Minimal disease activity in Gaucher disease: Criteria for definition

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Abstract

Gaucher disease type I is a metabolic disorder caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of glucocerebroside in macrophages, thus causing damage in different organ systems. Enzyme replacement therapy with imiglucerase improves organ impairment and clinical manifestations, but patients differ in response to treatment. While clinical remission is the most desirable therapeutic outcome, a more realistic goal in patients with high disease burden is reasonably good clinical status despite persistence of residual biochemical or imaging abnormalities. Therefore, the concept of minimal disease activity – used in certain haematological or rheumatologic conditions – needs to be introduced in Gaucher disease, with a level of disease activity that patients and physicians consider a useful treatment target. In this paper, we propose specific parameters and criteria for defining minimal disease activity in Gaucher disease and its stability over time, based on three major systemic domains typically involved: haematological, visceral, and skeletal. Biomarker parameters were not included as criteria, because currently they do not adequately reflect disease evolution in individual patients. Neurological and respiratory domains were also excluded, as their involvement per se indicates severe disease unlikely to respond to enzyme replacement therapy and achieve minimal disease status. Our goal in defining minimal disease activity and stability is to identify a tool to facilitate treatment decisions in clinical practice.

Highlights

► Gaucher disease is the first lysosomal disease for which therapy became available. ► Gaucher patients with high disease burden are unlikely to achieve remission. ► Attaining reasonably good clinical status is realistic treatment goal for them. ► The Authors design the concept of minimal disease activity in Gaucher disease. ► Patients with minimal disease activity could be addressed to maintenance therapy.

Introduction

Gaucher disease (GD) type I is a multisystemic metabolic disorder caused by a genetic deficiency of lysosomal β-glucocerebrosidase that leads to accumulation of its substrate, glucocerebroside, in macrophages. These altered macrophages infiltrate the spleen, liver, bone marrow, bone, and lung, resulting in clinical manifestations that include hepatosplenomegaly, peripheral blood cytopenia and skeletal lesions [1]. Striking differences have been reported in phenotype and clinical progression, even among patients with the same genotype, with effects that differ according to organs involved [2]. Enzyme replacement therapy (ERT) with imiglucerase is effective in improving organ volume, anaemia, thrombocytopenia, bone disease, and biomarker levels in patients with GD [3], [4].

Clinical remission, defined as absence of disease activity, is the most desirable therapeutic outcome, and represents an achievable goal for patients with only hematologic and visceral involvement who are diagnosed and treated early. Patients with high disease burden are unlikely to achieve remission, even with high-dosage therapy. Attaining reasonably good clinical status despite residual biochemical or imaging abnormalities represents a more realistic treatment goal for these patients. Therefore, alongside the notion of clinical remission, we need to introduce the concept of minimal residual disease (MRD) or minimal disease activity (MDA) for Gaucher disease.

Assessment of MRD has gained a significant role in treatment protocols for patients with a number of onco-haematological disorders, like acute lymphoblastic leukaemia [5], lymphoma [6], or other neoplastic disorders based both on its high prognostic value and potential diagnostic utility in treatment stratification. In rheumatology, the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) program introduced the concept of low disease activity state (LDAS) or MDA for rheumatoid arthritis [7], [8]. This corresponds to the “state of disease activity deemed a useful target of treatment by both the patient and the physician, given current treatment possibilities and limitations” [7], and was shown to be useful in both clinical and epidemiological research [9], [10]. This characterization is an appropriate starting point for developing a definition of MDA in Gaucher patients.

In 2008, we published a severity score index, the Gaucher disease Severity Score Index—Type I (GauSSI-I) [11], a useful tool for measuring both global disease severity and the severity of single organ involvement (e.g., bone, lung, viscera); moreover, it can be used for optimising ERT dosage and monitoring treatment efficacy. However, GauSSI-I also assigns individual scores to abnormalities that cannot be modified by cause-specific therapy – splenectomy, prosthesis, Parkinson disease/parkinsonism, and pulmonary hypertension – so that a low GauSSI-I score cannot be considered equivalent to MDA. In 2010, Weinreb and co-workers proposed another severity scoring system [12]; here too, a low score does not correspond to the above mentioned characterisation of MDA. Thus, a new definition of MDA is needed for adult GD patients that can differentiate between these conditions.

The goal in defining MDA in GD and its stability over time, is to identify a tool that facilitates treatment decisions in clinical practice. Patients achieving durable MDA could be addressed to maintenance therapy, for example with oral substrate inhibitors, dose adjustments, or low frequency ERT. Such a tool could help to optimise treatment in terms of benefit/risk ratio, as well as cost/benefit ratio. In this article, we identify parameters and criteria that define MDA and MDA stability in adult patients with GD type I, and propose this definition as a tool for long-term management of the disease.

Section snippets

Expert panel and procedures

A panel of Italian experts in the diagnosis and management of Gaucher disease was gathered with the aim of identifying clinical, laboratory and imaging parameters, and the appropriate criteria for defining MDA and MDA stability in GD. A modified Delphi technique [13] was used in the form of analytical written rounds and individual face-to-face discussions. First the panel agreed on which systemic domains to include and the most appropriate parameters to measure within each domain. Subsequently,

Discussion

GD is an inherited lysosomal storage disease caused by an autosomal recessive defect in the gene encoding glucocerebrosidase that leads to accumulation of glucosylceramide in reticulo-endothelial cells (particularly in the liver, spleen, bone marrow and lung). Thus, GD is a chronic multi-organ disorder. The most prevalent form is the so-called non-neuronopathic form (type 1), characterised by anaemia, thrombocytopenia, enlargement of liver and/or spleen, skeletal abnormalities (osteopenia,

Conflict of interest disclosures

Maja Di Rocco has received honoraria from Genzyme ,Actelion and Shire. Generoso Andria has received travel support for meeting attendance by Actelion, Biomarin, Genzyme and Swedish Orphan;he has also received grants by Genzyme, Shire, Actelion, Biomarin and Amicus. Bruno Bembi has received honoraria and grants from Genzyme, Actelion and Shire. Maria Cappellini is member of speaker bureau for Novartis and member of advisory board for Novartis, Shire and Genzyme. Francesca Carubbi has received

Acknowledgments

The meeting to formulate this consensus was supported by Genzyme. Genzyme had no formative role in developing this consensus or in the decision to submit the manuscript for publication. All views expressed are solely those of Authors.

Authors would like to thank Elsevier for editorial assistance and Dr. Luigi Maria De Matteis for medical writing support.

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