Long-term treatment outcomes in Gaucher disease

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1 REVIEW Long-term treatment outcomes in Gaucher disease AJH Joel Charrow 1,2 * and C. Ronald Scott 3 Following the treatment of the first Gaucher disease patient with enzyme replacement therapy (ERT), it was clear that ERT had the potential to be transformative with dramatic improvements in systemic manifestations of the disease within 2 years. Following over 20 years existence of the International Collaborative Gaucher Group Gaucher Registry and evidence from ~6000 patients, the long-term effects of therapy have been documented. It has been shown that ERT can result in improvements in all clinical and laboratory parameters of nonneuronopathic disease. However, different aspects of the disease, such as hematologic parameters, organ volumes and bone disease do not necessarily respond to therapy at the same rate or to the same extent, and this has had major implications for disease monitoring and for the establishment of therapeutic goals for ERT. Response may be affected by factors such as the timing of therapy initiation, the presence of irreversible complications such as osteonecrosis, and by enzyme dose. It is also apparent that ERT has no impact on neurological aspects of disease and highlights the need for additional or alternative treatment strategies able to meet the needs of patients with neuronopathic disease. Am. J. Hematol. 90:S19 S24, VC 2015 Wiley Periodicals, Inc. Introduction Prior to 1991, the treatment of Gaucher disease was largely supportive and included analgesics for pain; orthopedic procedures and rehabilitation for bony complications; and transfusion and splenectomy for anemia and thrombocytopenia. While these treatments might have relieved symptoms in the short term, they were unable to alter the course of disease and left much to be desired. Rarely, stem cell transplantation was carried out, which has the potential to be curative but involves considerable procedural risk and may result in variable outcomes [1]. Although it was suggested by De Duve as early as 1964 that lysosomal storage disorders might be specifically treated by administration of exogenous enzyme [2,3], it was not until 1990 that the first successful attempt at enzyme replacement therapy (ERT) was reported [4]. In 1991 the US Food and Drug Administration approved alglucerase (Ceredase VR,Genzyme,aSanofiCompany,Cambridge,MA),the first human enzyme replacement product for the treatment of a lysosomal storage disease. The original product was derived from human placenta and was replaced in 1994 by the human recombinant form of the enzyme, imiglucerase (Cerezyme VR, Genzyme, a Sanofi Company, Cambridge, MA), produced in vitro in a tissue culture system. The first patient with Gaucher disease to be treated with ERT was a 4-year-old boy, treated at the National Institutes of Health (NIH) [4]. During the first 2 years of therapy his hemoglobin rose from 6.9 to 10.2 g/dl, platelet count from 30,000 to 54,000 per mm 3, there was reduction in the size of the liver and spleen, and improvement in the radiographic appearance of the long bones. The abdominal protuberance lessened and the boy became more physically active. The case illustrates two important aspects of ERT for Gaucher disease in the early 1990s: many patients were severely debilitated when therapy was initiated, and the results were typically dramatic, with improvements in all organs affected by the disease. In the over 20 years following this remarkable achievement, we have learned a great deal about the effects of ERT on Gaucher disease, and are now more often treating patients at an earlier stage, with near complete resolution of disease-related signs and symptoms. Improvements have been documented in the most prevalent aspects of nonneuronopathic disease: hemoglobin concentration; platelet count; liver and spleen volume; bone pain and the frequency of bone crises; bone mineral density (BMD) and marrow infiltration; and in children, growth, and pubertal maturation. The International Collaborative Gaucher Group (ICGG) Registry Many investigators and clinicians have documented the natural history of Gaucher disease and aspects of response to treatment. However, the Genzyme, a Sanofi company, sponsored ICGG Gaucher Registry (clinicaltrials.gov NCT ), which now houses longitudinal data on 6000 patients with Gaucher disease [5], has been an incredibly rich source of data, and permitted examination of much larger numbers of patients than is possible at any single center. This Registry, which has been open to all physicians caring for individuals with Gaucher disease, contains voluntarily submitted and anonymized data on all aspects of the disease regardless of treatment status and treatment choice. 