when mutations happen within the blood-forming cells — what are called the hematopoietic stem cells — and alter the behavior of those cells. Ultimately, they result in a scarring of the bone marrow. And that’s where the name comes from, fibrosis. There’s a scarring in the bone marrow, and that has consequences. Patients can have low blood counts. Then their bodies can try to make blood in other sites, particularly the spleen.

(Myelofibrosis is) characterized by a primary problem in the bone marrow, scarring and fibrosis in the bone marrow, and low blood counts over time. Patients can require blood transfusions, Scarring (fibrosis) in the bone marrow can result in an enlarged spleen because the bone marrow is not very good at making blood anymore and the spleen tries to make blood to compensate.

You mentioned low blood counts as well as an enlarged spleen. Aside from those indicators, are there other symptoms of myelofibrosis that patients should be aware of?

Myelofibrosis is a type of what we call myeloproliferative neoplasm, or MPN. And sometimes these MPNs can show up as incidental findings. Somebody can go to their primary care doctor, get (blood drawn) and (the results) can come back abnormal. In general with myelofibrosis, that’s a more uncommon way for it to present. Most times people present with some type of symptoms. They can have symptoms of having low blood counts — for example, fatigue, weight loss, fevers, sweats and abdominal pain.

With myelofibrosis, I think it’s more common that people develop symptoms that trigger tests that result in the diagnosis. In other myeloproliferative neoplasms, it can be that you just have a blood count and something incidental shows up, but I think with myelofibrosis, it is more common for people to have symptoms that precipitate getting a blood test drawn.

What are the types of myelofibrosis, and how do the different types affect how a patient is treated?

The thing with myelofibrosis is that there’s a lot of variability in this disease from patient to patient, and I think that’s something that’s very important for patients to understand because there are different gene mutations that cause it.

Sometimes it can occur de novo, so patients can have no history of any preceding myeloproliferative neoplasm. And their first presentation can be with myelofibrosis; that’s what's called primary myelofibrosis.

Sometimes it can be something that evolves over time, so patients have preceding myeloproliferative neoplasms, often for many years, even decades. And then over time, those diseases can change and evolve and progress into myelofibrosis.

So there’s a lot of variability depending on the individual patient situation and their phase of disease. For example, in the beginning, patients can have very high blood counts with myelofibrosis, and then over time, the blood counts can become low and they become transfusion dependent. There’s a lot of variation in terms of the presentation, the symptoms that somebody might experience and the genes that can contribute to the development of the disease.

And that all influences how patients are treated. And what might be applicable to one patient might not necessarily be applicable to another patient. So that’s why it’s important to see somebody who sees this disease reasonably frequently because you need experience understand what is relevant to each individual patient.

Looking at the disease in general, what are some of the unmet medical needs?

We have treatments that help counteract some of the symptoms that people experience. For example, if your spleen is very enlarged, that can cause pain or cause you to feel full, which is what we call early satiety; that can cause you to lose weight and can contribute to low energy levels. People can have fevers and sweats or itching. Our treatments (e.g. JAK2 inhibitors) are very good in general at helping with symptoms, such as shrinking the spleen and even controlling blood counts when they are high.

When somebody becomes anemic or has a low blood count, the primary treatment we have is to give them blood transfusions, which is OK, but if somebody becomes transfusion dependent, that can cause other issues. So we have an unmet need in the development of new drugs that are helpful for patients with myelofibrosis and low blood counts, specifically anemia.

And then I think the other place we’re deficient is we really have no way to eradicate the problem in the bone marrow. We deal with it and manage it, but we’re not definitively changing it or changing the natural history of the disease substantially. And the only real way we have to do that currently is to replace the bone marrow by doing a stem cell transplant or a bone marrow transplant. And we do that in some situations for myelofibrosis, but there are risks associated with that.

What are some treatment options available to patients?

There are a variety of things that we look at when somebody comes to the clinic. We try to focus on what the patient’s main problem is. Some people come in, and their main problem is that their spleen is very big and it’s uncomfortable, their blood counts are elevated and they’re losing weight. In a situation like that, something like a JAK2 (Janus kinase 2) inhibitor can be very helpful because it can bring down the blood counts, it can shrink the spleen and then it can help patients gain weight.

Other patients may have very low blood counts, and in those patients, we focus on blood transfusions to try to maintain their red blood cell count. Sometimes we use medicines like recombinant erythropoietin to try to stimulate their bone marrow to make its own red blood cells. There are some newer drugs being developed in this area, but we have less tools in our toolkit in that situation.

In a situation where somebody is of an age where they would be considered eligible to get a stem cell transplantation — and that’s generally considered up to the age of 70 years — and if they’ve had treatment and the disease has progressed on a JAK2 inhibitor or other treatments, then we do consider stem cell transplantation in certain situations. But that’s a pretty big decision because there are substantial risks associated with doing the transplant.

So we’re trying to weigh the risks of the myelofibrosis and of it causing the patient further problems versus the risk associated with doing the transplant. There’s tremendous variability in myelofibrosis from patient to patient, both in terms of the underlying biology of their disease and the problems that they face — and how we kind of address them — and it’s very much an individualized approach. But it can change over time.

In the beginning, a patient can have a certain problem, and then over time it can change and become a different problem. So patients come back to the clinic on a regular basis and are constantly being evaluated. And I think one very optimistic and positive thing is that we’re developing new treatments. We have several JAK2 inhibitors. We have two approved by the (Food and Drug Administration), we have more coming in advanced-phase clinical trials and then we have a lot of drugs that are separate from targeting the JAK/STAT pathway that are also in clinical trials. And that gives us more options. If a patient were to progress, for example, on a JAK2 inhibitor, then there can be options in terms of clinical trials or new drugs that are available and can be helpful. There’s been a lot of work in this area to try to develop new treatments for this disease.

What are some developments that could be on the horizon in the next year or so?

I think they’ll likely be approval of additional JAK2 inhibitors, on top of the two that we have, and there are slight differences between them. And, in general, having more drugs is always better because sometimes there are some idiosyncrasies, and some patients just don’t react well to one drug and might react well to another drug.

If patients progress and the JAK2 inhibitor is no longer working, then in general, we have a lot of clinical trials that add an additional agent to the JAK2 inhibitor. And those are generally things that are distinct and separate from the JAK/STAT pathway, (which) we think is good because you’re targeting a different mechanism of action. So if the cell is no longer responding to the JAK2 inhibitor, now we can target a different distinct pathway. And there have been several ongoing trials of agents that look to have clinical activity in myelofibrosis.

This interview has been edited for clarity and conciseness.

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