Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Factores de Edad , Anciano , Anciano de 80 o más Años , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/mortalidad , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies which are also characterised by immune dysregulation. The impaired immune response is mainly due to T lymphocytes (CD8 and T regulatory cells) with increased cell apoptosis. MDS could be associated in some cases with various clinical dysimmune features; however, only MDS with trisomy 8 is correlated with particular clinical phenotype. The latter is mainly Behçet's-like disease which includes orogenital aphtosis, skin features and severe ulcerative digestive disease of ileocaecal distribution. Other clinical manifestations, such as arthritis or neutrophilic dermatosis, have been also described in MDS patients with trisomy 8. The dysimmune manifestations, and among them the Behçet's-like disease, do not impact the overall survival or the risk of progression to acute myeloid leukemia. Immunosuppressive and immunomodulatory therapies, and among them TNF-α inhibitors, are usually ineffective to control the dysimmune manifestations. Targeting the underlying clonal disease with specific therapies, such as azacitidine, seems to be the best strategy to control these disorders, even in MDS patients with low-risk disease.
Asunto(s)
Síndrome de Behçet , Síndromes Mielodisplásicos , Azacitidina , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Cromosomas Humanos Par 8 , Humanos , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Trisomía/genéticaRESUMEN
Isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) mutations in Myeloid Neoplams (MNs) exhibit DNA hypermethylation via 2-hydroxyglutarate (2HG) over-production. Clinical impact of azacitidine (AZA) remains inconsistent in IDH1/2-mutated MNs and the potential of serum 2HG as a suitable marker of response to AZA is unknown. To address these questions, we retrospectively analyzed 93 MNs patients (78 AML, 11 MDS, 4 CMML) with IDH1/2 mutations treated with AZA. After a median of 5 cycles of AZA, overall response rate was 28% (including 15% complete remission) and median OS was 12.3 months (significantly shorter in AML compared to MDS/CMML patients). In multivariate analysis of AML patients, DNMT3A mutation was associated with shorter OS while IDH1/2 mutation subtypes had no independent impact. No difference was observed in serum 2HG levels upon AZA treatment between responding and refractory patients suggesting that serum 2HG cannot be used as a surrogate marker of AZA response.
Asunto(s)
Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Azacitidina/uso terapéutico , Humanos , Isocitrato Deshidrogenasa/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Estudios RetrospectivosRESUMEN
Myelodysplastic syndromes are a heterogeneous group of clonal myeloid disorders characterized by peripheral cytopenias and an increased risk of progression to acute myeloid leukemia. Inflammatory, auto-immune or syndromic symptoms can make the diagnosis difficult. Diagnosis is currently based on bone marrow cytology but cytogenetics and molecular features are currently overpassing their initial prognostic function (allowing early diagnosis and prediction of therapeutic response). The prognostic classification is based on the Revised International Prognostic Scoring System, which also provides guidance for therapeutic management. The treatment of low-risk myelodysplastic syndromes is based on the correction of cytopenias (erythropoiesis stimulating agents, transfusions, lenalidomide, etc.), whereas in high-risk group, the goal is the control of the leukemic clone (hypomethylating agents, allograft of hematopoietic stem cell transplantation). Other molecules are used to manage complications of cytopenias or transfusion (anti-infectious prophylaxis and treatments, martial chelation). New molecules are being studied with some interesting results (luspatercept, venetoclax). This article aims to provide an update on the knowledge that an internist should know for the practical management of myelodysplastic syndromes in 2019.
Asunto(s)
Síndromes Mielodisplásicos , Algoritmos , Humanos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/terapiaRESUMEN
The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for "hematological improvement" criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between "procedures" and "criteria" for hematologic improvement-erythroid assessment and a new categorization of transfusion-burden subgroups.
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Ensayos Clínicos como Asunto/normas , Hematología/métodos , Hematología/normas , Síndromes Mielodisplásicos/terapia , Transfusión Sanguínea , Linaje de la Célula , Progresión de la Enfermedad , Transfusión de Eritrocitos , Eritrocitos/citología , Humanos , Cooperación Internacional , Recuento de Leucocitos , Neutrófilos , Recuento de Plaquetas , Guías de Práctica Clínica como Asunto , Calidad de Vida , Recurrencia , Conducta de Reducción del Riesgo , Sociedades Médicas , Resultado del TratamientoRESUMEN
The IPSS-R proved to be a powerful tool for the assessment of prognosis in MDS patients. We aimed at a validation of the IPSS-R for patients with MDS harboring deletion (5q) isolated or accompanied by additional aberrations. The study was based on 444 MDS patients from MDS centers in Europe. 67% of the patients were female, median age was 69 years. 43.5% had MDS del(5q), 5.9% were diagnosed with RCUD, 2.0% RARS, 18.4% RCMD, 14.6% RAEB-I and 15.5% RAEB-II. According to the IPSS-R, there were 9.9% very low, 39.6% low, 16.6% intermediate, 12.8% high, 20.9% very high risk patients. For very low risk patients survival was 7.5 years, low 9.0 years, intermediate 6.5 years, high 1.5 years and very high 0.7 years (p < 0.001). For low and intermediate risk, the probability of AML evolution was significantly different (p = 0.03) as well as for high versus very high risk groups (p = 0.002). The IPSS-R proved to be an appropriate prognostic tool for MDS with del(5q).
