RESUMEN
Chromosomal translocations are rare in the myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). With the exception of t(3q), translocations are not explicitly considered in the cytogenetic classification of the IPSS-R and their impact on disease progression and patient survival is unknown. The present study was aimed at determining the prognostic impact of translocations in the context of the cytogenetic classification of the IPSS-R. We evaluated 1,653 patients from the Spanish Registry of MDS diagnosed with MDS or CMML and an abnormal karyotype by conventional cytogenetic analysis. Translocations were identified in 168 patients (T group). Compared with the 1,485 patients with abnormal karyotype without translocations (non-T group), the T group had a larger proportion of patients with refractory anemia with excess of blasts and higher scores in both the cytogenetic and global IPSS-R. Translocations were associated with a significantly shorter survival and higher incidence of transformation into AML at univariate analysis but both features disappeared after multivariate adjustment for the IPSS-R cytogenetic category. Patients with single or double translocations other than t(3q) had an outcome similar to those in the non-T group in the intermediate cytogenetic risk category of the IPSS-R. In conclusion, the presence of translocations identifies a subgroup of MDS/CMML patients with a more aggressive clinical presentation that can be explained by a higher incidence of complex karyotypes. Single or double translocations other than t(3q) should be explicitly considered into the intermediate risk category of cytogenetic IPSS-R classification.
Asunto(s)
Leucemia Mielomonocítica Crónica/genética , Síndromes Mielodisplásicos/genética , Translocación Genética , Anciano , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Pronóstico , España , Tasa de SupervivenciaAsunto(s)
Anticuerpos Monoclonales/uso terapéutico , Transfusión de Eritrocitos , Factores Inmunológicos/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , ADP-Ribosil Ciclasa 1/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Femenino , Fiebre/inducido químicamente , Estudios de Seguimiento , Humanos , Factores Inmunológicos/efectos adversos , Masculino , Glicoproteínas de Membrana/antagonistas & inhibidores , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/terapia , Neutropenia/inducido químicamente , Neumonía/inducido químicamente , Prueba de Estudio Conceptual , Riesgo , Trombocitopenia/inducido químicamenteRESUMEN
The infrequency of translocations in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemias (CMML) makes their identification and reporting interesting for the recognition of the recurrent ones and the genes involved in these neoplasias. The aims of this study were to identify new translocations associated with MDS and CMML and to establish their frequency in a cohort of 8,016 patients from the Spanish Group of MDS database. The karyotype was evaluable in 5,654 (70%) patients. Among those, 2,014 (36%) had chromosomal abnormalities, including 213 (10%) translocations identified in 195 patients. The translocations were balanced in 183 (86%) cases and unbalanced in 30 (14%) cases. All chromosomes were found to be involved in translocations, with the single exception of the Y chromosome. The chromosomes most frequently involved were in decreasing frequency: 3, 1, 7, 2, 11, 5, 12, 6, and 17. Translocations were found in karyotypes as the unique chromosomal abnormality (33%), associated with another chromosomal abnormality (11%), as a part of a complex karyotype (17%), and as a part of a monosomal karyotype (38%). There were 155 translocations not previously described in MDS or CMML and nine of them appeared to be recurrent.
Asunto(s)
Cromosomas Humanos/genética , Leucemia Mielomonocítica Crónica/genética , Síndromes Mielodisplásicos/genética , Translocación Genética/genética , Cromosomas Humanos/clasificación , Humanos , Cariotipo , Leucemia Mielomonocítica Crónica/patología , Síndromes Mielodisplásicos/patologíaRESUMEN
(1) Background: Despite the prognostic improvements achieved with tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML), a minority of patients still fail TKIs. The recent introduction of asciminib may be a promising option in intolerant patients, as it is a first-in-class inhibitor with a more selective mechanism of action different from the ATP-competitive inhibition that occurs with TKIs. Therefore, our goal was to analyze toxicities shown with asciminib as well as to study cross-toxicity with previous TKIs. (2) Methods: An observational, multicenter, retrospective study was performed with data from 77 patients with CML with therapeutic failure to second-generation TKIs who received asciminib through a managed-access program (MAP) (3) Results: With a median follow-up of 13.7 months, 22 patients (28.5%) discontinued treatment: 32% (7/22) due to intolerance and 45% (10/22) due to resistance. Fifty-five percent of the patients reported adverse effects (AEs) with asciminib and eighteen percent grade 3-4. Most frequent AEs were: fatigue (18%), thrombocytopenia (17%), anemia (12%), and arthralgias (12%). None of the patients experienced cardiovascular events or occlusive arterial disease. Further, 26%, 25%, and 9% of patients required dose adjustment, temporary suspension, or definitive discontinuation of treatment, respectively. Toxicities under asciminib seemed lower than with prior TKIs for anemia, cardiovascular events, pleural/pericardial effusion, diarrhea, and edema. Cross-toxicity risk was statistically significant for thrombocytopenia, anemia, neutropenia, fatigue, vomiting, and pancreatitis. (4) Conclusion: Asciminib is a molecule with a good safety profile and with a low rate of AEs. However, despite its new mechanism of action, asciminib presents a risk of cross-toxicity with classical TKIs for some AEs.
