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3207 Preliminary Safety and Efficacy of Luspatercept Initiated at Maximum Approved Dose in Patients with Transfusion Dependent Anemia Due to Very Low, Low and Intermediate Risk MDS with Ring Sideroblasts: First Results of the Lusplus Trial

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
MDS, Chronic Myeloid Malignancies, Diseases, Treatment Considerations, Myeloid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Katharina S. S. Götze, MD1,2,3, Anna Hecht, MD4*, Anne Sophie Kubasch, MD5, Maria Diez-Campelo, MD, PhD6*, Georg Stüssi, MD7*, David Valcarcel, MD, PhD8, Patricia Font Lopez, MD9*, Elvira Mora Castera, MD10*, Blanca Xicoy, MD11*, Teresa Bernal Del Castillo, MD, PhD12*, Dominik Wolf, M.D.13*, Nicola Andina, MD, PhD14*, Nicolas Bonadies, MD15, Gregor Stehle, MD16*, Karoline V. Gleixner, MD17*, Klaus H Metzeler, MD5, Arnold Schröder18*, Dorothea Schipp18*, Maria Tormo, MD19*, Ana Alfonso Pierola, MD, PhD20*, Aristoteles Giagounidis, MD21, Martin Puttrich18* and Uwe Platzbecker, MD5

1Department of Medicine III, Hematology and Oncology, Technical University of Munich (TUM) School of Medicine and Health, Munich, Bavaria, Germany
2German Cancer Consortium (DKTK), partner site Munich, Heidelberg, Germany
3Bavarian Center for Cancer Research (BZKF), Munich, Germany
4Department of Medicine III, Hematology and Oncology, Technical University of Munich (TUM) School of Medicine and Health, Munich, Germany
5Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany
6Hospital Clínico Universitario de Salamanca, Salamanca, Spain
7Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale, Bellinzona, Switzerland
8Department of Hematology and Oncology, Hospital Universitario Vall d'Hebron, Barcelona, Spain
9Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain
10Department of Hematology, University Hospital La Fe of Valencia, VALENCIA, ESP
11Department of Hematology, University Hospital Català d' Oncologia de Badalona (German University Trias y Pujol), Spain, Badalona, Spain
12Hospital Universitario Central de Asturias, Oviedo, Spain
13University Hospital of Internal Medicine V (Hematology and Oncology), Medical University of Innsbruck, Anichstraße 35, 6020, Innsbruck, Austria
14Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland
15Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
16University Hospital Basel, Department of Hematology, Basel, Basel Stadt, CHE
17Division of Hematology & Hemostaseology, Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria
18GWT-TUD GmbH, Dresden, Germany
19Department of Hematology, University Hospital of Valencia, Valencia, Spain
20University Hospital of Navarra, Pamplona, Spain
21Clinic for Hematology, Oncology and Palliative Care Marien Hospital Düsseldorf, Dusseldorf, Germany

Background

Luspatercept is a first-in-class erythroid maturation agent approved for patients with lower risk MDS with ring sideroblasts (MDS-RS) and transfusion dependent anemia at a starting dose of 1.0 mg/kg based on the results of the phase III randomized placebo-controlled MEDALIST trial (Fenaux et al, N Engl J Med 2020;382:140-51.). Adjustments of luspatercept to a dose of 1.33 mg/kg and a maximum dose of 1.75 mg/kg were allowed based on response and dose delays were initiated at a Hb level above 11.5 g/dl. 37.9% of patients receiving luspatercept achieved the primary endpoint of at least 8 weeks without a need for RBC transfusion. However, 30% of patients in the luspatercept arm of the MEDALIST trial did not receive the planned maximum dose of 1.75 mg/kg. The rationale of the LusPlus trial is thus to exploit the maximum dose of luspatercept from the first dose per patient to achieve an overall increase in response and demonstrate an acceptable safety profile of this dosing regimen.

