RESUMEN
The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 is a global public health crisis. Multiple observations indicate poorer post-infection outcomes for patients with cancer than for the general population. Herein, we highlight the challenges in caring for patients with acute leukaemias and myeloid neoplasms amid the COVID-19 pandemic. We summarise key changes related to service allocation, clinical and supportive care, clinical trial participation, and ethical considerations regarding the use of lifesaving measures for these patients. We recognise that these recommendations might be more applicable to high-income countries and might not be generalisable because of regional differences in health-care infrastructure, individual circumstances, and a complex and highly fluid health-care environment. Despite these limitations, we aim to provide a general framework for the care of patients with acute leukaemias and myeloid neoplasms during the COVID-19 pandemic on the basis of recommendations from international experts.
Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Control de Infecciones/normas , Leucemia/terapia , Trastornos Mieloproliferativos/terapia , Neumonía Viral/complicaciones , Guías de Práctica Clínica como Asunto/normas , Adulto , COVID-19 , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/virología , Manejo de la Enfermedad , Testimonio de Experto , Humanos , Leucemia/virología , Trastornos Mieloproliferativos/virología , Pandemias , Neumonía Viral/transmisión , Neumonía Viral/virología , Asignación de Recursos , SARS-CoV-2RESUMEN
The 2016 revision of the World Health Organization classification of tumors of hematopoietic and lymphoid tissues is characterized by a closer integration of morphology and molecular genetics. Notwithstanding, the myelodysplastic syndrome (MDS) with isolated del(5q) remains so far the only MDS subtype defined by a genetic abnormality. Approximately half of MDS patients carry somatic mutations in spliceosome genes, with SF3B1 being the most commonly mutated one. SF3B1 mutation identifies a condition characterized by ring sideroblasts (RS), ineffective erythropoiesis, and indolent clinical course. A large body of evidence supports recognition of SF3B1-mutant MDS as a distinct nosologic entity. To further validate this notion, we interrogated the data set of the International Working Group for the Prognosis of MDS (IWG-PM). Based on the findings of our analyses, we propose the following diagnostic criteria for SF3B1-mutant MDS: (1) cytopenia as defined by standard hematologic values, (2) somatic SF3B1 mutation, (3) morphologic dysplasia (with or without RS), and (4) bone marrow blasts <5% and peripheral blood blasts <1%. Selected concomitant genetic lesions represent exclusion criteria for the proposed entity. In patients with clonal cytopenia of undetermined significance, SF3B1 mutation is almost invariably associated with subsequent development of overt MDS with RS, suggesting that this genetic lesion might provide presumptive evidence of MDS in the setting of persistent unexplained cytopenia. Diagnosis of SF3B1-mutant MDS has considerable clinical implications in terms of risk stratification and therapeutic decision making. In fact, this condition has a relatively good prognosis and may respond to luspatercept with abolishment of the transfusion requirement.
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Médula Ósea/metabolismo , Eritropoyesis , Mutación , Síndromes Mielodisplásicos , Fosfoproteínas/genética , Factores de Empalme de ARN/genética , Humanos , Síndromes Mielodisplásicos/clasificación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/terapia , Pronóstico , Medición de RiesgoRESUMEN
Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS.
Asunto(s)
Leucemia Mieloide Aguda/patología , Síndromes Mielodisplásicos/patología , Telómero/patología , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/enzimología , Síndromes Mielodisplásicos/mortalidad , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Telomerasa/metabolismo , Adulto JovenRESUMEN
Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower-risk MDS in 82% of patients, with higher-risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub-analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub-types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease-risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia-free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease-modifying therapies are influenced by SES.
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Síndromes Mielodisplásicos/mortalidad , Clase Social , Adulto , Anciano , Anciano de 80 o más Años , Anemia Refractaria , Causas de Muerte , Transformación Celular Neoplásica , Femenino , Genómica , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/economía , Fenotipo , Pronóstico , Factores de Riesgo , Resultado del TratamientoRESUMEN
The diagnosis of myelodysplastic syndromes (MDS) remains problematic due to the subjective nature of morphologic assessment. The reported high frequency of somatic mutations and increased structural variants by array-based cytogenetics have provided potential objective markers of disease; however, this has been complicated by reports of similar abnormalities in the healthy population. We aimed to identify distinguishing features between those with early MDS and reported healthy individuals by characterizing 69 patients who, following a nondiagnostic marrow, developed progressive dysplasia or acute myeloid leukemia. Targeted sequencing and array-based cytogenetics identified a driver mutation and/or structural variant in 91% (63/69) of prediagnostic samples with the mutational spectrum mirroring that in the MDS population. When compared with the reported healthy population, the mutations detected had significantly greater median variant allele fraction (40% vs 9% to 10%), and occurred more commonly with additional mutations (≥2 mutations, 64% vs 8%). Furthermore, mutational analysis identified a high-risk group of patients with a shorter time to disease progression and poorer overall survival. The mutational features in our cohort are distinct from those seen in the healthy population and, even in the absence of definitive disease, can predict outcome. Early detection may allow consideration of intervention in poor-risk patients.
