LUSPATERCEPT INCREASES HEMOGLOBIN AND REDUCES TRANSFUSION BURDEN IN PATIENTS WITH LOW OR INTERMEDIATE-1 RISK MYELODYSPLASTIC SYNDROMES (MDS): PRELIMINARY RESULTS FROM THE PHASE 2 PACE-MDS STUDY
Author(s): ,
Uwe Platzbecker
Affiliations:
Universitatsklinikum Carl Gustav Carus,Dresden,Germany
,
Ulrich Germing
Affiliations:
Universitätsklinikum Düsseldorf,Düsseldorf,Germany
,
Aristoteles Giagounidis
Affiliations:
Marien Hospital Düsseldorf,Düsseldorf,Germany
,
Katharina Götze
Affiliations:
Technical University of Munich,Munich,Germany
,
Philipp Kiewe
Affiliations:
Onkologischer Schwerpunkt am Oskar-Helene-Heim,Berlin,Germany
,
Karin Mayer
Affiliations:
Universitätsklinikum Bonn,Bonn,Germany
,
Oliver Ottmann
Affiliations:
Klinikum der J.W. Goethe-Universität Frankfurt,Frankfurt/Main,Germany
,
Markus Radsak
Affiliations:
University Medical Center - Johannes Gutenberg-Universität,Mainz,Germany
,
Thomas Wolff
Affiliations:
OncoResearch Lerchenfeld UG,Hamburg,Germany
,
Detlef Haase
Affiliations:
Universitätsmedizin Göttingen,Göttingen,Germany
,
Monty Hankin
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
,
Dawn Wilson
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
,
Xiaosha Zhang
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
,
Abderrahmane Laadem
Affiliations:
Celgene Corporation,Summit, NJ,United States
,
Matthew Sherman
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
Kenneth Attie
Affiliations:
Acceleron Pharma,Cambridge, MA,United States
EHA Learning Center. Platzbecker U. Jun 13, 2015; 103098
Prof. Dr. Uwe Platzbecker
Prof. Dr. Uwe Platzbecker

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Abstract: S509

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 16:30 to 13.06.2015 16:45

Location: Room C1

Background
Luspatercept (ACE-536) is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased GDF11 levels (Suragani, Nat Med 2014) and aberrant Smad2,3 signaling in the bone marrow. Luspatercept binds TGF-β superfamily ligands, including GDF11, inhibits Smad2,3 signaling, and promotes late-stage erythroid differentiation, distinct from ESAs. In a healthy volunteer study, luspatercept was well-tolerated and increased hemoglobin (Hb) levels (Attie, Am J Hematol 2014).

Aims
This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of luspatercept on anemia in patients (pts) with low/int-1 risk MDS (IPSS classification). Study outcomes include erythroid response of increased Hb in low transfusion burden (LTB) pts (<4 RBC units/8 weeks), reduced transfusions in high transfusion burden (HTB) patients (≥4 RBC units/8 weeks), safety, PK, and PD biomarkers.

Methods
Inclusion criteria include age ≥ 18 yr, anemia, defined as being HTB or LTB with Hb <10.0 g/dL, EPO >500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. Luspatercept was administered by SC injection once every 3 weeks in sequential cohorts (n=3-6 each) at dose levels ranging from 0.125 to 1.75 mg/kg for up to 5 doses with a 3-month follow-up. Treatment of an expansion cohort is ongoing, with individual pt dose titration allowed. Patients completing this study may enroll into a 12-month extension study.

Results
Enrollment is complete for 27 pts in the dose escalation cohorts and 31 pts in the expansion cohort. Preliminary safety and efficacy data (as of 23Feb2015) were available for 44 pts (19F/25M, 15 LTB/29 HTB). Mean age was 68.1 yr, 61% had prior EPO therapy, and 21% had prior lenalidomide. 35 (80%) patients had ≥15% ring sideroblasts (RS) in bone marrow.

The mean baseline Hb for LTB patients was 8.6 g/dL, ranging from 6.8 to 10.1 g/dL. LTB pts treated at 0.75-1.75 mg/kg (n=13) had a 77% response rate for the primary endpoint (Hb increase ≥1.5 g/dL for ≥2 weeks) and a 69% IWG HI-E response rate (Hb increase ≥1.5 g/dL over 8 weeks). The mean (SD) maximum change in hemoglobin was 2.7 (1.1) g/dL in the higher dose groups compared with 0.9 (0.1) g/dL in the lower dose groups. HTB patients treated at 0.75-1.75 mg/kg (n=22) had a 50% HI-E response rate (reduction of ≥4 RBC units over 8 weeks).

Higher response rates were observed in pts with ring sideroblasts and/or mutations of SF3B1 (data to be presented). Of the patients with RBC transfusions during the 8 weeks prior to treatment, 10/28 (36%) patients were transfusion-free for ≥8 weeks during treatment.

Luspatercept was generally well-tolerated. Adverse events were mostly mild-moderate. The most frequent related adverse events (>10% patients) were bone pain, headache, diarrhea, myalgia, and pain in extremity.



Summary
Based on preliminary data in Low/Int-1 MDS patients, luspatercept treatment at therapeutic dose levels for 3 months led to HI-E response for increased Hb levels and/or decreased transfusion requirement in the majority of patients, with a favorable safety profile. Higher response rates were observed in patients with ring sideroblasts and/or SF3B1 mutations. These data strongly support further evaluation of luspatercept in patients with low to intermediate risk MDS.

Keyword(s): Anemia, Clinical trial, MDS, Phase II

Session topic: MDS Clinical
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