How I Treat: An Elderly Patient With Lower-Risk, Ringed Sideroblastic Negative MDS

Aditi Shastri, MD, Montefiore Einstein Comprehensive Cancer Center, New York, New York, discusses the treatment plan she recommends for an elderly patient with lower-risk, ringed sideroblastic negative myelodysplastic syndrome (MDS) who has become treatment-resistant to erythropoiesis-stimulating agents and luspatercept.

Transcript:

Hello everybody. My name is Aditi Shastri. I am an associate professor of oncology and attending physician at the Montefiore Einstein Comprehensive Cancer Center in the Bronx in New York. I look forward to sharing an interesting patient case that I have here with you.

The patient in question is someone I [have] known for the past few years. When I started taking care of her in 2020, she was an 81-year-old woman who lived alone and had hypertension, hyperlipidemia and depression. She was sent to me from her primary care physician with transfusion-dependent anemia. To cut a little bit of a long story short, she presented with anemia. She had mild thrombocytopenia and normal white blood cell counts. She had an extensive anemia workup to rule out nutritional causes of anemia, such as iron deficiency, B12, folate. They checked an [serum protein electrophoresis] SPEP; they evaluated her for micronutrient deficiencies like copper; they did an autoimmune workup. Multiple causes of anemia were ruled out.

The patient was slowly becoming transfusion-dependent, and at the time that I met her, she really needed 1 unit of [packed red blood cells] PRBCs every 2 weeks. At that point, after reviewing all the data, as all good hematologists do, I said, "Okay, let's go ahead and do a bone marrow aspiration and biopsy, send a next generation sequencing profile, check cytogenetics and [fluorescence in situ hybridization] FISH." We got some interesting findings back.

The biopsy did show us that our patient, although her counts were low, had a slightly hypercellular marrow with myeloid hyperplasia, had abnormal megakaryocytes, had reduced erythroid progenitors, and had 1% blasts on the bone marrow biopsy. Her cytogenetics [showed] a loss of the X chromosome, which can happen as people age. The next generation sequencing profile demonstrated a mutation in the splicing factor U2AF1 with a 33% variant allele frequency [and] a [BCL6 corepressor gene] (BCOR) mutation with 11% variant allele frequency.

I went ahead and diagnosed her with low-risk myelodysplastic syndrome (MDS), which was a non-ringed sideroblastic subtype. I would like to note when we talk about the ringed sideroblastic versus non-ringed sideroblastic type [that] although we do have a lot of molecular and epidemiologic data that tells us that patients with ringed sideroblasts are the ones that really have a better prognosis, they have the SF3B1 mutation. An important point to note is that 75% of patients that we see in our clinical practice with low-risk MDS are ring sideroblastic negative. They are vulnerable to poor clinical outcomes. So, this is something we should keep in mind when we see our patients in clinic and offer treatments.

I did some more work-up to see what the right choice of therapy for her at this time [would be]. What I noticed was her [erythropoietin] EPO level was low. Her EPO level was 70 milliunits/mLs. That told me that her EPO level was less than 500 unit per liters. We started her on erythropoietin, 40,000 units weekly, subcutaneous injections. And after 8 weeks or so, she started having a really good response to therapy. She became transfusion-independent. This improved her quality of life; she started feeling better. She had a sustained response for about 9 to 10 months. This period of time was good for her. It gave her energy back; her fatigue levels went down. She told me she could do trips with her friends.

However, at the end of this period, she became transfusion-dependent again, this time a little bit worse requiring 1 unit of PRBCs per week. However, her platelet counts continued to stay low normal in a range of 100,000 to 240,000 [platelets per microliter of blood]. At this point, we [thought]: Okay what do we do? To give some historical context, I [have] know[n] this patient for 4 years now, this was the year 2022.

I began her on luspatercept, which was at that point approved, not yet in a frontline indication, but after failure of [erythropoiesis-stimulating agents] ESAs. We started her on luspatercept and quickly accelerated the dose as is recommended from 1mcg/kg to 1.33 mcg/kg. She had a nice and sustained response to therapy after 4 months of treatment. This response was well-sustained until early 2024. Early this year she had become transfusion-independent again, she had some side effects related to therapy which we could manage quite well with just medical management. She had grade 1 fatigue. She had some worsening of her hypertension, which required adjustment of her anti-hypertensive medication. But we were able to manage these side effects quite well, and she was able to continue her treatment.

Now we come across the dilemma this year that she's starting to lose her response to therapy again. I noticed that her transfusion requirements were slightly worse than even before. She needs sometimes 4 or more units of PRBCs; maybe every week or so she needs 1 unit, definitely 4 or more over an 8-week period. Keep in mind, she's lost response to erythropoietin, as well as luspatercept. Now we are in this dilemma as to what to treat her with. We did another bone marrow biopsy, which continues to show this hypercellular marrow with myeloid predominant disease, many more dysplastic megakaryocytes than before, but no significant increase in blasts. She continues to have reduced erythroid progenitors.

At this point, our patient has lost response to the ESAs and luspatercept. Now that we're in 2024, we're lucky that we have a brand-new FDA approved option, which is imetelstat for low-risk MDS. This is now FDA approved for a low-risk MDS patients that have transfusion-dependent anemia, and we can use it for patients that have this transfusion-dependent anemia requiring 4 or more (red blood cell) RBC units over an 8-week period that have previously lost response to ESAs. This is exactly where my patient is at.

One point to note is we did say at the beginning of the case that she is ring sideroblastic negative. Patients that were ring sideroblastic negative as well as ring sideroblastic positive have both had a response to therapy with imetelstat. As we can see from the data that came from IMerge and the phase 3 study for imetelstat that aided this FDA approval, we also know, given that it's a novel mechanism of action, it's [also] a telomerase inhibitor [and] it could potentially have disease-modifying properties as well, that could reduce the chance of her having leukemic progression and reduce the burden of the mutations that she has as well.

Learn More About This Case Here:

How I Treat: Myelodysplastic Syndromes