During a Case-Based Roundtable® event, Andrew M. Brunner, MD, discussed dosing strategy for erythropoiesis-stimulating agents as well as dose modifications and safety for the novel agents imetelstat and luspatercept.
EVENT REGION Massachusetts and New York
PARTICIPANT LIST Ratesh Khillan, MD | Baruch Wieder, MD | Lan Mo, MD | Eric Bravin, MD
BRUNNER: Everybody has a different strategy for ESAs. I start at the top dose and see the response in patients with MDS. That’s in part because I’m usually waiting until they’re transfusion dependent. I’m in downtown Boston, [Massachusetts]. Nobody wants to drive in and see me…every few weeks for injections or transfusions. They often are not eager to do so. But I tend to start at 500 mg/kg every 3 weeks of darbepoetin alfa [Aranesp], if that’s what I’m using. Or, if I use epoetin alfa, I usually start at 60,000 units.
Many of the trials started with a moderate dose and ramped up. I find that I often have a number of patients who have kidney insufficiency, and they might be on a renal dose of ESA. I often have to check what they’re getting because that’s usually far lower than doses used in MDS, and that can be an easy fix for a lot of patients where they just need a higher [dose]. That tends to be my practice. Does anyone tend to ramp up in their clinic?
KHILLAN: I start with 20,000 units a week, like you do, 60,000 every 3 weeks… sometimes I use [it] every 4 weeks instead of 3 weeks.
BRUNNER: Sure, especially when you get a responder. It’s nice to be able to. Instead of dose reducing, I tend to lean toward giving them more time between doses.
DISCUSSION QUESTION
BRUNNER: There’s a lot of variability. To be honest, it can be hard to know.
Does anybody have a rubric by which they say you are now ESA refractory? Is it after a certain number of months with ESA if you haven’t had a response? Does that response need to be an increase in hemoglobin? Is stability OK? Do you just give them a certain number of months of therapy, no matter what, before you abandon it? Even if they’re needing transfusions, [do] you give everybody 6 months and see what happens? Do you do a minor ramp-up but then move on if that’s not enough? Do you use EPO levels during treatment to decide whether we should keep going? Is there a worsened transfusion [need] or worsened hemoglobin level that you would use as your metric?
WIEDER: I typically go by multiple factors. If you have somebody with a hemoglobin of [approximately] 8 g/dL and you put them on ESA, start treating them, and the number stays between 8 and 9 g/dL but they’re not needing transfusions, then I don’t consider that a failure. Maybe it would be worse without getting the ESA. I mostly go by need for transfusions. If I have a patient who is, despite getting ESA, still requiring more transfusions than I’d like them to—of course, that number could change based on the patient and scenario—that’s when I abandon it. I go by the number, but I don’t check EPO levels routinely. I do it before I start, but I don’t typically check it after that. It’s mostly transfusion dependence; if they still need more than 1 a month despite getting ESA, I would move on to something else.
KHILLAN: I saw a patient [with a hemoglobin level of] 8 g/dL, and I gave her [ESA] for 4 weeks. She’s still 8 g/dL but very symptomatic; she is so tired, and I cannot give a blood transfusion now…. In her case, I did change, so I ordered luspatercept-aamt [Reblozyl]. That’s a category where I use without transfusion [dependence], when the patient is very symptomatic. The patient is tired and not able to get out of bed. I don’t check that EPO level that much. Maybe once in a while we check it, but it is not that routine.
BRUNNER: That symptomatic anemia at higher levels is always tricky, especially for patients with cardiac [issues]. You find at some point, they just don’t get enough oxygen. Those are always a little hard, especially with blood bank issues. So, symptomatic anemia despite treatment, even if you’ve got some moderate benefit and transfusion needs—sounds like a pretty clear line in the sand [to be ESA refractory].
Are you setting expectations? When you meet somebody, do you [say], “This is how long we’re going to try this, and if I don’t get ‘X,’ we’re changing [treatment]?”
KHILLAN: After we start and it doesn’t improve, then they ask what we could expect.
BRUNNER: I’m often saying, “I’ll give you 3 months and we’ll see where we go.”
MO: Before starting the darbepoetin, we usually check the ferritin or transferrin saturation level. If it’s low, we have to give iron first and reach a ferritin level greater than 100 ng/mL before we can start.
KHILLAN: Absolutely. I give intravenous iron at this point before starting ESA.
BRUNNER: [That] can be great for the fatigue symptoms if they’re mildly iron deficient.
WIEDER: If it was a hemoglobin increase by 1 g/dL in 2 weeks, you can either decrease the dose or give a dose every 4 weeks from an every-3-weeks dose.
DISCUSSION QUESTION
What was the safety profile of imetelstat (Rytelo) in the phase 3 IMerge study (NCT02598661)?
BRUNNER: A big question as we adopt new drugs is how we manage them. There were a few toxicities that are worth noting that I think will impact when you might start this agent. There were 73% of patients who had a dose modification or infusion modification [Table 11]. Approximately 50% of patients had a dose reduction. It is something you do need to monitor. It’s mostly around thrombocytopenia and neutropenia. Fortunately, most patients, especially with RS-positive disease, tend to have preserved white blood cells and platelets, but it’s something to be considered.
If you look at how patients did with or without a dose reduction, you do see a bit of a reduction in the duration of transfusion independence [Table 21]. So, fewer patients achieve the longer time points, but it’s a little hard to interpret because if you’re having to stop, it’s hard to know how much is related to other factors.
