The Role of Hypomethylating Agents and Transplantation

Amy DeZern, MD, MHS: In terms of other patients who have lower-risk disease, tell me a little about how you manage those patients specifically and if they have ring sideroblasts. Maybe this is a very small subset compared with the broad lower risk I just mentioned.

Rami Komrokji, MD: There has been quite an interest recently in the MDS [myelodysplastic syndrome] with ring sideroblasts, or SF3B1 mutation, as we learn more about that category of the disease. Those are unique, and we started talking about the heterogeneity of the disease. The MDS ring sideroblasts, or SF3B1, is a unique subtype of MDS with a distinct mechanism of ineffective erythropoiesis and treatment. I looked recently in our database, looking at the patients with MDS ring sideroblasts; around 16% to 20% of the patients with MDS will have ring sideroblasts. Around 18% of the patients in our database at least had an SF3B1 mutation, so it’s not that uncommon. The diagnosis by the WHO [World Health Organization] was changed. Historically, if we had more than 15% ring sideroblasts, we called that MDS with ring sideroblasts. Now if we have more than 5% ring sideroblasts, or we have an SF3B1 mutation, then those can be called MDS with ring sideroblasts, and the WHO goes into unilineage dysplasia or multilineage dysplasia that, in reality, doesn’t matter. Once they have SF3B1 mutation, the behavior is probably the same.

There’s a new proposal by International Working Group, a paper by Luca Malcovati that was just published in Blood—a very nice paper actually—saying that SF3B1-mutant disease should be its own separate category with certain criteria. Those patients, in general, have favorable outcomes, good overall survival, low rate of acute myeloid leukemia transformation but ongoing ineffective erythropoiesis that most of those patients will end to be transfusion dependent over time. In our experience, almost half those patients, when we see them referred to us, are already transfusion dependent. Over time most of them become transfusion dependent, and the outcome in our experience for patients who are transfusion dependent is worse.  

Historically, we treated them again with all the available options, like ESAs [erythropoiesis stimulating agents]. Patients actually do pretty well with ESAs and have good responses. There are responses to lenalidomide, even in the 5q, probably sometimes in combination. In our experience, there is a little less response to hypomethylating agents than other subtypes. Also in our experience, albeit a small subset of patients, there are no responses to immunosuppressive therapy like ATG [anti-thymocyte globulin] or ATG-cyclosporine combination. I tend to shy away from immunosuppressive therapy in patients with ring sideroblasts, or SF3B1 mutation, and use the hypomethylating agents as a last-ditch effort. If I run out of everything, start with ESAs, and I think about which we’ll be probably discussing, we’ll spend a little more time talking about luspatercept. Luspatercept is probably becoming positioned as the first line for patients with ring sideroblasts after ESA failure.

Before we discuss more into the luspatercept and the excitement about a new drug approved for MDS, maybe we can talk a little more about the higher-risk disease and role of transplant because, no doubt, the transplant remains the only curative option for those patients. What’s your take on transplant, its role, and when to consider it?

Amy DeZern, MD, MHS: I wear 2 hats in our myeloid group, and I am an active transplanter. I’ll state that disclosure at the beginning. Your point is well taken. Azacitidine, ESAs, luspatercept, and all these other drugs that we’ve mentioned that have really advanced care for these patients are not a potential path to cure. I am always very careful to couch transplant like that to an MDS patient and their families. In allogeneic bone marrow transplant, which can be a bone marrow stem cell source or a peripheral blood stem cell source, we tend not to use an umbilical cord source in MDS. It is a potential path to cure, but it is really not for every patient. I do personally believe that any MDS patient, certainly with higher-risk disease, should have at least a onetime consultation with an active transplant physician to evaluate whether they truly are a candidate. I like to explain to a patient that there are disease-related factors, there are transplant-related factors, and then there are patient-related factors that bring us to the ultimate decision as to whether we proceed with transplant.

The higher-risk patients really must achieve a hematologic remission. I firmly believe that all the data support that you have to have a measure of disease control for a patient with higher-risk disease, usually evidenced by decrease of the blasts to less than 5%, hopefully elimination of the cytogenetic abnormality, and decrease the allele frequency of their molecular mutations. To feel as if you’re offering them a therapy that truly is high reward because it comes with high risk. That brings us to the next issue. The majority of transplant patients are of an age range where we consider only reduced-intensity conditioning regimens, but they’re still quite challenging. You have to ask a patient to take out a year of their life, even if they’re going to have a successful transplant outcome, because the potential toxicity is quite high.

Then there are patient-related factors. They may not want to do that. They may be more comfortable with transfusional support or hypomethylating support with response, or feature a clinical trial. They’re very nuanced discussions, but that’s the reason early referral to ask the question and think about a donor for an individual patient could be really important. Those are complex decisions, and that’s probably as much as we can say about it for that today.

Transcript edited for clarity.