Case 2 Discussion and Considerations for Second-Line Treatment Selection

Transcript:

Rami Komrokji, MD: Sanam, tell us about MDS [myelodysplastic syndrome] with ring sideroblast [RS] in SF3B1 mutations. Where is the story going?

Sanam Loghavi, MD: That’s 1 of the points that I wanted to bring up. When you mentioned that some of these complete molecular profiling tools aren’t available in resource-limited settings, there are morphological clues to some of these molecular alterations. A prime example is SF3B1 mutations. For resource-limited settings, it would be very helpful for the pathology report to include that there’s a high percentage of ring sideroblasts. Obviously, these patients have better prognosis. We have an approved therapy for patients with SF3B1 mutation.

This is 1 area where there are subtle differences in the newer classifications, the ICC [Integrated Comprehensive Care] and the WHO [World Health Organization]. The ICC recognizes only cases with SF3B1 mutation under this subclassifying category, whereas the WHO recognizes other MDS with ring sideroblasts without SF3B1 mutations. In this instance, ICC did a better job in classifying these, because the biology of SF3B1 is different from other surprising factors that may also give you some increase in ring sideroblasts. Here, it’s very important for the report to include the ring sideroblasts, to include that there’s an SF3B1 mutation with a high variance, a low frequency of 20%, more than 10%. That gives you the tools you need to deploy appropriate therapy for this patient.

Rami Komrokji, MD: RS is a prevalent subtype in MDS. It may not be the most common, but those patients have survival estimates in years. We see them in our practice, they become transfusion dependent, and they’re in need for treatment. Maybe we can spend some time talking about the therapy available for those patients, particularly luspatercept. It was very exciting for the field to have a drug approved for patients with MDS after almost 10 years of a drought with no new drugs approved. Uwe, you led a lot of the original studies with luspatercept. Tell us about the drug, how it works, and a summary of your work.

Uwe Platzbecker, MD: Do we have 2 hours?

Rami Komrokji, MD: Three hours is fine.

Uwe Platzbecker, MD: In the beginning, luspatercept was considered to be a bone drug because it’s a ligand trap for GDF8, GDF11, and minor binding of activin, and this was the driver to develop this drug. Rami, you and others developed it in postmenopausal women with bone disease and osteoporosis. As a matter of serendipity, it came out that hemoglobin levels rose in these patients. Then it was developed as a blood agent. The primary ligand, which is supposed to be the driver of ineffective earth poison in the bone marrow of patients MDS with, is GDF11. It’s not as simple as I say it, but this was the backbone for exploring luspatercept in the phase 2 program, in a bunch of low-risk patients with MDS who are ring sideroblast positive or negative. In the end, RS-positive patients responded better than the others.

This led to the phase 3 program. Now we have approval for luspatercept in RS-positive patients. More than 90% of the study population in the MEDALIST trial were SF3B1 mutated. But not every patient was restricted at this stage. Also, non-SF3B1-mutated patients with MDS-RS are eligible for luspatercept therapy, and they respond. Of course, they have a different biology, as you mentioned. The disease evolution needs to be captured by a better or more sophisticated surveillance strategy than with the SF3B1, but they also respond. That’s very important.

Lastly, we also had a press release by BMS [Bristol Myers Squibb] just a couple of weeks ago about the COMMANDS trial. This is a head-to-head comparison of EPO [erythropoietin] vs luspatercept in patients with ring sideroblastic phenotype who are ESA [erythropoiesis-stimulating agent] naïve. That was also positive. We don’t know more so far. The primary end point has been met, and this potentially opens the avenue that luspatercept may become a first-line therapy for a still-to-be-defined subset of low-risk patients with MDS.

Rami Komrokji, MD: Thank you for that summary. Guillermo, when do you think we’re going to be using luspatercept down the road?

Guillermo Garcia-Manero, MD: Everything that Uwe said is correct. One detail that I’ve experienced that’s also reflected on the trials is that it appears there’s an association with the transfusion burden and response. I haven’t seen the data in the frontline COMMANDS trial, but those are earlier than first-line patients. It’s clear that in second-line patients who have a little lower transition burden do better in terms of treatment response.

You’re asking why I’m bringing this point up. Is this in our practice? It’s imprinted that you will use this ESA for every patient, even if the patient isn’t clearly responding. We think the patient is stable. I’ve seen patients who have been receiving transfusions for many months and are still on an ESA. I’m wondering if these data from the MEDALIST trials should push us toward considering or maybe asking about the proper time to stop the ESA and move to second-line therapy. I don’t know if there’s a good answer, but heavily transfusion-dependent patients on ESA may not make clinical sense, and perhaps [we should] adopt drugs like luspatercept a little earlier in second line. This is why it will probably translate into what we mentioned, that this press release suggests that the COMMANDS trial is positive in the front line. Maybe the transfusion burden or at least the history of transfusion should be lower.

This is very exciting. This is the first drug, together with the oral decitabine, that got approved a couple of years ago after a 10-year hiatus. This is important, and we need to learn how to use them, combine them, and develop them.

Transcript edited for clarity.