1 Division of Genetics, Birth Defects and Metabolism, Ann and Robert H. Lurie Children s Hospital of Chicago, Chicago, Illinois; 2 Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois; 3 Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, Washington Conflict of interest: J.C. receives honoraria for consultation and advisory board participation from Genzyme, a Sanofi company, and Synageva, and has received such honoraria from Genzyme, a Sanofi company, Shire, BioMarin, National Gaucher Foundation, Synageva, and Pfizer/Protalix. He receives lecture fees or honoraria for speaking at the invitation of Genzyme, a Sanofi company, and SIMD North American Metabolic Academy. C.R.S. has received honoraria for advisory board participation from Genzyme, a Sanofi company and has received grants from Genzyme, a Sanofi company and from the Federal Government (ROI DK DK67859). *Correspondence to: Joel Charrow, MD, Division of Genetics, Birth Defects and Metabolism, Ann and Robert H Lurie Children s Hospital of Chicago, 225 East Chicago Avenue, no. 59, Chicago, IL jcharrow@northwestern.edu Contract grant sponsor: Genzyme, a Sanofi company. Am. J. Hematol. 90:S19 S24, DOI: /ajh VC 2015 Wiley Periodicals, Inc. doi: /ajh American Journal of Hematology, Vol. 90, No. S1, July 2015 S19

2 Charrow and Scott REVIEW Figure 1. Response to 2 years of treatment with ERT in a cohort of patients with Gaucher disease. (Adapted from Ref. 7 with permission from Elsevier). The Registry also provides tools to help clinicians follow the progress of their patients over time, and to see changes graphically in blood counts and organ volumes, and progress made toward the achievement of the therapeutic goals (see below). The graphical presentation of data makes it easy to review progress with patients in the clinic, and facilitates discussion and decision making regarding treatment. The ICGG Gaucher Registry was initiated in 1991, in part, to provide post marketing surveillance for alglucerase and, subsequently, imiglucerase enzyme therapies, which are considered to be therapeutically similar [6]. However, multiple treatments are now available for Gaucher disease, with oral miglustat substrate reduction therapy (ZavescaVR, Actelion Pharmaceuticals, South San Francisco, CA) becoming available in 2002 for patients who are not candidates for ERT, followed by velaglucerase alfa ERT (VPRIVVR ; Shire Human Genetic Therapies, Inc., Cambridge, MA) in 2010, taliglucerase alfa ERT (ElelysoVR ; Protalix, Carmiel, Israel) in 2012 and, most recently, oral eliglustat substrate reduction therapy (CerdelgaVR, Genzyme, a Sanofi Company, Cambridge, MA), approved in 2014 as a first-line therapy for adults with Gaucher disease type 1. Nonetheless, the vast majority of data concerning treatment outcomes held in the ICGG Gaucher Registry, and especially evidence on long-term treatment outcomes, are related to alglucerase or imiglucerase enzyme therapy, and this is reflected in this article. Response to ERT in Gaucher Disease Type 1 Hematologic response In a cohort of patients from the ICGG Gaucher Registry followed over 2 years, those with hemoglobin concentrations below 12 g/dl at initiation of ERT achieved significant increases during the first year of therapy, and continued increases, albeit at a slower rate, over the next year (Fig. 1) [7]. Similar changes occurred in platelet counts among those who started with fewer than 120,000/mm 3. Importantly, patients with initial hemoglobin concentrations of g/dl achieved higher levels than those with initial hemoglobin concentrations of less than 10 g/dl. The same phenomenon was apparent with the platelet counts comparing patients with initial values of ,000/mm 3 to those with initial values <60,000/mm 3. Examination of cross-sectional data from similar patients in the Registry showed continued improvement over a 5 year period (Fig. 2). Follow-up of a cohort of patients with data at initiation of therapy and 10 years later demonstrated similar and sustained improvements (Table I) [5]. Anemia resolved in 87.6% of nonsplenectomized patients, and thrombocytopenia improved markedly (Table II; only nonsplenectomized patients shown). Liver and spleen volumes A cohort of patients with hepatomegaly at the initiation of ERT showed very significant decreases in liver volume over a 2 year period (Fig. 1) [7]. Those with smaller liver volumes (mean 1.7 multiples of normal [MN]) achieved near normal volumes, while those with larger volumes (mean 3.4 MN) continued to have enlarged livers, despite an average 50% decrease in volume. A similar pattern of reduction of spleen size was observed in those with splenomegaly at the start of therapy. As with the hematologic response, examination of crosssectional data from the Registry showed continued improvement over a 5 year period (Fig. 2). Follow-up of a cohort of patients with data S20 American Journal of Hematology, Vol. 90, No. S1, July 2015 doi: /ajh.24056

