MDS: Clinical Primary Endpoints

Mikkael A. Sekeres, MD: Most clinical trials that I’ve seen have used CR, or complete response, as the primary endpoint. Why is that? Why is there this focus on CR in MDS [myelodysplastic syndrome]? What’s the distinction between a CR and a bone marrow CR?

Yazan Madanat, MD: The response criteria in MDS are complicated, to say the least. CR has traditionally been the perfect response where the blood counts are near normal and the bone marrow blasts are less than 5%. But in MDS, 5% is still a part of the CR. In AML [acute myeloid leukemia], it’s not. Nonetheless, it’s lower blasts, so less than or equal to 5%, with near normalization of blood counts and absence of blasts. The dysplasia is not part of the criteria. The reason for using CR as opposed to survival outcomes is quite obvious. They want a quick endpoint to get drugs approved, and maybe some of these endpoints correlate with survival. They just haven’t been validated as much until recently. Marrow CR, on the other hand, is having 5% or less blast in the bone marrow. The caveat is you have to have at least a 50% reduction in the blast percentage. If you’re starting with 6% blast and get to 5%, it’s not considered marrow CR, in the absence of count normalization.

Another endpoint that can be added to marrow CR is whether you have hematologic improvement. Marrow CR without hematologic improvement, where the patient is still pancytopenic, requiring blood and platelet transfusion, is clinically a very different response from someone who has become transfusion independent and also has a marrow CR.

The MDS Clinical Research Consortium recently published on the validation of the IWG [International Working Group] response criteria in higher-risk MDS. What they found is that any time you get the blasts low but also need that hematologic improvement, the survival outcomes are going to be better and longer. Whereas marrow CR without any hematologic improvements, stable disease, or progressive disease are the responses where patients are going to do quite poorly. The definition of hematologic improvement is also tricky. How many weeks to use is also complex. I usually have to look at those tables every time I’m assessing response in MDS.

Do you believe we should expect and strive for more than just a CR, or looking at event-free survival or overall survival as primary trial endpoints or things that are meaningful?

Mikkael A. Sekeres, MD: Yes. Yazan, fortunately or unfortunately, I’m old enough that I’ve seen a lot of clinical trials focused on CR. They do it because, reasonably, there had been retrospective studies that have shown that CR is an interim marker of a clinically meaningful benefit like overall survival. The assumption is if a patient achieves a CR, that means they must live longer. But in fact, there are a number of studies that have shown even a doubling of CR in patients with higher-risk MDS or older adults with acute myeloid leukemia, which is biologically almost identical without any difference in overall survival. It’s been disappointing. I don’t think CR alone is enough to say that there’s a drug that benefits a person.

The FDA uses the loose criteria of “lives longer or lives better.” If you can show that a drug allows someone to live longer and live better with the balance of safety, then that’s a drug that’s useful to have on the market. I’m focused on overall survival. I still think that should be the standard for higher-risk patients with MDS. That being said, we hold ourselves to a very high bar, and I think higher than a lot of solid tumors, where they’ve standardized progression-free survival or response duration as an interim marker of a clinically meaningful benefit. Even the FDA has hedged about saying progression-free survival itself may be clinically meaningful, although I don’t completely believe it in the absence of a patient also having an improved quality of life.

To sum it up, overall survival should be the standard in randomized studies exploring clinically meaningful benefits in patients with higher-risk MDS. I’ve been part of a study that’s focused on event-free survival, the event being either death or transformation to acute myeloid leukemia. Once a patient has higher-risk MDS and transforms to acute myeloid leukemia, that person deteriorates rapidly. The combined endpoint that constitutes event-free survival is clinically meaningful to patients. Unfortunately, we’ve been shown over and over again that CR alone doesn’t cut it.

I like thinking about quality-of-life endpoints as well. The problem is that the instruments we’ve been using to assess quality of life really stink when it comes to MDS, the most common of which is the EORTC QLQ-C30 [European Organization for Research and Treatment of Cancer Quality of Life Questionnaire version 3.0]. It doesn’t get at what a patient with MDS feels. The QUALMS [Quality of Life in Myelodysplasia Scale] instrument, which was developed by Gregory Abel at Dana-Farber Cancer Institute, is much more accurate at assessing quality of life. But what I’d love to see in future studies is the use of wearables to assess quality of life. Let’s use that. We can quantify what their quality of life is with real numbers in real time.

Transcript Edited for Clarity