Luspatercept in MDS Promotes Transfusion Independence and Anemia Response

Azra Raza, MD

Professor of Medicine

Director, Myelodysplastic Syndrome Center

Columbia University Herbert Irving Comprehensive Cancer Center

New York, NY

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