Risk Stratification of Myelodysplastic Syndromes and AML

Transcript:Rami Komrokji, MD: I think going back to what we understand about antecedent hematological diseases going to leukemia, for several years we had some clinical variables we used. So, we know that if patients had more blasts from the diagnosis of MDS, if they had poor cytogenetics, those are higher risk.

I think even on the clinical side with some of the new risk models you are applying, whether it's in myeloproliferative diseases or MDS, we refined that. So, for the IPS as revised, there was expansion in the knowledge of the cytogenetic grouping. We learned things, for example, that maybe monosomy 7 has worse outcomes than deletion 7 and maybe higher risk of transformation to AML. And as Rafael mentioned, I think we went to the next level now, where we were going at the level of the mutation or the somatic mutations.

Sometimes we don't see any alterations in cytogenetics, but then we see that the patients acquired a certain mutation. And I think what happens, like for MDS early on, the hallmark of the disease is apoptosis—accelerated cell death—and effective hematopoiesis. But then there are triggers that shift the whole thing to lack of differentiation cells, we start seeing an increase in myeloblast, and then obviously again of proliferation.

So, those are the triggers that happen at the time of their transformation. We've had some patients that had clear MDS and then their progression is to myeloproliferative neoplasm or CMML. And you look at those patients and you can sometimes find certain mutations at that time of transformation.

Ruben A. Mesa, MD, FACP: So you bring up several important points, and a key one is really around risk stratification. As you've been involved with the refining of the risk stratification of MDS, similarly we work to try to risk-stratify our acute leukemia patient that's come in to see us or we've seen in the hospital for a consult or things of that nature.

So, Rafael, at UCSD, your experience as we're thinking about trying to risk-stratify that early patient with AML, thinking about features such as cytogenetics or FLT3, NPM1, etc: what are things that you view in your standard panel? What sort of things do you like to act on in that early setting? And then later on we'll talk about the more refractory sort of cases.

Rafael Bejar MD, PhD: Cytogenetics is still incredibly important. They're diagnostic in some sense if certain translocations are present and actually can direct therapy in decisions about transplant in and of themselves. So, things like the core binding factor, leukemias, for example, are defined by those translocations.

And we treat those patients a little differently than we do patients who, for example, have normal cytogenetics or have the more typical cytogenetics that we see in MDS, like cases where there's loss of chromosomal material or entire deletions of chromosomes. And we still use this factor as important risk-stratification pieces. Complex karyotypes, many abnormalities are generally considered very poor risk, whereas having some of these disease-defining translocations are better risk.

Now, we've gone beyond that now and we're starting to look at individual genes and mutations in these genes. And I think still, today, the standard of care would be to look for mutations in FLT3, to look for mutations in NPM1, and in many centers, to look for mutations of C/EBP-alpha. These, again, are all mutations that define risk to some extent.

Those patients having FLT3-ITD mutations, particularly if there are a higher abundance of these mutations in a patient, are at a worse prognostic risk, and C/EBP-alpha patients are on the other end of the spectrum, having a better prognostic risk in the absence of other mutations.

And we know much more about the pathobiology of AML, the other mutations that are present. And we know that many of them are carrying important prognostic information. But until we have therapies that are really directed as mutations, they really haven't entered our daily clinical practice.

Ruben A. Mesa, MD, FACP: Well, you're absolutely correct. I think as we look at this information, there's really the two components. One, does it predict how the patient might do? And as we later talk about therapy, how that implicates for us medical therapy, transplant, or the timing of transplant.

It also can sometimes implicate the selection of therapy. In AML, we certainly are slowly moving from that era of a fairly uniform approach to perhaps it will be more nuanced moving forward in the future with targeted therapies if someone has a FLT3 mutation or some other component.

Rami Komrokji, MD: I think other things we don't know about is some of the features for which we know that maybe allogeneic stem cell transplant is preferable, so when the risk is higher as we proceed. But I think we learned from the Rafael paper and study that patients, for example, that have a p53 mutation may not do well even with intensive allogeneic transplant.

So, at the time, sometimes we are not sure whether offering more intensive therapies will benefit those patients. It may actually make us think in a different way that if patients have, for example, a p53 mutation, those patients may be better with newer drugs that can modulate p53 than going to allogeneic stem cell transplant.

Transcript Edited for Clarity