Improving the accuracy of MRI spleen and liver volume measurements: A phase III Gaucher disease clinical trial setting as a model

doi:10.1016/j.bcmd.2010.10.009

Blood Cells, Molecules, and Diseases

Volume 46, Issue 1, 15 January 2011, Pages 47-52

https://doi.org/10.1016/j.bcmd.2010.10.009 Get rights and content

Abstract

Purpose

To achieve minimal inter-observer variability in assessment of spleen and liver volume changes using a novel MRI reading method in the context of a phase III clinical trial of a new therapy for Gaucher disease.

Materials and methods

Abdominal MRI examinations at screening and after 6 and 9 months' exposure to a novel plant-cell-derived recombinant enzyme, taliglucerase alfa, were taken in 31 patients with Gaucher disease and at least 8-fold greater than expected splenomegaly. Transverse T2, T1, and in/out-of-phase, and coronal T1 sequences were performed using standardized settings across 11 sites globally. Spleen and liver volumes were semi-automatically delineated using an automatic segmentation algorithm followed by manual correction by experienced technologists using advanced editing tools. Data of all randomized patients were then submitted for efficacy evaluation to two independent experts blinded to time-point and treatment.

Results

Mean (± SD) percent variability over all time-points was 0.30% ± 0.46% for spleen and 0.53% ± 0.69% for liver using 178 spleen and liver volumes measured twice. Adjudication due to ≥ 5% variability between observers was not required.

Conclusion

The measurement method was found to be precise in monitoring spleen and liver volume changes over time, with a much lower variability than traditional manual methods, supporting the accuracy of the results. Given the observed minimal variability rates among multiple readers, a single read of each volume would be sufficient.

Introduction

Gaucher disease, the most prevalent lysosomal storage disease [1], [2], [3], is caused by mutations in the glucocerebrosidase gene (GCD), leading to a reduced activity of the lysosomal enzyme glucocerebrosidase and an accumulation of the substrate glucocerebroside in the cells of the monocyte–macrophage system. This storage leads to hepatosplenomegaly and consequent hypersplenism as well as skeletal involvement, and less frequently, lung and neurological involvement [4].

Identification of GCD deficiency as the etiology of Gaucher disease stimulated the development of the first enzyme replacement therapy (ERT) as a therapeutic strategy for this and eventually other single gene lysosomal diseases. ERT provides sufficient exogenous active enzyme to degrade the accumulated substrate in the macrophages and ameliorate the disease-specific visceral features. ERT, which has been available for Gaucher disease for nearly two decades, has been shown to be safe and clinically efficacious within 2–5 years [5], [6], [7], [8].

Clinical trials to introduce new ERTs or other therapeutic modalities in Gaucher disease have opted for multiple primary endpoints for proof of efficacy because of the need for stringent standardized criteria that are unambiguous. Since reduction in organomegaly is a clinically relevant feature of successful treatment that also translates into improvement in the hematological features, changes in spleen and liver volumes are common endpoints in clinical trials of Gaucher disease [9], [10]. Nonetheless, in designing efficacy endpoints for clinical trials in Gaucher disease, there may be confounding variables when choosing improvement in anemia or thrombocytopenia (e.g., concurrent iron-deficiency or idiopathic thrombocytopenic purpura, respectively) or reduction in hepatomegaly (especially when it is very minimal). Hence, change in spleen volume is the most ideal parameter as a marker of efficacy, but absolute accuracy in measurement would have to be proven to be independent of observer bias in order to accommodate a multi-center trial.

This paper describes a novel method to achieve a very low degree of inter-observer variability in MRI spleen and liver volume assessments as demonstrated in a phase III clinical trial of a new ERT for Gaucher disease.

Section snippets

Study methodology

The study used as a prototype for the methodology a phase III randomized double-blind parallel-group dose-ranging clinical trial involving 11 international sites that received IRB approval and recruited 31 treatment-naïve patients with Gaucher disease who consented to receive a plant-cell-derived recombinant ERT (taliglucerase alfa; Protalix, Carmiel, Israel). The single primary endpoint was reduction in spleen volume after 9 months of treatment in two-dose groups; liver reduction was a

Variability results

The variability in 178 volumes (89 each of spleen and liver) reviewed twice is presented in Fig. 5.

