Treatment Options for Your Unique MDS Genetics

How do MDS genetic mutations affect treatment decisions?

we now know that it's very crucial to know the underlying genetics of the MDS patient, because it does inform not only prognosis but treatment. And so specifically for SF3B1 mutations patients can benefit from treatment with luspatercept and then another one would be patients with deletion 5q 5q where patients benefit from treatment with lenalidomide. There are other ones, such as IDH1 mutations where patients can get IDH1 inhibitors. IDH2 That's sort of working its way into MDS now or IDH1 inhibition. And then importantly, understanding that, you know, if you have a TP53 mutation or a complex karyotype where you have three or more genetic or chromosomal aberrations, that can really inform your treatment in terms of whether a patient should have a hematopoietic stem cell transplant, whether a patient should not go for sort of the standard of care therapy and instead potentially pursue a clinical trial.

What are the gene mutations we currently have targeted drugs for?

So for MDS we have, there not many options actually. But we right now have two options. So one is called deletion 5q so it is changes in chromosome that caused MDS and patients with this mutation in their chromosome, have MDS, that's rather low risk compared to high risk. And a lot of times they have, anemia, which is low red blood cells. So they can have symptoms related to anemia such as fatigue, shortness of breath, or dizziness. Sometimes they require blood transfusion because their anemia is pretty significant. And when you have this 5q deletion in the chromosome, there is, medication called revlimid that's approved for this particular type of MDS. And the revlimid is a pill that's more commonly known to be given to multiple myeloma. But this also works in this type of specific type of MDS. And when you take this pill, about 60 to 70% of the times, these patients can improve their anemia, some people can become independent of their transfusions. So it will significantly improve their symptoms related to anemia.

There's another, mutation that has that we have, therapy for is called SF3B1 mutation. That's, that's, mutation in their DNA. And when you have this mutation and they have the MDS, we can also try a medication called reblozyl, another name for that. So luspatercept, this is, pretty relatively new medication that's recently approved a few years ago. And, this particular type of MDS can also cause anemia. They tend to be, lower or intermediate risk MDS. And this medication also treats anemia so patients can become transfusion independent if they require blood transfusions. So these two mutations are so far only mutations that we have a targeted, therapy for. There are many clinical trials looking into targeting other mutations.

Since this video was recorded, the FDA has approved the IDH inhibitor, ivosidenib for patients with relapsed or refractory MDS who have an IDH mutation. This approval was granted on October 24th, 2023.

We do have very, you know, discrete targets, genetic targets that we can utilize, whether it be FLT3, IDH1 and 2 where we have drugs to specifically target those mutations in MDS. You know, it's it's a little less defined. You know, we have lenalidomide, which doesn't specifically target a molecular mutation but targets a chromosomal change in 5q. which is, you know, a loss of a chromosome in the blood that leads to this, bone marrow dysfunction. And in those patients, lenalidomide has shown, to be very successful in, you know, allowing a lot of those patients to become transfusion independent. But in the genetic space, we don't really have a lot of specific targeted therapies. Luspatercept is really kind of the main one we currently have, with it, you know, seeming to potentially work better in the SF3B1 patients with a ring sideroblast patients, but outside of that, you know, we don't have a lot that, is specifically targeting the genetics of myelodysplastic syndrome.

There is, you know, kind of taking from acute leukemia. You know, there is, certain drugs that, we see that are being utilized in leukemia, that now we're moving into myelodysplastic syndrome. So that's been one strategy. So the IDH inhibitors, for example, which you know, are present more frequently in AML, but in a small subset of myelodysplastic syndrome, they're there. And we've seen great outcomes when using those inhibitors in MDS. In, you know, small, population of patients. FLT3 another inhibitor that we use in AML, we, you know, has been utilized in MDS. But again, you know, a rare genetic subset. So the question is, you know, can we start to, have better drugs for the more prevalent mutations in MDS? And I think that's, you know, something that, you know, we're, you know, everyone is looking into, you know, there's a lot of clinical trials and clinical research, in that but, right now we don't sort of have, you a genetic mutation that is in a huge number of patients that we're specifically targeting in myelomdysplastic syndrome.

Why is MDS sometimes difficult to treat?

MDS is particularly difficult to treat, mainly because, there is only way to cure MDS is a bone marrow transplant from someone else. So that process is, basically wiping out all your bone marrow, and blood cells and replacing it with someone else's bone marrow and blood. And as you can imagine, that process is pretty, pretty intense and difficult to tolerate. So, you have to be pretty fit. You have to be relatively young, usually less than 60, 70 years of age.

But the issue is MDS is a disease of the elderly. So most people are, over 60, 70 years of age. And and as people age, they tend to have more comorbid problems, comorbid conditions like hypertension, diabetes. So a lot of people may end up not being a suitable candidate for a bone marrow transplant. So that's the only way to cure, so if you cannot cure MDS, then you go for the next best option, which is, chemotherapy. If someone has low risk MDS, you give them supportive agents only without chemotherapy. We give them some agents to boost up their anemia to make them feel better.

But even then, even the chemotherapy is not, very effective compared to other cancers such as acute leukemia. It can be even, less responsive to chemotherapy compared to leukemia because, partially because MDS is rather slow growing. So they at the same time they take in less chemotherapy. So the response rate is not not as great compared to other chemotherapy. There are many clinical trials to improve upon them. So we'll see, if other therapies get approved. But so far it is not an easy disease to treat.