Ruben Mesa, MD, FACP, hematologist and executive director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center, talks about a new drug for leukemia that received “fast track status” from the FDA.
Interview conducted by Ivanhoe Broadcast News in April 2022.
What is myelofibrosis?
DR MESA: Myelofibrosis is a chronic leukemia. It affects about 20,000 patients in the United States. It can impact them in a whole range of ways – difficult enlargement of one of their organs called the spleen, it can affect the blood counts, it can rise to difficult symptoms that patients can face and decrease their quality of life. It can progress to acute leukemia and, sadly, can be a fatal disease.
Is there a typical prognosis for this? Is it something that you can live with and manage?
DR MESA: Myelofibrosis is a disease that affects people in a range of different ways. There are individuals that may sometimes live with the disease for many years. Overall, it is a disease that, historically, has been life-threatening within 3 to 5 years. But many of the advances we’re making in medical treatments we think are both extending life and improving quality of life.
When you hear about a lot of leukemias, you think about younger people. Is that the age for this leukemia as well?
DR MESA: When we speak of leukemias, it’s a very broad term. There is both acute leukemias, which are typically top of mind when people think about leukemias – acute myeloid and lymphoid leukemia. They’re actually the most common in adults, but in children they are a higher percentage of childhood cancers even though children get cancer much less frequently than adults. So, to some degree, it seems a bit more disproportionate for children. And obviously, any cancer in children is so heartbreaking that it really is very top of mind for us. But there are many adults who end up suffering from acute leukemia and can be very life-threatening. Now, there are many different types of chronic leukemias, so, probably 40 different types, of which myelofibrosis is one of them. And can affect people in ways that can very much mirror other chronic diseases. They can affect people over years. They can become life-threatening. But increasingly, some of them we look to control. There are some where we’ve had tremendous advances. Chronic myeloid leukemia itself with new therapies has been a disease that went from being life-threatening to one that we largely now control with medicines.
How do you traditionally treat myelofibrosis?
DR MESA: Traditionally, we have treated myelofibrosis in a range of ways. The first is it’s a disease where we estimate the prognosis for a patient as well as the burden that they’re facing. Because it’s a heterogeneous disease of how it affects people, we don’t treat everyone in the same way. We decide on whether or not to pursue an aggressive treatment, such as bone marrow transplant. Bone marrow transplant can cure myelofibrosis, but it’s a very complex therapy and we use it in a little under 10 percent of patients. Since 2012, we’ve had the first myelofibrosis-specific medicines in the JAK inhibitors. For Ruxolitinib, the first of the JAK inhibitors approved, a drug that I was involved with its development, has been the standard of care since 2012.
Is one of the problems with this type of leukemia that some of the patients can experience really low blood platelet counts?
DR MESA: In myelofibrosis, there are many limitations to the therapy that we have. You could think that patients may have low blood counts and/or enlargement of the spleen and/or difficult symptoms. Therapies we’ve had in the past – Ruxolitinib and now the approved drug Fedratinib – had helped to improve disease-associated symptoms and enlargement of the spleen, but we had great limitations in individuals that had that third difficulty of a drop in the blood counts, both because those medicines historically did not improve low blood counts but sometimes could even make those low blood counts worse. And that is a side effect of the treatment, the blood counts could be lowered even further. So, that was a limiter that we have been looking at many different options to try to see how we can improve all aspects of the disease – the spleen, the symptoms, and either improve low blood counts or most certainly not make low blood counts worse by the medicines that we’re using.
What’s the danger of low blood counts?
DR MESA: When we speak of low blood counts, if we have low platelets, which is the most relevant in myelofibrosis, we can have risk of bleeding. The platelets are involved with the clotting of the blood. And if our platelets are low enough, we can have bleeding even without an injury. So, we typically think about bleeding if we fall or scrape our knee, there’s bleeding or if we have a dental procedure or a delivery, that is where there’s normal bleeding and that bleeding could be worse. But if our platelets are low enough, we can have bleeding without anything being the stimulus for that, and that could be catastrophic – bleeding in the intestine or bleeding into the brain, which could be life-threatening. If the red blood cells are too low, then that creates a great strain on the heart. The red blood cells carry oxygen from our lungs to the rest of the body. So, when we don’t have enough red blood cells, we feel short of breath, we do not have enough oxygen carried out to our tissues. And if that level is low enough, that can lead to heart attack and stroke. And if we have too few white blood cells – not a common issue in myelofibrosis, but it can be in other chronic leukemias – we can have risk of infections, both common things that we think about, such as bacterial infections – but if they’re low enough, we can even be susceptible to the infections in our environment with fungi or viruses.
