Assessment of liver and cardiac iron overload using MRI in patients with chronic anemias in Latin American countries: results from ASIMILA study.

OBJECTIVES: A multicenter, noninterventional, observational study was conducted in the Latin American countries including Argentina, Brazil, Colombia, Mexico, and Venezuela to assess the prevalence of liver and cardiac iron overload using magnetic resonance imaging (MRI) in patients with chronic anemias except thalassemia. METHODS: Patients aged >10 years with transfusion-dependent anemias, except thalassemia, either with <20 units of red blood cell (RBC) transfusions with serum ferritin (SF) levels >2000 ng/mL or with ≥20 units of RBC transfusions regardless of SF level in their lifetime, were enrolled. Iron overload was assessed using MRI. RESULTS: Among 175 patients included, the majority had sickle cell disease (SCD; 52%), followed by aplastic anemia (AA; 17.7%), myelodysplastic syndrome (MDS; 8.6%), Diamond-Blackfan anemia (DBA; 4%), pure red cell aplasia (1.1%), and others (16.6%). Liver iron overload was observed in 76.4% of patients, while cardiac iron overload was seen in 19.2% when assessed by MRI. The prevalence of iron overload was 80.2% in patients with SCD, 73.3% in MDS, 77.4% in AA, 100% in pure red cell aplasia, 71.4% in DBA, and 68.9% in other transfusion-related disorders. A moderate correlation between liver iron concentration (LIC) and SF was observed in patients with SCD and MDS (r = 0.47 and r = 0.61, respectively). All adverse events reported were consistent with the published data for deferasirox or underlying disease. CONCLUSION: A high prevalence of iron overload in this patient population in Latin American countries indicates that a better diagnosis and management of iron overload is required in these countries.

Influence of TNF and IL6 gene polymorphisms on the severity of cytopenias in Argentine patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematologic disorders characterized by cytopenia(s) and predisposition to leukemic progression. An immune dysregulation and an aberrant bone marrow microenvironment seem to be key elements in the physiopathological process of MDS. In order to evaluate a possible association between susceptibility and clinic-pathologic features, we genotyped 153 MDS patients for functional cytokine polymorphisms: TNF (-308 G/A), IFNG (+874 A/T and +875 CAn), IL6 (-174 G/C), and TGFB1 (+869 C/T and +915 G/C). The frequency of TNF and IL6 polymorphisms was different between patients and healthy controls (n = 131), suggesting a relatedness to MDS susceptibility in our population. Furthermore, the presence of each or both high-producing genotypes [TNF: p = 0.048, odds ratio (OR): 3.979; IL6: p = 0.001, OR: 6.835; both: p = 0.010, OR: 6.068] and thrombocytopenia at platelet counts of <50,000/µL (p = 0.004, OR: 4.857) were independently associated with an increased risk of manifesting a hemoglobin level of <8 g/dL at diagnosis. In particular, a severe bicytopenia was more frequently observed in patients with the TNF (high)_IL6 (high) combined genotype (p = 0.004, OR: 8.357), who consistently became transfusion dependent earlier (2.9 vs. 34.6 months; p = 0.001); and this likelihood was more evident in patients with lower bone marrow blast counts. The contribution of the remaining functional polymorphisms to the disease phenotype was less relevant. Our results demonstrate that TNF and IL6 gene polymorphisms, as underlying host features, are likely to play a key role in influencing the severity of the cytopenias in MDS and they may be instrumental for tailoring cytokine-target therapies.

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.

Myelodysplastic syndromes in South America: a multinational study of 1080 patients.

There are previously reported data describing differences between Asian and European patients with Myelodysplastic Syndromes (MDS), few direct comparisons based on cancer registration characteristics or using cohorts to validate scoring systems. This is the first study from South-America, which attempts to describe demographic, clinical features, and outcome of MDS patients. We retrospectively analyzed 1,080 patients with de novo MDS from Argentina (635), Brazil (345), and Chile (100). Chilean patients were younger (P = 0.001) with female preponderance (P = 0.071). Brazilian series showed a higher predominance of RARS subtype regarding FAB and WHO classifications (P < 0.001). Hemoglobin levels were significantly lower in Brazilian and Chilean series (P < 0.001), and Chilean series also showed a lower platelet count (P = 0.028), with no differences concerning the neutrophil count, % BM blast, and the distribution of cytogenetic risk groups (P > 0.05). Chilean series depicted a lower overall survival (OS; 35 months vs. 56 months-Argentine; 55 months-Brazil, P = 0.030), which was consistent with a higher predominance of the high-risk group according both to the IPSS and IPSS-R (P = 0.046 and P < 0.001). The IPSS-R system and its variables showed a good reproducibility to predict clinical outcome for the whole South-American population. Epidemiological and clinical characteristics, distribution among prognostic subgroups, the OS, and the access to disease modifying therapies were more similar between Argentinean and Brazilian compared with Chilean MDS series. This will need further analysis in a larger group of patients. Descriptive and comparative studies are necessary to establish epidemiological features useful for public health attitudes to generate suitable therapeutic schemes.

