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Abstract

 ePoster EFFECTS OF LUSPATERCEPT ON SERUM FERRITIN IN PATIENTS (PTS) WITH LOWER-RISK MYELODYSPLASTIC SYNDROMES (MDS) WITH RING SIDEROBLASTS (RS) IN THE PHASE 3 MEDALIST TRIAL

Abstract: EP807

Type: e-Poster

Background
Iron overload resulting from red blood cell (RBC) transfusions is associated with significant morbidity in pts with MDS. In MDS with RS, iron overload may also occur prior to RBC transfusions, due to ineffective erythropoiesis. The safety and efficacy of luspatercept, a first-in-class erythroid maturation agent, is being assessed in the randomized, placebo (PBO)-controlled, phase 3 MEDALIST trial of pts with lower-risk MDS with RS (NCT02631070).

Aims
To assess changes from baseline (BL) in serum ferritin and iron chelation therapy (ICT) use in pts in the MEDALIST trial.

Methods
Pts had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS; were ≥18 y old; had unsatisfactory response to or were ineligible for EPO-based therapy; and required regular RBC transfusions. All pts provided informed written consent. Luspatercept (1.0 mg/kg, titration up to 1.75 mg/kg if needed) or PBO was administered subcutaneously every 3 wks.

Results
Of 153 luspatercept-treated pts, 87 (56.9%) and 66 (43.1%) pts had BL RBC transfusion burden <6 U/8 wks and ≥6 U/8 wks, respectively, vs 43 (56.6%) and 33 (43.4%) of 76 PBO pts. Median BL serum ferritin (range) was 1089.2 (64–5968) vs 1122.1 (165–5849) μg/L in luspatercept vs PBO arms. In pts with BL transfusion burden ≥6 U/8 wks, median (range) BL serum ferritin was 1306.1 (64–5968) vs 1492.9 (256–5280) μg/L in luspatercept vs PBO arms. 71 (46.4%) and 40 (52.6%) pts in luspatercept and PBO arms, respectively, received ICT at BL, including 50/66 (75.8%) luspatercept pts and 26/33 (78.8%) PBO pts with BL transfusion burden ≥6 U/8 wks.

A decrease from BL in mean serum ferritin was observed with luspatercept vs PBO in Wks 9–24 (least squares [LS] mean −2.7 vs +226.5 μg/L; P=0.0024) and Wks 33–48 (LS mean −72.0 vs +247.4 μg/L; P=0.0294). A difference in mean serum ferritin change from BL was also observed in luspatercept-treated pts not achieving hematologic improvement–erythroid (HI-E) in Wks 1–24 vs PBO (LS mean +73.4 vs +244.2 μg/L; P=0.0777). In luspatercept-treated pts with BL transfusion burden ≥6 U/8 wks, a decrease from BL in mean serum ferritin in Wks 9–24 was observed vs PBO (LS mean −63.5 vs 271.2 μg/L; P=0.0103). In luspatercept-treated pts with BL transfusion burden ≥6 U/8 wks who achieved HI-E in Wks 1–24, LS mean change from BL in serum ferritin in Wks 9–24 was −111.4 μg/L and in Wks 33–48 was −124.4 μg/L. In pts with BL transfusion burden ≥6 U/8 wks, a difference in mean serum ferritin change from BL in Wks 9–24 was also observed in luspatercept-treated pts not achieving HI-E in Wks 1–24 vs PBO (LS mean +3 vs +344.3 μg/L; P=0.0452).

LS mean change from BL in mean daily ICT dose in pts receiving luspatercept was 10.0 mg/d over Wks 9–24 and −148.8 mg/d over Wks 33–48. In luspatercept-treated pts with BL transfusion burden ≥6 U/8 wks, mean change from BL in mean daily ICT dose was −68.5 mg/d over Wks 9–24 and −327.1 mg/d over Wks 33–48.

