Luspatercept: A Challenge to Erythropoietin and Its Role in Boosting QOL in MDS

Targeted Therapies in Oncology: What are the advantages/disadvantages for choosing luspatercept vs an erythropoietin agent for initial therapy?

A: SOLLY CHEDID, MD: Luspatercept has some significant advantages. One significant advantage is the response rate. The response criteria in the phase 3 COMMANDS trial [NCT03682536] were determined as a hemoglobin [level] rise of 1.5 g/dL for 12 weeks as well as achieving transfusion independence.¹ Sixty percent of patients in the luspatercept arm met those criteria, whereas only 30% of patients receiving erythropoietin agents met those criteria.

Luspatercept duration of response was a full year longer at 2.5 years vs only 1.5 years for erythropoietin agents. The average rise in hemoglobin level for luspatercept was 2.0 g/dL as opposed to only 1.5 g/dL in terms of the peak response for erythropoietin agents.

What is probably most important to many of my patients is that they have to come in only once every 3 weeks over a course of 1 year [for treatment]. That is only 17 visits as opposed to 52 visits [with an erythropoietin agent]. A patient must come in every single week if they are receiving erythropoietin agents; thus, there are certainly some significant advantages to choosing luspatercept.

The advantage for erythropoietin agents is that they are a little older and a little less expensive. Thus, there are pluses and minuses to both treatments.

Please discuss the efficacy and safety f indings and how they inform your treatment choices.

A: From a patient quality-of-life [QOL] perspective, luspatercept has some significant advantages in terms of efficacy and safety, which were demonstrated in the COMMANDS trial.² Patients responded extremely well, and it was an extremely safe agent.

Initially, some patients had significant fatigue. In my patient population, I personally think that some of this fatigue was directly related to the fact that prior to the patient’s hemoglobin levels increasing, they had started to notice that their energy level was not quite as high as it used to be. That said, there is still some initial fatigue that is present in the first 1 to 2 months of therapy.

According to longitudinal data, patients’ overall symptoms that were present in the first and second months of therapy get significantly better after approximately 3 months of therapy.³ For patients who [have] ring sideroblasts–positive [status], the response rate is a little bit higher with luspatercept.

What factors do you consider most important when assessing QOL for patients with MDS?

A: One important QOL-assessment is that most patients with MDS experience significant anemia, which can lead to low energy levels and reduced activity. An increase in hemoglobin [level] over a longer period usually correlates directly with substantial improvements in QOL as observed in the post hoc analysis of the COMMANDS trial presented by Olivia et al and published in June 2024.⁴

In addition to this, the number of visits that a patient must undergo [can affect QOL]. For example, if the patient and their family member must drive back and forth every single week for treatment, it puts a substantial limitation on their ability to do things. In contrast, having to come in once every 3 weeks is quite liberating for many patients.

Please discuss the clinical benefit of luspatercept dose titration.

A: In terms of the clinical benefit of luspatercept titration, most patients, more than two-thirds of patients, need dose escalations. The treatment is given every 3 weeks after 2 doses (6 weeks).

If the patient is not achieving an adequate increase in hemoglobin, defined as a rise of at least 1.5 g/dL, the dose of luspatercept should be increased. The dosing sequence is as follows: increase the dose from 1.0 g to 1.3 g, and if further escalation is needed, increase to 1.75 g. In rare cases, if the hemoglobin level rises above 11.5 g/dL, the luspatercept should be held until the hemoglobin level drops below 11.0 g/dL. Once the level is below 11.0 g/dL, luspatercept can be restarted.

Please share your key takeaways for optimizing anemia management in lower-risk MDS, and where do you see the most significant unmet needs?

A: First, we need to make sure that we have assessed all the baseline criteria. For example, does the patient have a nutritional deficiency? Do they have alternative causes for anemias? These are very important.

In terms of key unmet needs for treating anemia and improving outcomes for low-risk MDS, if the patient has hypocellular marrow, they might be better served by simply administering an immunosuppressive agent. If the patient has 5q deletion, then we need to make sure that they are using lenalidomide [Revlimid] in that situation. If the patient has an IDF1 gene mutation, then using an IDF1 inhibitor is very important.

Are there any emerging agents, combination regimens, or ongoing trials in the pipeline?

A: Luspatercept is extremely effective. Almost two-thirds of patients had a rise in hemoglobin [level] and [achieved] hemoglobin transfusion [independence] for 2.5 years.¹ However, some patients do [have] therapy [that fails], and their hemoglobin [level] starts to drop. In that case, adding erythropoietin to luspatercept in the future may be effective.

There is a newly approved second-line agent called imetelstat [Rytelo].⁵ It is approved for patients who need 4 units of packed red blood cells within a preceding 8 weeks. Imetelstat is a telomerase inhibitor that inhibits apoptosis.

It is fabulous that we now have a second-line agent. Unfortunately, the response rate was only 13%.6 However, for some of those responders, there was a significant transfusion independence that lasted up to a year. In terms of the utility of this agent, it requires 30-minute premedication and then the infusion time is over 2 hours every 4 weeks. These are the primary options currently for MDS.

REFERENCES

1. Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/s23523026(24)00203-5

2. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/ s0140-6736(23)00874-7

3. Garcia-Manero G, Della Porta MG, Santini V, et al. Multilineage and safety results from the COMMANDS trial in RBC-TD, erythropoiesis-stimulating agent–naive patients with very low-, low- or intermediate-risk myelodysplastic syndromes. Abstract presented at: European Hematology Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract P780.

4. Oliva E, Yucel A, Lord-Besse J, et al. Relationship between hemoglobin and quality of life in RBC-TD patients with lower-risk myelodysplastic syndrome receiving luspatercept or epoetin alfa. Abstract presented at: European Hematology Association 2024 Hybrid Congress; June 13-16, 2024; Madrid, Spain. Abstract P774.

5. Geron announces FDA approval of RYTELO (imetelstat), a first-in-class telomerase inhibitor, for the treatment of adult patients with lower-risk MDS with transfusion-dependent anemia. News release. Geron Corporation. June 6, 2024. Accessed October 31, 2024. https://tinyurl.com/3cwu48nc

6. Uwe 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/s01406736(23)01724-5