The presence of -308A TNFα is associated with anemia and thrombocytopenia in patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematological diseases characterized by refractory cytopenia(s). MDS patients show increased levels of tumor necrosis factor alpha (TNFα) which is a multifunctional proinflammatory cytokine. The aim of this work is to examine the presence of -308A/G TNFα variants and to analyze whether it is associated with clinical parameters in a cohort of 101 Argentinean de novo MDS patients. The A/A+A/G genotype at TNFα -308 was overrepresented 2-fold in our population (p=0.0499, odds ratio-OR: 2.107) and these differences were more evident in RA-FAB subtype (p=0.0424, OR: 2.502). The presence of the high expressing -308A allele was associated with lower hemoglobin level (8.3 vs 9.9g/dL; p=0.0206), reduced platelet counts (89,000 vs 130,000/µL; p=0.0381) and younger age (59 vs 68years; p=0.0122) at diagnosis. Also, these patients showed 3.8-fold higher risk of transfusion requirement (76% vs 46%, p=0.0105) during the follow up. In conclusion, the presence of an inherited -308A TNFα, which increases its transcription level, was associated with the MDS phenotype in our cohort of Argentine MDS patients. Also, an overexpression of TNFα may promote an underlying proinflammatory state that cooperates with intrinsic defects within MDS progenitors to increase the severity of certain phenotypic features of the disease.

Partial and total monosomal karyotypes in myelodysplastic syndromes: comparative prognostic relevance among 421 patients.

Myelodysplastic syndromes (MDS) include a group of heterogeneous hematological disorders with a variable risk of leukemic evolution and short survival. Around 40-50% of patients show abnormal karyotypes that are mostly characterized by monosomies or deletions. Cytogenetic findings are an independent prognostic factor and the International prognostic scoring system (IPSS) differentiates three cytogenetic categories, despite the Intermediate one being heterogeneous. The aim of this study, including 421 Argentinean patients with primary MDS, is to characterize the cytogenetic profile, to test its prognostic value and to compare partial and monosomal karyotypes against other cytogenetic findings. An abnormal karyotype (median survival: 26 months) was observed in 176 patients. The presence of complex karyotypes, number of alterations, and the IPSS cytogenetic groups showed significant differences for predicting outcome. Behavior of patients with isolated deletions (median survival: 49 months) did not differ from those with normal karyotype (56 months, P = 0.654) or Good prognostic findings (43 months, P = 0.371). However, a worse prognosis was observed when another alteration was added (31 months, P = 0.043). Karyotypes with autosomal monosomies (median survival: 16 months) had a prognostic impact similar to other Poor cytogenetic findings (17 months, P = 0.626). In our population classified according to French-American-British (FAB) or World Health Organization (WHO), this new categorization of cytogenetic abnormalities, recognizing three different risk groups, showed an independent prognostic impact and a better discriminating power than the IPSS categories. It can be concluded that all isolate deletions (excluding 7q-) are good prognostic findings and all monosomies (excluding Y chromosome loss) are bad indicators.

Management of transfusional iron overload in Latin America: current outlook and expert panel recommendations.

The results of a meeting of physicians convening in Latin America to develop expert opinions on the diagnosis, monitoring and treatment of iron overload are as follows. An accurate diagnosis can be obtained by neonatal screening for haemoglobinopathies, especially sickle cell disease and the thalassaemias. Disease-specific registries are needed to demonstrate the extent of the problem to health authorities. Disparities in the quantity and quality of blood products must be addressed, and uniform transfusion guidelines are necessary. Serum ferritin level is a feasible marker for iron overload in the region, while magnetic resonance imaging assessment can improve the diagnosis and monitoring of cardiac and liver iron content. Medical specialists, including radiologists, pathologists and others, and health authorities, can help to implement these methods and provide adequate resources. The recently available oral deferasirox can be used to conveniently administer iron chelation to transfusional iron-overloaded patients.