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Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/mortalidad , Análisis Mutacional de ADN , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
We present a short case series of elderly patients with NK-AML and isolated NPM1 mutation who were treated with intensive chemotherapy, achieving significant CRs multiple times on reinduction, even with a single course.We hope to highlight the NPM1 as a molecular marker in elderly for consideration of aggressive treatment, even if abridged, as this subset may achieve a durable, good quality responses at diagnosis or subsequent relapses.
RESUMEN
We treated six patients who had relapsed after intensive chemotherapy, presenting initially with AML or RAEB, a hypocellular marrow and normal karyotype, and who were deemed unsuitable for re-induction with intensive chemotherapy, with low dose oral melphalan. Three of six patients achieved complete hematological response with no significant toxicity and with a duration of 12, 8 and 3+ months respectively. These three patients had received only two prior courses of chemotherapy each, in contrast to non-responders who were more heavily pre-treated. Low dose melphalan is highly effective therapy for this rare subtype of AML/RAEB, even in relapsed disease with limited prior chemotherapy.
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Antígenos de Neoplasias/biosíntesis , Síndromes Mielodisplásicos/metabolismo , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Perfilación de la Expresión Génica , Humanos , Estimación de Kaplan-Meier , Síndromes Mielodisplásicos/genéticaAsunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Sistema de Registros , Anciano , Anciano de 80 o más Años , Citarabina/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The myelodysplastic syndromes (MDS) are morphologically and genetically heterogeneous, and as such a single etiological factor is implausible. Therapy-related MDS has a clear etiology but the predisposition factors remain unclear. Most MDS (>90%) is not therapy-related and an etiology for this majority of patients, and indeed of better defined (morphological or genetic) subgroups cannot yet be ascertained. Exposure to occupational and environmental toxins is not obviously a major etiological contributor. The exceptions may be exposure to low concentrations of benzene and to tobacco smoke (which contains benzene amongst other carcinogens), but even these xenobiotics produce only modestly increased Hazard ratios for the development of MDS. It seems likely that low penetrance genetic variants may influence predisposition, and these may include pathways for xenobiotic metabolism, DNA repair and other quantitative trait loci.
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Benceno/toxicidad , Síndromes Mielodisplásicos , Exposición Profesional/efectos adversos , Contaminación por Humo de Tabaco/efectos adversos , Xenobióticos/efectos adversos , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Humanos , Síndromes Mielodisplásicos/inducido químicamente , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Penetrancia , Sitios de Carácter CuantitativoRESUMEN
An international working group within the European LeukemiaNet gathered, aiming to determine the role of flow cytometry (FC) in myelodysplastic syndromes (MDS). It was agreed that FC has a substantial application in disease characterization, diagnosis and prognosis. FC may also be useful in predicting treatment responses and monitoring novel and standard therapeutic regimens. In this article the rationale is discussed that flow cytometry should be integrated as a part of diagnostic and prognostic scoring systems in MDS.
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Citometría de Flujo/métodos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Evaluación de Resultado en la Atención de Salud/métodos , Humanos , Agencias Internacionales , Síndromes Mielodisplásicos/clasificación , Pronóstico , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Sociedades CientíficasRESUMEN
Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compound named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukaemic origin. When tested in culture against the acute myeloid leukaemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukaemia.
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Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Diferenciación Celular/efectos de los fármacos , Histona Desacetilasa 2/antagonistas & inhibidores , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/química , Leucemia/tratamiento farmacológico , Leucemia/patología , Benzamidas/síntesis química , Benzamidas/química , Proliferación Celular/efectos de los fármacos , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/síntesis química , Histona Desacetilasas/genética , Histona Desacetilasas/metabolismo , Humanos , Leucemia/enzimología , Células Tumorales CultivadasRESUMEN
In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positive predictive value for ring sideroblasts of 97.7% (95% confidence interval, 93.5%-99.5%). In multivariate analysis including established risk factors, SF3B1 mutations were found to be independently associated with better overall survival (hazard ratio = 0.15, P = .025) and lower risk of evolution into AML (hazard ratio = 0.33, P = .049). The close association between SF3B1 mutations and disease phenotype with ring sideroblasts across MDS and MDS/MPN is consistent with a causal relationship. Furthermore, SF3B1 mutations are independent predictors of favorable clinical outcome, and their incorporation into stratification systems might improve risk assessment in MDS.
