The efficacy and safety of luspatercept in patients with low-blasts myelodysplastic neoplasms in real world

Abstract Backgroud: Myelodysplastic neoplasms (MDS) are characterized by myelodysplasia and ineffective hematopoiesis leading to refractory cytopenia. Most of MDS patients had anemia at diagnosis requiring red blood cell (RBC) transfusion, which was an independent prognostic factor for poor overall survival of MDS. Therefore, improving anemia is one of the main goals of therapy in LR-MDS patients. Luspatercept, the transforming growth factor-β pathway inhibitor, showed good efficacy in low-risk MDS (LR-MDS) based on clinical trials. Aim: In this study, we analyzed the efficacy and safety of luspatercept in patients with low-blasts MDS (MDS-LB) compared to erythropoiesis-stimulating agents (ESA) in real world. Methods: The study planned to enroll MDS-LB patients newly diagnosed in the Department of Hematology, General Hospital of Tianjin Medical University from June 1st, 2022 to December 30th, 2024. The patients were divided into LR-MDS group (IPSS-R score ≤ 3.5) and HR-MDS group (IPSS-R score > 3.5) based on IPSS-R. The MDS patients in luspatercept group were received luspatercept treatment, as administered subcutaneously every 3 weeks. The starting dose of luspatercept was 1.0 mg per kilogram of body weight (mg/kg). If without erythroid response (HI-E, according to IWG 2018 criteria) and without disease progression after 2 cycles, patients could be received luspatercept with adjustment to a dose of 1.33 mg/kg and then to 1.75 mg/kg. The ESA group were received rhEPO ± roxadustat treatments. The primary end-point was the proportion of patients with HI-E. The key secondary end point was RBC transfusion independence (RBC-TI) for 8 weeks or longer. The adverse events (AE) were defined according to CTCAE 5.0. Results: The data-cutoff was June 30, 2024. A total of 48 MDS-LB were enrolled in this study (Luspatercept group n=27, ESA group n=21).(Table 1) Among luspatercept group, 11 (40.7%) had received treatments combined with ESA (including recombinant human EPO, roxadustat). The results showed that patients treated with luspatercept have a higher HI-E rate than those treated with ESA (73.9% vs. 55%), which might not be affected by SF3B1 mutation, serum erythropoietin level or transfusion burden. After 2 cycles of luspatercept treatment, the median Hb level increased significantly (P<0.05). The patients with first-line treatment, LR-MDS and combined treatments tended to have a higher response rate to luspatercept. The median time to achieve HI-E in luspatercept group was shorter than that of controls (1.5 vs. 5 months, P<0.01). (Table 1, Figure1) There was no serious AE observed. In luspatercept group, the median duration of response (mDOR) of patients received ≥ 3 cycle treatments was higher than that of < 3 cycles group (8 vs. 3 months, P<0.05). (Figure2) The HI-E group tend to have higher population of Treg, and lower concentrations of IL-2, IL-6, TNF-α and IFN-γ compared to non-HI-E group. The serum ferritin (SF), B-type natriuretic peptide (BNP) and C-reactive protein (CRP) levels in HI-E group tended to be lower than that of non-HI-E group. But there was no significant statistical difference between the two groups (all P>0.05). The BNP levels of patients with HI-E after luspatercept treatment were lower than the base-line (P <0.05). (Figure3) It indicated that inflammation factors might affect the response of luspatercept in MDS. Conclusions: This study showed that luspatercept was effective and tolerated well in MDS-LB patients. But inadequate treatments could affect the duration of response. It need to optimize the treatment of luspatercept in further. Key words: MDS-LB, luspatercept, EPO refractory, anemia, immune state