Patient Selection Considerations With Iron Chelation Therapy in MDS

Transcript:Jamile Shammo, MD: It definitely contributes to survival. The problem is that every time you talk about studies of that magnitude, then you’re looking at perhaps a selection bias. Why was this probably utilized? You’re probably utilizing the oral agents when people have better performance status. Maybe that’s a reflection of why their survival is a little bit better. It’s difficult, but I think it would be nice to demonstrate improvement in organ function by the use of iron chelation, which I tend to think is the Holy Grail of iron chelation therapy.

Vinod Pullarkat, MD: You talked about organ function, and one organ function that improves is often the bone marrow. In the EPIC trial, we saw that. There was some in the US03 trial. I think the data show that maybe up to 20% of patients can have erythroid responses and even transfusion independence. And, I think, it’s important to mention that these take time. They take about approximately 3 months or so. So, if you’re not persistent with the chelation, you probably don’t get the benefit. What’s your view on improvement in hematopoiesis with iron chelation?

Thomas Prebet, MD, PhD: I think it should not be a goal, and that may be a side benefit of the therapy. We don’t have any real prospective data addressing specifically these questions. But, there were several independent studies—Italian studies, European studies, a US study—basically having the same conclusion that we may have some modification in transfusion requirements for these patients. One thing to also keep in mind is that usually this response seems to be pretty short lived. So, we can’t just rely on iron chelation, and I think that should not be something that we stress for the patient as potentially one objective of the treatment.

Rami S. Komrokji, MD: I totally agree with you. I think you have to have that benefit/risk discussion with the patient. So, basically, there is some evidence that there is benefit of iron chelation. We know that iron overload is probably the same whether it’s thalassemia, MDS, or myelofibrosis. Iron overload, over time, will cause problems, but there are some risks with those medications, toxicities that we have to keep our eye on. And you are doing that balance. You present that story for the patient and decide. For the patients I usually think of offering iron chelation to, I agree with Thomas, I would not be aiming for a hematological improvement. But, if somebody has lower-risk disease that is in my risk assessment that those patients are going to have 8 to 10 years’ survival, I think iron overload is going to be an issue. So, I think of considering that in patients who have been through several lines of therapy and now are just on best supportive care, and are having transfusions all the time.

But, I also sometimes take the window of opportunity when the patients respond to treatment. Let’s say somebody came and they were getting transfusions for 2 years, now we put them on a trial or lenalidomide, and they had a good response, that could be a window of opportunity. They will actually do better on iron chelation. Now, if somebody has very high-risk disease, unfortunately, the disease factors are going to dictate the outcome in a very short time. I don’t think those patients will benefit from treatment. And the risk of adding toxicity to whatever you are treating is going to be more.

Jamile Shammo, MD: Definitely. And I just want to clarify to make sure that people don’t leave with the wrong idea. Hematological improvement with persistent chelation is proof of a concept that actually eliminating the toxic material from the bone marrow or adding on to it is what preserves organ function. So, it’s more of a building block of making sure that those patients are monitored adequately and taken care of in that type of fashion. Obviously, the goal isn’t to have hematological improvement, but it’s intriguing to see, that extended chelation can result in that, in a small number of cases.

Vinod Pullarkat, MD: You also briefly touched upon that group of patients who may not be very transfusion dependent, but may have ineffective hematopoiesis and erythropoiesis who may absorb more iron. And we do see this in some of the ring sideroblast types of MDS.

Rami S. Komrokji, MD: In most of the patients, actually like the data presented a few years ago, when they presented on the serum ferritin, the tremendous increase in risk of mortality was associated with the serum ferritin being high. When I asked him about how many of those were up front, one-third of the patients will have serum ferritin over 1000 up front. Again, we have to be cautious a little bit because this could be an inflammatory marker, not only just hematopoiesis. And, you’re right, obviously, there are subtypes of MDS that naturally will have better outcomes, like ring sideroblasts and deletion 5q perhaps, that will have longer survival on and off blood transfusions, and that, over time, iron will build up with blood transfusions.

Vinod Pullarkat, MD: That’s a particular subset. I think we have to look at them separately. And, there, I think iron chelation is much more important in that group of patients.

Thomas Prebet, MD, PhD: What can be debated is, is there any role for iron chelation in high-risk patients, for example, for the small subgroup of patients for whom we consider transplantation as a potential consolidation treatment? And that may be debated. We don’t have any real data on that, but based on the transfusion dependency of the patient before hypomethylating-agent therapy or others, for some I may consider, in that case, iron chelation.

Ellen K. Ritchie, MD: I think prior to transplant, if you really are planning on transplanting that patient, that is a higher-risk patient who is a candidate for chelation therapy.

Jamile Shammo, MD: I must say that it would be totally off label.

Thomas Prebet, MD, PhD: Correct.

Jamile Shammo, MD: Because for a platelet count less than 50,000 or intermediate-2 to high-risk disease, it’s not approved.

Rami S. Komrokji, MD: I think if you step back and look, obviously there are some data that suggest that ferritin level peri-transplant does affect outcome in terms of even increased infection, graft-versus-host disease. The challenge sometimes is that window of opportunity you have because you see those high-risk patients who are going to move to transplant directly, and you don’t have significant time. Most of the time, we are actually doing iron chelation after the transplant in some of those patients. But, every now and then, you see a patient who is lower risk, and is of younger age, that you know that after 2 or 3 lines of therapy, you are going to be thinking of transplant. Those patients I actually keep more iron chelation, that this is lower-risk patient, but after third-line therapy failure, I’m going to start taking this patient to transplant. I have a window of opportunity now to do the iron chelation, so that’s a patient I think of even more than the higher risk.

Jamile Shammo, MD: I couldn’t agree more with you on that one because this patient who needs to go to transplant at the time of progression, you don’t have a lot of time to optimize their iron parameters.

Transcript Edited for Clarity