Monitoring for Iron Overload in Transfusion-Dependent MDS

Transcript:Vinod Pullarkat, MD: Jamile, can you comment on how you assess iron overload in your transfusion- dependent patients?

Jamile Shammo, MD: I’m very cognizant of the fact that iron overload is a consequence of a transfusion-dependent state in MDS, but I have to say that I grapple with the same issues, like all of you, that relate to when should you actually start looking at ferritin levels. We don’t have any specific trigger or guideline. We have to sit down and count how many units. But, I think it’s fair to say most people who come to my clinic will get a baseline ferritin evaluation. The guidelines tell you that after 20 to 25 units of blood, somebody may become iron overloaded. So, I think periodic assessment of ferritin is something that we must keep in mind. Then, the guidelines for initiation of iron chelation varies by recommending bodies, and, again, nobody knows what the magic number is. But, if you have somebody who is going to be iron-transfusion—dependent or red cell-transfusion–dependent, then you can only imagine that that ferritin level is going to continue to rise. Perhaps we don’t have to wait until it gets to 2500 as per the NCCN guidelines, because then it’s really difficult to catch up with that number. What you would ideally like to do is bring it down below 500, at least. Those were the clinical trials that took place with iron chelators in MDS patients. You wouldn’t want them to be below 500 for theoretical reasons of making them iron deficient, and then, of course, you have to correlate your dosing according to their transfusion need, which is actually what was done in clinical trials looking at chelation. These are all very challenging issues that you deal with.

Vinod Pullarkat, MD: The common tools you use are the number of transfusions, as well as serum ferritin. Are any of you using an MRI instrument for iron concentration?

Ellen K. Ritchie, MD: We actually did a clinical trial at Weill Cornell—I don’t know if we’ve ever published the data—where we did T2* MRIs on patients who had had 50 or more units. And, interestingly, very few patients actually ended up having a positive T2* for cardiac iron deposition. But, I say that with a little concern, because one of the patients who had a negative T2* MRI, actually came in 3 months later with severe congestive heart failure, and, on autopsy, had profound iron overload. So, I don’t know if our technology is really where we need it to be, to assess cardiac iron overload.

Vinod Pullarkat, MD: I think that’s an important point. The standardization of all these techniques is critical, especially for cardiac MRI because if the center does not have expertise, you could miss some iron overload in the heart.

Rami S. Komrokji, MD: For me, I think with the iron overload, nobody would disagree that it’s a problem in patients with MDS. And, as Jamile mentioned, usually patients, when they get to 15 to 20 units of blood, each having about 200 mg of iron, they are at the threshold where they could get iron overload. As for the question on how to monitor that, ferritin level is the easiest method we use in practice. But, one-third of MDS patients come in with high-serum ferritin at diagnosis, which could really reflect kind of a down regulation of hepcidin, and the body sensing the anemia and actually almost getting more iron absorption, it could reflect the transfusions, but it could be an inflammatory marker. So, I think it’s reasonable to check baseline levels when the patients are diagnosed, and then follow after that. Sometimes I see this unnecessary monthly need. I don’t think we need to check ferritin monthly, and you don’t want to check it in a state where the patient is in inflammation in the hospital. You want to do it in the clinic, maybe every 3 to 4 months, and monitor that.

The other techniques, obviously we don’t do liver biopsies in patients with MDS because of the bleeding problems. The MRIs for the liver or for the heart are not widely used, and realize that, we are using ferritin. As Jamile mentioned, the guidelines vary on this. You have the NCCN guidelines saying you consider that when the serum ferritin level is above 2500, but the MDS Foundation says when they are above 1000. So, there is no agreement between the guidelines, and based on what? I do somewhere in between.

Ellen K. Ritchie, MD: I think you have to look at the patient. If you have a patient where you know that they’re going to need ongoing transfusions, and you really can’t see an end to this process, when they’re hitting a serum ferritin of 1000, it’s really time to jump on the bus and to start thinking about treating them. If you really are hoping that you have a modality where they’re going to be transfusion dependent, you may not have to be in such a rush. You also have to look at the tolerability of the drugs in older patients, especially those who are our constituency. You can’t start a high dose of iron chelation, all at once, and believe that they’re going to tolerate that therapy. It really has to be started at a low dose and slowly titrated up. So, for a long time, you’re going to be happy just to keep them at the same level without their ferritin rising. You may not be able to make a lot of progress in decreasing their ferritin as you accommodate them to a dose level where they can really tolerate the medication.

Jamile Shammo, MD: I couldn’t agree more with that statement because, especially when it comes to iron chelation, you need to extend the duration of therapy. In the EPIC trial, the primary endpoint was assessed at 12 months. So, you really need something that’s tolerable that people can take for an extended period of time, but keeping in mind that you may have to alter the dose accordingly, depending on transfusion needs.

Thomas Prebet, MD, PhD: I think we usually completely focus on our potentially disease-modifying agent. But, it’s true that we also need to keep in mind that this therapy with iron chelation also clearly needs our attention, to be sure that we manage dosage, potential side effects, of this iron chelation agent accordingly, because it can be a real challenge for the patient.

Ellen K. Ritchie, MD: And you don’t want to put them on a homeopathic dose of iron chelation and just leave them there without really having a certain dynamic, improvement in that dose. It’s tricky, and it really does require full attention as a clinician.

Thomas Prebet, MD, PhD: Just to be clear, it’s a learning curve—like with any disease-modifying agent—with this iron chelation agent, too, and we need a little bit of time to really manage this patient correctly.

Transcript Edited for Clarity