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Trasplante de células madre hematopoyéticas para la enfermedad de Gaucher

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Resumen

Antecedentes

La enfermedad de Gaucher es el trastorno de almacenamiento lisosómico más frecuente causado por una deficiencia de la enzima glucocerebrosidasa. El tratamiento actual de la enfermedad incluye la elección entre el tratamiento enzimático sustitutivo, la terapia de reducción de sustrato y el trasplante de células madre hemotopoyéticas (TCMH). El TCMH es un procedimiento de alto riesgo con posibles efectos beneficiosos a largo plazo en la regresión de los cambios óseos y neurológicos en pacientes con enfermedad de Gaucher. Ésta es una actualización de una revisión Cochrane publicada anteriormente.

Objetivos

Determinar la función del TCMH en los pacientes con enfermedad de Gaucher con respecto a: el riesgo de mortalidad asociado al procedimiento; la eficacia para modificar el curso de la enfermedad; y la detención o regresión de las manifestaciones neurológicas en las formas neuronales (tipos 2 y 3).

Métodos de búsqueda

Se realizaron búsquedas en el Registro de Ensayos de Errores Congénitos del Metabolismo del Grupo Cochrane de Fibrosis Quística y Enfermedades Genéticas (Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register) que comprende referencias identificadas mediante búsquedas exhaustivas en bases de datos electrónicas y búsquedas manuales en revistas relevantes y en libros de resúmenes de congresos.

Fecha de la búsqueda más reciente en el registro de ensayos de hemoglobinopatías del Grupo: 19 de enero de 2017.

También se buscó en los sitios web: www.clinicaltrials.gov; el portal de la WHO International Clinical Trials Registry Platform y www.genzymeclinicalresearch.com. Fecha de la búsqueda más reciente de estos sitios: 02 de marzo de 2017.

Criterios de selección

Todos los ensayos clínicos controlados, aleatorizados y cuasialeatorizados, que compararon el trasplante de células madre con el tratamiento enzimático sustitutivo, la terapia de reducción de sustrato, el tratamiento sintomático o ningún tratamiento en pacientes con enfermedad de Gaucher de todas las edades.

Obtención y análisis de los datos

Se evaluaron, de forma independiente, los ensayos para inclusión; sin embargo, no se identificaron ensayos relevantes.

Resultados principales

En las búsquedas se identificaron 32 ensayos, pero no fueron adecuados para su inclusión en la revisión.

Conclusiones de los autores

El TCMH es una forma de tratamiento que ofrece el potencial de una cura permanente. Sin embargo, ningún ensayo clínico evaluó la seguridad ni la eficacia del trasplante de células madre versus otras medidas conservadoras (tratamiento enzimático sustitutivo, terapia de reducción de sustrato) utilizadas en la actualidad.

No se incluyeron ensayos en la revisión y no se han identificado ensayos relevantes hasta marzo de 2017. Por lo tanto, no se prevé actualizar esta revisión hasta que no se publiquen ensayos nuevos.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Resumen en términos sencillos

Trasplante de células madre para el tratamiento de la enfermedad de Gaucher

Pregunta de la revisión

Se revisó la evidencia sobre el efecto del trasplante de células madre hematopoyéticas (TCMH) en pacientes con enfermedad de Gaucher.

Antecedentes

La enfermedad de Gaucher es un trastorno hereditario causado por una deficiencia de la enzima glucocerebrosidasa. Esta deficiencia conduce al almacenamiento de lípidos complejos en ciertos tipos de células sanguíneas. Debido a estas células anormales, los pacientes con enfermedad de Gaucher presentarán dolor, fatiga, anemia, ictericia y lesiones óseas. Algunos tipos de enfermedad de Gaucher también pueden causar trastornos neurológicos. En la actualidad, el principal tratamiento de la enfermedad de Gaucher es el tratamiento enzimático sustitutivo, que es costoso. En algunos casos graves, se utiliza el TCMH para tratar a los pacientes con enfermedad de Gaucher. Éste es un procedimiento de alto riesgo, que a veces provoca la muerte del paciente.

Fecha de la búsqueda

La evidencia está actualizada hasta: 19 de enero de 2017.

Características de los estudios

No se encontraron ensayos que muestren la efectividad ni los riesgos del procedimiento en pacientes con enfermedad de Gaucher.

