Luspatercept in MDS Promotes Transfusion Independence and Anemia Response

CASE SUMMARY

• A 70-year-old man​, diagnosed 1 year ago with low-risk ring sideroblast (RS)–positive myelodysplastic syndrome (MDS) with multilineage dysplasia - moderate anemia and thrombocytosis, RS in 4% of nucleated erythroid cells​
• SF3B1 mutation negative​
• No deletion 5q​
• No family history of cancer or significant genotoxic agent exposure​
• In the last 8 months, he received single-unit packed red blood cell transfusions 3 months apart​
• Revised International Prognostic Staging System (R-IPSS): Low​
• Work-up to assess disease status and response to anemia management:​
• Serum erythropoietin (EPO) - 250m U/L​
• RS negative​
• Hemoglobin: 8.3 g/dL
• White blood cell and absolute neutrophil count: within normal limits
• Platelet count: 450,000/μl​
• Treatment options were discussed with the patient – either continue transfusions as needed, erythropoietin-stimulating agent (ESA) subcutaneously every week, or luspatercept-aamt (Reblozyl) subcutaneously every 3 weeks.​
• Luspatercept was chosen as the appropriate option for this patient based on patient convenience/rationale​.

Targeted Oncology: Would you start on ESA before luspatercept or go straight to luspatercept?

Azra Raza, MD: Luspatercept is not only approved for RS. It has recently received approval for non-sideroblastic anemia as well.¹ This is why, even before ESAs, you can start the patient on luspatercept. Given that the patient's EPO level is low, I would prefer to start with the ESA, personally.

What data justifies the use of luspatercept in patients with anemia related to low-risk MDS?

This is the COMMANDS trial [NCT03682536] on the basis of which luspatercept is approved. Patients had to be more than 18 years of age, [have IPSS risk of] very low to intermediate risk, at least 2 to 6 red cell transfusions over 8 weeks, endogenous EPO has to be less than 500 U/L, and be ESA naive. Patients were stratified by baseline EPO level, baseline transfusion burden, and RS status; 178 patients were given luspatercept and 178 were given [epoetin alfa]. Response assessment was at day 169 and every 24 weeks thereafter, and then post-treatment safety follow-up [went for 5 years after first dose or 3 years from last dose].

The biological as well as clinical characteristics were well matched.² Patients were transfusion dependent, and fewer than 40% of patients were getting more than 4 units every 8 weeks, so that's 2 transfusions every other week.

The transfusion independence rate in the luspatercept arm vs the ESA arm was highly significant and dramatically better for the luspatercept arm [98 patients transfusion independent with luspatercept vs 71 patients with ESA at 12 weeks or greater, and 70 vs 45 patients at 24 weeks, respectively]. This is why the drug was approved for anemia. The primary end point was responder status by genetic mutation; most common mutations are epigenetic modifiers or splice-impacting mutations.

What notable safety outcomes were observed?

Some patients had infections [but the rate was] very low; there was no myelosuppression with this drug and it is a very safe drug to use. I participated in the phase 1, 2, and 3 trials, and I put on the most patients in the phase 3…we had lots of patients on this phase 3 trial, so our group has a lot of experience using luspatercept.

CASE UPDATE

• The patient was started on luspatercept at the starting dose [1.0 mg/kg]. ​
• After 9 weeks, the patient has received 2 transfusions and his hemoglobin was stable at 9.2 g/dL.​
• Serum EPO level increased from 250m U/L to 390m U/L​.

When do you consider treatment to be a failure? Do you dose escalate?

We dose escalate. The way we do it is we start at 1 mg/kg, and after 2 cycles, we go to 1.25 mg/kg, after 2 cycles to 1.33 mg/kg, and then to the final dose, 1.75 mg/kg, so each dose is given for 2 different cycles. Now, if you start seeing a response at 1 mg/kg, why go up? I would just keep it there, because then you're perhaps increasing toxicity, and the benefit is already there. That would be my suggestion.

CASE UPDATE

• Luspatercept was increased to 1.33 mg/kg per package insert.​
• After 9 weeks at this dose, the patient has not required a transfusion and hemoglobin is improved to 10.7g/dL.​

Would you stay at the same dose, increase to 1.75 mg/kg, or discontinue luspatercept?​

We would not increase, in my opinion, and we would not discontinue, unless hemoglobin reaches 11 g/dL, then you hold it until it comes down. For us, with hemoglobin of 10 g/dL and above is where we don't give [ESA].… If we order an ESA for a patient with hemoglobin over of 10 g/dL, we have to write a justification. I was involved in the phase 3 trial. We chose an 11 g/dL, partly based on the phase 1 trial when we were treating [patients regardless of level] in Europe.

What other data stand out from the COMMANDS trial?

The [red blood cell transfusion independence] response rates for luspatercept were much higher than with the ESA at more than 12 weeks [76.4% vs 55.8%, respectively] and more than 24 weeks [65.9% vs 45.3%, respectively], so the transfusion independence rates are comparable here with high significance.³

The time to red blood cell transfusion after treatment initiation is a median [of 155 days (95% CI, 80.0-266.0) for luspatercept vs 42.0 days (95% CI, 23.0-55.0) for ESA (HR, 0.579; 95% CI, 0.446-0.750; P < .0009]. I would say that the median time is [approximately] 4 months, generally.

The change in hemoglobin level was interesting that we see it with continued treatment. You can see continued improvement up to a year; we have seen things keep improving. So I don't recommend stopping the treatment early after 4 months or 6 months. If the patient is tolerating it well, and if there's any hint of slight prolongation of transfusions, then I would continue.

A mean hemoglobin increase of 1.5 g/dL was achieved in 70% of the patients [receiving luspatercept] and about half the patients [receiving ESA].⁴ It looks like it has performed better, and on the basis of this performance it has been given precedence even over an ESA.

REFERENCES:

1. FDA approves Bristol Myers Squibb’s Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed August 29, 2023. https://tinyurl.com/yz7y8uhe

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. Zeidan AM, Platzbecker U, Della Porta MG, et al. Clinical benefit of luspatercept treatment (tx) in transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)–naive patients (pts) with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) in the COMMANDS trial. J Clin Oncol. 2024;42(suppl_16):6565. doi:10.1200/JCO.2024.42.16_suppl.6565

4. Komrokji RS, Platzbecker U, Della Porta M, et al. MDS-234 reduction of transfusion burden (TB), hemoglobin increase, and dose titration in the COMMANDS study of luspatercept versus epoetin alfa (EA) in erythropoietin-stimulating agent (ESA)-naive patients with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). Clin Lymph Myel Leuk. 2023;23(suppl 1):S184. doi:10.1016/S2152-2650(23)00608-0