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)
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. 
Published: December 2024

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&lt;0.0001) and modified HI-E (mHI-E) response within 24 weeks was 57.1% (95% CI, 34.0-78.2%). Median time to HI-E was 26.5 days (range 14-85 days) within 24 weeks. Luspatercept showed response regardless of BL serum erythropoietin (EPO) and Hb levels. Patients with BL serum EPO level of &lt;=200U/L (vs &gt;200 U/L) or Hb level &gt;= 8g/dL (vs &lt;8g/dL) were more favorably associated with response.
Overall at BL, a median of 2 (range 0-4) of the 39 MDS-relevant genes analyzed were mutated per patient. Numbers of mutated genes at BL were similarly distributed in luspatercept responders and non-responders and luspatercept-elicited response was independent of mutational burden.
SF3B1 was the most frequently mutated gene (10/21 pts, 48% of pts). The other prevalent mutations were TET2 (38%), ASXL1 (14%), ZRSR2 (14%) and U2AF1 (10%). All SF3B1 mutations were found in the RS+ subgroup (with median VAF of 40%). Luspatercept responses were observed in 90% (9/10 pts) of SF3B1 and 62.5% (5/8 pts) of TET2 mutated pts. SF3B1 was predominantly co-mutated with TET2 (6/8 pts) and luspatercept responses in this pts subset was 83.3% (5/6 pts). Gene mutation profiles in the Japan cohort was similar to the Ph3 COMMANDS study, except DNMT3A mutations were not detected. IPSS-R LR-MDS pts showed clinical benefit across various mutational types. Luspatercept responses were also observed with ASXL1 (2/3), TP53 (1/1), IDH2 (1/1), U2AF1(2/2) and ZRSR2 (1/3) mutated pts. When the genes were aggregated by pathway, genes related to splicing, DNA methylation and chromatin modification were associated with luspatercept response.
Conclusions: ACE-536-MDS-003 was the first study in Japanese NTD LR-MDS pts to demonstrate clinical benefit of luspatercept. Luspatercept offered significant improvement of Hb values in the absence of RBCTs. Luspatercept showed clinical benefit in pts with LR-MDS across IPSS-R risk groups regardless of RS and mutational status, albeit having a significantly higher response in pts with an SF3B1 mutation. Further studies are warranted in a larger pts population to establish luspatercept efficacy in NTD LR-MDS.