Resultados clave

No se encontraron ensayos que evalúen la efectividad ni los riesgos del procedimiento en pacientes con enfermedad de Gaucher. No se han incluido ensayos en la revisión y no se han identificado ensayos relevantes hasta enero de 2017. Por lo tanto, no se prevé actualizar esta revisión hasta que no se publiquen ensayos nuevos.

Calidad de la evidencia

No se encontraron ensayos que evalúen la efectividad ni los riesgos del procedimiento en pacientes con enfermedad de Gaucher.

Authors' conclusions

Implications for practice

No randomised controlled trials (RCTs), quasi‐RCTs or controlled clinical trials (CCTs) on the efficacy of hemotopoietic stem cell transplantation (HSCT) were identified for inclusion in the review. The research evidence on which to base clinical decisions is limited to case reports. Given that there are no trials included in the review and we have not identified any relevant trials up to January 2017 we do not plan to update this review until new trials are published.

Implications for research

No RCTs, quasi‐RCTs or CCTs on the efficacy of HSCT were identified for inclusion in the review. There is a need for a well‐designed RCT to evaluate the benefits and risks of HSCT in comparison to other prevalent forms of treatment in people with Gaucher disease.

Background

Description of the condition

Gaucher disease is the most common lysosomal storage disorder. It is inherited as an autosomal recessive trait and characterised by the accumulation of glucocerebroside in the lysosomes due to a deficiency of the enzyme glucocerebrosidase (lysosomal acid β‐glucosidase) (Beutler 2001). The glucocerebrosidase gene (GBA) has been mapped to chromosome one, band q21. More than 200 disease‐causing mutations have been documented (Jmoudiak 2005).

The incidence of Gaucher disease in the general population is less than 1 in 30,000 to 40,000. It is more prevalent in people of Eastern European (Ashkenazi) Jewish descent with a prevalence of 1 in 1000 and a carrier frequency of 1 in 14 people (Mehta 2006). Classically three types of Gaucher disease have been identified based on the presence or absence of primary central nervous system involvement and the severity of the disease (Beutler 2001).

Non‐neuronopathic form

Type 1 Gaucher disease

This is the most common form accounting for 90 to 95 per cent of the cases. It is characterised by onset in adulthood and by the absence of primary central nervous system involvement. However, some individuals, who have severe mutations, present with an onset in early childhood.

Neuronopathic forms

Type 2 Gaucher disease

This is characterised by severe neurological involvement and an onset during infancy.

Type 3 Gaucher disease

This is characterised by the onset of neurological disturbances in the first decade of life.

Types 2 and 3 are very rare and occur in less than 1 in 100,000 of the population. The prototype of type 3 Gaucher disease is found with high frequency in the Norbottnian population of northern Sweden (Mehta 2006).

The pathophysiological feature of Gaucher disease is the presence of Gaucher cells derived from the monocyte‐macrophage system. Gaucher cells are present throughout the body, but the largest numbers are found in the spleen, liver, bone marrow, and lymph nodes causing enlargement and dysfunction of these organs resulting in clinical manifestations. Typically the infant is normal at birth, with clinical features only becoming apparent as the abnormal substrate accumulates. Bleeding due to thrombocytopenia (low platelet count), anemia and hepatosplenomegaly (abnormal enlargement of the liver and spleen) are the common early features. Bone involvement is common but is not always associated with symptoms. The symptoms of bone disease range from mild pain to severe bone crises. Growth retardation is seen in moderate to severe forms of disease. The neurological symptoms seen in types 2 and 3 include oculomotor apraxia (difficulty moving the eyes), opisthotonus (extreme backward arching of the spine), bulbar signs (problems with breathing, swallowing and talking) and seizures (Beutler 2001; Beutler 2006). Type 1 Gaucher disease has a broad spectrum of severity ranging from individuals who have been diagnosed in their eighth or ninth decade to children who die of complications during their first or second decade. Most infants with type 2 disease die within the first two years of life; and the severity of type 3 is intermediate between types 1 and 2 (Beutler 2001). A confirmed diagnosis can be made by measuring the glucocerebrosidase activity of peripheral blood leucocytes or cultured skin fibroblasts. Alternatively DNA analysis can be used to diagnose Gaucher disease and also to establish a disease prognosis (Beutler 2006).

