Cancer risk and gammopathies in 2123 adults with Gaucher disease type 1 in the International Gaucher Group Gaucher Registry.

There are numerous reports of cancers in Gaucher disease (GD) from mostly small single-center studies; however, precise risk estimates and cancer types involved have not been delineated. We conducted a study involving 2123 patients with GD type 1 (GD1) to assess the incidence of hematological malignancies, gammopathies, and solid tumors in an international observational study, the International Cooperative Gaucher Group Gaucher Registry (Clinicaltrials.gov: NCT00358943). Risk for cancer overall and for each type of malignancy was compared to the United States (US) population using the Surveillance, Epidemiology, and End Results database. Natural history of gammopathy was determined through assessing the progression from a diagnosis of monoclonal gammopathy of unknown significance (MGUS) to multiple myeloma (MM). Risk for hematological malignancies was more than four times higher than expected compared to the general population: non-Hodgkin lymphoma was approximately three times higher; MM was approximately nine times higher. Age-specific incidence rates of MGUS were unexpectedly high among younger patients. The 10-year cumulative incidence of MM after diagnosis of MGUS was 7.9%, comparable to the general population. Compared to the general US population, GD1 patients were at higher risk for solid malignancies of liver (2.9 times), kidney (2.8 times), melanoma (2.5 times), and breast (1.4 times). Colorectal, prostate, and lung cancer risks were lower than expected. These findings help advance care of patients with GD1 by supporting recommendations for individualized monitoring for malignancies and antecedents such as MGUS for MM and provoke important questions of the role of glucosylceramide and related sphingolipids in cancer biology.

Outcomes after 8 years of eliglustat therapy for Gaucher disease type 1: Final results from the Phase 2 trial.

Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) and poor, intermediate or extensive CYP2D6-metabolizer phenotypes (>90% of patients). We report the final results of a Phase 2 trial and extension (NCT00358150) in previously untreated adult GD1 patients who had splenomegaly with thrombocytopenia and/or anemia and received 50 or 100 mg eliglustat tartrate (equivalent to 42 or 84 mg eliglustat) twice daily for 8 years. In total, 19 of 26 patients completed the trial. After 8 years of eliglustat, mean spleen and liver volumes decreased by 69% and 34%, respectively. Mean hemoglobin concentration and platelet count increased by 2.2 g/dL and 113%, respectively. All patients met at least 3 of 4 therapeutic goals established for patients on long-term enzyme replacement therapy. Mean final values for patients with severe splenomegaly (n = 6), moderate-to-severe anemia (n = 6), or severe thrombocytopenia (n = 8) were similar to patients with milder disease at baseline and within long-term therapeutic goal thresholds. Biomarker median percent changes from baseline were -91% for chitotriosidase, -87% for CCL18, -92% for glucosylsphingosine, and -80% for plasma glucosylceramide. Mean lumbar spine T-score increased by 0.96, moving from the osteopenic to the normal range. Mean quality-of-life scores, mostly below normal at baseline, moved into ranges seen in healthy adults. Eliglustat was well-tolerated; 98% of adverse events were mild or moderate and 94% were considered unrelated to treatment. Clinically meaningful improvements in all parameters continued or were maintained over 8 years, with the largest margins of improvement seen in the most severely affected patients.

Doença de gaucher tipo 1 no esqueleto: revisão da américa latina / Gaucher disease type 1 in the skeleton: review of latin america / Enfermedad de gaucher tipo 1 en el esqueleto: revisión de américa latina

RESUMO A doença de Gaucher (DG) é a doença de depósito lisossômico mais prevalente, que se caracteriza pelo acúmulo de glicosilceramida e glucosilesfingosina em todos os tecidos do corpo. Com o advento da terapia de reposição de enzimas, o prognóstico dos pacientes com DG melhorou acentuadamente. Ainda assim, as manifestações esqueléticas associadas à DG respondem lentamente à terapia de reposição de enzimas e são as que contribuem de forma mais significativa para a morbidade do paciente. Esta revisão das manifestações ósseas da DG apresenta as mais recentes teorias sobre a sua fisiopatologia e uma revisão sistemática de estudos com pacientes latino-americanos que relataram a frequência das manifestações ósseas e os efeitos da terapia de reposição de enzimas sobre seu tratamento. Concluímos, destacando a importância da identificação precoce e do manejo adequado das doses apropriadas da terapia de reposição de enzimas para reduzir a morbidade causada pela DG.

ABSTRACT Gaucher disease (GD) is the most prevalent lysosomal storage disease, and is characterized by the accumulation of glucosylceramide and glucosylsphingosine in tissues throughout the body. With the advent of enzyme replacement therapy, the prognosis for patients with GD has dramatically improved. Still, the skeletal manifestations associated with GD respond slowly to enzyme replacement therapy and are the most significant contributor of disease related patient morbidity. This review of bone manifestations in GD presents the most recent theories on its pathophysiology, and gives a systematic review of studies with Latin American patients that report the frequency of bone manifestations and the effects of enzyme replacement therapy on their treatment. We conclude by emphasizing the importance of early identification and proper management at appropriate dosage levels of enzyme replacement therapy to reduce the morbidity caused by GD.

