Low-Risk Mutations vs. High-Risk Mutations in MDS

What are some of the low risk mutations in MDS?

The nice thing about MDS is there's only one mutation that is considered truly a low risk mutation. That's a SF3B1.

You know, if you have that mutation, those patients have a very specific, you know, disease characteristic. They generally have isolated anemia. You know, they have a ring sideroblasts in their bone marrow.

And those patients tend to respond really well to, you know, red blood cell stimulating agents, they respond to luspatercept and a lot of those patients, we, you know, we observed for many years, even prior to even starting these therapies, so that is, you know, the low the the mean, low risk mutation that we have.

What are some of the high risk mutations in MDS?

Outside of that, you know, the rest of the mutations are, you know, primarily high risk.

And then we have, you know, a lot of, a lot of mutations that, you know, are either controversial and what their risk looks like or is kind of somewhere in the middle.

And I think, you know, the highest risks mutations are TP53 that I mentioned. You know, ASXL1, a very high risk mutation.

You know, I think those are the main ones that you really want to focus on because those are, you know, the ones that I think, you know, have therapeutic implications as well.

So with SF3B1 being sort of our low risk disease subset, TP53, ASXL1 being the primarily high risk, mutations and then everything else sort of falls somewhere in the middle.

We do know that if you have additional mutations, so even if you have a good risk mutation, if you have 5 or 6, you know, mutations in your blood, that is going to predict a worse risk than if you have, you know, one mutation in your blood.

And so the more mutations you have, the more your disease, you know, kind of has had a chance to evolve and change and become resistant to certain therapies.

And thus, you know, leading to an overall, you know, generally a worse outcome there.

And again, you know, those are the patients that when I see in clinic, I'm really trying to direct to, you know, okay, you might be doing well now, but let's start thinking about clinical trials.

Let's start thinking about transplant seeing if you're eligible. So we have that available when we might need it later.

Yeah. So there's a lot of controversy in this area.

However, there are several mutations that are associated with higher risk in our MDS patients.

Specifically, these mutations are TP53, IDH2, ASXL1, CBL, DNMT3A.

So these mutations generally have been shown to be associated, with a poorer prognosis for patients who have MDS.

Also mutations in TET2, DNMT3A, and SF3B1 have been associated with a better response to hypomethylating agents like as azacitidine and decitabine which are the drugs that we often use to treat higher risk forms of MDS.