The Therapeutic Toolkit for MDS-Associated Anemia Adds Luspatercept

The approval of Luspatercept-AAMT (Reblozyl) for the treatment of anemia in patients with myelodysplastic syndromes (MDS) offers a new option to reduce red blood cell (RBC) transfusion dependence, which, in addition to affecting the majority of these patients, can lead to serious health complications such as transfusion site reactions and infections.¹

On April 3, 2020, the FDA approved luspatercept for the treatment of anemia failing an erythropoiesis-stimulating agent (ESA) and requiring 2 or more RBC units over 8 weeks in adults with very low- to intermediate-risk MDS with ring sideroblasts (MDS-RS) or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).¹

The approval for the erythroid maturation agent was based on efficacy results from the phase 3 MEDALIST trial (NCT02631070), which showed that treatment with luspatercept increased RBC-transfusion independence (RBC-TI) among patients with MDS-RS.

In an interview with OncologyLive®, Joseph G. Jurcic, MD, director of the Hematologic Malignancies Section of the Division of Hematology/ Oncology, and professor of medicine at Columbia University Medical Center in New York, New York, discussed strategies to optimize patient selection for luspatercept.

Please expand upon the characteristics of this patient population and the efficacy data that led to the approval.

In [MDS/MPN], RS must comprise 15% of the total nucleated cells in the marrow, or 5% of the total nucleated cells in the presence of an SF3B1 mutation. Older studies reported RS in only 10% of MDS patients, but the numbers may be higher. For example, a more recent study showed SF3B1 mutations in up to 30% of patients with MDS and 20% of patients with MDS/MPN.2 It is important to accurately diagnose MDS with RS. If you look for RS, you will diagnose it at a greater frequency. Interestingly, the MPN-RS-T population [for which luspatercept is approved] was not included in the MEDALIST study but has a lot of biologic similarities with the study population.

In the [MEDALIST] trial, patients with very low–risk, low-risk, or intermediate- risk MDS-RS defined according to the Revised International Prognostic Scoring System who had been receiving regular RBC transfusions were randomized to receive either luspatercept at a dose of 1.0 mg/kg up to 1.75 mg/kg or placebo, administered subcutaneously every 3 weeks.

Investigators randomly assigned 153 patients to receive luspatercept and 76 to receive placebo. TI greater than 8 weeks was observed in 38% of the patients in the luspatercept group, compared with 13% of those in the placebo group. A higher percentage of patients in the luspatercept group than in the placebo group were TI for weeks 1 to 24 [28% vs 8%] and weeks 1 to 48 [33% vs 12%].

How does luspatercept enact its anticancer activity?

Luspatercept is a recombinant fusion protein derived from human activin receptor type IIb and linked to a protein derived from immunoglobulin G. Luspatercept has a completely different mechanism of action than ESAs. The agent binds transforming growth factor β superfamily ligands [to] reduce SMAD2 and SMAD3 signaling, which contributes to ineffective erythropoiesis.

What adverse effects do health care providers need to be aware of?

In general, the drug is well tolerated. The most common luspatercept-associated adverse effects [AEs] are fatigue, diarrhea, asthenia, nausea, and dizziness. The incidence of these effects decreased over time. This was particularly true in individuals who experienced fatigue, which can be seen in up to 20% of patients. Clinicians need to be aware of fatigue. They need to warn the patients ahead of time to stick with luspatercept: the fatigue is going to [attenuate] and patients will hopefully have responded after the first 1 or 2 injections. Their anemia will improve, and so will their overall fatigue with a little more time. Fatigue resolves quickly, in just a few weeks.

Are there any factors to consider as to how this agent will fit into the current treatment paradigm?

Lower risk patients with MDS with del(5q) [deletion 5q] should still receive lenalidomide [Revlimid], but the majority do not have del(5q). Lower-risk patients without del(5q), anemia, and an erythropoietin level less than 500 should receive a 3-month trial of an ESA with or without a granulocyte colony-stimulating factor.

Prior to luspatercept’s approval, therapeutic options were limited either to single-agent lenalidomide or lenalidomide with ESAs. Hypomethylating agents have also been used but come with AEs. Open questions currently include the utility of luspatercept in lower risk MDS patients without RS and whether luspatercept would be more effective than ESAs as first-line therapy.

How can the benefit of luspatercept be optimized in this patient population?

It is important for clinicians to work closely with pathologists to accurately diagnose MDS-RS. The number of RS must be quantified in reports. It can be a bit tricky to determine who has MDS with rings that are sideroblasts, and this is not always well highlighted in pathology reports. It is critically important that the number of rings that are sideroblasts are quantified. In order to accurately diagnose this disease, you need to see 15% RS in the marrow. Clinicians really need to push the pathologists to give them that information so they can accurately diagnose this disorder.

[Further, the] availability of luspatercept also points out the need for routine molecular testing to identify patients with SF3B1 who may benefit from luspatercept. Molecular testing is crucial in determining what treatments patients will respond to. Clinicians need to conduct molecular tests to identify the patients who might respond to luspatercept. All patients with MDS should undergo molecular typing at the time of diagnosis.

References

1. Reblozyl. Prescribing information. Celgene Corporation; 2020. Accessed November 6, 2020. https://bit.ly/355zz4K
2. Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233-241. doi:10.1182/ blood-2015-03-633537