The mean inter-observer variability per time-point is summarized in Table 1. Overall, mean variability in spleen measurements was 0.30% compared to 0.53% for liver measurements.

Variability being less than 5% for all cases, no adjudication was required.

The outlier which can be seen at screening on both spleen and liver measurements corresponds to an examination of poor quality which could not be

Factors influencing accuracy

Given the large variety of scanners used across sites, which is inevitable in the context of an international multi-center trial, the accuracy of a cross-sectional analysis may be decreased, unless one is able to monitor the variability induced by the systems themselves and make sure it is minimal. This could be addressed by scanning abdominal phantoms multiple times at different sites. The influence of field strength would also be a subject of interest, even though here all scans were

Conclusion

A semi-automatic organ volume measurement methodology utilizing an automatic segmentation software method was found to be precise in monitoring spleen and liver volume changes over time, with a much lower variability than traditional fully manual methods. Given the observed minimal variability rates among multiple central imaging expert readers, a single read of each case would be sufficient to accurately measure spleen and liver volumes, and detect response to treatment on follow-up

Disclosures

As a contract research organization (CRO), BioClinica was selected by Protalix for managing the MRI component of their phase III study. The services performed were invoiced as stated in the CRO contract. BioClinica staff and the central imaging expert readers remained blinded to treatment groups and declared no conflicts of interest in this work. Besides, Einat Brill and Raul Chertkoff are full time Protalix employees.

References (17)

N.J. Weinreb et al.
Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher registry
Am. J. Med.
(2002)
A. Zimran et al.
Phase 1/2 and extension study of velaglucerase alfa replacement therapy in adults with type 1 Gaucher disease: 48-month experience
Blood
(2010)
M. de Fost et al.
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
Blood
(2006)
L.W. Poll et al.
Correlation of bone marrow response with hematological, biochemical, and visceral responses to enzyme replacement therapy of nonneuronopathic (type 1) Gaucher disease in 30 adult patients
Blood Cells Mol. Dis.
(2002)
N.J. Weinreb et al.
Gaucher disease type 1: revised recommendations on evaluations and monitoring for adult patients
Semin. Hematol.
(2004)
G.M. Pastores et al.
Therapeutic goals in the treatment of Gaucher disease
Semin. Hematol.
(2004)
E. Beutler et al.
The clinical course of treated and untreated Gaucher disease. A study of 45 patients
Blood Cells Mol. Dis.
(1995)
E. Catmull et al.
A class of local interpolating splines

There are more references available in the full text version of this article.

Cited by (19)

