PACE-MDS Extension Study: Luspatercept Beneficial in Myelodysplastic Syndromes

di Mary Mosley

The robust hematologic improvement and reduced transfusion burden achieved with luspatercept in patients with lower risk myelodysplastic sundromes (MDS) in the PACE-MDS extension study had led to the start of the phase 3 MEDALIST trial in this population, according to Aristoteles Giagounidis, MD, PhD, Marien Hospital Düsseldorf, Düsseldorf, Germany.

The phase 2, multicenter, open-label study enrolled patients with low- or intermediate low-risk MDS and anemia (hemoglobin [Hb] <10.0 g/dL) who were classified as having a low transfusion burden (LTB; <4 Units per 8 weeks) or high transfusion burden (HTB; ≥4 Units per 8 weeks). Their erythropoietin (EPO) levels had to be greater than 500 U/L or they were refractory or intolerant of erythropoiesis stimulating agents (ESAs). Patients were to be naïve to azacitidine and decitabine, and could not be receiving treatment with an ESA, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), or lenalidomide.

The dose-escalation, 3-month base study of 58 patients established a starting dose of 1.0 mg/kg, with titration up to 1.25 mg/kg, administered subcutaneously [NCT01749514]. The ongoing extension study includes 32 of these patients, who will receive an additional 24 months of treatment with luspatercept [NCT02268383].

The median age of the patients was 71.5 years (range, 29-90) and 69% (n=22) were men. Six (19%) had prior lenalidomide treatment and 19 (59%) prior ESA treatment. Most patients (63%) had a baseline EPO <200 U/L. Ring sideroblasts ≥15% was found in 91% of patients, and 72% had an SF3B1 mutation. The 13 LTB patients had a median Hb of 8.5 g/dL (range, 6.3-10.1) and the 19 HTB patients had a median of 6 Units per 8 weeks (range, 4-14).

Nine of the 13 (69%) LTB patients had an improvement in the mean Hb increase, as measured as an International Working Group (IWG) high-intensity erythroid (HI-E) increase ≥1.5 g/dL for 8 weeks. In the HI-E high responders, the mean increase was about 2-3 g/dL, which was relatively stable. Although it did not reach the level of the IWG HI-E, luspatercept increased Hb in the 4 nonresponders.

Of the HTB patients, 13 (68%) achieved an IWG HI-E response, and 8 (42%) were independent of transfusions. Notably, the 3 LTB patients who had required 2 Units per 8 weeks also became transfusion independent. These patients achieved a sustained increase in Hb and 5 patients had sustained transfusion independence.

The response rates in relation to baseline characteristics is detailed in the Table 1. Most of the patients who were positive for Ring sideroblasts responded to treatment with luspatercept. Prior exposure to EPO did not affect the IWG HI-E response or transfusion independence.

No serious or grade ≥ 3 treatment-related adverse events occurred during the extension study. Seven of the 32 (22%) patients stopped treatment early, 3 because of the patient request, and 2 because of a lack of effect. One patient had progressive disease and 1 patient died.

Treatment for up to 1 year with luspatercept was associated with a sustained increase in hemoglobin and prolonged independence from transfusions. As measured by the IWG HI-E, there was a robust hematologic improvement. Patients who were refractory to prior ESA or had serum EPO up to 500 IU/L responded particularly well to luspatercept. These results provided the basis for the phase 3 study of luspatercept that is now recruiting patients with MDS who are at very low, low, or intermediate risk [NCT02631070]

A phase 3 study of acalabrutinib in high-risk, pretreated patients with CLL is now underway (NCT02477696).


Source: ASH 2015,
abs 92


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