Conclusion
Luspatercept treatment resulted in serum ferritin decreases, particularly in pts with higher BL transfusion burden and in those with high BL serum ferritin who experienced significant RBC transfusion reduction. This suggests that the effect of luspatercept on serum ferritin may be due not only to transfusion reduction, but also potentially to a more direct effect of the drug on ineffective erythropoiesis and/or iron metabolism. Overall, ICT use was reduced with luspatercept.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Clinical trial, Ferritin, Iron, MDS

Abstract: EP807

Type: e-Poster

Background
Iron overload resulting from red blood cell (RBC) transfusions is associated with significant morbidity in pts with MDS. In MDS with RS, iron overload may also occur prior to RBC transfusions, due to ineffective erythropoiesis. The safety and efficacy of luspatercept, a first-in-class erythroid maturation agent, is being assessed in the randomized, placebo (PBO)-controlled, phase 3 MEDALIST trial of pts with lower-risk MDS with RS (NCT02631070).

Aims
To assess changes from baseline (BL) in serum ferritin and iron chelation therapy (ICT) use in pts in the MEDALIST trial.

Methods
Pts had IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS; were ≥18 y old; had unsatisfactory response to or were ineligible for EPO-based therapy; and required regular RBC transfusions. All pts provided informed written consent. Luspatercept (1.0 mg/kg, titration up to 1.75 mg/kg if needed) or PBO was administered subcutaneously every 3 wks.

Results
Of 153 luspatercept-treated pts, 87 (56.9%) and 66 (43.1%) pts had BL RBC transfusion burden <6 U/8 wks and ≥6 U/8 wks, respectively, vs 43 (56.6%) and 33 (43.4%) of 76 PBO pts. Median BL serum ferritin (range) was 1089.2 (64–5968) vs 1122.1 (165–5849) μg/L in luspatercept vs PBO arms. In pts with BL transfusion burden ≥6 U/8 wks, median (range) BL serum ferritin was 1306.1 (64–5968) vs 1492.9 (256–5280) μg/L in luspatercept vs PBO arms. 71 (46.4%) and 40 (52.6%) pts in luspatercept and PBO arms, respectively, received ICT at BL, including 50/66 (75.8%) luspatercept pts and 26/33 (78.8%) PBO pts with BL transfusion burden ≥6 U/8 wks.

A decrease from BL in mean serum ferritin was observed with luspatercept vs PBO in Wks 9–24 (least squares [LS] mean −2.7 vs +226.5 μg/L; P=0.0024) and Wks 33–48 (LS mean −72.0 vs +247.4 μg/L; P=0.0294). A difference in mean serum ferritin change from BL was also observed in luspatercept-treated pts not achieving hematologic improvement–erythroid (HI-E) in Wks 1–24 vs PBO (LS mean +73.4 vs +244.2 μg/L; P=0.0777). In luspatercept-treated pts with BL transfusion burden ≥6 U/8 wks, a decrease from BL in mean serum ferritin in Wks 9–24 was observed vs PBO (LS mean −63.5 vs 271.2 μg/L; P=0.0103). In luspatercept-treated pts with BL transfusion burden ≥6 U/8 wks who achieved HI-E in Wks 1–24, LS mean change from BL in serum ferritin in Wks 9–24 was −111.4 μg/L and in Wks 33–48 was −124.4 μg/L. In pts with BL transfusion burden ≥6 U/8 wks, a difference in mean serum ferritin change from BL in Wks 9–24 was also observed in luspatercept-treated pts not achieving HI-E in Wks 1–24 vs PBO (LS mean +3 vs +344.3 μg/L; P=0.0452).

LS mean change from BL in mean daily ICT dose in pts receiving luspatercept was 10.0 mg/d over Wks 9–24 and −148.8 mg/d over Wks 33–48. In luspatercept-treated pts with BL transfusion burden ≥6 U/8 wks, mean change from BL in mean daily ICT dose was −68.5 mg/d over Wks 9–24 and −327.1 mg/d over Wks 33–48.

Conclusion
Luspatercept treatment resulted in serum ferritin decreases, particularly in pts with higher BL transfusion burden and in those with high BL serum ferritin who experienced significant RBC transfusion reduction. This suggests that the effect of luspatercept on serum ferritin may be due not only to transfusion reduction, but also potentially to a more direct effect of the drug on ineffective erythropoiesis and/or iron metabolism. Overall, ICT use was reduced with luspatercept.

Session topic: 10. Myelodysplastic syndromes - Clinical

Keyword(s): Clinical trial, Ferritin, Iron, MDS

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