Lysosomal functions and dysfunctions: Molecular and cellular mechanisms underlying Gaucher disease and its association with Parkinson disease
2022, Advanced Drug Delivery Reviews
Citation Excerpt :
In ERT, the missing enzyme is infused intravenously. It is usually a recombinant enzyme produced in different tissue culture systems such as Chinese Hamster Ovary (CHO) [15], human fibrosarcoma [16], or plant-derived cell lines [17,18]. Mannose targeted recombinant enzyme reaches affected cells, such as the reticuloendothelial system in GD, but mostly the access to various tissues and organs such as the brain is limited.
Lysosomes have a critical role in maintaining normal cellular homeostasis mediated by their involvement in secretion, plasma membrane repair, cell signaling and energy metabolism. Lysosomal storage disorders (LSDs) are a group of approximately 50 rare disorders caused by lysosomal dysfunction that occur due to mutations in a gene of a lysosomal protein. Gaucher disease (GD), an autosomal recessive disorder and one of the most common LSDs, is caused by the deficiency of the lysosomal enzyme acid-β-glucocerebrosidase (GCase), due to biallelic mutations in the GBA1 gene. Reduced GCase activity leads to the accumulation of glucosylceramide (GlcCer), which is deacylated by lysosomal acid ceramidase to a toxic metabolite, glucosylshpingosine (GlcSph). Most GBA1 variants are recognized as misfolded in the ER, where the retention for refolding attempts initiates stress and activates the stress response known as the Unfolded Protein Response (UPR).
The distinct clinical subtypes of GD are based on whether there is primary involvement of the central nervous system. Type 1 GD (GD1) is the nonneuropathic type, however, the recent recognition of the association of GD with the development of parkinsonism defies this classification. Patients with GD1 and carriers of GBA1 mutations are at risk for the development of parkinsonian manifestations. Parkinson disease (PD), the second most prevalent neurodegenerative disease, culminates in a movement disorder with the premature death of the patients. In PD and related disorders, collectively called synucleinopathies, the hallmark pathology is α-synuclein positive aggregates referred to as Lewy bodies or Lewy neurites and the death of dopaminergic neurons. While PD is mostly sporadic, in ∼5–10% of cases, the disease results from pathogenic variants in a growing number of genes. The most common genetic cause of PD is mutations in GBA1. Two mechanisms have been proposed for this link: (A) a “gain of function” mechanism, in which mutant GCase (protein) contributes to aggregate formation and to the development of PD, and the (B) “haploinsufficiency” (“loss of function”) model, suggesting that one normal GBA1 allele is insufficient to carry adequate GCase activity and functional deficiency of GCase impedes α-synuclein metabolism. Lysosomal dysfunction, compromised autophagy and mitophagy further enhance the accumulation of α-synuclein, which results in the development of PD pathology.
The present review will elaborate on the biology of GD, its association with PD and related disorders, and discuss the possible mechanisms underlying this association.
Long-term efficacy and safety results of taliglucerase alfa through 5 years in adult treatment-naïve patients with Gaucher disease
2019, Blood Cells, Molecules, and Diseases
Taliglucerase alfa, the first available plant cell–expressed recombinant therapeutic protein, is an enzyme replacement therapy approved for Gaucher disease (GD). PB-06-001, a pivotal phase 3, multicenter, randomized, double-blind, parallel-dose study investigated taliglucerase alfa 30 or 60 U/kg every other week through 9 months in treatment-naïve adults with GD; 30-month extension study PB-06-003 followed. Patients completing PB-06-001 and PB-06-003 could continue treatment in PB-06-007. Nineteen patients enrolled in PB-06-007 (30 U/kg, n = 8; 60 U/kg, n = 9; dose adjusted, n = 2); 17 completed 5 total years of treatment. In these 3 groups, respectively, taliglucerase alfa resulted in mean decreases in spleen volume (− 8.7, − 6.9, − 12.4 multiples of normal), liver volume (− 0.6, − 0.4, − 0.5 multiples of normal), chitotriosidase activity (− 83.1%, − 93.4%, − 87.9%), and chemokine (CC motif) ligand 18 concentration (− 66.7%, − 83.3%, − 78.9%), as well as mean increases in hemoglobin concentration (+ 2.1, + 2.1, + 1.8 mg/dL) and platelet count (+ 31,871, + 106,800, + 34,000/mm³). The most common adverse events were nasopharyngitis and arthralgia. Most adverse events were mild/moderate; no serious adverse events were considered treatment-related. These results demonstrate continued improvement of disease parameters during 5 years of taliglucerase alfa therapy in 17 treatment-naive patients with no new safety concerns, extending the taliglucerase alfa clinical efficacy and safety dataset. This study was registered at www.clinicaltrials.gov as NCT01422187.