RESUMEN La enfermedad de Gaucher (EG) es la patología de depósito lisosomal más prevalente, que se caracteriza por la acumulación de glucosilceramida y glucosilesfingosina en todos los tejidos del cuerpo. Con el advenimiento de la terapia de reemplazo enzimático el pronóstico de los pacientes con EG ha mejorado notablemente. Sin embargo, las manifestaciones esqueléticas asociadas a la EG responden lentamente a la terapia de reemplazo enzimático y son las que contribuyen más significativamente a la morbilidad del paciente. Esta revisión de las manifestaciones óseas de la EG presenta las últimas teorías sobre la fisiopatología y una revisión sistemática de estudios de pacientes latinoamericanos que informaron la frecuencia de manifestaciones óseas y los efectos de la terapia de reemplazo enzimático en el tratamiento. Como conclusión, destacamos la importancia de la identificación temprana y del manejo adecuado de las dosis apropiadas de terapia de reemplazo enzimático para reducir la morbilidad causada por la EG.

Skeletal involvement in Gaucher disease: An observational multicenter study of prognostic factors in the Argentine Gaucher disease patients.

Patients with Gaucher type 1 (GD1) throughout Argentina were enrolled in the Argentine bone project to evaluate bone disease and its determinants. We focused on presence and predictors of bone lesions (BL) and their relationship to therapeutic goals (TG) with timing and dose of enzyme replacement therapy (ERT). A total of 124 patients on ERT were enrolled in a multi-center study. All six TG were achieved by 82% of patients: 70.1% for bone pain and 91.1% for bone crisis. However, despite the fact that bone TGs were achieved, residual bone disease was present in 108 patients on ERT (87%) at time 0. 16% of patients showed new irreversible BL (bone infarcts and avascular osteonecrosis) despite ERT, suggesting that they appeared during ERT or were not detected at the moment of diagnosis. We observed 5 prognostic factors that predicted a higher probability of being free of bone disease: optimal ERT compliance; early diagnosis; timely initiation of therapy; ERT initiation dose ≥45 UI/kg/EOW; and the absence of history of splenectomy. Skeletal involvement was classified into 4 major phenotypic groups according to BL: group 1 (12.9%) without BL; group 2 (28.2%) with reversible BL; group 3 (41.9%) with reversible BL and irreversible chronic BL; and group 4 (16.9%) with acute irreversible BL. Our study identifies prognostic factors for achieving best therapeutic outcomes, introduces new risk stratification for patients and suggests the need for a redefinition of bone TG. Am. J. Hematol. 91:E448-E453, 2016. © 2016 Wiley Periodicals, Inc.

Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat.

OBJECTIVE: Eliglustat is an investigational oral substrate reduction therapy for Gaucher disease type 1 (GD1). Its skeletal effects were evaluated by prospective monitoring of bone mineral density (BMD), fractures, marrow infiltration by Gaucher cells, focal bone lesions, and infarcts during an open-label, multi-site, single-arm phase 2 trial (NCT00358150). MATERIALS AND METHODS: Institutional review board approval and patient informed consent were obtained. Eliglustat (50 or 100 mg) was self-administered by mouth twice daily; 19 patients completed 4 years of treatment. All were skeletally mature (age range, 18-55 years). DXA and MRI assessments were conducted at baseline and annually thereafter. X-rays were obtained annually until month 24, and then every other year. RESULTS: Lumbar spine BMD increased significantly (p = 0.02; n = 15) by a mean (SD) of 9.9% (14.2%) from baseline to year 4; corresponding T-scores increased significantly (p = 0.01) from a mean (SD) of -1.6 (1.1) to -0.9 (1.3). Mean femur T-score remained normal through 4 years. Femur MRI showed that 10/18 (56%) patients had decreased Gaucher cell infiltration compared to baseline; one patient with early improvement had transient worsening at year 4. There were no lumbar spine or femoral fractures and no reported bone crises during the study. At baseline, 8/19 (42%) patients had focal bone lesions, which remained stable, and 7/19 (37%) patients had bone infarctions, which improved in one patient by year 2. At year 4, one new asymptomatic, indeterminate bone lesion was discovered that subsequently resolved. CONCLUSIONS: Eliglustat may be a therapeutic option for treating the skeletal manifestations of GD1.

Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 years of treatment.

