Video

Recent Data Updates in Higher-Risk MDS

The panelists touch on emerging data in the higher-risk MDS space, including updates presented at ASH 2022.

Transcript:

Rami Komrokji, MD: A lot of studies have been conducted in the past in higher-risk MDS [myelodysplastic syndrome]. There was 1 editorial calling it the “boulevard of broken dreams,” trying to get a new drug approved for higher-risk MDS. But now we have some promising drugs. Let’s have each of us cover 1 of them. Guillermo will start by discussing venetoclax combinations with hypomethylating agents [HMAs].

Guillermo Garcia-Manero, MD: We just completed the phase 3 trial known as VERONA. It’s going to be really important. This follows the VIALE-A study in AML [acute myeloid leukemia], and it has over 500 patients. We’re all very familiar with venetoclax. Some colleagues fear cytopenia and so forth, but we just published a paper in The Lancet Haematology showing a low mortality rate up front. It’s cytopenia, so you’re stepping up a little compared with single-agent azacitidine. But the rate of response was over 80%, and CR [complete response] was over 35%. The duration looks positive, meaning median survival. I don’t have a magic ball. We’ll see what happens with the study. What’s happening that’s very important is that new phase 3 trials are pivoting in survival, not just responses. Overall survival is key, and we have to wait. It’s not innovative therapy. We’re just using a lower dose of the venetoclax. We’ll see if this works in high-risk MDS as it worked in AML.

Rami Komrokji, MD: Absolutely. In that case, we’re looking at different strategies up front vs add-back strategy, and the question will be always be the sequence of those. If it improves survival up front, then that’s more important. But there could be some role.

Guillermo Garcia-Manero, MD: In the paper I mentioned from The University of Texas MD Anderson Cancer Center, there are 2 cohorts. People are focusing on the first cohort, but we reported on the HMA failure cohort. Improvement is marginal. I heard some people saying, “Why don’t we reserve venetoclax for the second line?” I don’t think this makes sense with the current data unless there’s a switch in some of these mutations. Eventually, you’ll pick up an IDH1 or IDH2 mutation that wasn’t present, or maybe you didn’t do the NGS [next-generation sequencing]. We know that those patients respond well to venetoclax in case you don’t have the drugs Thomas Cluzeau was talking about, like the IDH1 and IDH2 inhibitors. I’m not saying it’s futile to add back venetoclax, but I don’t think this is the solution for HMA failure in high-risk MDS. It’s a little benefit. I’d prefer to use the combo up front rather than later. If you start with a single-agent HMA, then there’s nothing wrong with what Dr Platzbecker is saying.

Rami Komrokji, MD: Even in the up-front setting, we may identify this as a good bridge for transplant to do the combination. In our data, there were small numbers. But when you look at azacitidine-venetoclax going to transplant, 2-year survival is almost 90%. There’s a lot of selection bias, but it looks very promising. There are some data showing that it may overcome the ASXL1 mutation resistance that we see for hypomethylating agents.

Guillermo Garcia-Manero, MD: You bring up a very good point. We’re going to hear about the other approaches, but I don’t think we should say it’s going to be 1 for everybody. You mentioned something key: the molecularity of this disease is such that we’ll be able to say—this is already happening—that there may be specific molecular subsets that do particularly well with a doublet with venetoclax. Maybe other medications do well with some of these other interventions. That’s very important.

Rami Komrokji, MD: The paper you published recently was amazing, showing that the components of the bone marrow—like the CMPs [common myeloid progenitors]—could predict response. You have different phenotypes. That can guide you for the next line of therapy because you can predict that. Thomas, talk a little about sabatolimab?

Thomas Cluzeau, MD, PhD: During the [American Society of Hematology Annual Meeting, or ASH], the STIMULUS clinical trial was reported. This was a phase 2 randomized clinical trial with more than 100 patients. We continue with the “broken dreams” because there was a long median follow-up, of about 2 years. There’s no significant in comparative remission and no significant improvement in progression-free survival or overall survival. Unfortunately, this study is negative in this setting.

Rami Komrokji, MD: With sabatolimab, there was a lot of excitement about the mechanism of action. It’s a dual mechanism of action. It engages the T cells. It targets leukemia stem cells. There was a lot of excitement about the preclinical data. Unfortunately, the studies presented at this meeting aren’t showing activity in higher-risk MDS, or at least the way we are doing it now.

Uwe Platzbecker, MD: But there’s a completed phase 3 study that will be reported. The jury is still out. It could still be positive.

Rami Komrokji, MD: Another drug to talk little about is magrolimab. Uwe, bring us up to speed on magrolimab.

Uwe Platzbecker, MD: Magrolimab is a CD47 antibody, and CD47 is a so-called don’t-eat-me signal. It’s expressed in red blood cells, but it’s also overexpressed in myeloid progenitor cells. By capturing this—macrophages, monocytes—we can target leukemic cells. That’s the concept. It was pioneered in patients with lymphoma with the addition of rituximab, sensitizing lymphoma cells to rituximab. There’s a lot of evidence from phase 1 and 2 trials of azacitidine-magrolimab and azacitidine-magrolimab-venetoclax for MDS and AML. Some of these trials were reported at ASH, or there’s an update. There seems to be a decent activity in TP53-mutated cases. Randomized trials are running, and the readout is expected.

Transcript edited for clarity.

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