Description of the intervention

The treatment of Gaucher disease before the 1990s was essentially symptomatic. The advent of enzyme replacement therapy (ERT) has revolutionised the treatment approach to this disorder. Human placental β‐glucocerebrosidase was modified to expose variable numbers of mannose residues, so that it can be targeted to the macrophages (Danuta 1995). This is the preferred form of treatment for symptomatic individuals with type 1 disease. Treatment results in significant regression of disease in these individuals and has very few side effects (Morales 1996). The main drawbacks of ERT are that weekly infusions of the enzyme are required, and the treatment is very expensive. The cost of therapy for a child weighing 50 kg (at a dose of 130 units per kg per month) is approximately USD 300,000 per year for the medication alone (Beutler 2005). Moreover, the enzyme does not cross the blood brain barrier so it cannot be effective in types 2 and 3 diseases to improve neurological symptoms (Erikson 1993; Zimran 1995).

Since the pathophysiology of Gaucher disease is due to accumulation of lipid laden macrophages, bone marrow transplantation was thought of as a logical treatment for the disease. The first allogeneic bone marrow transplantation was done in the 1980s. The individual died due to sepsis but had shown regression of disease manifestations (Rappeport 1984). Since then many people have undergone hematopoietic stem cell transplantation (HSCT) (August 1984; Chan 1994; Hobbs 1987; Ringden 1988; Ringden 1995; Svennerholm 1991; Tsai 1992). Initially the HSCT was performed using donor bone marrow from siblings with an identical tissue type. With major improvements in the various areas of transplantation, the choice of donor cells has now expanded to include peripheral blood stem cells (PBSC) mobilised into the blood of the donor using granulocyte colony stimulating factor (G‐CSF), marrow from matched or mismatched family members or unrelated donors and cord blood from siblings and unrelated babies. There is also increasing use of haploidentical tissue from parents.

How the intervention might work

The outcomes of HSCT are affected by numerous aspects of the transplant such as donor enzyme level, degree and persistence of donor chimerism, and post‐transplant complications (Peters 2003; Steward 2005). Benefit of transplantation varies between organ systems. Hematological and physical improvement is rapid and sustained. Reticuloendothelial organs, such as the liver and spleen regress within a few months (Peters 2003) and there is evidence that most of the skeletal changes seen in Gaucher disease regress (Starer 1987). The evidence on the beneficial effect of bone marrow transplantation on the regression of the neurological disease in people with types 2 and 3 is conflicting (Ringden 1988; Svennerholm 1991; Tsai 1992). The response is slow and the effectiveness appears to depend on the age of the individual, severity of the disease and its progression at the time of treatment.

Newer modes of Intervention

Besides ERT and HSCT there are a few other promising treatments. A recently introduced therapy is substrate reduction therapy (SRT). Miglustat (Zavesca, N‐butyl deoxynojirimycin, OGT 918) has been licensed for the treatment of Gaucher disease in those who are not able to receive ERT. This compound inhibits glucosylceramide synthase, preventing new synthesis of glucosylceramide. The clinical trials show it is effective in most people with mild and stable disease, but is less well‐tolerated. The drug crosses the blood brain barrier, and its effectiveness in the treatment of the types 2 and 3 Gaucher disease is under investigation. A new generation of therapeutic recombinant enzymes is under development which has an in‐frame fusion to HIV‐1 trans‐activator protein transduction domain (TAT). The TAT modification improves the delivery of the enzyme to cells without mannose ‐specific endocytic receptors on the plasma membrane. Another option is the use of more specific small molecules that inhibit substrate synthesis (substrate deprivation), or act as chaperones to increase the activity of the enzyme (enzyme enhancement therapy). Various gene transfer methods are also in different trial phases (Schmitz 2007).

Why it is important to do this review

HSCT is a less expensive procedure that offers the potential of permanent cure when compared to other conservative measures now in use (ERT, SRT). However, the procedure is associated with a mortality ranging from less than 5% to more than 10% depending on the availability of human leucocyte antigen (HLA)‐matched sibling and the source of the stem cells (Kumar 2007). The mortality is expected to be higher in the severely compromised individuals with Gaucher disease. The choice between HSCT and conservative measures to treat people with Gaucher disease depends on the assessment of the long‐term benefits of HSCT over the significant mortality and morbidity associated with the procedure. Another issue to be resolved in this area is whether HSCT can correct metabolic abnormalities of the central nervous system in individuals with type 2 and 3 Gaucher disease. This is an updated version of a previously published review (Somaraju 2008b; Somaraju 2010; Somaraju 2012).