Eliglustat is an investigational, oral substrate reduction therapy for Gaucher disease type 1 (GD1). Nineteen treatment-naïve patients have now completed 4years of an open-label study (NCT00358150). Mean hemoglobin level and platelet count increased by 2.3±1.5g/dL (baseline: 11.3±1.5g/dL) and 95% (baseline: 68,700±21,200/mm(3)), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (baseline: 17.3±9.5 MN) and 28% (baseline: 1.7±0.4 MN), respectively. Median chitotriosidase and CCL-18 each decreased by 82%; plasma glucosylceramide and GM3 normalized. Mean bone mineral density T-score for the lumbar spine increased by 0.8 (60%) (baseline: -1.6±1.1). Femur dark marrow, a reflection of Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Most adverse events were mild and unrelated to treatment. These results extend the safety and efficacy of eliglustat reported at 1 and 2 years to 4 years.

Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study.

Eliglustat tartrate is an investigational oral substrate reduction therapy for Gaucher disease type 1 that is pharmacologically distinct from intravenous enzyme replacement therapy. Eliglustat tartrate improved clinical manifestations in patients who received 50 or 100 mg twice daily for 1 year during an open-label phase 2 study (Blood. 2010;116(6):893-899). We report further improvements after 2 years of treatment in 20 patients (11 females, 9 males; mean age, 33 years) with baseline splenomegaly and thrombocytopenia and/or anemia. Statistically significant (P < .001) percentage improvements from baseline occurred in platelet count (mean ± SD, 81% ± 56%), hemoglobin level (20% ± 15%), spleen volume (-52% ± 11%), and liver volume (-24% ± 13%). Mean platelet count increased ∼ 50 000/mm(3). Mean hemoglobin level increased 2.1 g/dL overall and 3.1 g/dL in 10 patients with baseline anemia. Organ volume reductions were greatest in patients with severe baseline organomegaly. Seventeen (85%) patients met established therapeutic goals for ≥ 3 of the 4 parameters. Lumbar spine bone mineral density increased 7.8% ± 10.6% (P = .01) and T-score 0.6 ± 0.8 (P = .012), with major gains in osteoporotic and osteopenic patients. Magnetic resonance imaging assessment showed that bone marrow infiltration by Gaucher cells was decreased (8/18 patients) or stable (10/18 patients). No safety-related trends emerged during 2 years of treatment. This multisite, open-label, single-arm phase 2 study is registered at www.clinicaltrials.gov as NCT00358150.

A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1.

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1.

Manejo actual de los linfomas / Current concepts: management of lymphomas

Lymphomas constitute a heterogeneous group of neoplastic diseases of the lymphatic system. Between all the varieties of malignancies, lymphomas show problems and special opportunities for the diagnosis and detections. The existence of numerous histologic subtypes and the similarity of malignant lymphocytes with the normal lymphocytes in their distinct stages of differentiation and activation, had led to the development of sophisticated diagnosti methods to assist the morphology in the recognition of them. Special considerations are made about the non-Hodgkin's lymphomas and the Epstein-Barr virus. The author also details the classification, the treatment and the epidemiology.

Comparison of Epstein-Barr virus presence in Hodgkin lymphoma in pediatric versus adult Argentine patients.

CONTEXT: In developed countries and high socioeconomic groups, Hodgkin lymphoma has an initial peak in young adulthood, whereas in undeveloped countries and low socioeconomic groups, it shows an early childhood peak. In developing countries, 90% of children are infected with the Epstein-Barr virus (EBV) by the age of 6 years, but in developed countries, only 30% to 40% are seropositive by that age. Early childhood EBV infection in 75% of Argentine patients was demonstrated. OBJECTIVE: To explore the epidemiology of Hodgkin lymphoma and its relationship with EBV in Argentine patients. METHODS: The presence of EBV was assessed by Epstein-Barr encoded RNA in situ hybridization and latent membrane protein 1 immunohistochemistry. We studied 92 pediatric and 42 adult Hodgkin lymphoma cases from a public center as well as 39 adult cases from a private center. RESULTS: The mixed cellularity Hodgkin lymphoma had a prevalence of 52% in the pediatric group, while similar frequencies of both nodular sclerosis Hodgkin lymphoma (47%) and mixed cellularity Hodgkin lymphoma (44%) were observed in adults. As for Epstein-Barr encoded RNAs, 55% of the pediatric cases and 31% of the adult cases were positive. Among adult EBV+ cases, 38% were from the public hospital, and 23% were from the private center. EBV was present in 77% of the pediatric mixed cellularity Hodgkin lymphoma cases when compared with the other histologic subtypes of Hodgkin lymphoma. EBV was mainly detected in mixed cellularity cases (39% in the adult group). CONCLUSION: Our findings strengthen the argument that EBV is involved in the pathogenesis of Hodgkin lymphoma in most children younger than 10 years. Our findings of EBV prevalence, along with both childhood and second-decade peaks as well as comparable frequencies for Hodgkin lymphomas of mixed cellularity and nodular sclerosis, distinguish our population from others in developing countries.

