Critical Role of Luspatercept in the Treatment of Lower-Risk Myelodysplastic Syndrome

On the Oncology Brothers podcast, Thomas LeBlanc, MD, MA, of Duke Cancer Center, joined cohosts Rahul Gosain, MD, MBA, of Wilmot Cancer Institute, and Rohit Gosain, MD, of Roswell Park Comprehensive Cancer Center, to discuss the treatment algorithm for myelodysplastic syndrome (MDS).

The experts explored therapeutic options for lower-risk MDS, including the use of ESAs and luspatercept, the significance of ring sideroblasts and del(5q) in treatment selection, and the importance of dose escalation.

IPSS-M and IPSS-R for Risk Stratification

The first step in creating a treatment algorithm for MDS is risk stratification, which can be conducted using the IPSS-M (Molecular International Prognostic Scoring System) or IPSS-R (Revised International Prognostic Scoring System). However, although these calculators, particularly the IPSS-M, can facilitate decision-making,  they don’t inform who really needs and benefits from disease-modifying therapy or hypomethylating agents versus who has biologically lower-risk and lower-grade disease, Dr. LeBlanc said. “We should be talking about more supportive care therapies,” he said. “We’re at a bit of a transition point right now.”

Hypomethylating Agents: A Last Resort

For patients with low- to intermediate-risk MDS with anemia, treatment is indicated in those who are transfusion-dependent or have a hemoglobin level less than 10 g/dL. Before assigning therapy, Dr. LeBlanc advised ensuring that patients don’t have a significant amount of blasts, which can be done using one of the classification schemas. In some instances, there might be a need for disease-modifying therapy. However, for low-risk patients, it’s unlikely.

He cautioned against the use of hypomethylating agents (HMAs), except as an absolute last resort for the overwhelming majority of patients with lower-risk MDS, as the response rates are low. “They’re challenging therapies to give, and nothing works after failure of HMA,” Dr. LeBlanc said.

Luspatercept in RS-Positive and RS-Negative Populations

In cases of MDS with del(5q), lenalidomide is the recommended course, although ESAs and luspatercept can also be prescribed. For patients with ring sideroblast–positive or ring sideroblast–negative MDS, luspatercept is a preferred option. 

“This is the easiest group to decide what to do with because we know that luspatercept is especially effective in ring sideroblast–positive disease,” Dr. LeBlanc said. “If you see RS positivity or even if you have an SF3B1 mutation without a huge amount of ring sideroblasts, usually they have the phenotype of the RS-positive disease, and they respond very well, and for longer, to first-line luspatercept.”

Dr. LeBlanc cited findings from the randomized phase 3 COMMANDS trial, which found that 60% of patients with ESA-naive, transfusion-dependent, lower-risk MDS who received luspatercept achieved the primary end point, compared with 35% of those who received epoetin alfa. “Luspatercept is clearly the superior drug,” he said. “Even though we know it is less effective in RS–negative disease than in RS–positive disease, I still try it first for all patients with lower-risk MDS, except for those with a 5q deletion.”

Regarding how erythropoietin (EPO) levels factor into treatment decisions, Dr. LeBlanc recommended administering luspatercept regardless of where the numbers fall. He also cautioned against trying EPO first because it’s cheaper and easier to obtain. “We’d never say that in any other cancer setting. We don’t even have that discussion. You use the best drug first,” Dr. LeBlanc said, which in this case, is luspatercept. “After that, we can figure out what to do based on various factors.”

Dose Escalation

The dosing element is “critically important” with luspatercept, which is administered as a subcutaneous injection once every 3 weeks. The recommended initial dose is 1 mg/kg, with a maximum of 1.75 mg/kg based on key responses such as improved hemoglobin levels and a reduction in transfusion requirements. “With luspatercept, we know that dose escalation is really important to achieve the kind of efficacy that was seen in the COMMANDS trial,” he said. ”Nearly 80% of patients required titration to achieve the maximum benefit.”

Typically, patients will have to increase by at least one dose level, according to Dr. Rohit Gosain.

MAXILUS Trial

Where there should be hesitation is in abandoning therapy too soon, Dr. LeBlanc explained, noting that it can take up to 24 weeks to experience benefits, which can be frustrating for both patients and physicians. “I find that I have to do a lot of very explicit expectation setting at the beginning,” he said. “I’ll tell them, ‘I’m going to push you to stay on this, and we’re going to titrate it up slowly.’”

However, a phase 3b trial currently underway could simplify the dose escalation process. The MAXILUS trial is investigating the administration of luspatercept directly at its maximum approved dose of 1.75 mg/kg from the first treatment cycle for lower-risk MDS, which would bypass the traditional dose-escalation protocol. Thus far, results have been “impressive,” Dr. LeBlanc said. “It’s encouraging,” he added. “My hope is that there will be a label update this year or next year.”