Assessment of the liver and spleen in children with Gaucher disease type I with diffusion-weighted MR imaging
2018, Blood Cells, Molecules, and Diseases
To assess hepatic and splenic apparent diffusion coefficient (ADC) in children with Gaucher disease type I with diffusion-weighted MR imaging and to correlate hepatic and splenic ADC with parameters of disease severity.
Prospective study was conducted upon 25 children (11 treated and 14 untreated) with Gaucher disease and 12 age and sex matched control children. They underwent diffusion-weighted MR imaging of abdomen. Hepatic and splenic ADC and volume were calculated.
There was statistically difference in hepatic and splenic apparent diffusion coefficient (P = 0.001) between patients and controls. The cutoff ADC of liver and spleen used to differentiate patients from controls were 0.47 and 0.39 × 10^− 3 mm² with area and curve of 0.947 and 0.886 respectively. There was significant difference in hepatic and splenic ADC between untreated and treated patients (P = 0.003 and 0.001). Hepatic ADC correlated with splenic volume (r = − 0.721), hepatic volume (r = − 0.555) and chitotriosidase (r = − 0.413). Splenic ADC correlated with splenic volume (r = − 0.652), hepatic volume (r = − 0.544) and chitotriosidase (r = − 0.355).
Hepatic and splenic ADC can detect hepatic and splenic infiltration in Gaucher disease and correlated with some parameters of disease severity.
Long-term safety and efficacy of taliglucerase alfa in pediatric Gaucher disease patients who were treatment-naïve or previously treated with imiglucerase
2018, Blood Cells, Molecules, and Diseases
Citation Excerpt :
Exclusion criteria were presence of severe complex neurological signs and symptoms characteristic of neuronopathic GD other than long-standing oculomotor gaze palsy; any medical, emotional, behavioral, or psychological condition that would interfere with study participation; and current use of another investigational agent. Spleen and liver volumes were measured using a volumetric MRI technique employing automatic segmentation software methodology, which allows for lower variability and more precise monitoring of changes over time than traditional, fully manual methods [13]. Volume was calculated in multiples of normal (MN), where normal spleen volume is 2 mL/kg and normal liver volume is 25 mL/kg.
Taliglucerase alfa is an enzyme replacement therapy approved for treatment of Gaucher disease (GD) in children and adults in several countries. This multicenter extension study assessed the efficacy and safety of taliglucerase alfa in pediatric patients with GD who were treatment-naïve (n = 10) or switched from imiglucerase (n = 5). Patients received taliglucerase alfa 30 or 60 U/kg (treatment-naïve) or the same dose as previously treated with imiglucerase every other week. In treatment-naïve patients, taliglucerase alfa 30 and 60 U/kg, respectively, reduced mean spleen volume (− 18.6 multiples of normal [MN] and − 26.0 MN), liver volume (− 0.8 MN and − 0.9 MN), and chitotriosidase activity (− 72.7% and − 84.4%), and increased mean Hb concentration (+ 2.0 g/dL and + 2.3 g/dL) and mean platelet count (+ 38,200/mm³ and + 138,250/mm³) from baseline through 36 total months of treatment. In patients previously treated with imiglucerase, these disease parameters remained stable through 33 total months of treatment with taliglucerase alfa. Most adverse events were mild/moderate; treatment was well tolerated. These findings extend the taliglucerase alfa safety and efficacy profile and demonstrate long-term clinical improvement in treatment-naïve children receiving taliglucerase alfa and maintenance of disease stability in children switched to taliglucerase alfa. Treatment was well-tolerated, with no new safety signals. This study is registered at www.clinicaltrials.gov as NCT01411228.
Safety and efficacy of two dose levels of taliglucerase alfa in pediatric patients with Gaucher disease
2015, Blood Cells, Molecules, and Diseases
Citation Excerpt :
Patients were excluded based on any of the following criteria: presence of complex neuronopathic features other than longstanding oculomotor gaze palsy; unresolved anemia due to iron, folic acid, or vitamin B12 deficiency; currently taking another investigational drug for any condition; previous hypersensitive reaction to alglucerase or imiglucerase; history of allergy to carrots; inability of parents or guardians to understand the nature, scope, and consequences of study participation; and presence of any medical, behavioral, psychological/emotional condition that would, in the investigator's opinion, interfere with full participation in the study. Spleen and liver volumes were measured using magnetic resonance imaging as previously reported [15] and were assessed at BioClinica, Lyon, France. Beta-glucocerebrosidase activity, chitotriosidase or CCL18 activity, and DNA sequencing were performed at a centralized laboratory, the Academic Medical Center in Amsterdam, The Netherlands.
