Efficacy of Luspatercept on Transfusion Burden and Cytopenias in Intermediate, High, and Very High Risk Myelodysplastic Syndromes
Authors: Leonard Daniel , Sallman David , Pugh Kelly , Bell Christopher S. , Al Ali Najla H. , Borate Uma , Komrokji Rami S. , Brunner Andrew M. 
Published: December 2024

Introduction:
Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis resulting in peripheral cytopenias and an increased risk in progression to acute myeloid leukemia (AML). Patients with red blood cell (RBC) transfusion dependence have shorter overall survival and frequent RBC transfusions have profound consequences on quality of life. Luspatercept, a recombinant fusion protein that acts as a TGF-beta ligand trap, is approved in low to intermediate risk MDS patients with RBC transfusion dependence. Patients with higher-risk MDS have a significant burden of transfusions and complications from chronic severe cytopenias. We evaluated the impact of luspatercept in patients with IPSS-R intermediate, high, or very high-risk MDS, to characterize IWG responses, RBC transfusion burden, and impact on other cytopenias.
Methods:
We utilized electronic medical records to retrospectively query clinical charts and identify patients who had received luspatercept with a diagnosis of MDS with IPSS-R ≥ 3.5 (intermediate risk disease and higher) and had received care at Mass General Cancer Center, Moffitt Cancer Center, or The Ohio State University Cancer Center. We extracted responses to luspatercept based on changes in serum hemoglobin, platelet, neutrophil count and respective transfusion burdens at 16 weeks pre- and post-treatment (IWG 2018 criteria).
Results:
We identified 62 patients with intermediate (n=38), high (n=18), or very high (n=6) IPSS-R risk MDS, who were treated with luspatercept between 2019 to 2024. The median age at the time of luspatercept initiation was 78 years old and 47% were male. WHO 2022 categorization included MDS-SF3B1 (n=19), MDS-del5q (n=6), MDS-LB (n=19), MDS-IB1 (n=8), MDS-IB2 (n=2) and MDS/MPN (n=8). The median blast count at luspatercept initiation was 2 (range, 0 - 16), and 63% (n=39/62) of patients had ring sideroblast positive disease. The most frequent mutations in the cohort included SF3B1 (47%; n=29), ASXL1 (21%; n=13), DNMT3A (19%; n=12), TET2 (19%; n=12), and U2AF1 (15%; n=9). The median baseline hemoglobin at luspatercept initiation was 7.4 g/dL (range 5.9 - 9.7), and patients were non transfusion dependent (NTD, n=10), low transfusion burden (LTB, n=15), or high transfusion burden (HTB, n=37). A total of 31 patients had a platelet count &lt; 100k (median of 52, range 2 - 97), and a total of 17 patients had an ANC &lt; 1000 (median ANC of 650, range 160 - 990). Patients received a median of 7 cycles of luspatercept (range 1 - 74). The luspatercept doses were 1 mg/kg (n=12), 1.33 mg/kg (n=15), and 1.75 mg (n=31).
48% of patients (n=30) achieved an IWG 2018 response on luspatercept (50% intermediate risk (n=15), 40% high risk (n=12), 10% very high risk (n=3)), including hemoglobin response (39%; n=24/62 evaluable), platelet response (16%; n=5/31 evaluable), or neutrophil response (59%; n=10/17 evaluable). Hemoglobin responses among HTB patients were a 38% HI-E rate (14/37; 22% HI-E minor, and 16% HI-E major response). Among LTB patients, 33% achieved HI-E (n=5/15); while NTD patients had a 50% HI-E rate with a &gt;1.5g/dL increase in serum hemoglobin levels (n=5/10). 16% of patients (n=10/62, 4 HTB, 6 LTB) reached transfusion independence. Among patients with platelets less than 100K, 16% (n=5/31) achieved a platelet response (HI-P); while 59% (n=10/17) of patients with an ANC &lt;1000/uL achieved neutrophil response (HI-N) during luspatercept therapy. Analysis of available NGS data did not reveal any genetic markers associated with response.
Conclusions:
These findings demonstrate clinical activity with luspatercept in patients with intermediate, high, and very high risk MDS, characterized by improvement in RBC transfusion needs across NTD, LTB, and HTB patients, as well as evidence of platelet and neutrophil responses among thrombocytopenic and neutropenic patients, respectively. Given the high burden of cytopenias in patients with higher-risk MDS, these data support further evaluation of luspatercept in this population, including better understanding of mechanisms of response and combination agents.