Detección de grupos de riesgo en síndromes mielodisplásicos. Un estudio multicéntrico / Detection of risk groups in myelodisplastic syndromes. A multicentric study

Los síndromes mielodisplásicos (SMD) comprenden un grupo heterogéneo de desordenes hematólogicos con riesgo de evolución a leucemia mieloide aguda (LMA). El Grupo Franco-Americano-Británico (FAB) los clasifica en cinco entidades morfológicas y el Sistema Pronóstico Internacional (IPSS) propone cuatro grupos de riesgo basándose en variables clínicas y citogenéticas. El objetivo del trabajo fue evaluar la aplicación del IPSS en población Argentina, analizar el valor pronóstico de sus variables y determinar si dicho sistema permite identificar subgrupos pronósticos de riesgo dentro de los subtipos FAB. Se evaluaron 234 pacientes con SMD de novo (Media de seguimiento: 28 meses), con el fin de determinar sobrevida (SV) y sobrevida libre de LMA (SLL). Se analizaron la clasificación FAB y el IPSS, así como sus variables (número de citopenias, porcentaje de blastos, grupos de riesgo citogenético). Los resultados mostraron diferencias significativas para SV y SLL. La aplicación del IPSS permitió la diferenciación de los cuatro grupos de riesgo y ayudó a identificar subclases pronósticas dentro de los subtipos FAB: 5 , 15 y 19 por ciento de pacientes con peor pronóstico dentro de los subtipos Anemia Refractaria (AR), AR con sideroblastos en anillo (ARSA) y AR con exceso de blastos (AREB), respectivamente. El IPSS no fue informativo para el subtipo AREB en transformación, ni tampoco en pacientes con leucemia mielomonocítica crónica.

El estudio citogénito como variable pronóstica en los síndromes mielodisplásicos / cytogenetic study as prognostic factor in myelodysplastic disorders

Los Síndromes Mielodisplásicos (SMD) comprenden un grupo heterogéneo de desórdenes hematológicos con riesgo de evolución leucémica. En este trabajo se evaluó el valor pronóstico del cariotipo al momento del diagnóstico, teniendo en cuenta el International Prognostic Scoring System (IPSS). Dicho puntaje propone 3 grupos pronósticos para la variable citogenética: Bueno (cariotipo normal, del(5q), del(20q) o -Y), Intermedio (+8 y misceláneas) y Malo (-7/del(7q) o alteraciones complejas). En este estudio se evaluaron 198 pacientes (95 AR, 13 AS, 43 AREB, 23 AREBt y 24 LMMC) distribuidos, de acuerdo al IPSS en: 60 Bajo riesgo, 76 Intermedio 1, 32 Intermedio 2 y 30 Alto riesgo (media de seguimiento: 28 meses). Los resultados citogenéticos de médula ósea se agruparon en: 126 Bueno, 41 Intermedio y 31 Malo, con una mediana de Sobrevida de 60, 34 y 28 meses (p=0.013) y una Evolución Leucémica (25porciento) de 46, 19 y 5 meses (p<0.001), respectivamente. El cruzamiento entre los grupos citogenéticos y el IPSS mostró que el 84 porciento de los pacientes pertenecientes al grupo citogenético Bueno correspondían al riesgo Bajo e Intermedio-l, el 61 porciento del grupo citogenético Intermedio presentaban riesgo Intermedio-l; mientras que, el 84 porciento perteneciente al grupo citogenético Malo pertenecían a los grupos de riesgo Intermedio-2 y Alto. Estos datos muestran una importante asociación (p<0.001) entre el estudio citogenético y los grupos de riesgo determinados por el IPSS. Lo cual indica la importancia del cariotipo, aparte del porcentaje de blastos y las citopenias, para individualizar grupos pronósticos en los SMD.

El estudio citogénito como variable pronóstica en los síndromes mielodisplásicos / cytogenetic study as prognostic factor in myelodysplastic disorders

Los Síndromes Mielodisplásicos (SMD) comprenden un grupo heterogéneo de desórdenes hematológicos con riesgo de evolución leucémica. En este trabajo se evaluó el valor pronóstico del cariotipo al momento del diagnóstico, teniendo en cuenta el International Prognostic Scoring System (IPSS). Dicho puntaje propone 3 grupos pronósticos para la variable citogenética: Bueno (cariotipo normal, del(5q), del(20q) o -Y), Intermedio (+8 y misceláneas) y Malo (-7/del(7q) o alteraciones complejas). En este estudio se evaluaron 198 pacientes (95 AR, 13 AS, 43 AREB, 23 AREBt y 24 LMMC) distribuidos, de acuerdo al IPSS en: 60 Bajo riesgo, 76 Intermedio 1, 32 Intermedio 2 y 30 Alto riesgo (media de seguimiento: 28 meses). Los resultados citogenéticos de médula ósea se agruparon en: 126 Bueno, 41 Intermedio y 31 Malo, con una mediana de Sobrevida de 60, 34 y 28 meses (p=0.013) y una Evolución Leucémica (25porciento) de 46, 19 y 5 meses (p<0.001), respectivamente. El cruzamiento entre los grupos citogenéticos y el IPSS mostró que el 84 porciento de los pacientes pertenecientes al grupo citogenético Bueno correspondían al riesgo Bajo e Intermedio-l, el 61 porciento del grupo citogenético Intermedio presentaban riesgo Intermedio-l; mientras que, el 84 porciento perteneciente al grupo citogenético Malo pertenecían a los grupos de riesgo Intermedio-2 y Alto. Estos datos muestran una importante asociación (p<0.001) entre el estudio citogenético y los grupos de riesgo determinados por el IPSS. Lo cual indica la importancia del cariotipo, aparte del porcentaje de blastos y las citopenias, para individualizar grupos pronósticos en los SMD.(AU)

