Luspatercept stimulates erythropoiesis, increases iron utilization, and redistributes body iron in transfusion-dependent thalassemia.

Luspatercept, a ligand-trapping fusion protein, binds select TGF-ß superfamily ligands implicated in thalassemic erythropoiesis, promoting late-stage erythroid maturation. Luspatercept reduced transfusion burden in the BELIEVE trial (NCT02604433) of 336 adults with transfusion-dependent thalassemia (TDT). Analysis of biomarkers in BELIEVE offers novel physiological and clinical insights into benefits offered by luspatercept. Transfusion iron loading rates decreased 20% by 1.4 g (~7 blood units; median iron loading rate difference: -0.05 ± 0.07 mg Fe/kg/day, p< .0001) and serum ferritin (s-ferritin) decreased 19.2% by 269.3 ± 963.7 µg/L (p < .0001), indicating reduced macrophage iron. However, liver iron content (LIC) did not decrease but showed statistically nonsignificant increases from 5.3 to 6.7 mg/g dw. Erythropoietin, growth differentiation factor 15, soluble transferrin receptor 1 (sTfR1), and reticulocytes rose by 93%, 59%, 66%, and 112%, respectively; accordingly, erythroferrone increased by 51% and hepcidin decreased by 53% (all p < .0001). Decreased transfusion with luspatercept in patients with TDT was associated with increased erythropoietic markers and decreasing hepcidin. Furthermore, s-ferritin reduction associated with increased erythroid iron incorporation (marked by sTfR1) allowed increased erythrocyte marrow output, consequently reducing transfusion needs and enhancing rerouting of hemolysis (heme) iron and non-transferrin-bound iron to the liver. LIC increased in patients with intact spleens, consistent with iron redistribution given the hepcidin reduction. Thus, erythropoietic and hepcidin changes with luspatercept in TDT lower transfusion dependency and may redistribute iron from macrophages to hepatocytes, necessitating the use of concomitant chelator cover for effective iron management.

Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.

The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status.