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Treating a Patient With Lower-Risk Myelodysplastic Syndrome
Amer Zeidan, MBBS, Yale University, New Haven, Connecticut highlights his treatment choices for the case of a 74-year-old patient diagnosed with lower-risk myelodysplastic syndrome (MDS).
Transcript:
Hi everyone, my name is Amer Zeidan, I'm an associate professor of medicine at Yale University, where I direct the leukemia program and the hematology early therapeutics research at Yale University and Yale Cancer Center.
I have a patient in her mid-seventies who had lower-risk MDS without an increasing in blasts, but [with] an increase in ring sideroblasts, which is an accumulation of iron in the mitochondria surrounding the nucleus—more than 1/3 of the circumference to call it ring sideroblasts. More than 15% of those abnormal erythroid precursors were present. So, the patient was classified as MDS with ring sideroblasts. And indeed, she did have the SF3B1 mutation, which is associated with ring sideroblasts in many patients with lower-risk MDS.
The patient initially responded to erythropoiesis-simulating agents (ESAs). She was expected to respond very well because she had a low erythropoietin level and was not deeply dependent on red blood cell transfusions. However, as most patients do after initial response to ESAs, she stopped responding after 1.5 years, which is around the median time that most patients would stop responding to erythropoiesis-simulating agents. And this is a point at which I met with the patient.
At that point, what I did is I repeated the bone marrow biopsy to confirm that the patient had not progressed in her disease in terms of increase in the blasts count or new clonal evolution, evidenced by new chromosomal abnormalities or new mutations. She did not have any of this. So, it was secondary failure of ESAs. And the question became what do you do at this point?
Of the 4 treatment options I entertained, we would not consider bone marrow transplantation at this point because she had no evidence of clonal evolution, and her white cell count and platelet count was still preserved and she did not have higher risk by the IPSS-R or the molecular IPSS.
The options I discussed with the patient included lenalidomide and hypomethylating agents. Both of those can worsen the platelet count and the neutrophils. They can cause cytopenias; they can cause significant fatigue, as well as rashes, GI upset, et cetera. I tend to use lenalidomide in patients who have deletion 5q, although it does have activity in patients without deletion 5q. It's given daily. It's an expensive drug, and as I mentioned, can cause side effects in many patients. So, I tend to reserve it after luspatercept, which was the drug I chose for the patient.
The reason why I did not use hypomethylating agents is again, I tend to keep these as a last option for lower-risk MDS patients because of the cytopenias that can be induced as well as the other side effects that can come with these agents. If I use hypomethylating agents, I usually use a lower dose or 3 days of decitabine or azacitidine. And that's in an effort to try to mitigate the risk of neutropenia or thrombocytopenia.
I recommended luspatercept, which is the on-label indication for patients who have ring sideroblasts after failure of ESA in patients who are anemic with lower-risk MDS. And especially, when they have SF3B1 mutation. The response rate [of luspatercept] in a trial in terms of transfusion independence was around 38%. The median duration was around 9 months. However, some patients responded much longer. The side effects are generally mild, mostly fatigue that tends to wear off in the first few cycles. And the rate of discontinuation or serious side effects is very low.
The drug is given subcutaneously every 3 weeks. This is what we started for the patient, and she became transfusion-independent. Another option would be immunosuppressive therapy. However, older patients don't tolerate ATG, or antithymocyte globulin, very well. So, if I use it, I tend to use cyclosporine by itself. Clinical trials also would be an option.
One, I think, very interesting option is imetelstat, which was shown in the IMerge study to lead to responses in patients after ESA failure of around 40% with a median duration of response of 50 weeks, regardless of the presence of ring sideroblasts. However, this is still an investigational agent. It potentially could be an option for this patient in the future, if she stops responding to luspatercept. Thank you so much for listening.