3 REVIEW at initiation of therapy and 10 years later demonstrated similar and sustained improvements (Table I) [5]. Bone pain and bone crises Chronic bone pain, which can be generalized or localized to specific regions, has been reported in 49 82% of patients with Gaucher disease prior to initiation of therapy [8,9]. It is more prevalent among splenectomized patients. In a cohort from the ICGG Gaucher Registry, bone pain was reported by 49% of patients before starting ERT, and by only 30% after 1 year of treatment. The prevalence of bone pain remained at this level even after 3 years of treatment [9]. A similar decrease was observed after 10 years of therapy in nonsplenectomized patients [5], but the prevalence of bone pain increased in splenectomized patients, despite ERT. In untreated patients, bone crises are reported by 22% of nonsplenectomized patients and 55% of splenectomized patients [9]; 18% of patients reported a bone crisis prior to initiation of ERT, and only 4.6% had a crisis after 1 year of treatment. The prevalence of bone crises remained at or below this level over a period of 3 years. Patients who had not experienced a bone crisis before starting therapy very rarely experienced one after starting treatment. Among non-splenectomized patients who had a bone crisis in the month prior to data submission, only 7.4% experienced a crisis after 10 Figure 2. Response to 5 years of treatment with ERT. MN: multiples of normal (based on body weight: 2.5% for liver; 0.2% for spleen). (Based on data from Ref. 7 with permission from Elsevier). years of therapy; 16.7% of splenectomized patients had a crisis after 10 years [5]. Avascular necrosis (AVN), especially of the femoral head, is a well-documented but unpredictable complication of Gaucher disease. Analysis of ICGG Gaucher Registry data demonstrated that the relative incidence of AVN in patients who started ERT within 2 years of diagnosis was 59% that of patients whose treatment began more than 2 years after diagnosis [10]. Bone mineral density Although the most crippling aspect of Gaucher disease for many people is related to its effects on bone, changes in bone related to ERT have been the most difficult to document, and appear to be the slowest to improve. Nonetheless, BMD (bone mineral density; analyzed by dual energy x-ray absorptiometry [DXA]) slowly improves with enzyme treatment, and mean DXA Z-scores have been shown to increase from 21.2 to as much as over 8 years. A significant dose-response relationship was noted, with the most significant gains occurring in patients treated with 60 Units/ kg/2 weeks (BMD of 20.12). Patients treated with 30 units/kg/2 weeks achieved a BMD of 20.48, and those treated with 15 units/ kg/2 weeks achieved a BMD of Individuals who were not treated showed no gains in BMD [11]. Similar changes occur in children, who may improve more rapidly and achieve greater benefit [12,13]. Improvements in marrow fat composition (with a reduction in Gaucher cell infiltration) are visible on magnetic resonance imaging (MRI) T-2 weighted signal sequences, and have been quantitatively shown to improve by Dixon quantitative chemical shift imaging (QCSI) in as little as 1 year after the initiation of ERT, with normalization after years [14]. Although this MRI method is the most sensitive means of monitoring bone marrow changes in response to treatment, it is not widely available in routine clinical practice because of its technical complexity [15]. Growth Long-term treatment outcomes in Gaucher disease Growth in children affected by Gaucher disease may be normal during the first 2 years of life, but then may slow. One study showed that 50% of children and adolescents were at, or below the fifth percentile for age and midparental height. In addition, 22% of children who were above the fifth percentile for age were still below the 50th percentile for midparental height [16]. An analysis of data from the ICGG Gaucher Registry has shown that growth may be improved by ERT. In this study, 42% of 702 children were below the fifth percentile for height at baseline; the median Z score for the study population was After 8 years of ERT the median score was 20.3, a value that was not substantially different from that of the general population [12]. Quality of life. A number of studies have documented diminished health-related quality of life for patients with Gaucher disease using the Medical Outcomes Study 36-Item Short Form (SF-36) [17,18] and improvement in physical and mental health status within 2 years of TABLE I. Response after 10 Years of ERT in Nonsplenectomized and Splenectomized Patients Nonsplenectomized Splenectomized Parameter At start of ERT After 10 years At start of ERT After 10 years Hemoglobin (g/dl) Platelets ( /mm 3 ) Liver volume (MN) Spleen volume (MN) MN: multiples of normal (based on body weight: 2.5% for liver; 0.2% for spleen). Adapted from Ref. 5 with permission from Springer. doi: /ajh American Journal of Hematology, Vol. 90, No. S1, July 2015 S21

