Transcript:Mikkael A. Sekeres, MD, MS: Rami, let’s say you have a patient who has lower risk MDS, and who has anemia. Can you talk a little bit about some of the treatment options, including immunomodulatory agents, or immunosuppressive therapy, or growth factors?
Rami S. Komrokji, MD: The first step we look at, which we discussed, is, are they symptomatic, do they need treatment or not? Once you think that you need treatment to restore hematopoiesis, the next step is it an isolated anemia, pure anemia only, or are there also cytopenias? Sometimes other cytopenias might be the indication for treatment, which is not common, but they sometimes could impact your choice of the treatment for anemia, as well. So, if the platelets are 50 or 60, they probably don’t need a treatment for their thrombocytopenia per se, but they may impact your choice of the treatment for the anemia. I think if somebody is anemic, the first step, as mentioned, is for the transfusion burden to be acceptable to look at; if they are getting blood, the endogenous serum EPO (erythropoietin) level needs to be acceptable. And if the EPO level is less than 500, most times those patients have a relatively good chance of response to erythroid-stimulating agents (ESA).
So, that’s usually the first step. I think the summary of the use of ESA agents—whether one is using short-acting or long-acting—is probably about almost equivalent. It’s reasonable to give a good trial of 8 to 12 weeks. If there is a response, you continue. If it’s not, then you stop. A starting dose should be probably equivalent to 40,000 of EPO short-acting, and then could be up to 60,000. Europeans tend to go more with the 60,000, then de-escalate down. One step would be adding a growth factor like GCSF (granulocyte-colony stimulating factor), and that’s really been in European studies, that they have been shown to double the erythroid response so it’s not for neutropenia, it’s for the anemia. With that, responses have been reported to be doubled. The studies did this on a daily basis. In real practice, it’s very difficult. Like if I try it, I try it once a week. Every now and then, that’s a trick that could work, but the bone pain and the limitations of doing it on a more frequent basis really make it not an optimal choice for all patients.
Once we decide that the ESA did not work or if the patients had a response and then there was an ESA failure, then we look at other options. Obviously, in the lower risk, the currently available options are immunosuppressive therapy, lenalidomide, and hypomethylating agents. I still think that if there is a clinical trial, it is absolutely okay and acceptable to be the first step of the ESA failure. It doesn’t have to be one of the currently approved drugs. So, if we have a study, we consider the patients to study. The selection for ATG (anti-thymocyte globulin), cyclosporine, or immunosuppressive therapy—which is really under-utilized treatment in MDS—depends on most likely patient’s age, the transfusion burden, and HLA-DR15 status. This is what at least the NIH (National Institutes of Health) model suggested, that patients younger than age of 60 probably have the highest chance of response. And I definitely think that’s valid. In our experience—and we both have contributed to studies using rabbit ATG, equine ATG—I think also it matters where it is applied in the disease. It’s usually much higher responses in the first couple of years of the disease. Later on, you probably see less. So, I think it’s a very acceptable choice to think of, in younger patients, the advantages. It’s one course of treatment. Patients could get durable responses for a year or 2, and you could get TI (transfusion independence)-leading responses.
We tried recently to look on the molecular mutations and their impact to response to ATG cyclosporine, and basically those that had SF3B1 mutation actually had less chance of response. Presence of mutations did not predict much of the response—yes or no—but it did predict a little bit less durable responses and higher chance of transformation, regardless of the mutation. Lenalidomide use of at least deletion 5q, everybody knows about it. It’s the standard of care, 67% transfusion independence. I think that’s set, now that we could use it. The question is how to use it in non-deletion 5q, and I think we have several studies that showed around 25% to 30% responses of transfusion independency with non-deletion 5q. So, we look at patients who are purely anemic. I’ve had patients with platelets of 50, non-deletion 5q; I may not go for lenalidomide because I think thrombocytopenia baseline could predict a response for those patients. I look at patients that are just purely anemic, and, if that’s the case, I think lenalidomide is a reasonable option where you could get 30% responses.