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Mutación , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/fisiopatología , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/fisiopatología , Fosfoproteínas/genética , Ribonucleoproteína Nuclear Pequeña U2/genética , Anciano , Alelos , Codón , Análisis Mutacional de ADN , Eritroblastos/patología , Femenino , Estudios de Seguimiento , Estudios de Asociación Genética , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/patología , Enfermedades Mielodisplásicas-Mieloproliferativas/diagnóstico , Enfermedades Mielodisplásicas-Mieloproliferativas/patología , Pronóstico , Factores de Empalme de ARN , Caracteres Sexuales , Análisis de SupervivenciaRESUMEN
It is now well established that epigenetic phenomena and aberrant gene regulation play a major role in carcinogenesis. These include aberrant gene silencing by imposing inactive histone marks on promoters, aberrant methylation of DNA at CpG islands, and the active repression of promoters by oncoproteins. In addition, many malignant cells also show aberrant gene activation due to constitutively active signalling. The next frontier in cancer research will be to examine how, at the molecular level, small mutations that alter the regulatory phenotype of a cell give rise after a number of cell divisions to the vast deregulation phenomena seen in malignant cells. This review outlines recent insights into how normal cell differentiation in the haematopoietic system is subverted in leukaemia and it introduces the molecular players involved in this process. It also summarises the results of recent clinical trials trying to reverse aberrant epigenetic regulation by employing agents influencing global epigenetic regulators.
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Medicina Clínica , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Hematopoyesis/genética , Animales , Antineoplásicos/uso terapéutico , HumanosRESUMEN
The diagnosis of myelodysplastic syndrome (MDS) currently relies primarily on the morphologic assessment of the patient's bone marrow and peripheral blood cells. Moreover, prognostic scoring systems rely on observer-dependent assessments of blast percentage and dysplasia. Gene expression profiling could enhance current diagnostic and prognostic systems by providing a set of standardized, objective gene signatures. Within the Microarray Innovations in LEukemia study, a diagnostic classification model was investigated to distinguish the distinct subclasses of pediatric and adult leukemia, as well as MDS. Overall, the accuracy of the diagnostic classification model for subtyping leukemia was approximately 93%, but this was not reflected for the MDS samples giving only approximately 50% accuracy. Discordant samples of MDS were classified either into acute myeloid leukemia (AML) or "none-of-the-targets" (neither leukemia nor MDS) categories. To clarify the discordant results, all submitted 174 MDS samples were externally reviewed, although this did not improve the molecular classification results. However, a significant correlation was noted between the AML and "none-of-the-targets" categories and prognosis, leading to a prognostic classification model to predict for time-dependent probability of leukemic transformation. The prognostic classification model accurately discriminated patients with a rapid transformation to AML within 18 months from those with more indolent disease.
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Leucemia Mieloide/epidemiología , Modelos Teóricos , Síndromes Mielodisplásicos/clasificación , Análisis de Secuencia por Matrices de Oligonucleótidos , Medición de Riesgo/métodos , Índice de Severidad de la Enfermedad , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/etiología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Pronóstico , ARN Mensajero/genética , Método Simple Ciego , Resultado del TratamientoRESUMEN
CD33 (Siglec-3) is expressed on most acute myeloid leukemia (AML) cells and is currently being exploited as a therapeutic target. The purpose of this study was to investigate the expression pattern and potential utility of the seven recently described CD33-related siglecs as markers in AML. Besides CD33, Siglec-9 was the most highly expressed, particularly on AML cells with features of monocytic differentiation that also expressed Siglecs-5 and -7. Siglec-9 was absent from normal bone marrow myeloid progenitors but present on monocytic precursors. Using primary AML cells or transfected rat basophilic leukemia cells, Siglec-9 mediated rapid endocytosis of anti-Siglec-9 mAb. In contrast to CD33 and Siglec-5, levels of soluble Siglec-9 were low or undetectable in bone marrow plasma from AML patients and serum from normal donors. These features suggest that Siglec-9 provides not only a useful marker for certain subsets of AML, but also a potential therapeutic target.