Overview of Luspatercept-aamt as MDS Treatment

Amy DeZern, MD, MHS: I’d love to transition back to some of your expertise on therapies that can stave off transplant or transfusion burden. You had mentioned luspatercept-aamt a moment ago. Can you tell me a little bit more about that? How does it work? Is it just supportive care? What do you think? 

Rami Komrokji, MD: As you know, luspatercept-aamt is the first drug to be approved in more than 10 years in MDS [myelodysplastic syndromes]; that’s very exciting. We have a new option for our patients. In my experience, whenever we get a new drug approved in a disease, we get some momentum. Hopefully this is the beginning of getting many other drugs. We’ve worked on this compound for several years and a prior similar compound. Luspatercept-aamt is a fusion trap protein; it’s a monoclonal antibody that will neutralize or bind the ligands for a pathway called TGF [transforming growth factor]-beta in the serum before they bind the receptor. It turns out that the TGF-beta pathway is important in patients with MDS, evident by overexpression of some of the downstream markers of that pathway that contributes to the myelosuppression. Some of the ligands of that pathway affect the terminal erythroid differentiation. Erythroid-stimulating agents help with the early stage of erythroid differentiation, but there is a regulation of the terminal erythroid differentiation that some of the ligands of the TGF-beta pathway act as negative regulators, like GDF11, for example.

Luspatercept-aamt will bind those ligands and release that terminal block on erythroid maturation, and now we’re starting to use the term erythroid maturation agent. Basically, it’s a fusion trap protein that traps those ligands and helps with the erythroid maturation. It was tested in phase 1/2 studies, with the notion or the signal that maybe there are higher-risk patients with ring sideroblasts or SF3B1 mutation. That led to the MEDALIST study [NCT02631070] that randomized patients with lower-risk MDS, ring sideroblasts, and transfusion dependence after ESA [erythropoiesis-stimulating agent] failure to luspatercept-aamt versus placebo, and met the primary end point of transfusion independence. There was also benefit of hematological improvement with transfusion reductions in patients who were not heavily transfusion dependent and significant increase in the hemoglobin. It’s typically an injection given every 3 weeks. There is no doubt that for that subset of patients, I think it’s going to be a very helpful treatment. Maybe I’ll ask you because you also have been involved in this, how do you use those drugs? Where are you positioning them? What’s the dosing with those medications, and how has your experience been since the approval?

Amy DeZern, MD, MHS: I think you had a great point that we have enthusiasm with luspatercept-aamt. I had always done diagnostic iron stains, but I feel like I’ve been ordering them more and rigorously encouraging my hematopathology colleagues to count the ring sideroblasts quite precisely, not in just a range. I have been fortunate to have treated patients both on trial and then since its approval in April. I had a lot of patients with known ring sideroblasts, patients with SF3B1, sitting in the queue, and it’s been very gratifying. Certainly there are patients who had been densely red cell transfusion-dependent for many months and sometimes years, that we’ve initiated this therapy in. It’s a subcutaneous injection. One milligram per kilogram is the starting dose given as a shot every 3 weeks. After the first couple of doses, you can augment to 1.33 mg/kg and then 1.75 mg/kg to get a response. I will say in my hands, in the real-world population, I have had to dose increase the majority of patients. That could be my patient population, but I actually think it’s relatively safe to do, and I try to stay quite attentive to the schedule to do so, to make sure that we can increase their hemoglobin to safe levels and maintain some transfusion independence.

You sent me a patient who lived in Florida who now lives up here, who we’ve just toggled along, and it’s gone very well. Certainly, no drug is without adverse effects, but as you alluded to, the mechanism as an erythroid maturation agent, it is well tolerated. A few patients have commented to me on loose stools. None of my patients have had life-threatening or life-altering diarrhea. I don’t know if you’ve had any, but I’ve had a couple of patients who thought they could have had lower extremity swelling and some shortness of breath related to it, and I think that may have correlated. Again, none of these for my patient population have been life altering in any way, but the demonstrable increase in hemoglobin has been good. Have you had any other safety signals or things that are pearls as you manage it that you might mention?

Rami Komrokji, MD: No, I think you covered most of it. I totally agree with you. I think one of the things that’s important to stress is the escalation of the dosing. I’m seeing a lot of patients, we send them back to the community oncologist, and they come back after 3 or 4 months on the same dose. After each couple of doses, if there is not a good response, one should escalate up to the maximum dose, which is 1.75 mg/kg. I think the escalation is key.

As you mentioned, my experience has been very similar to yours, and most of the patients have to escalate. If you look at the data from the study and later on, it’s been presented by Ryan Platzbecker, MD, that if patients are heavily transfusion dependent, there are really not many responses on the 1 mg/kg. We should probably be going for higher doses, especially if patients are heavily transfusion dependent. So it’s key to escalate the dose quickly, after 2 injections, go up to the next dose. I don’t see a lot of dose-dependent toxicity, and I don’t see the adverse effects increasing as we increase the dose. 

Amy DeZern, MD, MHS: Me either.

Rami Komrokji, MD: My experience with the adverse effects is very similar to yours. Fatigue, that’s typically in the first couple of rounds. In a couple of patients, it was profound, but most patients tolerated it well. Some aches; I’ve had a couple of patients mentioning diarrhea, but nothing that’s like what we experience with using FLT3 inhibitors, for example. Leg edema, some shortness of breath that temporarily could correlate with the treatment. But in general, in 80% of the patients it’s very well tolerated. I think the key is rapid escalation of the dose, and once you get the higher dose, and after 2 or 3 injections if there is no response, there is no point to use it.

The other clinical pearl is introducing the drug early a little bit. When you look at the data, those patients who were heavily transfusion dependent, more than 6 units of blood, we do see some benefit in transfusion reductions. The rate of transfusion dependency was definitely lower. In my practice, I think we’re now in transition because many of the patients, as you mentioned, have been waiting. Many of the patients have had prior hypomethylating agents, lenalidomide, which is a population that was not even studied on the trial, but we use it and we have some success. In patients, classically what our position is, is somebody who had ESA, and is starting to have ESA failure, before becoming heavily transfusion dependent. Once they’re starting to be transfusion dependent by the label, obviously, is to introduce the drug before they start needing 6 to 8, so using it early on is probably going to yield better responses in the patients.

Transcript edited for clarity.