Higher-Risk MDS: First- and Second-Line Therapies and Case 3 Presentation/Discussion

Transcript:

Rami Komrokji, MD: Let’s move to higher-risk disease. Thomas, if you can just set the stage, tell us about the options available.

Thomas Cluzeau, MD, PhD: It doesn’t depend on anemia or symptomatic anemia. For higher-risk myelodysplastic syndrome [MDS], the only treatment available for us in France is azacitidine. For you in the United States, it’s a hypomethylating agent [HMA], but we have no decitabine in Europe. Azacitidine improved overall survival based on the other treatment at the year 2000, but today this is the only treatment.

We could also discuss allogeneic stem cell transplantation for the frontline setting or after azacitidine treatment. For younger patients, we could also discuss intensive chemotherapy, which is still a treatment for high-risk myelodysplastic syndrome, for a subset of patients. It could be also a good treatment to undergo allogeneic stem cell transplantation, which is the only a curative treatment for this patient.

Rami Komrokji, MD: Thank you. With that, we’ll ask Dr Platzbecker to tell us how to approach a case of high-risk MDS.

Uwe Platzbecker, MD: Thank you, Rami. This is a patient, at the age of 80 years old, who presented to his primary physician with increasing fatigue and dyspnea. As a reflection of this, a blood count was taken, and the hemoglobin was 7.2 g/dL, also with neutropenia and thrombocytopenia. To make a long story short, MDS was diagnosed. This wasn’t done at our institution, but at this time he has 15% blasts. You can see also the molecular abnormalities. There are multiple mutations within the variety of allele burden.

According to the new classification, this was MDS-IB2, and the IPSS [International Prognostic Scoring System], IPSS-R [Revised International Prognostic Scoring System], and IPSS-M [Molecular International Prognostic Scoring System] are also given. There’s a clear indication, at age 80 ... at this stage for first-line HMA-based therapy, which is approved in our country [Germany] and is the backbone of treatment.

This was given, and the patient was not treated at our center at this time. The patient came to our site for a second opinion after having received 5 cycles of azacitidine. Blood counts basically remained the same. There was no red blood cell transfusion dependence. We did another assessment, and blast counts were the same. The molecular abnormality was the same. The patient, however, was more symptomatic with regard to fatigue and anemia. After 5 cycles, we considered this a stable disease, but there was no benefit from azacitidine monotherapy. After applying for venetoclax, which was approved by the insurance company. We did an add-on strategy, with azacitidine first. At cycle 6 we started with venetoclax at a lower dose than is recommended so far: 200 mg over 14 days every 28 days. This is what we observed.

What you see on the left side is that after 8 cycles of azacitidine or 3 cycles of azacitidine-venetoclax, we observed a CRi [incomplete count recovery], so a 16% blast at the beginning, then 4%. The molecular abnormalities were the same, but the patient had an increase of hemoglobin to 10.8 g/dL in bone marrow CR [complete response]…. Also, the platelet count went from 80 to 270 per mm3. After 12 cycles of azacitidine or 7 cycles of combination with venetoclax, the blast count stayed the same, but the mutation allele burden went to 0% and the STAG2 went to 1%. CR is also associated with a significant decline in molecular abnormalities.

After a combined 12 cycles of azacitidine-venetoclax or 19 cycles of azacitidine total, the patient had a deterioration of blood counts. We did a bone marrow, and the blast count was still less than 4%, but allele burden of RUNX1 and STAG2 went up. Also, the patient had a new translocation in the side genetic work-up, a 1q jumping translocation.

The point I want to make is that, No. 1, an add-on strategy with venetoclax is feasible. The phase 1/2 data, with the first author Amer Zeidan, was just published in the American Journal of Hematology. This is feasible. Second, the increase of the molecular abnormalities of RUNX1 and STAG2 were already present a couple of months before the blast count went up. What is MRD [minimal residual disease] here? MRD with bimolecular abnormalities is a future tool, especially if it’s accessible from the peripheral blood. There, you can detect earlier than the morphology when resistance to a given therapy develops. This allows them also to change the treatment before the full-blown hematologic relapse is visible.

Rami Komrokji, MD: Thank you. The blast percentage is always challenging. Sanam how do you count those blasts? What do you use? In the United States, most doctors depend on the flow for the percentage of blood. You get the aspirate, the flow, and the biopsy IHC [immunohistochemistry screening] percentage of blasts. Which 1 should we use?

Sanam Loghavi, MD: The gold standard—in the perfect setting—if you have a good specimen, is still the aspirate smear. Flow cytometry can be a hemodiluted specimen; it’s not the first tool. Other technical factors can influence the percentage that you get by flow cytometry. Fortunately, MDS blasts are typically CD34 positive, unlike AML [acute myeloid leukemia], which can be CD34 negative in a subset of cases. If you don’t have a good aspirate, a CD34 IHC stain on the core biopsy is more informative than using flow cytometry. Aspirate is the gold standard if you have a good aspirate specimen and morphology counting, then CD34 IHC.

But I want to praise the bone marrow biopsy because when I was looking at the bone marrow the way it was described, you saw every little detail and every piece of information that you need to molecularly profile this patient and to risk stratify this patient. That was perfect. It was a work of art.

Uwe Platzbecker, MD: Thank you.

Sanam Loghavi, MD: You’re welcome. But in terms of the blast count, once you get into the higher ranges, it’s not difficult to do it if you have a good specimen.

Transcript edited for clarity.