4 Charrow and Scott REVIEW TABLE II. Percentage of Non-Splenectomized Patients with Thrombocytopenia after 10 Years of ERT Platelet count ( /mm 3 ) at first infusion Platelet count ( /mm 3 ) after 10 years <60 60 < < < Adapted from Ref. 5, with permission from Springer. starting ERT. In a prospective study of patients with skeletal manifestations (bone pain, AVN, medullary infarctions, and lytic lesions), significant improvements were observed for all eight components of the SF-36 following 2 years of ERT [19]. Mean physical and mental component scores increased to the normal range. Significant gains occurred even in patients with the most advanced disease. Dose response For many years there was considerable debate about the optimal ERT dose, and whether enzyme treatment shows a dose-response relationship. Analyzing data from the ICGG Gaucher Registry, Grabowski et al. (2009) [20] used propensity scoring to determine outcomes. This is a statistical method for creating three dosage groups (15, 30, and 60 units/kg per 2 weeks), with patients in each group matched for measures of disease severity (age at diagnosis, age at treatment initiation, hemoglobin and platelet levels, and hepatic and splenic volumes at the time of first infusion). Using nonlinear mixed effects models, the maximal effect (E max) during 96 months of treatment, and the time required to reach 50% of E max were modeled for each of four parameters: hemoglobin, platelet count, liver volume, and spleen volume. Statistically significant dose response relationships were found for all four parameters: the higher the dose, the greater the response. Therapeutic goals To facilitate appropriate individualization of therapy and the evaluation of effectiveness in individual patients, an international panel of clinicians with extensive experience of Gaucher disease met in 2003 to review the literature on treatment outcomes and, based on that review and expert opinion, developed consensus, system-based therapeutic goals for Gaucher disease type 1 [21]. These goals included specific targets for hemoglobin, platelet count, liver and spleen size, and bone pain, crises, osteonecrosis and BMD. They incorporated consideration of the pretreatment conditions (e.g., the severity of thrombocytopenia), considerations for children related to growth, functional health, and well-being. In a later study, the extent to which patients with Gaucher disease type 1 achieved these goals was evaluated (Fig. 3). One hundred and ninety-five patients who had data in the ICGG Gaucher Registry for hemoglobin, platelet count, liver volume, spleen volume, bone pain, and bone crises at first infusion and 4 years later, were included. The proportion of patients who met all six therapeutic goals increased from 2.1% at first infusion to 41.5% at 4 years; 5 goals from 12.8 to 76.9%; 4 goals from 37.4 to 92.8%; and 3 goals from 70.8 to 99.0% [22]. Neuronopathic forms of Gaucher disease On the severe end of the spectrum for Gaucher disease are the neuronopathic forms of the disorder, Gaucher disease types 2 and 3. Young children affected by Gaucher disease type 2 may first manifest by massive storage of lipids within the reticuloendothelial system. Figure 3. Achievement of specific therapeutic goals after 4 years of ERT. (Adapted from Ref. 22, with permission from Wiley). This results in prominent enlargement of the spleen and liver. Such children have early evidence of neurological involvement, typically before the age of 2 years [23]. The obvious physical finding of young children who develop neurologic involvement is a massively enlarged spleen (>15 times normal) and liver (>2 times normal) for their age. The early neurologic signs are respiratory stridor, difficulty feeding because of swallowing difficulties, and an ataxic gait. More detailed neurological exams demonstrate difficulty with lateral gaze (impaired ocular saccades) and head movement to follow moving objects rather than lateral eye movements. Children eventually develop growth failure, tremor, and seizure activity and succumb from pulmonary infections or inadequate nutrition. Attempts at effective therapy for Gaucher disease types 2 and 3 have been discouraging. Administration of the standard dose of ERT at 60 units/kg/2 weeks, and doses as high as 120 units/kg/2 weeks have been helpful in improving the somatic features of patients with type 3 disease, but are largely unsuccessful in altering neurologic symptoms [24]. This does not, however, totally discourage the use of ERT for children with type 3 disease as their quality of life can be improved by reducing liver and spleen size, improving respiratory symptoms and hematologic parameters, and by simplifying their medical care. The primary reason attributed to the ineffectiveness of ERT in addressing neurologic disease is its inability to cross the bloodbrain barrier. Small molecule inhibitors of glucosylceramide (glucocerebroside) synthesis may provide an alternative approach. Although no neurological benefit was reported in one randomized clinical trial for one such compound (miglustat) [25], there are anecdotal reports of short-term benefit from the combined use of ERT and miglustat with diminishment in organ volumes, stabilization of neurological status, and a reduction in the frequency of seizure activity [26,27]. However, no formal studies have investigated the effectiveness of ERT combined with small molecule substrate inhibition therapy. Based on the above limited data, it is reasonable that children affected with the type 2 and 3 neuronopathic forms of Gaucher disease be treated with ERT at 60 units/kg/2 weeks to improve the quality of their shortened lives by minimizing somatic effects, and that serious consideration be given to the adjunct of small molecule therapy that can cross the blood brain barrier for its theoretical beneficial effect on neurologic involvement. Prior to initiating therapy for children with neuronopathic forms of Gaucher disease, it is imperative to S22 American Journal of Hematology, Vol. 90, No. S1, July 2015 doi: /ajh.24056

