Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis

Abstract

Dosing of enzyme replacement therapy (ERT) for Gaucher disease type 1 is still a subject of debate and varies from 15 to 130 U/kg/mo, making a huge economic difference of US $70 000 to US $380 000 (€55 000-300 000) per patient per year. To investigate whether this difference in dosing ultimately translates into a different response, we retrospectively compared long-term outcome of ERT at 2 large European treatment centers, Academic Medical Center, Amsterdam, The Netherlands (n ‫؍‬ 49, median dose, 15-30 U/kg/4 wks) and Heinrich-Heine University, Duesseldorf, Germany (n ‫؍‬ 57, median dose, 80 U/kg/4 wks). These adult cohorts had a similar genetic background. All follow-up parameters were matched separately at baseline, to avoid bias with respect to disease severity. Improvement in hemoglobin, platelet count, and hepatosplenomegaly was not significantly different between both cohorts, whereas plasma chitotriosidase and bone marrow involvement by magnetic resonance imaging improved more quickly and was more pronounced in the higher-dosed group. Major bone complications rarely occurred in both groups.

Enzyme replacement therapy with velaglucerase alfa in Gaucher disease: Results from a randomized, double‐blind, multinational, Phase 3 study

“…Statistical testing for plasma chitotriosidase and CCL18 levels were not controlled for multiple testing. For statistical analysis of chitotriosidase, values were multiplied by two in patients who were heterozygous for the chitotriosidase mutation [8]; patients who were homozygous deficient or had baseline chitotriosidase activity<5,000 nmol/mL/h were excluded [13,14].…”

Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy

“…2 Whether it is useful to continue high dose or increase the dose in these cases is currently unknown. We describe one illustrative case and compared GD patients with and without persistent bone disease with respect to disease markers and the effect of dose.…”

Using the International Gaucher Disease Registry data: Can we devise a virtuous circle for treated patients?

“…Although we have not seen any effect of genotype on response to enzyme therapy [13], the analysis of genotype based on the full ICGG cohort may elucidate the apparent conundrum where some investigators have recommended higher doses in patients ''resistant'' to lower doses [14] although these same authors have not found a real difference in clinically important disease parameters by virtue of higher doses [15]. More than a decade ago, Beutler [16] maintained that there are patients who will respond poorly to any dose while others will respond well regardless of dose.…”