Of the estimated 16,000 patients in the U.S. diagnosed with MDS every year, approximately 3.6% of them have an IDH1 mutation.
The recent approval of Tibsovo (ivosidenib) for certain patients with relapsed/refractory myelodysplastic syndromes (MDS) represents an important step forward in treating this population, although more progress is needed to address the greater group of patients with this disease, an expert said.
In October 2023, the Food and Drug Administration (FDA) approved Tibsovo for the treatment of adults with relapsed/refractory MDS who have a susceptible IDH1 mutation.
According to a press release from Servier Pharmaceuticals, the manufacturer of Tibsovo, of the estimated 16,000 patients in the U.S. diagnosed with MDS every year, approximately 3.6% of them have an IDH1 mutation.
“We’re excited that there is a potential option in this space because our patients unfortunately really have not had too many options in the past,” Dr. Uma Borate, clinical associate professor at The Author G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University Comprehensive Cancer Center in Columbus, said in an interview with CURE. “We hope there will be more and more approvals of different agents that will be effective and safe for patients in the setting.”
Borate discussed the importance of this FDA approval for patients with MDS who harbor an IDH1 mutation, treatment options before this approval and the unmet needs that persist.
Why was the recent FDA approval of Tibsovo important for these patients?
Unfortunately, currently, for relapsed/refractory MDS, which is a type of blood cancer, there is really no therapy that is standard of care when patients reach this point. We have treatments for patients when they’re diagnosed with MDS, but when those treatments stop working, they don’t really have a lot of options, and generally, survival at that point can be sometimes less than six months. So, the fact that we have a drug that is approved in this setting is a very, very important step forward for patients.
This is a very specific approval for patients with MDS with an IDH1 mutation. This is not a very common mutation for patients. They occur in maybe 1% to 3% of myelodysplastic syndrome patients. However, the drug, this IDH1 inhibitor that received this recent FDA approval is a very specific inhibitor of this mutation. It’s an oral agent, a pill that’s taken every day. So patients don’t really have to go back and forth to infusion centers, hospitals or clinics to get this treatment; they can take it in their home. The study showed that it was extremely well tolerated, so there were not a lot of side effects requiring people to end up back in the hospital, which I think is a big deal when you’re doing this treatment after the first-line therapy has not worked.
It’s also important because it’s precision medicine, a personalized medicine-type of strategy, where patients with a particular mutation get a therapy that inhibits the outcomes of that mutation in the disease.
Are there any side effects that may occur with Tibsovo?
One of the side effects that we see fairly commonly in acute myeloid leukemia patients — they’re not the same patient population, so it’s not the MDS patient population we’re talking about right now — but the AML population is a side effect that we commonly call differentiation syndrome. What this means is when patients start this treatment, the immature cells that were sitting in the bone marrow then start slowly maturing and developing into normal white blood cells that then come out into the circulation. And sometimes this process can be extremely quick and brisk to the point where you have just a large number of these cells in the circulation. And that can lead to several complications that present with a certain set of symptoms. And the most common way a patient with differentiation syndrome presents is they feel really short of breath, they develop a cough, they can develop significant swelling, especially in their legs. And that’s how it comes to medical attention. That is one of the most unique and specific side effects of Tibsovo that we always watch for. It isn’t as common in MDS patients, which is where this approval is, because there’s just not as much disease in their bone marrow when they’re at that point compared to acute myeloid leukemia or AML patients.
Some of the other side effects to watch for is it can impact your liver functions. So when we measure bloodwork looking at the liver, we can sometimes see that the bilirubin can be elevated when patients are on Tibsovo. And then there are always side effects of a pill, which is patients just sometimes don’t really feel good in terms of nausea. They can sometimes have vomiting along with that. And so those are things that we obviously help our patients to make sure they have medications to support them through this.
How is differentiation syndrome typically managed?
Typically, the first step in the management of anything is recognition. So we try to be very proactive in describing this to our patients when they get counseled about the drug and its side effects prior to starting. And then we teach them about the different symptoms that may be one of the first signs that they’re developing this.
And then once we recognize it and diagnose it, we very aggressively treat it. The main treatment for differentiation syndrome is, if they do have increased fluid on themselves or fluid overload, then we give them diuretics to get the fluid off their bodies. We also treat aggressively with steroids, which are one of the very effective treatments of differentiation syndrome because they can control the white blood cell count quite quickly.
Findings from the AG123-C-001 trial, which this FDA approval was based on, also focused on patients who were dependent on red blood cell and/or platelet transfusions at the start of the study, and then they became independent of those over time. Why is this important?
When somebody is dependent on transfusions, it means that their disease is pretty severe to where their bone marrow is not able to produce red blood cells in a healthy manner. And that, itself, indicates how severe the disease might be. So that’s a hallmark of patients that have more severe disease.
For the patient, being dependent on red blood cell transfusions can be very, very challenging for their quality of life. Not only does it mean they have to go into the hospital or the clinic frequently, but they also have to wait for several hours to find a compatible unit of blood, and then they have to sit there while they get the blood. And then they have to do it all over again. So obviously, not having enough blood or being anemic, being red blood cell transfusion dependent means you don’t have a great quality of life to begin with. And then on top of that, you have a lot of different challenges to the amount of time you’re spending actually getting the blood. So, the fact that treatment with Tibsovo made this group of patients that had red blood cell transfusion dependent, it made them over time independent, meaning that they did not need these transfusions I think was a huge win for the patients and their quality of life
Is treatment with Tibsovo meant for all patients with relapsed/refractory MDS with a potential IDH1 mutation?
We always recommend treatment on a case-by-case basis, even though the indication is very broad in the sense that anybody with an IDH1 mutation whose MDS has not responded to traditional therapies could be a candidate. We obviously want to be thoughtful about the patients that get started on this therapy. For example, if somebody has not really good liver function, maybe this is not something that they would be able to tolerate. Similarly, if their kidneys aren’t working really well or they have a really weak heart, we have to think thoughtfully about whether those patients would benefit from a drug like this. But overall, I do think this would be a therapy that most patients would be suited for because it’s really well tolerated in general in this patient population.
What unmet needs persist?
The IDH1 mutation is not the most common mutation in MDS patients. It’s a rare mutation. And we now thankfully have a therapy directed towards those patients specifically. But then there’s a huge population of patients that do not have this mutation that really doesn’t have any other therapeutic options. They really lack options that are effective once the more traditional frontline therapies have failed. So, this is a huge unmet need in the relapsed/refractory MDS population.
This transcription has been edited for clarity and conciseness.
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