5 REVIEW obtain baseline laboratory and imaging test results so that the effectiveness of therapy can be followed [28]. Documentation of subsequent clinical and laboratory parameters and their entry into the Registry will allow for the eventual evaluation of therapeutic effectiveness. A major priority of clinical care for families with a child affected with Gaucher disease is the availability of genetic counselling. Genetic information can answer concerns on inheritance, recurrence risk, family planning, and prenatal diagnosis for future pregnancies. Discussion Overall, these data show that ERT results in improvements in the majority of clinical and laboratory parameters of nonneuronopathic disease and these may be demonstrable as early as 6 months after the initiation of therapy. Continued improvement in some parameters occurs over many years, and sustained benefits have been documented over 10 years [5]. Most of the pathology that occurs in Gaucher disease type 1 is reversible, with the exception of osteonecrosis and remodeling resulting from pathologic fracture. Recent evidence indicates that earlier treatment may prevent AVN, and is associated with a better long-term outcome [10]. In the neuronopathic forms of Gaucher disease, similar results may be seen outside of the central nervous system. It is important to note that the various aspects of Gaucher disease do not necessarily respond to ERT at the same rate or to the same extent, and that the extent of change in one parameter may not be reflective of changes in other parameters. To fully appreciate how an individual is affected by Gaucher disease, and how that individual is responding to treatment, it is necessary to evaluate all aspects of the disease: blood counts, organ volumes, quality of life, bone pain and crises, bone remodeling, marrow fat, and BMD. Assessment of growth in children, with reference to both their age- and sex-matched cohort and their midparental height, is also very important. The timing of the initiation of ERT in relation to Gaucher disease status may have a significant impact on treatment response as demonstrated not only by AVN, as described above, but also by persisting thrombocytopenia in patients with established and severe splenomegaly at the time of therapy initiation [29], and the finding that a failure to achieve peak bone mass during adolescence may be a determinant of peak bone mass attained in later years [13]. Treatment also needs to be maintained to sustain benefit; treatment interruptions may lead to a worsening of disease signs and symptoms [30,31]. We have concentrated on the classical manifestations of Gaucher disease in the assessment of treatment response, but in recent years evidence has emerged of comorbidities strongly associated with Gaucher disease type 1, such as multiple myeloma [32] and Parkinson s disease [33]. The possible impact of therapy on the incidence of these comorbidities has yet to be investigated and will likely form future ICGG Gaucher Registry studies. Conclusion It is clear that ERT has dramatically improved the outlook for patients with Gaucher disease. The future holds promise of new therapies, which may help address as yet unmet needs. These include pharmacologic chaperones, and the potential development of molecules able to cross the blood-brain barrier that might lead to effective treatment for neuronopathic disease. Acknowledgments Long-term treatment outcomes in Gaucher disease The authors thank Pam Pickering of Conscience Creative and Cheryl Lathrop for editorial assistance, which was funded by Genzyme, a Sanofi company, and Laura Croal, PhD (medical communications manager for Gaucher disease, Genzyme Global Medical Affairs) for critical review of the manuscript. This article was supported by an unrestricted grant from Genzyme, a Sanofi company. The opinions expressed in this article are those of the authors and do not necessarily reflect those of Genzyme. References 1. Cox T. Gaucher disease: Clinical profile and therapeutic developments. Biologics 2010;4: De Duve C. From Cytases to Lysosomes. Fed Proc 1964;23: De Duve C. The significance of lysosomes in pathology and medicine. Proc Inst Med Chic 1966;26: Barton NW, Furbish FS, Murray GJ, et al. Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. 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