RESUMEN
BACKGROUND: Thrombocytopenia is very common in myelodysplastic syndrome (MDS); however, its clinical impact in low-risk patients remains controversial. METHODS: The authors analyzed the incidence and prognostic significance of thrombocytopenia at diagnosis in 2565 de novo MDS patients included in the Spanish MDS Registry. RESULTS: Thrombocytopenia (platelet count <100 × 10(9) /L) was identified in 842 patients (32.8%). Severe thrombocytopenia (platelet count <30 × 10(9) /L) was observed in 7.1% of patients and was significantly associated with a higher-risk World Health Organization subtype (P = .026) and intermediate-2/high-risk International Prognostic Scoring System (IPSS) score (P = .046). Severe thrombocytopenia was the most important prognostic factor and had negative effects on the low/intermediate-1 risk group. Median overall survival of patients with a platelet count <30 and ≥ 30 × 10(9) /L was 16 months and 71 months, respectively (hazard ratio, 4.66; 95% confidence interval, 2.74-7.90; P < .0001). The negative effect of severe thrombocytopenia in low/intermediate-1 risk patients was caused by increased risk of bleeding. CONCLUSIONS: MDS patients with low/intermediate-1 IPSS risk score and severe thrombocytopenia should no longer be regarded as low risk, and must be considered for disease-altering approaches at diagnosis.
Asunto(s)
Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/complicaciones , Trombocitopenia/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , España/epidemiología , Análisis de Supervivencia , Trombocitopenia/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The prognostic value of cytogenetic findings in chronic myelomonocytic leukemia is unclear. Our purpose was to evaluate the independent prognostic impact of cytogenetic abnormalities in a large series of patients with chronic myelomonocytic leukemia included in the database of the Spanish Registry of Myelodysplastic Syndromes. DESIGN AND METHODS: We studied 414 patients with chronic myelomonocytic leukemia according to WHO criteria and with a successful conventional cytogenetic analysis at diagnosis. Different patient and disease characteristics were examined by univariate and multivariate methods to establish their relationship with overall survival and evolution to acute myeloid leukemia. RESULTS: Patients with abnormal karyotype (110 patients, 27%) had poorer overall survival (P=0.001) and higher risk of acute myeloid leukemia evolution (P=0.010). Based on outcome analysis, three cytogenetic risk categories were identified: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). Overall survival at five years for patients in the low, intermediate, and high risk cytogenetic categories was 35%, 26%, and 4%, respectively (P<0.001). Multivariate analysis confirmed that this new CMML-specific cytogenetic risk stratification was an independent prognostic variable for overall survival (P=0.001). Additionally, patients belonging to the high-risk cytogenetic category also had a higher risk of acute myeloid leukemia evolution on univariate (P=0.001) but not multivariate analysis. CONCLUSIONS: Cytogenetic findings have a strong prognostic impact in patients with chronic myelomonocytic leukemia.
