Impact of Velaglucerase Alfa in the Inflammatory Status of Type 1 Gaucher Disease Patients after One Year on Therapy. A Prospective Multicentre Study

Gaucher disase(GD), the most studied lysosomal rare disorder, is characterized by an inflammatory status involved in the high incidence of complications, immune impairment and comorbidities (infections, bone, pulmonary involvement, gammapathies and parkinsonism). The role of cytokines in this inflammatory state is partially known, and the modifications in this profile in GD patients under enzymatic replacement therapy have not been reported and neither included in clinical trial. Our group has reported some changes on the cytokine profile in patients with severe bone involvement and some inflammatory biomarkers of macrophage activation related to the iron profile. (Gervas 2015, Medrano 2015). However there are not specific studies related to different therapies.

Here we are presenting the final outcomes of a multicentre prospective non interventional study to explore the changes in the biomarkers of immune response in a cohort of Spanish type 1 Gaucher disease patients after one year on Velaglucerase alfa therapy.

Patients and Methods: A total of 17 type 1 GD from 15 centers, were included in a prospective protocol following these criteria: symptomatic patients of both sexes, aged older than 4 years, naïve or previously treated but without ERT at least one month previous to be included. The study was approval by ethical committees and designed according Helsinki declaration rules; every one patient signed the informed consent and commitment to complete all study. Current recommendation for ERT with Velaglucerase alfa were followed in every centre.

The study included hematological parameters, goals of therapy assessment, bone disease assessment were carried out in every visit and bone marrow MRI evaluated by Spanish-MRI score (Roca et al 2004) and densitometry were performed at baseline and in the final visit according the availability in each centre. GD biomarkers (Chitotriosidase, CCL18/PARC), proinflammatory biomarkers (ferritin level, serum protein electrophoresis and gammapathy profile including free light chain analysis) and the following cytokine profile: IL-10, IL-13, IL-4, IL-6, IL-7, Mip1a, Mip1b,TNFa, performed at baseline and 12 months after therapy.

Results: General characteristics: 9 males, 8 females, mean age: 37.5 years (9-72). 3 splenectomized patients (17.6%); genotype: 3 N370S homozygous one heterozygous for N370S/L444P and the rest heterozygous for N370S/other. Seven patients (41.2%) have previous history of bone disease complications. All patients received velaglucerase alfa (30U/kg-60U/kg) iv every two weeks for 1 year in every day clinical practice, and achieving an bjective response on goals of disease (hemoglobine, platelets count, spleen reduction and clinically asymptomatic),bone marrow burden decrease and stabilization were registered by MRI in 14 patients, bone mineral density improvement were reported during the year of therapy in those patients. No infusion reactions were reported, neither antibodies against velaglucerase alfa; concerning to biomarkers, a reduction or stabilization of CT activity and CCL/18PARC concentration were significantly reduced (p=0.011; p=0.041 respectively), no modification in the ferritin concentration were registered, no monoclonal gammopathy were found but polyclonal gammopathy were observed in the majority of patients, a tendency of normalization were detected. The cytokine profile showed a decrease in all inflammatory cytokines tested however for Mip1a (p=0.017) and TNFa (p=0.023) a significant reduction were achieved. Table 1

Conclusion: Velaglucerase alfa is a well-tolerated therapy in every day clinical practice, with a positive impact in the immune response with a significant decrease on the inflammatory state reflected through the cytokine reduction and preventing development of bone complications in this cohort independently of previous therapies.

Acknowledgments: This work was partially supported by a grant from Shire and FIS: PS12/01219

A significant decrease on Mip1a (p=0.017) and TNFa (p=0.023) and the end of study