Objectives

To determine the role of HSCT in people with Gaucher disease in relation to:

  1. mortality risk associated with the procedure;

  2. efficacy in modifying disease course, and;

  3. arrest or regression of neurological manifestations in neuronopathic forms (types 2 and 3).

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs). Non‐randomised allocation to HSCT due to availability of HLA‐matched donor was considered acceptable. We planned to include controlled clinical trials (CCTs) including quasi‐randomised controlled trials if the controls were sufficiently comparable to the treatment group.

Types of participants

Children and adults diagnosed with Gaucher disease by measuring glucocerebrosidase levels in peripheral blood leucocytes or fibroblasts or by analysis of DNA.

Types of interventions

HSCT compared with ERT, SRT, symptomatic treatment or no treatment.

Types of outcome measures

We planned to group the outcome data into those measured at 3, 6, and 12 months and annually thereafter. We also planned to collect change from baseline data for these outcomes where reported. Some treatment effects may show progressively higher efficiency in causing a regression of the disease and this we think can best be established by comparison of treatment effect from baseline.

Primary outcomes

  1. Hematological assessment ‐ hemoglobin concentration and platelet counts

  2. Visceral assessment ‐ liver and spleen volumes by volumetric computer tomography (CT) or magnetic resonance imaging (MRI) or ultrasound

  3. Mortality and morbidity

    1. overall mortality

    2. transplant‐related mortality

    3. transplant‐related morbidity

Secondary outcomes

  1. Skeletal system assessment ‐ osteoporosis and marrow infiltration by magnetic resonance imaging (MRI) or plain radiography or other imaging techniques

  2. Neuropsychiatric evaluation using Weschler scale or any other comparable scale

  3. Evaluation of changes in neurophysiologic parameters such as electroencephalogram (EEG), MRI Brain, visual evoked potentials (VEP), brainstem auditory evoked responses (BAER)

  4. Growth and pubertal development

  5. Quality of life

  6. Duration of hospitalisation

  7. Complications due to transplantation

Search methods for identification of studies

There will be no restrictions regarding language or publication status.

Electronic searches

Relevant trials were identified from the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Trials Register using the term: gaucher.

The Inborn Errors of Metabolism Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated with each new issue of the Cochrane Library), weekly searches of MEDLINE and the prospective handsearching of one journal ‐ Journal of Inherited Metabolic Disease. Unpublished work is identified by searching through the abstract books of the Society for the Study of Inborn Errors of Metabolism conference and the SHS Inborn Error Review Series. For full details of all searching activities for the register, please see the relevant section of the Cochrane Cystic Fibrosis and Genetic Disorders Group's website.

Date of the last search of the Group's Inborn Errors of Metabolism Trials Register: 19 January 2017.

We also conducted searches of the websites: www.clinicaltrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) portal; and www.genzymeclinicalresearch.com. Please refer to the appendices section of the review for further details (Appendix 1; Appendix 2; Appendix 3).

Date of most recent search of these sites: 02 March 2017.

Data collection and analysis

Selection of studies

We undertook new searches for the review in January and March 2017 and identified 17 new trials, taking the total number of trials identified to 32. Two authors (US and KT) independently applied the inclusion criteria to the 32 trials identified by the searches. We performed this without any blinding. We planned to resolve any disagreements arising through discussions. However, none of the trials identified were relevant to the review.

Data extraction and management

As no trials have yet been included in the review, we are unable to carry out any analysis. If we find trials for future updates of this review, we will independently extract data from the selected trials using standardised data extraction forms.

Assessment of risk of bias in included studies

We will assess every trial using a simple form and will follow the domain‐based evaluation as described in the Cochrane Handbook for Systematic Reviews of Interventions 5.3 (Higgins 2011).

We will assess the following domains as having either a low, unclear, or high risk of bias:

  1. randomisation;

  2. concealment of allocation;

  3. blinding (of participants, personnel and outcome assessors);

  4. incomplete outcome data;

  5. selective outcome reporting.

