Impact of imiglucerase supply constraint on the therapeutic management and course of disease in French patients with Gaucher disease type 1

Abstract

BackgroundIn 2009, a worldwide supply constraint of imiglucerase led to treatment modifications or interruptions for patients with Gaucher disease (GD) type 1. In France, joint treatment recommendations were issued to protect the most vulnerable patients. This observational study evaluated the impact of imiglucerase treatment modifications on the clinical and biological course of GD.MethodsRetrospective data on patients’ characteristics, treatment, clinical and biological parameters from 01 June 2009 to 31 October 2010 were collected during a single visit.ResultsNinety-nine GD1 patients, aged 7–84 years, were included (median age 47 years); 10 were children. Patients experienced a median of 4 different treatment modifications. Median change from pre-supply constraint dose (92 U/kg/4-weeks) was −69, −51, −29 and −60 U/kg/4-weeks at 3, 6, 9 and 12 months after first modification, respectively, with imiglucerase discontinuation reported for 70%, 47%, 29% and 55% of patients at these timepoints. Replacement with another ERT was reported for 35 patients. Results show a statistically significant decrease in hemoglobin (−0.8 g/L/month) and platelets (−5905.103/mm3/month) and an increase in chitotriosidase (+537 nmol/mL/h/month) and angiotensin-converting enzyme (+4 IU/L/month) in the subgroup of 61 patients who discontinued treatment for at least 3 months; this magnitude of change was not seen in the subgroup (32 patients) treated with reduced imiglucerase for at least 3 consecutive months. GD-related events were spontaneously reported by the study investigators for 39% of the whole study population, including asthenia/fatigue (8%), bone infarction and bone pain (4% each), and hepatomegaly (3%). A Kaplan-Meier estimate of the probability for a patient to present a bone, hematological or visceral event during the constraint was 37% for patients who discontinued the treatment and 10% for patients treated with a reduced imiglucerase dose.ConclusionThe release of recommendations and individuals’ close follow-up allowed satisfactory management of patients during the imiglucerase supply constraint in France. This study suggests that during this period, lowering the dose of imiglucerase had less impact on the outcomes of patients than interrupting treatment. However, general effects (such as fatigue, bone pain) reported in some patients, emphasize the importance of maintaining appropriate individualized dosing.

Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy

“…Although it has been suggested that relapse is uncommon once patients with Gaucher disease type 1 have had their bulk disease controlled with enzyme therapy, 21 the effects of the constrained supply of imiglucerase from 2009 through 2012 show that clinical deterioration does occur in as little as 3 months with treatment interruption. 22,23 In our study, clinical stability was maintained with respect to hemoglobin concentration, platelet count, liver and spleen volumes, bone mineral density, and Gaucher biomarkers for up to 4 years, well beyond the interval that might be attributed to residual effects of prior long-term enzyme therapy. Although we are encouraged by the long-term maintenance of bone health, because the population had no active bone disease at baseline, data from this trial do not address the question of whether eliglustat can reverse preexisting bone disease.…”

Treatment Efficiency in Gaucher Patients Can Reliably Be Monitored by Quantification of Lyso-Gb1 Concentrations in Dried Blood Spots

“…Several studies subsequently reported consequences of the resulting treatment breaks and/or dose reductions. Laboratory parameters responded early, and most affected patients also showed a continuous clinical deterioration (e.g., [ 20 , 21 , 22 ]). Treatment interruptions are thus not considered for the management of GD patients any longer [ 23 ].…”

Rethinking fatigue in Gaucher disease

“…Fatigue was reported as an adverse event possibly or probably related to velaglucerase alfa treatment and as an infusion-associated reaction in 2 patients [ 24 ]. In an observational retrospective study of 99 French patients with GD, data regarding demographics, GD history, treatment, and biological and clinical characteristics were collected; other GD-related data could also be spontaneously reported by the investigators [ 25 ]. Fatigue was the most frequently reported GD-related event (8 %); no mention was made of any formal tools used to assess fatigue [ 25 ].…”