Luspatercept Shows Activity in Patients With Lower-Risk MDS and Anemia

Erythropoiesis-stimulating agents (ESAs) are a standard treatment for patients with myelodysplastic syndromes (MDS) and anemia; however, only around one-third of patients have an erythroid response to ESAs, suggesting that improving erythropoiesis in MDS might be best achieved by targeting downstream processes independent of erythropoietin regulation.

In the phase II, dose-finding PACE-MDS study with long-term extension, Uwe Platzbecker, MD, from the Department of Internal Medicine I at the University Hospital Carl Gustav Carus in Dresden, Germany, and co-authors evaluated whether the recombinant fusion protein luspatercept could provide a new therapeutic approach in anemic patients with lower-risk MDS.

The trial enrolled adult patients with lower-risk MDS (low or intermediate 1 per the International Prognostic Scoring System [IPSS]) or non-proliferative chronic myelomonocytic leukemia (white blood cell count <13,000/μL) and anemia with or without red blood cell (RBC) transfusion support who were refractory to or ineligible to receive ESAs.

Enrolled patients were classified as having low transfusion burden (LTB; requiring <4 RBC units in the 8 weeks before treatment and baseline hemoglobin <10 g/dL) or high transfusion burden (HTB; requiring ≥4 RBC units in the 8 weeks before treatment). The primary efficacy endpoint was the proportion of patients achieving modified International Working Group–defined hematologic improvement–erythroid (HI-E). In LTB patients, HI-E was defined as a hemoglobin increase of ≥1.5 g/dL from baseline for ≥14 days; in HTB patients, HI-E was defined as a reduction in RBC transfusion of 4 RBC units or more or a ≥50 percent reduction in RBC units over eight weeks versus pre-treatment transfusion burden.

The PACE-MDS study was conducted in two stages: a 12-week base study (consisting of the dose-finding cohorts and expansion cohorts) and an extension study. In the base study, 58 patients received up to five doses (over a maximum of 12 weeks) of luspatercept administered subcutaneously once every 21 days at either lower dose concentrations (0.125-0.5 mg/kg) or higher dose concentrations (0.75-1.75 mg/kg).

Six patients discontinued from the base study and 20 patients did not enroll in the extension study. After reviewing safety and efficacy data after 12 weeks, the investigators selected the higher luspatercept concentrations for the 32 patients who entered the extension study (13 LTB and 19 HTB).

The median duration of treatment for all patients across both the base and extension studies was 6.8 months (range = 2.0-19.8 months).

At three-month follow-up, 32 of the 51 patients (63%) treated with higher dose concentrations of luspatercept across both the base and extension studies achieved HI-E (TABLE). Only two of the patients who received lower dose concentrations during the base study achieved HI-E.

The results showed “a clear dose-dependent efficacy response,” the authors reported. Across both study stages, HI-E response rates were higher in patients who received higher dose concentrations of luspatercept, compared with those who received lower dose concentrations, for both LTB and HTB patients (p values not reported):

  • lower dose concentrations: 0 of 2 (0%) LTB patients and 2 of 7 (29%) HTB patients
  • higher dose concentrations: 11 of 17 (65%) LTB patients and 21 of 34 (62%) HTB patients

In the extension study, the 13 patients with LTB who received higher dose concentrations “showed sustained increases from baseline in mean hemoglobin for at least 15 months,” the authors reported, adding that 11 of these patients (85%) achieved HI-E for a median duration of 8.3 months (range = 2.3-9.9 months). Patients with HTB in the extension study also had high rates of durable response rates: 15 of 19 patients (79%) achieved HI-E with a median duration of response of 11.6 months (range = 2.3 months to not estimable).

Of the 42 patients across both stages who were evaluable for RBC transfusion independence (TI; 8 LTB and 34 HTB), 16 patients (38%) achieved TI. Of the 22 patients with previous transfusions in the base study who carried over into the extension study, 11 (50%) were transfusion-free for eight weeks or longer (median duration of RBC-TI = 15.3 months; range = 3.6 months to not estimable).

Previous ESA use did not appear to affect response rates: 21 of the 34 patients (62%) with prior ESA use and 11 of the 17 patients (65%; p value not reported) without prior ESA use who received higher dose concentrations of luspatercept achieved HI-E.

As seen in the TABLE on, ring sideroblast status, SF3B1 mutation status, and erythropoietin concentration at baseline were associated with HI-E response.

“Although higher response rates occurred in patients with baseline serum erythropoietin <200 IU/L, HI-E was also observed in 58 percent of patients with erythropoietin ≥200 [to] ≤500 IU/L and 43 percent of patients with erythropoietin >500 IU/L,” the researchers wrote, suggesting “that luspatercept is effective even in patients with higher erythropoietin concentrations, which are associated with poor ESA response.”

No treatment-related deaths were reported during study follow-up. The most common grade 1/2 treatment-related adverse events (AEs) were fatigue (n-4; 7%), bone pain (n=3; 5%) diarrhea (n=3; 5%), myalgia (n=2; 3%), headache (n=2; 3%), hypertension (n=2; 3%), and injection-site erythema (n=2; 3%). Three grade 3 treatment-related AEs were reported in three patients (5%), including two reversible events (myalgia and general physical health deterioration) and one who had an increase in blast percentages.

The study is limited by its single-arm, open-label design and the small number of patients in certain subgroups. “Due to the small number of ring sideroblast–negative patients included [in] the study, the likelihood of response to luspatercept cannot be accurately determined in these patients,” the authors added. Based on data from the present trial, a randomized, placebo-controlled, phase III study of luspatercept in patients with lower-risk, ring sideroblast–positive MDS is ongoing.

The trial was funded by Acceleron Pharma, the manufacturers of luspatercept.

Contributing authors report financial relationships with Acceleron Pharma, Celgene Corporation, Novartis, Bristol-Myers Squibb, and Gilead.


Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017 September 1. [Epub ahead of print]

TABLE. Factors Associated With
Response in Patients Treated With High Dose Concentrations of Luspatercept
All patients 32/51 (63%) 16/42 (38%)
Transfusion burden
High 11/17 (65%) 6/8 (75%)
Low 21/34 (62%) 10/34 (29%)
Serum erythropoietin concentration
<200 IU/L 19/25 (76%) 10/19 (53%)
≥200 IU/L to ≤500 IU/L 7/12 (58%) 4/9 (44%)
>500 IU/L 6/14 (43%) 2/14 (14%)
Ring sideroblast status
Positive (≥15% ring sideroblasts) 29/42 (69%) 14/33 (42%)
Negative (<15% ring
3/7 (43%) 2/7 (29%)
Unknown 0/2 0/2
SF3B1 mutation status
Positive 24/31 (77%) 11/25 (44%)
Negative 6/15 (40%) 5/13 (39%)
Unknown 2/5 (40%) 0/4
IWG HI-E = International Working Group-defined hematologic improvement-erythroid; RBC-TI = red blood cell transfusion independence