Asociación del virus de Epstein Barr (EBV) y el Linfoma de Hodgkin (LH): estudio comparativo de población pediátrica y adulta / Comparative study of Epstein Barr virus and Hodgkinïs lymphoma in adult and pediatric population

El LH presenta una curva bimodal en la distribución por edades que no se encuentra en otros linfomas. El primer pico corresponde a adultos jóvenes en países económicamente desarrollados, mientras que el segundo pico corresponde siempre a adultos (> 50años). La asociación de LH con el EBV ha sido documentada en diversos trabajos. Nuestro objetivo es analizar comparativamente la presencia de dicho virus en casos de LH en niños y adultos. Material y Métodos: biopsias de pacientes con LH: 79 ganglios de niños, 65 ganaglios de adultos y 1 pieza de esplenectomía, todas fijadas en formol e incluídas en parafina. Detección de proteínas virales LMP-1 por inmunohistoquímica y EBER-1, -2 por Hibridización in situ. Resultados: distribución por edades y sexo: niños: 2 a 15 años (mediana 8) 76.5 porciento varones, adultos: 16 a 80 años (mediana 38), 51 porciento varones. Detección de EBV: a)población pediátrica:42 casos + (53 porciento) con ambas técnicas. 67 porciento corresponden al subtipo histológico celularidad mixta (CM) (p=0,01), uno de ellos se diagnosticó como CM interfolicular. En los menores de 7 años se halló EBV en el 74 porciento de los casos (p=0.006); b) población adulta: en 18 casos se detectó genoma de EBV por hibridización in situ (27 porciento), siendo el 55.5 porciento para la CM y el 33 porciento para la EN. Conclusiones: 1) La asociación del LH con EBV es más frecuente en niños que en adultos (53 porciento vs 27 porciento), 2) La subpoblación de menores de 7 años presentó una altísima asociación (74 porciento), 3) La presencia del virus en los dos grupos estudiados comparte el patrón epidemiológico descripto para países económicamente desarrollados, 4) Con respecto a los subtipos histológicos, tanto en niños como en adultos predominó el EBV en los casos de CM, destacándose en los adultos la presencia de 1 caso de LH rico en linfocitos y uno diagnosticado en bazo. 5) En los pacientes adultos la asociación de LH y EBV mostró diferencias entre los provenientes de hospital público (38 porciento) y medio no hospitalario (20 porciento).

Asociación del virus de Epstein Barr (EBV) y el Linfoma de Hodgkin (LH): estudio comparativo de población pediátrica y adulta / Comparative study of Epstein Barr virus and Hodgkin´s lymphoma in adult and pediatric population

El LH presenta una curva bimodal en la distribución por edades que no se encuentra en otros linfomas. El primer pico corresponde a adultos jóvenes en países económicamente desarrollados, mientras que el segundo pico corresponde siempre a adultos (> 50años). La asociación de LH con el EBV ha sido documentada en diversos trabajos. Nuestro objetivo es analizar comparativamente la presencia de dicho virus en casos de LH en niños y adultos. Material y Métodos: biopsias de pacientes con LH: 79 ganglios de niños, 65 ganaglios de adultos y 1 pieza de esplenectomía, todas fijadas en formol e incluídas en parafina. Detección de proteínas virales LMP-1 por inmunohistoquímica y EBER-1, -2 por Hibridización in situ. Resultados: distribución por edades y sexo: niños: 2 a 15 años (mediana 8) 76.5 porciento varones, adultos: 16 a 80 años (mediana 38), 51 porciento varones. Detección de EBV: a)población pediátrica:42 casos + (53 porciento) con ambas técnicas. 67 porciento corresponden al subtipo histológico celularidad mixta (CM) (p=0,01), uno de ellos se diagnosticó como CM interfolicular. En los menores de 7 años se halló EBV en el 74 porciento de los casos (p=0.006); b) población adulta: en 18 casos se detectó genoma de EBV por hibridización in situ (27 porciento), siendo el 55.5 porciento para la CM y el 33 porciento para la EN. Conclusiones: 1) La asociación del LH con EBV es más frecuente en niños que en adultos (53 porciento vs 27 porciento), 2) La subpoblación de menores de 7 años presentó una altísima asociación (74 porciento), 3) La presencia del virus en los dos grupos estudiados comparte el patrón epidemiológico descripto para países económicamente desarrollados, 4) Con respecto a los subtipos histológicos, tanto en niños como en adultos predominó el EBV en los casos de CM, destacándose en los adultos la presencia de 1 caso de LH rico en linfocitos y uno diagnosticado en bazo. 5) En los pacientes adultos la asociación de LH y EBV mostró diferencias entre los provenientes de hospital público (38 porciento) y medio no hospitalario (20 porciento). (AU)