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Abstract: S131

Type: Oral Presentation

Presentation during EHA21: On Friday, June 10, 2016 from 12:15 - 12:30

Location: Hall C14

Background
Splicing factor mutations in MDS patients (pts), notably SF3B1, correlate with bone marrow ring sideroblasts (RS) and ineffective erythropoiesis (IE). Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia due to IE in MDS.  Luspatercept binds GDF11 and other TGF-β superfamily ligands to promote late-stage erythroid differentiation and increase hemoglobin (Hgb) levels (Suragani R, Nat Med and Attie K, Am J Hematol, 2014).

Aims
This is an ongoing, phase 2, multicenter, open-label, dose-finding study followed by a long-term extension study to evaluate the effects of luspatercept in pts with low-intermediate risk MDS.  Endpoints included erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI, ≥8 weeks), duration of HI-E, pharmacodynamic and iron metabolism biomarkers, safety, and pt-reported QOL.

Methods
Inclusion criteria included age ≥18 yr, Hgb <10 g/dL (if <4U RBC/8 weeks), ESA refractory or EPO >500 U/L, no prior HMA, and no current lenalidomide or ESA.  Luspatercept was administered SC every 3 wks for up to 5 doses in the base study, including 7 dose escalation cohorts (n=27 total, 0.125 to 1.75 mg/kg) and an expansion cohort (n=31, starting dose 1.0 mg/kg, max. 1.75 mg/kg).  An amendment to the base study allows for additional pt subgroups (n=~50).  A 2-year extension study (n=32 to date) is ongoing.

Results
Data (as of 31 Aug 2015) were available for 58 pts. Of these, 39 pts received ≥4U RBC/8 weeks (high transfusion burden, HTB) and 19 pts <4U RBC/8 weeks (low transfusion burden, LTB).  Median age was 72 yr (range 27-90 yr) and 66% had prior ESA. Median RBC transfusion burden was 6U/8 weeks (range 4-18 units, HTB pts) and median Hgb was 8.7 g/dL (range 6.4-10.1 g/dL, LTB pts). 82% pts were RS+ (≥15% RS in bone marrow), including 19% RARS and 50% RCMD-RS.LTB: IWG HI-E was achieved in 8/17 (47%) pts in the higher dose groups, compared with 0/2 in the lower dose groups in the base study.  In the extension study, 9/13 (69%) pts achieved HI-E. Mean Hgb increase at Week 12 was 2.9 g/dL in HI-E responders and 1.3 g/dL in HI-E non-responders. 3/3 LTB pts who had 2U RBC/8 weeks at baseline became RBC-TI.HTB: IWG HI-E was achieved in 16/32 (50%) in the higher dose groups (≥0.75mg/kg), compared with 2/7 (29%) in the lower dose groups, and 8/32 (25%) became RBC-TI in the base study.  In the extension study, 13/19 (68%) achieved HI-E and 8/19 (42%) became RBC-TI (duration up to 50+ wks).IWG HI-E was achieved in 22/40 (55%) RS+ pts and 2/7 (29%) RS- pts. Response rates were 64% for EPO <200 U/L, 36% for EPO 200-500 U/L, 57% for ESA-naïve, and 46% for those refractory to prior ESA treatment. 18/30 (60%) pts with SF3B1 mutation responded; other potential predictors of response are being explored.Luspatercept was well tolerated, with 3 possibly related grade 3 adverse events of myalgia, worsening of general condition, and blast cell count increase. The most common possibly related AEs in the base study were diarrhea, fatigue (3 pts each), injection site erythema, bone pain, myalgia, and hypertension (2 pts each).

Conclusion
Luspatercept treatment was well tolerated and led to erythroid response in ~50% of low-intermediate risk MDS pts.  Higher response rates were observed in RS+ and SF3B1mut pts, and responders included pts who were both ESA naïve and ESA-refractory, or with EPO up to 500 U/L.  A Phase 3 study of luspatercept in regularly-transfused RS+ patients with lower-risk MDS according to IPSS-R is ongoing (MEDALIST study; clinicaltrials.gov NCT02631070).

Session topic: Myelodysplastic syndromes - Clinical

Keyword(s): Clinical trial, Erythropoieisis, MDS, TGF-