Detection of risk groups in myelodysplastic syndromes. A multicenter study.

BACKGROUND AND OBJECTIVES: Myelodysplastic syndromes (MDS) comprise a group of heterogeneous hematologic disorders with risk of leukemic evolution (LE). The French-American-British (FAB) co-operative group classifies them into five morphologic entities and the International Prognostic Scoring System (IPSS) proposes four groups of risk on the basis of clinical and cytogenetic variables. The aim of this study was to evaluate the application of the IPSS in our Argentine population, to test the prognostic value of its variables and to determine whether this score helps to associate prognostic subgroups of risk into FAB subtypes. DESIGN AND METHODS: Two hundred and thirty-four patients with primary MDS and a median follow-up of 28 months were evaluated using univariate analyses to determine median survival (SV) and the time to LE. The variables analyzed were FAB classification, IPSS, percentage of myeloblasts, cytogenetic groups of risk and number of cytopenias. RESULTS: Univariate analyses showed that all variables analyzed were predictive for SV and for LE in our MDS population. Application of the IPSS allowed discrimination into the 4 groups of risk and helped to identify prognostic subclasses among the FAB classification, associating 5%, 15% and 19% of cases with worse prognosis within the FAB classification of refractory anemia (RA), RA with ringed sideroblasts and RA with excess of blasts (RAEB), respectively. The IPSS was not informative for RAEB in transformation cases and would not be applied to patients with chronic myelomonocytic leukemia. INTERPRETATION AND CONCLUSIONS: This score could be applied to our MDS population, showing no geographic differences. Stratification of FAB patients according to IPSS would be helpful to develop risk-adapted therapeutic strategies.

Infecciones en pacientes leucémicos granulocitopénicos: análisis de 57 episodios febriles / Infections in leukemic leukopenic patients: analysis of 57 febrile episodes

Se estudiaron 57 episodios febriles en 42 pacientes internados con el diagnóstico de leucemia aguda, y cifras iguales o menores de 1000 neutrófilos por milímetro cúbico. Las combinaciones antimicrobianas empíricas utilizadas más frecuentemente fueron Cefalotina + Amikacina y Cefuroxine + Mezlocilina; no pudimos establecer la superioridad terapéutica de ningún régimen sobre el otro. De los 57 episodios febriles, 37 cursaron desde el inicio con neutrófilos inferiores a 500/mm3. Los focos probables de infección fueron fundamentalmente el mucocutáneo y el pulmonar (49 y 31,5%, respectivamente). El foco abdominal se asoció a pronóstico severo. Hubo aislamientos microbiológicamente documentados en un 60%, con predominio de agentes Gram positivos con respecto a enterobacterias y Pseudomonas aeruginosa. La evolución de los procesos infecciosos mantuvo estrecha relación con la posibilidad de recuperación de la enfermedad de base

Infecciones en pacientes leucémicos granulocitopénicos: análisis de 57 episodios febriles / Infections in leukemic leukopenic patients: analysis of 57 febrile episodes

Se estudiaron 57 episodios febriles en 42 pacientes internados con el diagnóstico de leucemia aguda, y cifras iguales o menores de 1000 neutrófilos por milímetro cúbico. Las combinaciones antimicrobianas empíricas utilizadas más frecuentemente fueron Cefalotina + Amikacina y Cefuroxine + Mezlocilina; no pudimos establecer la superioridad terapéutica de ningún régimen sobre el otro. De los 57 episodios febriles, 37 cursaron desde el inicio con neutrófilos inferiores a 500/mm3. Los focos probables de infección fueron fundamentalmente el mucocutáneo y el pulmonar (49 y 31,5%, respectivamente). El foco abdominal se asoció a pronóstico severo. Hubo aislamientos microbiológicamente documentados en un 60%, con predominio de agentes Gram positivos con respecto a enterobacterias y Pseudomonas aeruginosa. La evolución de los procesos infecciosos mantuvo estrecha relación con la posibilidad de recuperación de la enfermedad de base (AU)