Understanding the variability of rare blood cancer

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According to an expert from the Dana-Farber Cancer Institute, there is a need to focus more on developing new drugs that treat low blood counts and new therapies that eradicate bone marrow disruption in patients with myelofibrosis.

In a recent interview with TO CURE® Dr. Ann Mullally, Associate Professor of Medicine at Harvard Medical School and Physician Scientist at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, spoke about this rare, higher risk blood cancer and some indicators of the disease. She also noted some unmet medical needs in the treatment of myelofibrosis, as well as some exciting developments on the horizon.

TO CURE®: When people think about types of cancer, myelofibrosis is not often what comes to mind. Can you explain what it is and who is most at risk?

Mullally: Myelofibrosis is a type of blood cancer that is rare. Like all cancers, it is associated with aging, so it is more common in people aged 60, 70 and over. Sometimes, however, younger patients can get it.

It is mainly a problem in the bone marrow. Bone marrow is the factory that makes blood for the body. All cells in our blood come from the bone marrow, and myelofibrosis occurs when mutations occur in hematopoietic cells – called hematopoietic stem cells – and change the behavior of these cells. Ultimately, they lead to scarring of the bone marrow. And that’s where the name comes from, fibrosis. There is a scar in the bone marrow, and it has consequences. Patients may have a low blood count. Then their body may try to draw blood from other sites, especially the spleen.

(Myelofibrosis is) characterized by a primary problem in the bone marrow, scarring and fibrosis in the bone marrow, and a low blood count over time. Patients may require blood transfusions. Scarring (fibrosis) in the bone marrow can lead to an enlarged spleen because the bone marrow is no longer very efficient at producing blood and the spleen tries to produce blood to compensate.

You mentioned a low blood count and an enlarged spleen. Apart from these indicators, are there other symptoms of myelofibrosis that patients should be aware of?

Myelofibrosis is a type of what we call a myeloproliferative neoplasm, or MPN. And sometimes these MPNs can appear to be chance discoveries. Someone may go to their primary care doctor, get (blood test), and (the results) may come back abnormal. Usually with myelofibrosis it is a rarer way to present itself. Most of the time, people have some type of symptom. They may have symptoms of low blood counts – for example, fatigue, weight loss, fever, sweating, and abdominal pain.

With myelofibrosis, I think it’s more common for people to develop symptoms that trigger tests that lead to the diagnosis. In other myeloproliferative neoplasms, you may just have a blood count and something accidental comes on, but I think with myelofibrosis it’s more common for people to have symptoms that precipitate a blood test. .

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

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

Sometimes this can happen de novo, so that patients may not have a history of previous myeloproliferative neoplasm. And their first presentation may be myelofibrosis; this is called primary myelofibrosis.

Sometimes this can be something that changes over time so that patients have previous myeloproliferative neoplasms, often for many years or even decades. And then over time, these diseases can change and evolve and develop into myelofibrosis.

There is therefore a lot of variability depending on the individual situation of the patient and his phase of illness. For example, at first, patients may have a very high blood count with myelofibrosis, then over time the blood count may become low and become dependent on the transfusion. There is a lot of variation in terms of the presentation, the symptoms someone may experience, and the genes that can contribute to the development of the disease.

And all of this influences the way patients are treated. And what might apply to one patient might not necessarily apply to another patient. This is why it is important to see someone who sees this disease quite frequently, as you need experience to understand what is relevant for each patient.

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

We have treatments that help deal with some of the symptoms that people experience. For example, if your spleen is very enlarged, it can cause pain or make you feel full, which we call early satiety; which can cause you to lose weight and contribute to low energy levels. People may have a fever, sweating, or itching. Our treatments (eg JAK2 inhibitors) are generally very effective in relieving symptoms, such as reduced spleen and even controlling blood counts when it is high.

When someone becomes anemic or has a low blood count, the main treatment we have is to give them blood transfusions, which is okay, but if someone becomes dependent on the transfusions it can cause other problems. We therefore have an unmet need in the development of new drugs which are useful for patients with myelofibrosis and low blood count, particularly anemia.

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

What treatment options are available to patients?

There are a variety of things we look at when someone comes to the clinic. We try to focus on the main problem of the patient. Some people come and their main problem is that their spleen is very big and it’s uncomfortable, their blood count is high and they lose weight. In a situation like this, something like a JAK2 (Janus kinase 2) inhibitor can be very helpful because it can lower 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 these patients we focus on blood transfusions to try and maintain their red blood cell count. Sometimes we use drugs like recombinant erythropoietin to try to stimulate their bone marrow to make its own red blood cells. New drugs are being developed in this area, but we have fewer tools in our toolbox in this situation.

In a situation where a person is at an age where they would be considered eligible for a stem cell transplant – and this is generally considered up to the age of 70 – and if they have received treatment and the disease has progressed through a JAK2 inhibitor or other treatments, so we are considering stem cell transplantation in certain situations. But this is a pretty important decision as there are substantial risks associated with the transplant.

So we try to weigh the risks of myelofibrosis and causing other problems for the patient against the risk associated with the transplant. There is huge variability in myelofibrosis from patient to patient, both in terms of the underlying biology of their disease and the issues they face – and how we treat them – and that. is a very individualized approach. But that can change over time.

At first a patient may have a certain problem, then over time they may change and become a different problem. Patients therefore return to the clinic regularly and are constantly evaluated. And I think a very optimistic and positive thing is that we are developing new treatments. We have several inhibitors of JAK2. We have two approved by the (Food and Drug Administration), we have more coming into late stage clinical trials and then we have a lot of drugs that are distinct from the targeting of the JAK / STAT pathway that are also in clinical trials. And that gives us more options. If a patient was progressing, for example, on a JAK2 inhibitor, then there may be options in terms of clinical trials or new drugs that are available and may be of use. There has been a lot of work in this area trying to develop new treatments for this disease.

What are the developments that could be on the horizon over the next year?

I think they will probably be approving additional JAK2 inhibitors, in addition to the two we have, and there are slight differences between them. And, in general, having more drugs is always better because sometimes there are idiosyncrasies, and some patients just don’t respond well to one drug and might respond well to another drug.

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

This interview has been edited for clarity and brevity.

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