Transcript:Azra Raza, MD: Also, I’d just like to point out, James, that many of the guidelines suggest that only lower-risk patients should be treated with erythroid-stimulating agents. However, you know the incidence of transfusion-dependent anemia for low-risk MDS is actually lower than it is for high-risk disease. So, high-risk disease actually requires more supportive care, and even though we may think that at diagnosis, according to the IWG [International Working Group] criteria, the patient has high-risk disease. But, as we discussed earlier, those criteria not etched in stone. They are correct maybe 50% of the time. So it’s like throwing up dice: 50% chance of that patient really having high-risk disease, 50% chance that they look like they have high-risk disease but could go along for a long time.

So I don’t think there should be such a hard-and-fast rule that if they have this, we should give ESA. If they don’t have this classification, we hold it. As you pointed out earlier, we see the patient, we judge the patient, we look at the natural history of the disease, we look at the EPO level, and we look at the transfusion requirement. And irrespective of what their risk is, we go ahead and we treat the patient.

James M. Foran, MD, FRCPC: I like that point. I think it comes back to something that we discussed a few minutes ago, which is that you do have to be patient early on to see how the disease will evolve and have a low threshold to repeat a bone marrow biopsy after three or six months if something doesn’t make sense, or if the cytopenias are worsening, or to confirm that you know what you’re dealing with. And that sometimes helps you know if it’s higher-risk disease or not. The issue of transfusion support in the higher-risk disease is underemphasized, and you’re absolutely right. And to me, that’s a trickier area because it’s a reason to start a disease-modifying drug like a hypomethylating agent in the hopes that we’ll get a transfusion response as well. So we tend to go to a systemic therapy with azacitidine or decitabine, for instance, rather than an ESA, with higher-risk disease to try to address the anemia. I know there was some combination data, not a lot. But I think it’s an important point that that’s a very big symptom burden for patients with high-risk disease.

Azra Raza, MD: I want to ask you a question: I want to know what your practice is. If you have a patient with isolated deletion 5q, the patient’s hemoglobin is trending down, and you know sooner rather than later you have to do something. In that patient, would you begin by starting lenalidomide, because that is the FDA-approved treatment for them? Or would you start with ESAs?

James M. Foran, MD, FRCPC: That’s a really great question. I would typically use lenalidomide to address the anemia. If there’s another cytopenia, lenalidomide is tricky. But I would typically start with lenalidomide because I think it works faster. And even though there’s not a lot of data for this, I think the patients who do respond, and two-thirds do respond, have a better prognosis; they seem to live longer. And I want to make people feel better. I want to make people live longer. Those are the two things I want to accomplish. So if I can get their hemoglobin up and try to get a survival improvement, then that’s meaningful to me.

Now, I realize this is off a phase II study, and there’s no randomized study to show that. But I like the fact that the responders do better in long-term follow-up. And when you look at the data with an ESA alone, it doesn't seem like that really modifies the natural history of the disease. I don’t know if that’s what you’re reading is as well. And so, I think lenalidomide is a good option in that situation, but you can fall back to an ESA. And I still get people to respond if it doesn’t work. And I don’t think there’s a rule that says you have to do one versus the other. That’s just our reasoning for doing that. That’s a great question though.

Azra Raza, MD: But, I do just the opposite.

James M. Foran, MD, FRCPC: Yes, I knew you were going to say that.

Azra Raza, MD: It’s a good thing for us to have this kind of a debate, simply because there’s no one way of doing the correct thing right now in MDS in many situations. And I think it’s important for our colleagues all over to realize that just between the two of us, we have a completely different management style. So when I have a patient who has an isolated deletion 5q and they start trending down, I feel that we don’t have 10,000 drugs for them. We don’t even have two drugs for them. We have one FDA-approved drug and one supportive care agent. So let’s try and get mileage out of both. Why not start with an erythroid stimulating agent and, especially if their EPO level is low, let’s see if we can get some improvement out of that? Maybe we can get six months, a year, two years of remaining transfusion independent.

Actually, I have gotten, in some patients, more than two years. And then once they stop responding, we either add lenalidomide or stop the agent completely. This way you have the sequential use of relatively nontoxic therapy first and then with a slightly more toxic therapy, which has some myelosuppressive effect earlier on, at least, and then things settle down. And I’m not saying that what you’re doing is wrong at all, because what you said is, we can always use ESAs afterwards if the patients don’t respond. And I’m saying yes, we use ESA first and then go to lenalidomide.

James M. Foran, MD, FRCPC: That’s really an excellent perspective. Thank you for that. I wanted to make a comment in that same vain, that maybe the ECOG E2905 study will help us learn about the combination of the two together with prospective data.

Azra Raza, MD: ESA and lenalidomide.

James M. Foran, MD, FRCPC: Yeah, that might be helpful also in combination.

Transcript Edited for Clarity