A number of patients get some degree of thrombocytopenia [75%, any grade; 62%, grade 3/4] and neutropenia [74%, any grade; 68%, grade 3/4], so you do have to monitor them. I usually do a weekly blood count check. Other toxicities are pretty limited. Infusion site reactions, [gastrointestinal] adverse events [AEs], liver toxicities, or other AEs are pretty uncommon at grade 3 or 4, where you might worry about them, but thrombocytopenia and neutropenia can happen at grade 3 to 4.
If you look at the actual number of transfusions needed or febrile neutropenia events, where they’re sick from those complications, those were also extremely low. There’s a disconnect where patients are getting thrombocytopenic, but they’re not having a complication, or they’re getting neutropenic, but it’s not enough to cause an infection. It’s a bit like monitoring lenalidomide [Revlimid], where you need to have a closer eye on blood counts, especially in the first month or 2. When I start patients for the first 2 months, I…check their blood counts weekly. Most of these events should happen early, based on what we saw in the studies, and that’s played out in my practice. If they’re going to have a change, it’s usually early in the course of treatment.
They do have some dose modifications recommended [Figure2]—and there are some delays if you have a platelet count under 50,000/μL—until it recovers and then starting at lower dose levels if it’s a grade 4 thrombocytopenia.2 Similarly for neutropenia, you delay if they get mild neutropenia. If they get grade 4, delay and do a dose reduction. For infusion-related reactions, there’s a monitoring period immediately after imetelstat, and there are some premedications that you give patients to try to reduce that risk.
DISCUSSION QUESTION
BRUNNER: [Luspatercept] has a different AE profile [from imetelstat]. Those hematologic AEs are not seen with luspatercept.3 I’ve had some patients who have a modest improvement in platelets or neutrophils. Sometimes people will have hypertension and you have to watch their blood pressure, but that’s usually manageable. However, some patients will have wooziness, fatigue, or just won’t feel well—often despite hematologic improvement. Their hemoglobin would be 11 g/dL and you expect them to feel great, but they just still have some sort of malaise. It’s a small percentage of patients, but I’ve had a few where that fatigue element doesn’t go away with treatment, and that’s borne out if you look at the fatigue and asthenia compared with a placebo [grade 3 fatigue in 27% vs 13%; asthenia in 20% vs 12%, respectively]. It’s a small subset of patients where it’s severe, but there are some patients where it just seems to cause more systemic symptoms.
WIEDER: I’ve seen it where the fatigue lags after the rise in the hemoglobin. Like you said, when they come in, the numbers are much higher. I expect them to be feeling better, and sometimes they aren’t, but I do find [that the fatigue gets better] at some point, when hemoglobin levels out. Eventually, they start to admit…that they’re doing more, are more active, and they do feel a little better.
KHILLAN: With one of my patients, the hemoglobin went up from 7 to 11 g/dL within 2 weeks [on luspatercept]…so I stopped it, but it went down within a week or 2. I started at 1 mg/kg, and it did work.
BRUNNER: Yes, the fast responses are nice.
DISCUSSION QUESTION
BRAVIN: I like the fact that it’s something you can offer patients and hope that it is going to help them in the near term. They’re not going to have to wait a couple months to see what works.
BRUNNER: The benefits were often…within the first week or 2 at a given dose, so we may need to dose escalate, but you should get a quick signal often.
WIEDER: Is there information in terms of how to dose it if the patient has a good response? Are there levels that you’re supposed to hold it for or lower the dose…? I’ve had patients where they’ve done so well that the hemoglobin shot up to 11 or 12 g/dL. Then I’m wondering whether I should give it less often or [reduce] the dose.
BRUNNER: I don’t think there are any reported prospective data. There’s a lot of heterogeneity in how people manage. I have done both. I’ve dose decreased. I also tend to try to space [infusions] out. If I can get you 4, 5, or 6 weeks between doses at the same dose level that was working, that’s more like the strategy I’ve been employing more recently, to give bigger gaps. In the trial, with hemoglobin above 11.5 g/dL, you were supposed to hold. In our practice, we tend to do that at 11 g/dL, which is mostly around consistency with our ESA use so we don’t have different hold levels. Aside from that, I don’t know of prospective data for a strategy.
You can get a response with dose escalations…the number of patients who benefit went from about a little under one-half to [approximately] two-thirds of patients with dose escalations.4 You can try to increase them through the dose escalation; you should see some benefit by the top dose after 3 doses. At the top dose, within that 9-week period, you should see at least a reduction in your transfusion needs.
REFERENCES
1. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5
2. Rytelo. Prescribing information. Geron Corporation; 2024. Accessed November 20, 2024. https://tinyurl.com/yc5rr6c5
3. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892
4. Patel K, Chatterjee D, Hughes C, et al. Real-world dose escalation and outcomes among patients with lower-risk myelodysplastic syndromes receiving luspatercept in clinical practice. Presented at: 29th European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P768. Accessed November 20, 2024. https://tinyurl.com/yck3kpwt
Resistance Spurs Evaluation of Early-Phase BTK Degraders
January 10th 2025During the 66th American Society of Hematology Annual Meeting and Exposition, investigators revealed early-phase 1 data evaluating various BTK degraders that leverage different strategies to overcome resistance.
Read More
Novel Therapies and Combinations Lead the Way in Women’s Cancers in 2024
January 3rd 2025Potential practice-changing therapies in gynecologic cancer include the emergence of carboplatin, paclitaxel, and PD-1 blockade, or the use of fam-trastuzumab deruxtecan-nxki in endometrial cancer.
Read More
Novel Frontline Treatments Add Layer of Complexity in Urothelial Carcinoma
January 2nd 2025The past 12 months have seen the FDA approvals of enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic urothelial cancer and nivolumab plus cisplatin and gemcitabine for patients with unresectable or metastatic urothelial carcinoma.
Read More