Asunto(s)
Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crónica/genética , Anciano , Aberraciones Cromosómicas/clasificación , Cromosomas Humanos Par 7/genética , Cromosomas Humanos Par 8 , Femenino , Humanos , Cariotipificación , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Crónica/complicaciones , Leucemia Mielomonocítica Crónica/mortalidad , Leucemia Mielomonocítica Crónica/patología , Masculino , Análisis Multivariante , Pronóstico , Medición de Riesgo , Índice de Severidad de la Enfermedad , España , Tasa de Supervivencia , Trisomía/patologíaRESUMEN
BACKGROUND: More than 50% of patients with myelodysplastic syndromes present cytogenetic aberrations at diagnosis. Partial or complete deletion of the long arm of chromosome 5 is the most frequent abnormality. The aim of this study was to apply fluorescence in situ hybridization of 5q31 in patients diagnosed with de novo myelodysplastic syndromes in whom conventional banding cytogenetics study had shown a normal karyotype, absence of metaphases or an abnormal karyotype without evidence of del(5q). DESIGN AND METHODS: We performed fluorescence in situ hybridization of 5q31 in 716 patients, divided into two groups: group A patients (n=637) in whom the 5q deletion had not been detected at diagnosis by conventional banding cytogenetics and group B patients (n=79), in whom cytogenetic analysis had revealed the 5q deletion (positive control group). RESULTS: In group A (n=637), the 5q deletion was detected by fluorescence in situ hybridization in 38 cases (5.96%). The majority of positive cases were diagnosed as having the 5q- syndrome. The deletion was mainly observed in cases in which the cytogenetics study had shown no metaphases or an aberrant karyotype with chromosome 5 involved. In group B (n=79), the 5q deletion had been observed by cytogenetics and was confirmed to be present in all cases by fluorescence in situ hybridization of 5q31. CONCLUSIONS: Fluorescence in situ hybridization of 5q31 detected the 5q deletion in 6% of cases without clear evidence of del(5q) by conventional banding cytogenetics. We suggest that fluorescence in situ hybridization of 5q31 should be performed in cases of a suspected '5q- syndrome' and/or if the cytogenetic study shows no metaphases or an aberrant karyotype with chromosome 5 involved (no 5q- chromosome).
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Síndromes Mielodisplásicos/genética , Estudios de Casos y Controles , Aberraciones Cromosómicas , Citogenética/métodos , Femenino , Eliminación de Gen , Hematología/métodos , Humanos , Hibridación Genética , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Metafase , Síndromes Mielodisplásicos/diagnósticoAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Niacinamida/análogos & derivados , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Humanos , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: The fungal infections remain an important problem in the allogeneic stem cell trasnsplantation (allo-SCT) setting and thus, anti-fungal prophylaxis is commonly used. The antifungal drug should offer activity, at least against Candida and Aspergillus spp., a good safety profile and low probability interactions. Micafungin could theoretically fulfill these requisites. The aim of the study was to describe the experience with micafungin as primary prophylaxis in patients undergoing allo-SCT in a cohort of Spanish centres, and to evaluate its efficacy and tolerability in this population. MATERIAL AND METHODS: Retrospective multicentre observational study including all consecutive adult patients admitted for allo-SCT in participating centres of the Grupo Español de Trasplante Hematopoyético (GETH), from January 2010 to December 2013, who received micafungin as primary prophylaxis during the neutropenic period. RESULTS: A total of 240 patients from 13 centres were identified and 159 patients were included for the analysis. Most patients (95.6%) received 50 mg/day of micafungin. During the follow-up, 7 (4.4%) patients developed breakthrough invasive fungal disease, 1 proven and 6 probable; one patient discontinued the drug because of serious drug interactions. Prophylaxis with micafungin was considered effective in 151 (94.9%) patiens. CONCLUSIONS: According to our experience, micafungin is an appropriate alternative for antifungal prophylaxis in patients undergoing an allo-HSCT, because its efficacy, its low profile of drug interactions and side-effects
INTRODUCCIÓN: Las infecciones fúngicas siguen representando un problema en el trasplante alogénico de progenitores hematopoyéticos (alo-TPH) por lo que es habitual el uso de profilaxis antifúngica en estos PACIENTES: El tratamiento antifúngico debe presentar al menos actividad frente a Candida y Aspergillus spp, un buen perfil de seguridad y baja probabilidad de infecciones, siendo micafungina una de las opciones que podría cumplir todos estos requisitos. El objetivo del estudio fue describir la experiencia con micafungina como profilaxis primaria en pacientes sometidos a alo-TPH en una cohorte de hospitales españoles, y evaluar su eficacia y seguridad en esta población. MATERIAL Y MÉTODOS: Estudio retrospectivo multicéntrico observacional consecutivo de todos los pacientes adultos ingresados para alo-TPH en los centros del Grupo Español de Trasplante