Updates in Myelodysplastic Syndrome - Episode 8

Iron Chelation Therapy for MDS


Mikkael Sekeres, MD, MS: Let’s talk about complications of getting transfusions. What’s the big deal? Why don’t we just transfuse people frequently?

Rami Komrokji, MD: Obviously, there are short-term complications. We just talked about the logistics, the social factors, and the commitment factors that we always forget, also, about transfusions and the burden on the system. For patients, obviously, there are still infusion reactions and then we will have patients who will have reactions to transfusions. There is fluid overload, or volume overload, which is again not uncommon because, as we mentioned, most of those patients are in their 70s.

With platelets particularly, alloimmunization is an issue. After a while, half of the patients become alloimmunized. They are not responsive to platelet transfusions and fewer with the blood cell transfusion, but it becomes more challenging to match the blood for those patients. In MDS [myelodysplastic syndrome], obviously for the recurrent blood transfusions in the long-term, iron overload is one of the major things that we worry about. Once patients are up to 15 or 20 units of blood transfusion, they have evidence or enough level of iron to cause iron overload with known long-term complications. So, I think we can think of the complications in short-term and long-term as well.

Mikkael Sekeres, MD, MS: Nicely stated. Is there a way to minimize those complications?

Rami Komrokji, MD: In the short-term, sometimes premedication will decrease some of the infusion reactions. Sometimes you can use diuretics to treat fluid overload, like the usual tricks that we use. In the long term, obviously you can use iron chelation, which is a very important topic and there’s always debate whether you should chelate and in which patients. So I think in the short-term, again, the usual medical practices to … In platelets, maybe it’s helpful to try to restrict the transfusion sometimes when they are really needed, to avoid that alloimmunization. For the iron overload, the question is when do you introduce or use iron chelation therapy?

Mikkael Sekeres, MD, MS: Do you use iron chelation therapy?

Jamile M. Shammo, MD: I think about iron chelation therapy in everybody who is transfusion-dependent. Ideally, you’d like them to come off transfusion with the treatments that you are offering. But, if you are not successful and your patient is acquiring frequent transfusion, then yes. The question is at what threshold do you start to chelate, and I think that’s hotly debated. There are a couple of guidelines, any ferritin over 1000 by the MDS Foundation or the NCCN [National Comprehensive Cancer Network] guidelines tell you a ferritin of 2500. Frankly, I think it has to do with the frequency of transfusion dependency. If your patient is requiring frequent blood transfusions, well, perhaps you started at 2500, you’re never going to get down to where you need to be. It’s totally patient dependent. But, yes, I think it’s important to consider it.

The next question becomes if they able to tolerate the iron chelator I’m about to prescribe in terms of their kidney function, in terms of their liver function tests, in terms of their auditory, ocular. There are all the things that you need to worry about with the chelation. Those are all things that are going through my mind. But I’m a believer, I believe that chelating the iron, we do think that the damage that may come from the non—transferrin-bound iron, or labile plasma iron, those are the 2 fractions that are chelatable, by the way. I think it will be probably associated with a reduction in risk for cardiac events. It’s been shown in the TELESTO study even though it wasn’t powered enough for detecting an improvement in survival, I think it was sufficient for me to say, “OK, that’s something we really need to do.”

Ellen K. Ritchie, MD: The problem is being able to get an older patient to tolerate the appropriate dose of chelation, which I find to be a real challenge. I have very few patients that can actually take the adequate dose of chelator to be able to be effective. That has to do with the tolerance of the medication, what happens to their creatinine clearance, and complications that they may have. These are older patients that are already on a whole lot of medicines for a whole lot of other things. You’re adding medicines that may tip the balance with their ability to deal with the side effects of them all.

I find, ideally, you want to chelate the patients who are receiving frequent transfusions, and particularly those that you’re hoping to get to transplant at some point in time. But it can be very hard to get your patient to tolerate an adequate dose.

Rami Komrokji, MD: I think it’s important to emphasize first the population of patients with MDS that will benefit probably from iron chelation are the lower risk patients. I often see that brought as an issue in the higher risk. In the higher risk, the disease tempo and the treatment take over. So, the lower risk patients are the group to consider.

I think when you put all the evidence together, there are several retrospective prospective observation studies. One randomized clinical trial that suggested benefit for patients, as mentioned, the TELESTO study, showed decreased hospitalization for patients, decreased heart failure. It’s a trend for overall survival but not significant, obviously.

In lower-risk patients I do consider iron chelation, I discuss it. I do individualize it because of the toxicity profile. Half of those patients may not be able to stay on this treatment for a year or more.

My approach to it is also if I’m introducing treatment for the disease, I don’t introduce the iron chelation at the same time. This is because then if we had adverse effects, I’m not going to be able to know which caused what. Either if patients had no other options and they are now just transfusion dependent, then I bring it. Sometimes if I have a patient that I started on a treatment and had a response and they still have evidence of iron overload from prior transfusions, I take that window of response to a treatment to do chelation because it becomes more effective, they’re not getting more blood transfusions.

I do discuss it and individualize. I don’t have a magical number of the ferritin. It has to be lower-risk patients, and that’s my approach.

Mikkael Sekeres, MD, MS: Hearing slightly different opinions on iron chelation therapy. I actually don’t chelate patients, so I’m more on the chelation nihilist side of things, because I keep waiting for some prospective study to show clinically meaningful advantage to patients. The TELESTO study, which was a good effort towards this goal, unfortunately was accruing so slowly they had to ratchet down the number of patients who were eventually enrolled which left it terribly underpowered. While it was “blinded,” in reality, ferritin levels were followed, right? For all the stones I throw at chelation therapy, it does lower iron levels. It’s a real phenomenon. That lack of true blinding impacted the number of patients who were admitted to hospitals, and those who may have had certain comorbidities actually recorded.

Ellen K. Ritchie, MD: I think I’m a nihilist if we’re ever going to know the answer, because on that study when we tried to accrue patients, it was literally impossible.

Mikkael Sekeres, MD, MS: Why was it impossible?

Ellen K. Ritchie, MD: I think that 1 of the problems was that patients that were sent to us for referral had already been place on chelation by their outpatient community doctor. In some cases, patients just were not excited about going on a trial for iron chelation, it was a hard sell for patients on this randomized trial.

Randomized trials can be very difficult for some patients because they’re interested if they’re on the treatment arm, but they’re not interested at all if there’s a non-treatment arm. So it can be difficult to get patients to commit. After working to try and get patients on this study I don’t know if we’ll ever going to have a study that will be powered to answer the question about iron chelation, which means that we’re all left to our own devices and opinions as to whether or not it’s the best thing to do. It’s a question waiting to be answered. I would love to see the trial that would answer it, but I’m skeptical that we’re ever going to get that.

Mikkael Sekeres, MD, MS: I think that we can all agree, and I’m sure you’ve all had patients as I have who come to me and all they want to talk about is their iron levels, probably as a result of a lot of direct-to-consumer marketing.

Ellen K. Ritchie, MD: Right.

Mikkael Sekeres, MD, MS: They’d rather talk about their iron levels than they would about treating their MDS. So I think we can all agree that the priority should be treating the MDS. Then, go with your conscience on whether or not to reduce the iron levels.

Transcript Edited for Clarity