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Treatment Decisions in Hemophilia A
New York, NY
Hematology and Oncology
The Mount Sinai Hospital
What are the most pressing complications of hemophilia A and how do you answer them?
The first major problem is the development of inhibitors in patients. Second is that currently — although the field is changing — the level of factor that one can use is really limited. There’s a very short half-life, and you have to give factor intravenously, so it’s terribly inconvenient to use, and even if you use it as well as we suggest patients use it, patients still bleed. It’s certainly effective, it’s better than nothing, and it’s gotten better over the years, but the goal is for patients not to bleed anymore, and the way we’re currently administering factor just doesn’t allow you to do that very well. We give this factor in a setting where patients still bleed, it’s incredibly expensive, and there’s a high risk of developing the inhibitory antibody, which means you can’t use that drug unless you go through all sorts of treatments to get rid of the antibodies to the drug in the first place.
How does the heterogeneity of hemophilia (in terms of bleeding pattern, severity, etc.) affect your treatment decisions?
We know these distinctions, in terms of levels of factor, correlate pretty well — not exactly, but pretty well — with the risk for spontaneous bleeding. So, if you have basically undetectable factor levels — less than 1% — you will have spontaneous bleeds in your joints or muscles or anywhere really frequently. If you have a little bit more factor — say 2% to 5% — that risk goes down, but you still have it, and you still bleed.
What is really a black box is a factor level anywhere between 5% and 50%, which characterizes mild disease. No one has really studied those patients because, to be honest with you, they don’t bleed very often. The hallmark of hemophilia is spontaneous bleeding, and mild patients don’t really have that. What they do experience is that if they are traumatized, they’re beaten or fall down or do something in sports or have an operation, they can bleed excessively. So that’s where they need to be treated. The goal is to convert all patients with severe and moderate disease into patients with mild disease and not even try to get them to have normal levels of factor, which is greater than 50%.
It’s a poorly studied group of patients, but it’s extremely heterogeneous. Patients with a factor level of 6% can have a few bleeds that are significant enough that they need a joint replaced. I have patients like that. Most patients who are in the 40% to 50% range, or the 30% to 40% range, don’t bleed. Clinicians don’t feel comfortable having them go for an emergency appendectomy without getting any treatment, yet there are instances where that occurs. Nobody writes about that, but that does occur. It means in certain circumstances, you can get away with significant bleeding, but most of us don’t feel comfortable doing that. But again, it really hasn’t been studied. And so the heterogeneity, which is seen in every genetic disease that I’m aware of, is no different in hemophilia, and the factor level, as I said, fairly well correlates with the risk of bleeding.
What steps do you take to evaluate and, if necessary, improve your patients’ health-related quality of life?
What I do has always been technology driven. I’ve already explained the problems with current treatment with factors; we need something better, and what is that? Well, there are new drugs now that you don’t give intravenously, so you don’t have to poke around and find a vein. You can give a simple shot, like an insulin injection, every few weeks instead of every couple of days. And the drugs, at least in my opinion, are superior to factor, meaning if you take them, you really don’t bleed very often. I’m not saying you never bleed, but you don’t bleed very frequently. Is that a better of quality of life? I would think so.
Companies have done quality-of-life studies, which I don’t really pay attention to because they are only done for a year or so. If you do these studies over a period of say 10 years, I would suspect that would improve patients’ quality of life. But I will tell you, the one drug that’s available now, emicizumab, even in the period of a year and half has dramatically changed the lives of several patients. I’ve never seen that before.
This is a nonfactor drug, but it acts like a factor, and patients don’t develop antibodies to it — or not nearly as frequently — and it’s easy to give, and in my opinion, I think it’s a better drug. Addressing inhibitors, ease of use, and prevention of bleeding — that’s the trilogy that you need for effective treatment, and that’s what this drug does. Is it a perfect drug? Absolutely not. We still see patients bleeding, but they’re bleeding because now they’re trying to exercise and do all sorts of things they haven’t done before, and their joints are already set up to bleed because of all the previous bleeding episodes they’ve had in their lives. My educated guess would be that if you put, starting today, every child on this drug, in 20 or 30 years, we probably wouldn’t have much in the way of significant bleeding.
What are the challenges of aging in patients with hemophilia and how do you address them?
Hemophilia is not significantly different from any other chronic disease. The life expectancy for our patients is normal, with a few exceptions such as the development of HIV, hepatitis, or liver cirrhosis. Ultimately, as patients with hemophilia age, they have to manage the challenges of having a bleeding phenotype embedded with their disease. It’s also important to note that these patients are still vulnerable to other chronic diseases such as cancer, heart disease, and diabetes.
Five categories are important to consider when treating aging patients, and these categories come out of the World Health Organization.
1. Diet and exercise. Appropriate diet is necessary for patients to keep their weight down so they don’t develop obesity and then are at risk for umpteen other diseases.
2. Cognition and mental health. Depression has been established as having higher rates in older people.
3. Prevention of falls. I believe the data show that if an elderly person breaks their leg, their risk for death a year later is very, very high. From this we can theorize that patients with hemophilia who have bad joints are at higher risk for death, because their joint health isn’t that good and their bones aren’t that strong. However we don’t know this definitively as it hasn’t been studied.
4. Maintaining urinary function. This is for both men and women. We revert back to when we were infants, essentially, in the last phase of our lives. This actually has a tremendous burden, due to self-catheterization, frequent urination, benign prostatic hyperplasia, etc.
5. Sensory well-being. Cataracts are very common and hearing loss is very common. So patients lose their perception, which also occurs with falls and obesity. These categories are all interlocked.
Instead of delving into particular diseases like atrial fibrillation or different tumors patients could be at risk for, managing that broader, general set of complications is what I subscribe to.
What do you think the role of gene therapy is for hemophilia? Do you see gene therapy becoming a mainstay of hemophilia treatment?
I think, eventually, all patients will be offered gene therapy, and most will accept it, but this will not happen immediately because it’s a technology where there are still too many unanswered questions. We need clinical trials and we need to answer some basic questions about gene therapy.
How effective is it? It’s basically putting a virus that transfers DNA into a patient’s cells, and then the patient can make their own protein that they should have been making in the first place. Is it sort of effective, or is it very effective? Is it effective for all people, in all the same ways? Right now, the trials are all designed for patients with severe disease. They’re not designed for patients with moderate or mild disease. Why not? Because that’s where they’re starting from. How long will it work? Can a patient get it again? If they can, how many times? Is that a good thing, or is that a bad thing? Putting all this virus into a patient — what are the risks? I mean, it’s a virus, it’s like getting a cold, right?
What’s going to happen in the next few weeks or months? And then what would happen in this group of patients who are especially sensitive to HIV and hepatitis C, where these viruses languish for decades — what’s this stuff going to do? Is this stuff just going to sit there and do nothing, or is it going to cause problems and unintended consequences?
These are all questions that have to be addressed, and because it’s a new technology, it’s going to take some time to address them. But do I think that different versions of gene therapy will be available? Absolutely. And will most patients in the future be on it? Yeah. Yeah, I truly believe so.