Hematopoyético (GETH) desde enero de 2010 a diciembre de 2013 y que recibieron micafungina como profilaxis primaria durante el periodo de neutropenia. RESULTADOS: Se identificaron 240 pacientes de 13 hospitales y 159 fueron incluidos para el análisis. La mayoría (95.6%) de ellos recibieron dosis de 50mg/día de micafungina. Durante el seguimiento, 7 (4.4%) pacientes desarrollaron infecciones de brecha, 1 probada y 6 probables; en un paciente se suspendió el tratamiento por interacciones medicamentosas graves. La profilaxis con micafungina se consideró efectiva en el 94,9% de los pacientes (151 de 159). CONCLUSIONES: En base a nuestros resultados, consideramos que micafungina es una buena alternativa como profilaxis antifúngica en pacientes sometidos a alo-TPH, por su eficacia, el bajo riesgo de interacciones y de efectos adversos
Asunto(s)
Humanos , Masculino , Femenino , Persona de Mediana Edad , Antifúngicos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Micafungina/uso terapéutico , Micosis/prevención & control , Aloinjertos , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Interacciones Farmacológicas , Infecciones Fúngicas Invasoras/epidemiología , Micafungina/administración & dosificación , Micafungina/efectos adversos , Estudios Retrospectivos , España/epidemiologíaRESUMEN
BACKGROUND: We aimed to compare the ability of recently developed prognostic indices for myelodysplastic syndromes to identify patients with poor prognoses within the lower-risk (low and intermediate-1) categories defined by the International Prognosis Scoring System (IPSS). METHODS: We included patients with de-novo myelodysplastic syndromes diagnosed between Nov 29, 1972, and Dec 15, 2011, who had low or intermediate-1 IPSS scores and were in the Spanish Registry of Myelodysplastic Syndromes. We reclassified these patients with the new prognostic indices (revised IPSS [IPSS-R], revised WHO-based Prognostic Scoring System [WPSS-R], Lower Risk Scoring System [LRSS], and the Grupo Español de Síndromes Mielodisplásicos [Spanish Group of Myelodysplastic Syndromes; GESMD]) and calculated the overall survival of the different risk groups within each prognostic index to identify the groups of patients with overall poor prognoses (defined as an expected overall survival <30 months). We calculated overall survival with the Kaplan-Meier method. FINDINGS: We identified 2373 patients. None of the prognostic indices could be used to identify a population with poor prognoses (median overall survival <30 months) for the patients with low IPSS scores (1290 individuals). In the group with intermediate-1 scores (1083 individuals), between 17% and 47% of patients were identified as having poor prognoses with the new prognostic indices. The LRSS had the best model fit with the lowest value in the Akaike information criteria test, whereas the IPSS-R identified the largest proportion of patients with poor prognoses (47%). Patients with intermediate-1 scores who were classified as having poor prognoses by one or more prognostic index (646 [60%] individuals) had worse median overall survival (33·1 months, 95% CI 28·4-37·9) than did patients who were classified as having low risk by all prognostic indices (63·7 months, 49·5-78·0], HR 1·9, 95% CI 1·6-2·3, p<0·0001) INTERPRETATION: Recently proposed prognostic indices for myelodysplastic syndromes can be used to improve identification of patients with poor prognoses in the group of patients with intermediate-1 IPSS scores, who could potentially benefit from a high-risk treatment approach. FUNDING: None.
Asunto(s)
Síndromes Mielodisplásicos/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/clasificación , Pronóstico , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Análisis de SupervivenciaRESUMEN
There are concerns of a reduced effect of liposomal amphotericin B (L-AmB) given sequentially after mold-active azoles due to a possible antagonism in their antifungal mechanism. To investigate this possible effect in the clinic, we retrospectively studied 182 high risk hematologic patients with invasive fungal infections (IFI) who were treated with L-AmB. Overall, 96 patients (52.7%) had possible, 52 (28.6%) probable and 34 (18.7%) proven IFI according to EORTC classification. Most had suspected or proven invasive aspergillosis. We compared patients with prior exposure to mold-active azoles (n=100) to those having not (n=82). The group with prior mold-active azoles included more patients with poor risk features for IFI as acute myeloid leukemia (p<0.05) and prolonged neutropenia (p<0.05). A favorable response in the IFI, defined as a complete or partial response, was achieved in 75% and 74.4% of patients in the whole cohort, and in 66% and 74.4% of patients with probable or proven IFI in the two groups. None of these differences were significant. Multivariate analysis showed that refractory baseline disease and renal dysfunction were adverse factors for response in the IFI (p<0.05). Survival was poorer for patients with prior broad spectrum azoles (p<0.05), and for those who did not recover from neutropenia (p<0.05). In conclusion, the effectiveness of treatment of breakthrough fungal infection with L-AmB is not likely to be affected by prior exposure to mold-active azoles prophylaxis, but survival largely depends on host and disease factors.
