The Gaucher Registry: What 10 Years of Data Say

The International Collaborate Gaucher Group (ICGG) Gaucher Registry, financially and logistically supported by Genzyme Corporation, tracks routine clinical outcomes for patients with Gaucher disease. Physicians from all over the world are welcome to submit patient data to the registry, regardless of treatment status, which is maintained confidentiality and used to help determine response to treatment or establish other trends among individuals with Gaucher disease. Neal Weinreb, University Research Foundation for Lysosomal Storage Disorders, Coral Springs, Florida, gave a presentation on “Long-term Data from the ICGG Gaucher Registry: 10 Years of Treatment” at the Lysosomal Disease Network World Symposium. Weinreb said he hoped with his presentation “to provide some context and food for thought” for some of the data being presented at the symposium.

He started out by describing how much the registry has expanded in the past decade. “Ten years ago or so, there were approximately 1500 type 1 Gaucher patients enrolled in the registry and a small number of type 2 and 80 or so patients with type 3 disease,” he said. “Over a year ago, a little more than 3000 patients had been added to that total.” In 2008, there were approximately 4700 patients with type 1 Gaucher disease included in the database, a number that Weinreb said has continued to grow. Many of the new patients have been added from the United States and Israel. People of Ashkenazi Jewish descent have a higher risk of type 1 Gaucher disease, and organizations in these countries have worked steadily to increase awareness of the disease in Jewish communities.

Weinreb said the registry shows that progress has been made over the past decade. Whereas early studies focused on “discussing growth retardation in children with Gaucher disease,” said Weinreb, the addition of adolescents to the registry demonstrates that “there’s been rather robust growth and development that has taken place.” There has been a lot of recent focus among the ICGG on long-term outcomes. He noted that the registry has previously examined malignancy in Gaucher disease and plans to release data soon relating to the incidence of Parkinson’s in Gaucher patients in the registry.

One of the problems, said Weinreb, is that the registry presents a “very mixed bag” of Gaucher patients. “We have patients that were waiting many years to start treatment—some that began treatment at an elderly age were carrying the burden of disease for a long time.” Weinreb said it can be difficult to draw universal conclusions from such a diverse group of patients and praised the increasing number of pediatric patients represented in the Gaucher registry who started treatment early in life. “We hope that this population will actually constitute the true population, which can be followed over many years to try to determine what shifts actually occur…[and how] starting people on treatment earlier…affects the longer-term outcomes of this disease,” Weinreb explained.

One of Weinreb’s concerns about the presentations at the symposium on Gaucher was whether the short-term trial results would be representative of “true clinical outcomes” and the relevancy of outcomes such as spleen size and platelet count to the extent of clinical benefit. He pointed out that all the parameters looked at in terms of short-term response typically normalize in children treated with imiglucerase for Gaucher disease. The exception, he said, is bone density data, which require several years of treatment before normalization becomes evident. He gave an example of data the ICGG hopes to publish later this year: “There is a group of children who are started on treatment in adolescence whose bone mineral density is low to begin with—much lower than is depicted here—and their response seems not to be as complete.”

Weinreb said this calls into question a sensitive, controversial issue; namely, what is the right time to initiate treatment for Gaucher disease? According to Weinreb, the registry suggests that as recently as 2007 to 2008, approximately 6 years elapsed between diagnosis and the initiation of therapy.

When evaluating the studies presented at the symposium, Weinreb questioned whether the appropriate therapeutic goals have been established. “We’re sort of stuck in this mode where we’re looking at laboratory outcomes rather than clinical outcomes,” he said. The concept of therapeutic goals, he said, was molded more than 10 years ago and based on the 2- to 5-year responses of patients in the registry to enzyme replacement therapy (ERT).

Weinreb outlined two philosophical approaches to treatment. One approach is tailored treatment, which he said involves conducting a risk assessment and then delivering a fixed dose of treatment based on the outcome. “This concept has been popularized in the treatment of high cholesterolemia,” he said. The other approach is a targeted approach, which involves modifying the dose based on the attainment of certain therapeutic goals.

The tailored approach is problematic in Gaucher disease, said Weinreb. “One has to have an accurate way of assessing clinical risk and that is by no means a simple problem in Gaucher disease.” He said that even with all the diagnostic tools available today, there is no “real way” to predict the risk of a Gaucher patient at diagnosis. To aid in risk assessment, the ICGG has been working on a scoring system that they hope to evaluate in a larger study soon.

As to the targeted approach, Weinreb said most of today’s therapeutic goals, with the exception of bone health, appear to have little clinical meaning except in patients with “severe anemia or severe thrombocytopenia or organ enlargement.” He questioned why normalcy is not the therapeutic goal when discussing platelet count or spleen size and added that there is no biologic basis for the measures currently used.

Weinreb said the problem with the tailored and targeted approaches is that they suggest outcomes are dose dependent but the registry contradicts this in some ways. “It’s quite apparent that patients responded to all doses of imiglucerase, even as low as or less than 15 U/kg every 2 weeks up to the more traditional 60 U/kg per week,” he said. He said overall, the differences in responses are subtle, with most patients achieving normalcy on treatment and the majority maintaining responses on intermediate dose levels. “In terms of rapid increase in improvement of hemoglobin, concentrations within the first year of treatment tend to be sustained after 10 years,” Weinreb explained.

Weinreb suggested several areas for future investigation, including whether very high hemoglobin levels, of 13 or greater, might be detrimental in terms of certain aspects of bone disease. He suggested additional research is needed to determine why half of patients, even after 10 years of treatment, theoretically continue to be thrombocytopenic and whether this has any relationship to bone disease. Splenomegaly is another concern, Weinreb said, with few patients achieving normal spleen volume and little known about the life cycle of the Gaucher cell within the spleen. He said when to start treatment to minimize the risk of splenectomy is another area that should be looked at. “Looking to the future, we are certainly interested in issues of continuing to examine response to treatment, looking at the effects of enzyme therapy on type 3 disease, the whole issue of looking at how to properly apply biomarkers in clinical practice, the effect of ERT interruptions, the whole issues of new therapies and how the Gaucher registry is going to relate to them,” Weinreb said.

Concerning the future of the registry, Weinreb said a major makeover of the registry platform is currently underway. “The new features of the registry should enhance the speed of entry and delivery,” he said. He concluded that the ICGG also hopes to deliver a patient accessible mode in the future. It is clear that the registry has proved to be a valuable resource to clinicians and researchers alike, making it easier to assess the development of this disease in what is a small worldwide patient population.