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/terapia , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
Immunosuppressive treatment is a disease-modifying therapy for lower-risk myelodysplastic syndromes (MDS). However, IST is relatively rarely used and long-term outcomes of patients are seldom reported. We retrospectively studied outcomes of 20 patients with lower-risk non del 5q MDS with transfusion dependency, with horse or rabbit antithymocyte globulin⯱â¯ciclosporine A, and frontline eltrombopag in two of them. IPSS-R was low, intermediate and high in 30%, 55% and 10% of the patients, respectively. Fifty-five percent of the patients had hypocellular bone marrow (BM). Baseline mutations were detected in 31.5% of the patients and were more frequent in patients with normo/hypercellular MDS than in patients with hypocellular MDS. Transfusion independence rate for both red blood cells (RBC) and platelets was achieved in 45% of patients. RBC transfusion duration ≤6 months, B-cell counts >0.2â¯G/L and, marginally, BM blasts ≤2% were associated with higher transfusion independence rate. Age and cellularity did not influence the response rate. Median transfusion independence duration was 53 months. Cumulative incidence of progression to a more aggressive myeloid disease was 0 in patients without baseline mutations and 33% in patients with baseline mutations (Pâ¯=â¯.008). Median progression-free and overall survival after treatment onset and median overall survival after loss of transfusion independence were 45.5 months, 68 months and not reached, respectively. In conclusion, antithymocyte globulin⯱â¯ciclosporine A results in durable responses in MDS, irrespective of age, in patients with lower-risk disease without B-cell lymphopenia and treated early in the course of the disease.
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Suero Antilinfocítico/uso terapéutico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Anciano , Análisis Mutacional de ADN , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Estudios Retrospectivos , Resultado del TratamientoAsunto(s)
Médula Ósea/efectos de los fármacos , Cromosomas Humanos Par 5/efectos de los fármacos , Cromosomas Humanos Par 5/genética , Lenalidomida/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Myelodysplastic syndromes (MDS) represent a heterogeneous group of hematological clonal disorders. Here, we have tested the bone marrow (BM) cells from 38 MDS patients covering all risk groups in two immunodeficient mouse models: NSG and NSG-S. Our data show comparable level of engraftment in both models. The level of engraftment was patient specific with no correlation to any specific MDS risk group. Furthermore, the co-injection of mesenchymal stromal cells (MSCs) did not improve the level of engraftment. Finally, we have developed an in vitro two-dimensional co-culture system as an alternative tool to in vivo. Using our in vitro system, we have been able to co-culture CD34+ cells from MDS patient BM on auto- and/or allogeneic MSCs over 4 weeks with a fold expansion of up to 600 times. More importantly, these expanded cells conserved their MDS clonal architecture as well as genomic integrity.
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Células de la Médula Ósea/patología , Síndromes Mielodisplásicos/patología , Animales , Biomarcadores , Trasplante de Médula Ósea , Aberraciones Cromosómicas , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Genes Reporteros , Xenoinjertos , Humanos , Inmunofenotipificación , Masculino , Células Madre Mesenquimatosas , Ratones , Ratones Noqueados , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/metabolismoAsunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/análogos & derivados , Azacitidina/uso terapéutico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Adulto , Anciano , Metilación de ADN/efectos de los fármacos , Decitabina , Femenino , Humanos , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/tratamiento farmacológico , Enfermedades Mielodisplásicas-Mieloproliferativas/tratamiento farmacológico , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6-43.9%)) vs AZA (14.3% (5.4-28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50-80%); AZA, 70% (50-80%)) or time to progression (PAN+AZA, 70% (40-90%); AZA, 70% (40-80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/patología , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/patología , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Médula Ósea/patología , Femenino , Humanos , Ácidos Hidroxámicos/administración & dosificación , Indoles/administración & dosificación , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/mortalidad , Leucemia Mielomonocítica Crónica/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Panobinostat , Resultado del TratamientoRESUMEN
BACKGROUND: The EUMDS registry is an unique prospective, longitudinal observational registry enrolling newly diagnosed patients with lower-risk myelodysplastic syndrome (MDS) from 17 European countries from both university hospitals and smaller regional hospitals. OBJECTIVE: The aim of this study was to describe the usage and clinical impact of erythropoiesis-stimulating agents (ESAs) in 1696 patients enrolled between 2008 and 2014. METHODS: The effects of ESAs on outcomes were assessed using proportional hazards models weighting observations by propensity to receive ESA treatment within a subset of anaemic patients with or without a regular transfusion need. RESULTS: ESA treatment (median duration of 27.5 months, range 0-77 months) was administered to 773 patients (45.6%). Outcomes were assessed in 897 patients (484 ESA treated and 413 untreated). ESA treatment was associated with a nonsignificant survival benefit (HR 0.82, 95% CI: 0.65-1.04, P = 0.09); this benefit was larger amongst patients without prior transfusions (P = 0.07). Amongst 539 patients for whom response to ESA treatment could be defined, median time to first post-ESA treatment transfusion was 6.1 months (IQR: 4.3-15.9 months) in those transfused before ESA treatment compared to 23.3 months (IQR: 7.0-47.8 months) in patients without prior transfusions (HR 2.4, 95% CI: 1.7-3.3, P < 0.0001). Responding patients had a better prognosis in terms of a lower risk of death (HR 0.65, 95% CI: 0.45-0.893, P = 0.018), whereas there was no significant effect on the risk of progression to acute myeloid leukaemia (HR 0.71, 95% CI: 0.39-1.29, P = 0.27). CONCLUSION: Appropriate use of ESAs can significantly delay the onset of a regular transfusion need in patients with lower-risk MDS.
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Transfusión Sanguínea , Hematínicos/uso terapéutico , Síndromes Mielodisplásicos/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Estudios Prospectivos , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenAsunto(s)
Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Tasa de SupervivenciaRESUMEN
After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.