Luspatercept reduces cardiac stress and improves cardiac function in a TET2-deficient mouse model with features of heart failure with preserved ejection fraction: Evidence from phase 3 commands trial and pre-clinical studies Free

Introduction:

Luspatercept (inhibitor of activin receptor-Smad2/3 signaling) is approved as first-line treatment of anemia in adult patients with lower-risk myelodysplastic syndromes (LR-MDS) based on the COMMANDS trial (NCT03682536). Most frequent MDS-related somatic mutations (e.g., SF3B1, TET2, DNMT3A, ASXL1) can lead to dysregulated immune signaling which may drive both hematological malignancies and cardiovascular complications. Recent evidence also indicates a higher prevalence of TET2 and SF3B1 mutations in patients with heart failure with preserved ejection fraction (HFpEF). Additionally, loss of TET2 in murine studies has shown to induce anemia, drive HFpEF pathogenesis with enhanced pro-inflammatory signaling. Currently, no treatments are available to address cardiovascular disease (CVD)-risk in patients with MDS. Here, we used clinical data and a preclinical model that displays features of HFpEF to identify potential novel mechanisms of luspatercept that may modulate cellular signaling pathways and have impact on cardiac function.

Methods:

In the COMMANDS trial, the primary endpoint was red blood cell transfusion independence for ≥ 12 weeks with a concurrent mean hemoglobin increase of ≥ 1.5 g/dL (Weeks 1-24). Baseline and Week 24 samples (serum and bone marrow) were used for transcriptomics and proteomics analyses. Genomic DNA was extracted from baseline bone marrow mononuclear cells (n = 350), and myeloid specific 82 genes mutations were identified by targeted next-generation sequencing (median exon coverage of 2400× and 3% sensitivity [NovaSeq 6000, Illumina®]). Multivariable Cox regression analyses of prognostic factors were performed to investigate the survival outcomes. Murine analogue of luspatercept (RAP-536) was used in an experimental HFpEF model in wild type (WT) and TET2-knockout (TET2-KO) C57BL/6 mice. Echocardiographic assessment was done for cardiac hypertrophy and function. Blood parameters were measured following 4 weeks treatment with RAP-536.

Results:

At baseline, 87% (306/350) of patients from the COMMANDS trial had ≥1 of the most frequent MDS-related mutations (e.g., SF3B1, TET2, DNMT3A, ASXL1) with a median VAF ranging from 3% to 50%. Patients with frequent MDS-related mutations had higher NT-proBNP levels (median, 2200 pg/ml) compared to other mutations (median, 1725 pg/ml). Consistent with this, cardiac disorders reported as adverse events (AEs) and/or cause of death were observed in 20% of the patients, of which 89% were enriched with frequent MDS-related mutations. In responding patients (achieving primary endpoint), luspatercept treatment reduced inflammatory signaling and downregulated cardiac stress marker, NT-proBNP levels (∆ median, –620 pg/mL, P = 0.002). Additionally, we observed a reduction in levels of hepcidin (∆ median, –44ng/ml, P ≤ 0.0001), a peptide hormone that regulates iron homeostasis whose elevated levels have been associated with CVD. In a multivariable Cox regression analyses of prognostic factors, elevated NT-proBNP and hepcidin carried a higher risk of mortality in patients with LR-MDS (HR, 1.83, P = 0.003 and HR, 2.13, P ≤ 0.001, respectively) and luspatercept reduced this risk (HR, 0.78, P = 0.2), likely via reduction of NT-proBNP, hepcidin, and inflammatory signaling. Finally, using a novel mouse model recapitulating features of HFpEF and anemia due to TET2 deficiency, we showed that the murine analogue of luspatercept (RAP-536) significantly reduced cardiac hypertrophy (P < 0.01), diastolic dysfunction (P ≤ 0.0001) and improved anemia (P < 0.0001).

Conclusions:

Our exploratory reverse and forward translational approach demonstrates the potential beneficial effects of luspatercept in patients with anemia and HFpEF harboring frequent MDS-related somatic mutations. These findings reveal a previously unrecognized, cardioprotective action of luspatercept, highlighting its potential to address the substantial cardiovascular morbidity in LR-MDS and establishing a new paradigm for therapeutic benefit beyond hematologic improvement.