Asunto(s)
Anfotericina B/uso terapéutico , Antifúngicos/uso terapéutico , Fungemia/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Triazoles/uso terapéutico , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Aspergilosis/tratamiento farmacológico , Aspergilosis/etiología , Candidiasis Invasiva/tratamiento farmacológico , Candidiasis Invasiva/etiología , Niño , Preescolar , Terapia Combinada , Infección Hospitalaria/tratamiento farmacológico , Evaluación de Medicamentos , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/cirugía , Trasplante de Células Madre Hematopoyéticas , Humanos , Huésped Inmunocomprometido , Lactante , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/cirugía , Neutropenia/inducido químicamente , Neutropenia/complicaciones , Complicaciones Posoperatorias/tratamiento farmacológico , Complicaciones Posoperatorias/microbiología , Estudios Retrospectivos , Riesgo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
Existe cierta inquietud sobre una reducción del efecto de la anfotericina B liposomal (L-AmB) administrada secuencialmente después de la administración de azoles activos frente a mohos debido a un posible antagonismo en su mecanismo antifúngico. Para investigar este posible efecto en la práctica clínica, hemos estudiado retrospectivamente 182 pacientes hematológicos con infecciones fúngicas invasivas (IFI) de alto riesgo que fueron tratados con L- AmB. En total, 96 pacientes (52,7%) tenían IFI posible, 52 (28,6%) probable y 34 (18,7%) probada de acuerdo con la clasificación de la EORTC. La mayoría presentaban aspergilosis invasiva. Comparamos los pacientes con exposición previa a azoles activos frente a mohos (n=100) con aquellos no expuestos (n=82). El grupo con exposición previa a azoles activos frente a mohos incluía más pacientes con características de alto riesgo de IFI, como leucemia mieloide aguda (p<0,05) y neutropenia prolongada (p<0,05). Se alcanzó una respuesta favorable en la IFI, definida como una respuesta completa o parcial, en 75,0% y 74,4% de los pacientes de la cohorte completa y en 66,0% y 74,4% de los pacientes con IFI probable o probada en los dos grupos. Ninguna de estas diferencias fue significativa. El análisis multivariante mostró que la enfermedad basal y la disfunción renal eran factores adversos para la respuesta en la IFI (p<0,05). La supervivencia fue peor en los pacientes tratados con azoles de amplio espectro (p<0,05) y en aquellos en los que no se resolvió la neutropenia (p<0,05). En conclusión, la eficacia del tratamiento con LAmB de una infección fúngica de brecha probablemente no se vea afectada por la exposición previa a un tratamiento profiláctico con azoles activos frente a mohos, dependiendo la supervivencia más bien de los factores del huésped y de la enfermedad de base(AU)
There are concerns of a reduced effect of liposomal amphotericin B (L-AmB) given sequentially after mold-active azoles due to a possible antagonism in their antifungal mechanism. To investigate this possible effect in the clinic, we retrospectively studied 182 high risk hematologic patients with invasive fungal infections (IFI) who were treated with L-AmB. Overall, 96 patients (52.7%) had possible, 52 (28.6%) probable and 34 (18.7%) proven IFI according to EORTC classification. Most had suspected or proven invasive aspergillosis. We compared patients with prior exposure to mold-active azoles (n=100) to those having not (n=82). The group with prior mold-active azoles included more patients with poor risk features for IFI as acute myeloid leukemia (p<0.05) and prolonged neutropenia (p<0.05). A favorable response in the IFI, defined as a complete or partial response, was achieved in 75% and 74.4% of patients in the whole cohort, and in 66% and 74.4% of patients with probable or proven IFI in the two groups. None of these differences were significant. Multivariate analysis showed that refractory baseline disease and renal dysfunction were adverse factors for response in the IFI (p<0.05). Survival was poorer for patients with prior broad spectrum azoles (p<0.05), and for those who did not recover from neutropenia (p<0.05). In conclusion, the effectiveness of treatment of breakthrough fungal infection with L-AmB is not likely to be affected by prior exposure to mold-active azoles prophylaxis, but survival largely depends on host and disease factors(AU)