Mutational Profile and Analysis of Lower-Risk Myelodysplastic Syndromes (MDS) Patients Treated with Luspatercept: Phase 2 PACE-MDS Study

Background: Management of anemia is a common therapeutic challenge in patients (pts) with MDS. Luspatercept (ACE-536), a fusion protein containing modified activin receptor type IIB, is being developed for treatment of anemia in lower-risk MDS. Luspatercept acts as a ligand trap for GDF11 and other TGF-β family ligands to suppress Smad2/3 signaling, promote late-stage erythroid differentiation, and increase hemoglobin (Hgb) levels (Suragani R, Nat Med, 2014; Attie K, Am J Hematol, 2014). Luspatercept has demonstrated clinical activity in ring-sideroblast positive (RS+,≥15% in bone marrow) MDS pts and comparable responses in non-RS+ pts with EPO<500 U/L. While RS+ pts have distinct clinical and molecular features including SF3B1 splicing mutations, non-RS+ pts have a more heterogeneous population of mutations.

Aims: This ongoing, phase 2, multicenter, open-label study followed by a long-term extension (ext) study evaluates the effects of luspatercept in pts with lower-risk MDS. Endpoints include long-term safety and tolerability, erythroid response (IWG HI-E), RBC transfusion independence (RBC-TI,≥8 weeks), and duration of HI-E. New analyses focus on clinical, molecular, and bone marrow morphological features of disease and factors associated with luspatercept response.

Methods: Inclusion criteria: MDS IPSS low or int-1, age ≥18 yr, Hgb<10 g/dL (if <4U RBC/8 wks), no prior HMA, no current lenalidomide or erythropoiesis-stimulating agent (ESA). The dose-escalation phase of the study is completed. An expansion cohort was added to this phase 2 study to evaluate response in pts not qualified for the phase 3 MEDALIST trial (for regularly transfused RS+ pts refractory to ESA or EPO>200 U/L). These include pts with low transfusion burden (<4U RBC/8 weeks) and either 1) RS+ with baseline EPO ≤200 U/L or 2) non-RS+ and any EPO level. Non-RS+ pts allowed up to 6U RBC/8 wks. Pts treated every 3 weeks subcutaneously for up to 5 doses (titration up to 1.75 mg/kg) in the base study (NCT01749514) and are then eligible for long-term treatment up to 5 additional years (NCT02268383).

Results: Data (as of 13Apr2017) were available for 88 pts treated at therapeutic dose levels (≥0.75 mg/kg) in both the base and ext studies. 88 pts were evaluable for IWG HI-E and 60 pts were evaluable for RBC-TI (baseline transfusions of ≥2 units/8 wks). 75 pts were evaluable for mutational data analysis.

Baseline characteristics are shown in Table 1. In pts with mutational data, the most common mutations were SF3B1 (57%), TET2 (39%), DNMT3A (21%), ASXL1 (17%), and SRSF2 (11%). Response by subgroup is shown in Table 2.

Responses were observed in both RS+ and non-RS+ pts of various mutational backgrounds. Many pts possessed mutations in multiple genes; pts carrying SF3B1 mutations tended to have increased response rates compared to SF3B1 WT pts. Other commonly observed (>10%) mutations (TET2, DNMT2A, ASXL1, and SRSF2) demonstrated similar responses in pts when either mutated or not. Longer-term data on all pts plus additional exploratory analyses of molecular, cellular, and morphologic parameters and their relationship to response will be presented at the meeting.

Luspatercept has been well tolerated, with seven possibly related grade 3 non-serious adverse events (AE): ascites, blast cell count increase, blood bilirubin increase, bone pain, hypertension, platelet count increase, and pleural effusion and four possibly related SAEs as of 15June2017: ataxia, general physical health deterioration, muscle weakness, and myalgia. Related AEs in >2 pts were headache, fatigue, hypertension, bone pain, diarrhea, arthralgia, injection site erythema, myalgia, and peripheral edema.

Conclusions: Lower-risk MDS pts treated long-term with luspatercept demonstrated robust and sustained increases in Hgb and decreases in transfusion burden and a high rate of RBC-TI. Encouraging responses were seen across EPO levels up to 500 U/L in both RS+ and non-RS+ patients. The presence of an SF3B1 mutation was associated with a higher response in this initial cohort of pts and responses were also observed in SF3B1 WT pts with mutations typically associated with poor prognosis (e.g., ASXL1). The data support continued study of luspatercept in MDS pts, including aPhase 3 study in regularly-transfused RS+ pts with lower-risk MDS according to IPSS-R (MEDALIST study; NCT02631070; fully enrolled) and a future Phase 3 study planned in first-line lower-risk MDS pts.

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