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Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from the Phase 2 PACE-MDS Extension Study

Giagounidis, Aristoteles, Platzbecker, Uwe, Germing, Ulrich, Goetze, Katharina, Kiewe, Philipp, Mayer, Karin Tina, Ottmann, Oliver, Radsak, Markus, Wolff, Thomas, Haase, Detlef, Hankin, Monty, Wilson, Dawn, Zhang, Xiaosha, Laadem, Adberrahmane, Sherman, Matthew L. and Attie, Kenneth M. 2015. Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from the Phase 2 PACE-MDS Extension Study. Blood 126 (23) , 92.

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Abstract

Background: Luspatercept is a fusion protein (modified activin receptor IIB-IgG Fc) being investigated for the treatment of anemias with ineffective erythropoiesis. MDS patients have increased Smad2/3 signaling in the bone marrow, leading to ineffective erythropoiesis. Luspatercept inhibits Smad2/3 signaling and promotes late-stage erythroid differentiation, thereby correcting the ineffective erythropoiesis. Aims: This is an ongoing, phase 2, multicenter, open-label, 24-month extension study (following a 3-month base study) to evaluate the longer-term 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), transfusion independence, safety, PK, and PD biomarkers. Methods: In the base study, eligibility criteria included 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 once every 3 weeks by SC injection in sequential cohorts (n=3-6 each; total n=27) at dose levels ranging from 0.125 to 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=31) with a starting dose level of 1.0 mg/kg was enrolled with individual pt dose titration allowed. Patients completing the 3-month base study were eligible to enroll into this extension study (with or without interruption ≥3 months) where they continue to receive luspatercept every 3 weeks for up to 24 months. Results: Enrollment is complete for this extension study (n=32). Preliminary safety and efficacy data (as of 17-Apr-2015) were available for 22 of 32 patients (9 LTB/13 HTB) with continuous luspatercept treatment for a median of 8 cycles (range 5-12). Median age was 70.5 yr, 64% had prior ESA therapy, and 18% had prior lenalidomide. All 22 patients had ≥15% ring sideroblasts (RS+) in bone marrow. Eight of 9 (89%) of LTB patients achieved an IWG HI-E response for hemoglobin increase (≥1.5 g/dL for ≥8 weeks). Mean change in hemoglobin in these patients exceeded 1.5 g/dL for a median duration of 17 weeks (range 5-22 weeks) as of the data cutoff date in this ongoing study. Ten of 13 (77%) of HTB patients achieved an IWG HI-E response (reduction of ≥4 RBC units transfused over 8 weeks). Of the 14 patients who received transfusion of ≥2 RBC units over 8 weeks prior to the start of treatment, 6 (43%) patients achieved transfusion independence for at least 8 weeks (median 23 weeks, range 10-30 weeks as of the data cutoff date). All 6 patients were continuing to receive treatment as of the data cutoff date; updated data for duration of response will be presented. Luspatercept has been generally well-tolerated in the extension study, with no grade 3 or higher related adverse events. Conclusions: Based on preliminary data from the 24-month extension study in lower risk MDS patients, luspatercept treatment led to sustained HI-E response for increased Hb levels, decreased transfusion requirement or transfusion independence in the majority of patients, with a favorable safety profile. Phase 3 studies in patients with anemia due to lower risk MDS are planned.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Society of Hematology
ISSN: 0006-4971
Last Modified: 14 Jun 2019 09:52
URI: http://orca-mwe.cf.ac.uk/id/eprint/96759

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