Methods

The LusPlus trial is a phase IIIb, open-label, single arm study evaluating the efficacy and safety of luspatercept initiated at a maximum dose of 1.75 mg/kg in transfusion dependent patients with lower-risk MDS and ring-sideroblastic phenotype who are refractory, intolerant, or ineligible to prior erythropoiesis-stimulating agent (ESA) treatment. Patients receive luspatercept at a starting dose of 1.75 mg/kg on day 1 of each 21-day cycle for 24 weeks. The Hb threshold for administration of luspatercept is set at 13 g/dl for females and 14 g/dl for males, above which dosing must be delayed until the Hb falls below these levels. The primary endpoint is red blood cell transfusion independence (RBC-TI) ≥ 8 weeks according to IWG 2018 modified criteria from week 1 through week 24. Secondary endpoints include safety and tolerability of the luspatercept dosing regimen, time to and duration of transfusion independence, increase in mean hemoglobin ≥1 g/dL for ≥8 weeks, and quality of life based on patient reported outcomes. We report preliminary results on safety and secondary efficacy endpoints (i.e. Hb increase ≥1g/dl for ≥8 weeks) for the first 41 of 55 planned patients from 14 sites in Europe treated in the trial. This trial is registered under ClinicalTrials.gov: NCT05181592; EudraCT: 2020-004899-18

Results

As of July 28, 2024, 41 patients were treated at the maximum dose of 1.75 mg/kg luspatercept, 22 patients have completed 24 weeks of treatment. Median age was 72 years (range 48-88), 53.7% were male and 90.2% Caucasian. 29.3% of all enrolled patients (12/41) showed a response with a mean Hb increase of ≥1g/dl for ≥8 weeks. Of the 22 patients completing 24 weeks of treatment, 45,5% (n=10) responded. Median time to response was 2 weeks (range 1.0-22.9). 7 patients (17.1%) experienced at least one dose delay. A total of 10 dose delay events were reported, 3 of these for an Hb level above the predetermined threshold. Other reasons for dose delays were adverse events in 4 cases and serious adverse events in 2 cases. All adverse events leading to dose delays were judged as unrelated to luspatercept. No thromboembolic events were observed thus far. Adverse events of special interest that have been reported concerned one patient who progressed to AML during the screening phase and one patient who developed basal cell carcinoma during cycle 2.

Conclusion

Treatment initiated with luspatercept at the maximum dose of 1.75 mg/kg is well tolerated. Raising the Hb threshold for implementation of dose delay has not led to any new safety signals thus far. Contingent on the final results after complete enrollment, our preliminary data indicate that initiation of luspatercept treatment at maximum dose is safe and may improve response rates. Confirmation of these preliminary findings after at least 50 patients have completed 24 weeks of treatment is necessary.

Disclosures: Götze: BMS: Honoraria; JAZZ: Honoraria; Otsuka: Consultancy; Abbvie: Consultancy, Honoraria; Amgen: Honoraria. Kubasch: Curis: Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria, Research Funding. Diez-Campelo: HEMAVAN: Membership on an entity's Board of Directors or advisory committees; AGIOS: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASTEX/OTSUKA: Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL TO MEETINGS; CURIS: Membership on an entity's Board of Directors or advisory committees; SYROS: Membership on an entity's Board of Directors or advisory committees; BLUEPRINT MEDICINES: Consultancy, Membership on an entity's Board of Directors or advisory committees; KEROS: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Other: Travel reimbursement; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board fees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Stüssi: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Roche: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Incyte: Consultancy, Honoraria. Valcarcel: Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Kite/Gilead: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticials: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Gebro: Honoraria, Speakers Bureau; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Research Funding, Speakers Bureau; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Agios: Honoraria, Other: Meeting and travel accommodation, Speakers Bureau; AbbVie: Consultancy, Other: Meeting and travel accommodation; Sanofi: Consultancy, Honoraria, Other: Meeting and travel accommodation, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Speakers Bureau. Mora Castera: BMS: Honoraria. Xicoy: BMS: Honoraria. Metzeler: Janssen: Consultancy, Honoraria; AstraZeneca: Honoraria; BMS/Celgene: Consultancy, Honoraria; Menarini Stem Line: Honoraria; Astellas: Honoraria; Abbvie: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Servier: Honoraria; Sysmex: Honoraria. Pierola: Abbvie, BMS, Jazz Pharma, Novartis, Syros: Speakers Bureau; AstraZeneca: Research Funding; Astellas, BMS, Jazz Pharma, Syros: Consultancy. Giagounidis: Amgen: Consultancy; BMS: Consultancy. Platzbecker: Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding.

*signifies non-member of ASH