Additional Updates in Second-Line Treatment of Lower-Risk MDS

Video

Experts summarize recent updates on other approved or emerging second-line therapies for lower-risk MDS.

Transcript:

Rami Komrokji, MD: There are ongoing efforts on combinations. There are studies looking at luspatercept and lenalidomide. In Europe they’re looking at the combination of luspatercept with an ESA [erythropoiesis-stimulating agent]. We reported at ASH [American Society of Hematology] Annual Meeting a very small case series at Moffitt Cancer Center that treated a combination. We can see if patients had a secondary filler, so if luspatercept stops working, you add ESA. You can recapture the response in one-third of the patients, which is interesting. There’s more to explore, but we have a new option for our patients after 10 years of no other approval for a drug. Thomas, part of this is led by the French group. Tell us about IDH1 and IDH2 inhibitors, particularly in lower-risk disease.

Thomas Cluzeau, MD, PhD: There are 2 clinical trials ongoing in lower-risk and higher-risk IDH1 and IDH2 MDS [myelodysplastic syndrome]. In the low-risk disease, it’s a very small subset of patients, but these patients exist with IDH1 or IDH2 mutation. In this clinical trial, we try to evaluate a targeted therapy like ivosidenib in IDH1 and enasidenib in IDH2 in monotherapy in this subset. At ASH, Marie Sebert, MD, PhD, and Lionel Ades, MD, PhD, presented the first results. In this subset, not a lot of patients were included at this time, but we showed there was some response. It could be interesting to treat this patient with targeted therapy. We’re waiting for the results of this clinical trial.

Rami Komrokji, MD: Thank you. Guillermo, talk about hypomethylating agents [HMAs] and lower-risk disease and also a little about oral hypomethylating agents. You’ve done a lot of work to get them approved. The lower-risk patient is really a US phenomenon, but tell us a little more about what you think about hypomethylating agents, and bring us up to speed on oral hypomethylating agents.

Guillermo Garcia-Manero, MD: There’s a division between Europe and the United States. It’s all based on how the registration trials were designed. In the United States, both azacitidine and decitabine were included in patients with lower-risk disease. But because of the data from the earlier studies with oral azacitidine, CC-486, is now approved for acute myeloid leukemia [AML]. We saw that patients with a low PK [pharmacokinetics] profile had significant activity. Then we thought we could use this so-called attenuated dose as carriers of decitabine-azacitidine. These are incorporated in the American NCCN [National Comprehensive Cancer Network] Guidelines as part of therapy for patients with lower-risk disease. It’s common to use these drugs. You tend to use them not in patients we’ve seen. It’s more for patients with bicytopenias and refractory anemia who fail an ESA, maybe lenalidomide, maybe luspatercept. I’m not saying that this is something we do up front in patients with lower-risk disease, but as second-line therapy, this is commonly used in the United States.

Can we study this systematically? Yes. This year we’re going to have a final report of the randomized study that we did in North America. This is a center representative study that we did with a low-dose HMA. We’ll see what that data looks like. We’re starting to see data with oral hypomethylating agents. We have 2. One is the oral decitabine cedazuridine. This is approved in the United States for the same indication as IV [intravenous] decitabine. It’s being studied in AML in Europe. This drug is approved. We commonly use it. It’s a nice story to have an oral hypomethylating agent. It’s being studied in lower-risk MDS.

Lastly, Astex Pharmaceuticals had subset analysis known as the ASCERTAIN trial. That was a phase 3 registration trial of oral decitabine with nice data. I showed data at ASH from phase 1 of the low-dose oral decitabine in lower-risk MDS. In pretreated patients, that looks positive. There’s now a phase 2 randomized study. In parallel, we have CC-486. All of us worked together on that. That was the first drug. We were so excited with it the randomized study. But because of design issues and because the patient population enrolled was negative, there was excess death. That study has been redesigned. I’m pretty sure everybody here is part of that randomized study. It’s possible that we may have positive data for CC-486 in a few years.

There’s a third agent that’s going to be very important, a drug known as ASTX030. This is oral azacitidine with cedazuridine, and the goal is to render an oral azacitidine with the same PK of IV subcutaneous azacitidine. That’s going through very advanced phase 1 studies. If that moves fast, we may have a true PK-equivalent oral ESA. These drugs are still the backbone. We’re going to hear soon about high-risk disease. It’s going to be very nice to have an oral compound in a lower dose for a specific subset of patients with lower-risk disease. I’m not saying this is a blanket statement. We’re trying to figure out who benefits from this type of intervention. It will be nice to have.

Rami Komrokji, MD: Thank you. I agree. In the United States, oral decitabine is now available. The message always is oral decitabine is 100% bioequivalent to the IV. They can be used interchangeably. The available azacytidine, which we use for maintenance and AML, isn’t equivalent and shouldn’t be exchanged to be used. We’ve seen cases where individuals are using the oral azacitidine that’s only for the maintenance AML.

The other point is that it’s easier for patients who are using it for higher-risk or lower-risk diseases, but an oral pill doesn’t eliminate the need for monitoring patients the same way we do with decitabine. Those patients still need to come to the clinic every week and check their blood counts. They can get myelosuppression. Particularly during COVID-19, a lot of patients shifted to total therapy that’s oral, rather than coming to the clinic a few days in a row. Maybe we’ll finish the lower-risk MDS by talking a little about the next drug that Dr Platzbecker is working to get approved.

Uwe Platzbecker, MD: Which 1 was that?

Rami Komrokji, MD: Of the 10 you’re working on, pick 1. At ASH I presented data on the imetelstat. You’ve been leading phase 3 of the study. Can you tell us a little about imetelstat?

Uwe Platzbecker, MD: Imetelstat was pioneered in MPNs [myeloproliferative neoplasms]. There were 2 back-to-back to papers in the New England Journal of Medicine 8 or 9 years ago in patients with myelofibrosis and ET [essential thrombocythemia]. The driver to use it there was that the drug is a telomerase inhibitor. By doing so, it’s cytotoxic. It’s also been shown to be very active in AML in mouse models. The drug was further developed in myelofibrosis. It’s also active in the phase 2 IMerge trial in lower-risk MDS patients who are non-del(5q), lenalidomide and HMA naïve but heavily transfusion-dependent and ESA refractory. This phase 2 trial has been published a year ago. It showed a transfusion independence [TI] rate of more than 40%, and 29% of the entire patient population had a TI rate of more than 1 year. For a drug that you give every 4 weeks for over 2 hours as a single IV injection, that’s pretty impressive.

On the other hand, it’s a limited number of patients, only 38, which isn’t many; that’s highly selective. But this was the driver for the phase 3 program, which has been finished with regard to recruitment. The data became available in January, so we can determine whether to open a bottle of champagne for our patients but also ourselves. The jury is still out. But the drug, apart from its smaller toxicity, is pretty well tolerated. The presentation I gave on behalf of the coinvestigators is a subanalysis of patients with SF3B1 mutations, with a TI rate of more than 1 year. Also, molecular changes like reduction and allelic burden suggest that the drug has disease-modifying activity.

Transcript edited for clarity.

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