Have you worked to fast track this new drug through the FDA to help people with this problem?
DR MESA: Correct. The new drug that we have been working on that was approved in February, Pacritinib, is a JAK inhibitor we’ve worked on over more than the last 10 years that had its unique ability to be able to be given at full dose for individuals even with a low blood count, and to hopefully improve the low blood counts but, at a minimum, be able to be given at full dose. The limitation of the therapies we’ve had previously is that, if an individual had low blood counts, we had to use a very reduced dose to be able to give it safely. And the tradeoff was then much less effectiveness against the core aspects of the disease. So, it really didn’t shrink the spleen very much. It didn’t help the symptoms. It probably had less impact in terms of modifying the course of the disease.
What did you see as you were working with patients with this? Did you see it work in every patient or are there certain patients that it would work better in?
DR MESA: We found it to be a really good fit for those group of patients with myelofibrosis with low blood counts. One of the things we identified was, although this and other medicines have fallen into a certain category of medicines called JAK inhibitors, this one had some different properties. The JAK-STAT pathway is a pathway in our cells that help to grow when cells in the bloodstream grow and divide. And we found abnormalities in that pathway that are very important, in terms of this disease. Now, Pacritinib inhibits some other parallel pathways that make aspects of its benefit be different than some of those other therapies. So, in randomized clinical trials, we’ve been able to show that it was very superior to placebo, but that it was also superior particularly for these individuals with low counts – one, because we were able to give it a full dose, so people could have improvements in spleen and symptoms. And two, that the blood counts stayed the same or improved, which was a significant benefit over our other historical therapies.
How long have you been treating leukemia patients?
DR MESA: Thirty years.
So, would you say you’ve waited a long time for something like this to come up?
DR MESA: This is a very important new addition. My colleagues and I originated the National Treatment Guidelines for myelofibrosis in the United States, and we first developed those a little under 10 years ago through the NCCN guidelines, which are the standard ways that physicians treat a disease or even how third-party payers will reimburse for therapy. And for the beginning, we had identified that this group of individuals with low platelets had no options. So, the only option that really was listed was clinical trials because we had no standard option available. So, this immediately finds a clear niche for this group of individuals that is very impactful.
Is this drug going to lead to other discoveries that’s needed in this?
DR MESA: Without question. The addition of Pacritinib for therapies with myelofibrosis is very important. First, for the people immediately that have low counts that may benefit, and they’re already being prescribed the drug. Second, the future progress in treating the disease will be the combination of medicines like JAK inhibitors with other medicines. Now, with many of those other medicines, they can have the tendency of lowering blood counts in and of themselves. So, the ability for them to not lower the blood counts makes an attractive medicine to combine with the others that may allow for more effective dosing and a greater amount of impact. Likewise, as we study the difference between medicines, we learn more about the biology of the disease and how to really be able to drill down to continue to develop new therapies.
With myelofibrosis, you said it mimics a lot of other chronic diseases. What would those be? And does that delay the diagnosis of it?
DR MESA: When we think about the chronic leukemias as an entire group of individuals, it’s a much larger group of individuals. And there are group of diseases that are much more common as we age that can lead to low blood counts, that can lead to progression of acute leukemia, that can be life-threatening. Chronic leukemias, as we age into our 70s, 80s, 90s or 100 – the likelihood of us developing a blood disease goes up exponentially with age so that, if an individual lives to 100, the likelihood of developing a serious condition is by far the greatest at any point in time. Therapies that we learn are helpful in one disease may end up expanding to be helpful in other diseases alone or in combination. So, I’ll use, for example, even the prior therapies we’ve used in myelofibrosis – Ruxolitinib, the first JAK inhibitor, now, has had a benefit in a whole range of things that were in parallel and may be helpful for other chronic blood conditions. It can be helpful for individuals recovering from bone marrow transplantation, whether they had myelofibrosis or not. It has been helpful in diseases of inflammation such as psoriatic arthritis or rheumatoid arthritis. Its anti-inflammatory benefits were even used against COVID-related pneumonia and there were clinical trials around that. So, medicines like Pacritinib – they start in a particular disease, sometimes not a common disease, but their benefits sometimes might evolve to related diseases, but sometimes unrelated diseases because of the range of benefits that they have. It may well evolve, again, as therapy not only for chronic leukemias, but also for acute leukemias or anything.
END OF INTERVIEW
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