Measures of treatment effect

In future updates, if we are able to include any trials, for dichotomous outcomes, we plan to estimate treatment effects using the risk ratio (RR). For continuous outcomes we plan to record either mean relative change from baseline for each group or mean post‐treatment or post‐intervention values and standard deviation. If standard errors are reported (and if possible) we plan to convert these to standard deviations. We plan to calculate a pooled estimate of treatment effect by calculating the mean difference. Time‐to‐event data will be calculated as hazard ratios with 95% confidence intervals (Parmar 1998).

Assessment of heterogeneity

We plan to quantify the impact of statistical and clinical heterogeneity in the meta‐analysis using a measure (I²) of the degree of inconsistency in the studies' results (Higgins 2003). This measure describes the percentage of total variation across studies that is due to heterogeneity rather than chance (Higgins 2003). The values of I² lie between 0% and 100%, and a simplified categorization of heterogeneity that we plan to use is (Higgins 2003):

  • 0% to 40%: might not be important;

  • 30% to 60%: may represent moderate heterogeneity;

  • 50% to 90%: may represent substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

Assessment of reporting biases

We will use a funnel plot to assess whether the review is subject to publication bias. If asymmetry is detected we will also assess other possible causes.

Data synthesis

If significant heterogeneity is identified we will use the random‐effects model. If we do not identify significant heterogeneity we will compute pooled estimates of the treatment effect for each outcome under a fixed‐effect model.

Subgroup analysis and investigation of heterogeneity

If we find sources of heterogeneity and if there are sufficient data, we will conduct meta‐analysis by subgroups. We will investigate the possible causes of this further by exploring the impact of the different types of Gaucher disease, severity of the disease at baseline, and a difference in the dosage of enzyme in the individuals.

Sensitivity analysis

We plan to perform a sensitivity analysis based on the methodological quality of trials, including and excluding quasi‐RCTs and CCTs.

Results

Description of studies

We found no trials that were eligible for inclusion in this review. The 32 trials listed as excluded studies were not eligible for all or some of the following reasons: not a RCT or quasi‐RCT or CCT (Baker 1999; Barranger 1999; Mankoski 2014; Orchard 2008) or the interventions were not relevant (Abbas 2015; Almon 2008; Charrow 2014; Cox 2014; de Fost 2007; Elstein 2001; Elstein 1998; Garcia 2014; Gonzales 2010; Grabowski 1995; Kishnani 2009; Lukina 2013; Lukina 2016; Medrano‐Engay 2013; Mehta 2008; Mistry 2013; Nuzhnyi 2014; Schiffmann 2008; Turpault 2015; Weinreb 2008; Wenstrup 2004; Zimran 2011; Zimran 2012; Zimran 2013; Zimran 2014; Zimran 2015; Zimran 2016a; Zimran 2016b). Please see the 'Characteristics of excluded studies' table for more details.

Risk of bias in included studies

We found no trials eligible for inclusion in this review.

Effects of interventions

We found no trials eligible for inclusion in this review.

Discussion

We have not found any relevant RCTs, quasi‐RCTs or CCTs assessing the role of HSCT for treating Gaucher disease.

At present HSCT is a treatment that can provide a permanent source of enzyme to people with Gaucher disease and is a considerably less expensive procedure when compared to the more commonly used intervention, ERT. A number of case‐series reports have shown that, where engraftment takes place, HSCT leads to a favorable clinical outcome with a growth spurt, reversal of organomegaly, and a possible regression of skeletal changes. People with type 3 Gaucher disease showed no further neurological deterioration. One non‐randomised study has suggested that HSCT may be more effective than ERT at currently used dosage levels, in reducing total body stores of glucocerebroside (Young 1997).

However, the important limitations of HSCT are the mortality and morbidity associated with the procedure and the non‐availability of HLA‐matched donors. For these reasons HSCT is postponed as a treatment until very late in the course of disease, when a cure is less likely. But the recent technological advances in the field of transplantation have expanded the sources of stem cells and also reduced the risks associated with the procedure. It is therefore important to re‐evaluate the risks and benefits of HSCT in comparison with the more conservative but noncurative options such as ERT and substrate reduction therapy in the treatment of people with Gaucher disease. Until adequate data from appropriate clinical trials become available, clinicians will need to balance the possible benefits against the possible risks of transplantation.