Will luspatercept become the new treatment standard after ESA failure in RS-positive LR-MDS patients with TD anemia?

Erythropoiesis-stimulating agents (ESAs) are the standard first-line treatment for low-risk anemic patients with myelodysplastic syndrome (MDS). They work by promoting the proliferation of early erythroid progenitor cells. Erythropoietin (EPO) and its receptor (EPO-R) are ESAs that have had preclinical and clinical success by promoting the survival of late-stage maturation of primitive erythroid precursors. Similarly, luspatercept, an ESA, works by decreasing SMAD signaling, which improves anemia by promoting terminal erythroid maturation. Luspatercept has been approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) as a second-line treatment of patients with transfusion-dependent (TD) lower-risk (LS) myelodysplastic syndrome (MDS) with ring sideroblasts (RS) and/or SF3B1 mutation who are ineligible for, or failed, ESAs. Anne Kubasch et al.¹ reported on the clinical evolution of luspatercept in this patient subset and the results of the phase III MEDALIST trial that led to its approval in an article published in Blood Advances. Here, we provide a review.

Study design

In the placebo-controlled, phase III MEDALIST trial (NCT02631070), patients were randomly assigned placebo (n = 76) or administered luspatercept (n = 153) once every 3 weeks for a minimum of 24 weeks (dose range, 1.0–1.75 mg/kg of body weight). Eligible patients were ESA refractory, had TD anemia, and were defined according to the Revised International Prognostic Scoring System (IPSS-R) as very low risk, low risk, or intermediate risk if they were RS positive.   

• The primary endpoint was transfusion independence (TI) ≥8 weeks during Weeks 1–24.
• The main secondary endpoint was TI for ≥12 weeks during Weeks 1–48 and Weeks 1–24.
• Other secondary endpoints:

• Erythroid response (measured as hematologic improvement in erythrocytes [HI-E] according to the International Working Group [IWG] 2006 response criteria in myelodysplasia)
• Prolonged duration of primary response
• Mean increase in hemoglobin levels of ≥1.0 g/dL
• Progression to acute myeloid leukemia
• Mean change in the serum ferritin level
• Safety

Results

The baseline characteristics (Table 1) of the patients were balanced between the two arms.²

Table 1. Baseline characteristics*

ESA, erythropoiesis-stimulating agent; IPSS-R, Revised International Prognostic Scoring System; MDS, myelodysplastic syndrome; WHO, World Health Organization. *Adapted from Fenaux, et al.2
Characteristic	Luspatercept (N = 153)	Placebo (N = 76)	Total (N = 229)
Median age, years	71	72	71
Male gender, %	61	66	63
WHO classification of MDS, %
MDS with refractory anemia with ring sideroblasts	5	3	4
MDS with refractory cytopenia with multilineage dysplasia	95	97	96
IPSS-R risk group, %
Very low	12	8	10
Low	71	75	72
Intermediate	16	17	17
Median serum erythropoietin level, U/L	156.9	130.8	153.2
Serum erythropoietin level category, %
<100 U/L	33	41	36
100 to <200 U/L	24	25	24
200 to 500 U/L	28	20	25
>500 U/L	14	14	14
Mutated SF3B1, %	93	86	91
Median red-cell transfusion burden, no. of units/8 week over 16-week period	5	5	5
Red-cell transfusion burden group, %
≥6 units/8 week	43	43	43
4 to <6 units/8 week	27	30	28
<4 units/8 week	30	26	29
Previously received ESA, %	97	92	95
Disease refractory to ESA, %	97	99	98
ESA discontinuation due to adverse event, %	3	1	2
Previous iron chelation therapy, %	46	53	48

Efficacy

The primary endpoint of red blood cell (RBC) TI for a minimum of 8 weeks was achieved by 37.9% of patients receiving luspatercept vs 13.2% in the placebo arm (p < 0.0001).

Of the patients receiving luspatercept, 28.1% reached the main secondary endpoint vs 7.9% in the placebo arm (p < 0.0002).

 HI-E was achieved in 52.9% receiving luspatercept treatment compared with 11.8% in the placebo arm during the initial 24 weeks. During Weeks 1–48, the luspatercept arm had an HI-E of 59% compared with 17% in the placebo arm.

The median duration of the longest single continuous response from luspatercept treatment was 30.6 weeks. The lengthiest single period of TI in the luspatercept group was 30.6 weeks vs 13.6 weeks in the placebo group. Patients with low transfusion burden that were treated with luspatercept had higher RBC-TI rates.

TI was reached by 80% of patients who received <4 RBC units per 8 weeks before treatment initiation vs 37% of patients who received 4 to <6 units per 8 weeks vs 9% of patients who received a minimum of 6 units per 8 weeks before beginning treatment. Patients who received luspatercept reached 62.5% hematologic improvement in platelet count compared with 33% of those who received placebo.

The luspatercept-treated patients had 20% hematologic improvement in neutrophil count vs 10% in the placebo arm; however, neutrophil or platelet count analysis revealed that there were no overall significant differences with luspatercept treatment. Moreover, SF3B1 mutation and the total number of baseline somatic mutations played no significant role in response to luspatercept treatment.

Safety

Treatment with luspatercept led to a few low-grade toxicities. The most frequent treatment-associated adverse events of any grade (mostly Grade 1 or 2) were fatigue, diarrhea, asthenia, nausea, and dizziness. Serious adverse events were seen in 31% of patients receiving luspatercept vs 30% of patients in the placebo arm. There was a low incidence of disease progression in both treatment groups: one patient from each group progressed to higher-risk MDS, and acute myeloid leukemia developed in three patients treated with luspatercept and one patient who received placebo.

Conclusion

The results from the MEDALIST trial led to FDA and EMA approval of luspatercept for TD LR-MDS patients with RS and/or SF3B1 mutation who were refractory to ESA. However, future clinical trials exploring luspatercept are warranted, such as clinical studies assessing the synergistic potential of combination treatments that evaluate the efficacy and safety of luspatercept with ESA, as first-line treatment or in the relapsed/refractory setting. Currently, there are a few ongoing clinical studies, e.g., the phase 1b/2 trial (NCT04539236) evaluating the combination of luspatercept plus lenalidomide. Moreover, the efficacy of luspatercept in patients with different subsets of MDS disease, such as patients with advanced, high-risk disease or those with overlapping MDS and myeloproliferative neoplasms (MDS/MPN), warrants future clinical investigation.