Impact of Mutational Landscape and Biomarkers on Response of Luspatercept (ACE-536) Treatment of Anemia in Non-Transfusion Dependent IPSS-R Lower Risk MDS Japanese Subjects (ACE-536-MDS-003- a Ph2 single-arm study)

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.6725-6725
• Main Authors: Jaiswal, Bijay Shankar, Ugidos, Manuel, Kosugi, Hiroshi, Matsue, Kosei, Murakami, Hiromi, Hayakawa, Jin, Lopes de Menezes, Daniel, Gandhi, Anita K., Suragani, Rajasekhar N.V.S.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-201883

Background: Myelodysplastic syndromes (MDS) are among the most common hematologic malignancies affecting older adults characterized by ineffective hematopoiesis and typically manifest as anemia, cytopenia, an increased risk of infection and hemorrhage and often leading to acute myeloid leukemia (AML). For most patients (pts) with MDS, anemia and associated transfusion dependency (TD) are the most prominent clinical problems and determinants of quality-of-life. Patients with lower-risk (LR) MDS become TD and erythropoiesis-stimulating agents are the standard of care to treat anemia, increase hemoglobin (Hb) levels and decrease transfusion burden. Luspatercept is a first-in-class erythroid maturation agent, approved for red blood cell (RBC) TD LR-MDS for reducing the severity of anemia. However, the evidence of luspatercept efficacy among pts with non-TD (NTD) LR-MDS is currently limited. The ACE-536-MDS-003 study investigated the safety and efficacy of luspatercept in the treatment of anemia in NTD LR-MDS Japanese subjects. Objective: To evaluate impact of baseline (BL) mutational burden and biomarkers on clinical outcomes of luspatercept in NTD LR-MDS Japanese pts. Methods:ACE-536-MDS-003 (NCT03900715) is a Ph2, multi-center, single-arm study where 21 Japanese pts received luspatercept (starting dose 1.0 mg/kg, titration allowed to 1.75 mg/kg) Q3W for 24 weeks. The primary endpoint of HI-E (hematologic improvement-erythroid response) based on IWG (Cheson, 2006), was defined as the proportion of subjects meeting HI-E criteria of ≥ 1.5 g/dL increase of Hb over any consecutive 56-day period in the absence of RBC transfusions (RBCTs) from Week1 Day1 through Week24. Mutational analysis was performed on DNA isolated from bone marrow (BM) mononuclear cell using a panel targeting 39 MDS-relevant genes. Individual patient BM samples were prepared for sequencing using the Illumina® DNA prep with enrichment and hybridization capture of DNA libraries. Sequencing libraries were run on the NovaSeq6000 (Illumina®) system and statistical analyses were conducted using R. Results:The study met its primary end point, i.e., luspatercept response (HI-E response within 24 weeks) was 47.6% (95% CI, 25.7-70.2%, P