We also try to look at the sequence of using those therapies. We use lenalidomide before hypomethylators or not. Again, this is single institution experience. We are also trying to look at it within the MDS Consortium. The bottom line, many, if not all of the randomized studies that we’ve done, patients did not have hypomethylating agents on the study before lenalidomide. So, we looked at the patients that got hypomethylating agents first and then lenalidomide, and the responses were much less. In our experience, it was 13% versus lenalidomide first. The responses were in the range of 30%, which has been reported. Azacitadine responses, where there were first-line or second-line, were the same. In our mind, when we sequence those—if patients are purely anemic and I’m going to use lenalidomide—I will use it before a hypomethylating agent. Finally, the hypomethylating agents—and to be the default for many patients when all other options did not work for anemia—if they have thrombocytopenia or neutropenia, probably we have a choice. What we have learned also recently is that there is some encouraging data about shorter courses of use of hypomethylators. And at the time of hypomethylator failures, even in the lower risk, the outcome is poor. So, we tend now, a little bit, to be more conservative about using them.
Mikkael A. Sekeres, MD, MS: It was a good description of the different types of therapies. I want to pile on a little bit about the use of ATG. We did both participate in a phase II study in the United States in which we basically enrolled patients who had refractory cytopenia with multilineage dysplasia, so not your textbook patients who have a hypocellular bone marrow. And we didn’t enroll based on HLA-DR status, and we had a response rate of 32%. That was eerily similar to the European experience, which is a randomized phase III study in which patients got ATG and cyclosporine versus supportive care—and they had the identical response rate. To me, it always validates a response rate if you’re seeing it in two different continents in two different patient populations. What was really neat about our ATG experience is that a patient is admitted to the hospital for 4 days, is then discharged on a prednisone taper for 30 days to avoid the serum sickness reaction, and then is on almost homeopathic doses of cyclosporine long-term. And you will see these folks who basically had to endure a 4-day hospitalization to then get, on average, about a year-and-a-half of response.
So, the classic teaching about looking for a hypocellular marrow I think really doesn’t necessarily hold with ATG. My ideal patient is someone who, at age 70, says to me, ‘You know, the funniest thing, 2 years ago I was diagnosed with having a low thyroid function, and I started to develop this eczema.’ So, other stigmata of autoimmune conditions that can signal to you that they may have an autoimmune destruction of the bone marrow, as well, that’s contributing to their MDS picture.
Jamile Shammo, MD: I would agree with that, and I typically get a PNH clone testing as well in people who have low-risk MDS and, possibly, hypocellular because that, too, would support utilization of immunosuppressive therapy. Now, I haven’t used ATG cyclosporine in older individuals. I might try cyclosporine as a single agent, and I actually have had some reasonable successes with that. I realize the combination is better than either one alone and it’s been shown in trials, but that would be the other thing I would do.
Ellen K. Ritchie, MD: It’s a challenge in the really older patients in their 80s, for example, to use ATG so I have also used cyclosporine alone in some of those patients and have done well. I think it’s important to try and avoid—especially in lower risk patients—going to a hypomethylating agent for as long as possible because once a patient fails a hypomethylating agent, we really don’t have a good solution for them. So, I always worry about putting a lower risk patient on a hypomethylating agent because I’ve already played my deck of cards. All I have is a possible clinical trial drug at the end of it that may or may not work. You play your whole hand and you have not a whole lot left. So, I really try and avoid, in those lower risk patients, moving to the hypomethylating agent for as long as I can.
Mikkael A. Sekeres, MD: I think we’re emphasizing the same theme here. We have three drugs FDA approved for MDS, and then there are two others that we use off label, and that’s the erythropoiesis stimulating agents or ATG. We think about MDS, particularly lower risk MDS long-term, and don’t want to spend all of our drugs up front so we tend to take the approach of offering clinical trials to our patients when they’re available because we’ll always have the other drugs available to us.
Transcript Edited for Clarity