Low-dose versus high-dose therapy for Gaucher disease: goals and markers

Zimran et al state in their commentary¹  that the title of our study²  is misleading because the superior effect of a high dose of imiglucerase compared with a low dose is “limited to the response of 2 surrogate markers, serum chitotriosidase and MRI scanning of the marrow.”^1(p802) We agree that no superiority of the higher dose was established with respect to the most widely used parameters of disease (ie, cytopenia and organ volumes), although subtle differences may not have become apparent due to the limited number of matched pairs for each parameter. In fact, we have shown in the past that one ninth of the originally established dose leads to sustainable improvements in a subset of adults.³  The question arises: how do we best evaluate the efficacy of enzyme replacement therapy in Gaucher disease by optimally exploiting available biomarkers? By definition, biomarkers are either clinical markers or mechanism-based biochemical markers that correlate with observed outcomes. The biomarkers could be used in clinical studies as proof of concepts or clinical end points.⁴  For example, in diabetes, glycosylated hemoglobin can serve as a biochemical marker and measures of nephropathy as a clinical marker, which should be evaluated against clinical end points, such as life or death, cure or failure, or time to an event. Of interest, for Gaucher disease, these clinical end points are not at all clearly defined: the overall goals of treatment are still the subject of debate.⁵  Obvious goals are to achieve normal growth and development in children, normal blood counts, absence of symptomatic organomegaly, and absence of new skeletal events. Ultimately, complications such as fibrosis of the liver and the occurrence of malignancies should be prevented. How do these goals relate to the existing biomarkers? Earlier meta-analyses have focused on liver size as a clinical marker;⁶  however, its relation with these outcome measures was never thoroughly validated. The absence of a “gold standard” for disease severity in Gaucher patients hampers the validation of any marker, whether liver size or chitotriosidase. At least for chitotriosidase, there is the observation that in spleen tissue the relation between chitotriosidase levels and stored glucosylceramide is almost linear, and there is immunohistochemical evidence that chitotriosidase is secreted by Gaucher cells.⁷  Clinically, the enormous elevation in plasma, the prompt decrease upon successful treatment,²  and the increase of chitotriosidase upon treatment interruption⁸  indicate that it might even be the best of all biomarkers. As to the validity of decreased bone marrow fat fraction (the triglyceride content of the marrow and not the “Gaucher fat”) in relation to clinical bone disease, a decrease in the fat fraction of 10% is associated with an increased risk for occurrence of bone complications of 85%.⁹  No other marker for skeletal disease has proved superior.

In summary, there is novel evidence for dose dependence for the enzymatic effects of imiglucerase on 2 well-established markers. Apparently, this finding has aroused a discussion that hopefully will stimulate a critical evaluation of clinical and biochemical markers against predefined goals of therapy.