Taliglucerase alfa is a plant cell–expressed beta-glucocerebrosidase approved in the United States, Israel, Australia, Canada, and other countries for enzyme replacement therapy in adults with Type 1 Gaucher disease (GD), for treatment of pediatric patients in the United States, Australia, and Canada, and for the hematologic manifestations of Type 3 GD in pediatric patients in Canada. This multicenter, randomized, double-blind, parallel-dose, 12-month study assessed efficacy and safety of taliglucerase alfa in pediatric patients with GD. Eleven children were randomized to taliglucerase alfa 30U/kg (n = 6) or 60U/kg (n = 5) per infusion every other week. From baseline to month 12, the following changes were noted in the taliglucerase alfa 30-U/kg and 60-U/kg dose groups, respectively: median hemoglobin concentrations increased by 12.2% and 14.2%; the interquartile ranges of median percent change in hemoglobin levels from baseline were 20.6 and 10.4, respectively; mean spleen volume decreased from 22.2 to 14.0 multiples of normal (MN) and from 29.4 to 12.9 MN; mean liver volume decreased from 1.8 to 1.5 MN and from 2.2 to 1.7 MN; platelet counts increased by 30.9% and 73.7%; and chitotriosidase activity was reduced by 58.5% and 66.1%. Nearly all adverse events were mild/moderate, unrelated to treatment, and transient. One patient presented with treatment-related gastroenteritis reported as a serious adverse event due to the need for hospitalization for rehydration. No patient discontinued. These data suggest that taliglucerase alfa has the potential to be a therapeutic treatment option for children with GD. This study was registered at www.clinicaltrials.gov as NCT01132690.
Pivotal trial with plant cell-expressed recombinant glucocerebrosidase, taliglucerase alfa, a novel enzyme replacement therapy for Gaucher disease
2011, Blood
Citation Excerpt :
Pharmacokinetic graphs showing a dose-dependency were comparable with those described in healthy volunteers.13 This pivotal study, with approximately the same number of patients as in the other seminal ERT trials in Gaucher disease,1-3,19 demonstrates safety of plant cell–expressed taliglucerase alfa by virtue of no serious adverse events, low rate of Ab formation, no neutralizing Abs, and a low incidence of hypersensitivity reactions, which are similar to those of imiglucerase.1-4 Nonetheless, the small sample size is a limitation of the study.
Taliglucerase alfa (Protalix Biotherapeutics, Carmiel, Israel) is a novel plant cell–derived recombinant human β-glucocerebrosidase for Gaucher disease. A phase 3, double-blind, randomized, parallel-group, comparison-dose (30 vs 60 U/kg body weight/infusion) multinational clinical trial was undertaken. Institutional review board approvals were received. A 9-month, 20-infusion trial used inclusion/exclusion criteria in treatment-naive adult patients with splenomegaly and thrombocytopenia. Safety end points were drug-related adverse events: Ab formation and hypersensitivity reactions. Primary efficacy end point was reduction in splenic volume measured by magnetic resonance imaging. Secondary end points were: changes in hemoglobin, hepatic volume, and platelet counts. Exploratory parameters included biomarkers and bone imaging. Twenty-nine patients (11 centers) completed the protocol. There were no serious adverse events; drug-related adverse events were mild/moderate and transient. Two patients (6%) developed non-neutralizing IgG Abs; 2 other patients (6%) developed hypersensitivity reactions. Statistically significant spleen reduction was achieved at 9 months: 26.9% (95% confidence interval [CI]: −31.9, −21.8) in the 30-unit dose group and 38.0% (95% CI: −43.4, −32.8) in the 60-unit dose group (both P < .0001); and in all secondary efficacy end point measures, except platelet counts at the lower dose. These results support safety and efficacy of taliglucerase alfa for Gaucher disease. This study was registered at www.clinicaltrials.gov as NCT00376168.

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Improving the accuracy of MRI spleen and liver volume measurements: A phase III Gaucher disease clinical trial setting as a model

Abstract

Purpose

Materials and methods

Results

Conclusion

Introduction

Section snippets

Study methodology

Variability results

Factors influencing accuracy

Conclusion

Disclosures

Am. J. Med.

Blood

Blood

Blood Cells Mol. Dis.

Semin. Hematol.

Semin. Hematol.

Blood Cells Mol. Dis.