Real life data: follow-up assessment on Spanish Gaucher disease patients treated with eliglustat. TRAZELGA project.

BACKGROUND: The availability of multiple treatments for type 1 Gaucher disease increases the need for real-life studies to evaluate treatment efficacy and safety and provide clinicians with more information to choose the best personalized therapy for their patients. AIMS: To determine whether treatment with eliglustat produces, in adult GD1 patients, ans optimal response in daily clinical practice. METHODS: We designed a real-life study with 2 years of follow-up (TRAZELGA [GEE-ELI-2017-01]) to uniformly evaluate the response and adverse events to eliglustat treatment. This study, conducted in 30 patients across Spain and previously treated with other therapies, included the evaluation of safety and efficacy by assessing visceral enlargement, bone disease (DEXA and T and Z scores), concomitant treatments and adverse events, as well as a quality of life evaluation (SF-36). In addition, the quantification of classical biomarkers (chitotriosidase activity, CCL18/PARC and glucosylsphingosine (GluSph)) and new candidates for GD biomarkers (YKL-40, cathepsin S, hepcidin and lipocalin-2 determined by immunoassay) were also assessed. Non-parametric statistical analysis was performed and p < 0.05 was considered statistically significant. MAIN RESULTS: Thirty patients were enrolled in the study. The median age was 41.5 years and the male-female ratio was 1.1:1. 84% of the patients had received ERT and 16% SRT as previous treatment. The most common symptoms at baseline were fatigue (42%) and bone pain (38%), no patient had a bone crisis during the study, and two years after switching, 37% had reduced their use of analgesics. Patient-reported outcomes showed a significant increase in physical function scores (p = 0.027) and physical pain scores (p = 0.010). None of the enrolled patients discontinued treatment due to adverse events, which were mild and transient in nature, mainly gastrointestinal and skin dryness. None of the biomarkers show a significant increase or decompensation after switching. CCL18/PARC (p = 0.0012), YKL-40 (p = 0.00004) and lipocalin-2 (p = 0.0155) improved after two years and GluSph after one year (p = 0.0008) and two years (p = 0.0245) of oral therapy. CONCLUSION: In summary, this real-life study, showed that eliglustat maintains stability and can improve quality of life with few side effects. Significant reductions in classic and other novel biomarkers were observed after two years of therapy.

Co-occurrence of cohesin complex and Ras signaling mutations during progression from myelodysplastic syndromes to secondary acute myeloid leukemia.

Myelodysplastic syndromes (MDS) are hematological disorders at high risk of progression to secondary acute myeloid leukemia (sAML). However, the mutational dynamics and clonal evolution underlying disease progression are poorly understood at present. To elucidate the mutational dynamics of pathways and genes occurring during the evolution to sAML, next generation sequencing was performed on 84 serially paired samples of MDS patients who developed sAML (discovery cohort) and 14 paired samples from MDS patients who did not progress to sAML during follow-up (control cohort). Results were validated in an independent series of 388 MDS patients (validation cohort). We used an integrative analysis to identify how mutations, alone or in combination, contribute to leukemic transformation. The study showed that MDS progression to sAML is characterized by greater genomic instability and the presence of several types of mutational dynamics, highlighting increasing (STAG2) and newly-acquired (NRAS and FLT3) mutations. Moreover, we observed cooperation between genes involved in the cohesin and Ras pathways in 15-20% of MDS patients who evolved to sAML, as well as a high proportion of newly acquired or increasing mutations in the chromatin-modifier genes in MDS patients receiving a disease-modifying therapy before their progression to sAML.