RESUMEN
OBJECTIVES: This study evaluated data from six Swedish national registries to fill current evidence gaps on the epidemiology, clinical burden, and overall survival (OS) associated with light-chain (AL) amyloidosis. METHODS: Patients newly diagnosed with AL amyloidosis were identified using six linked Swedish nationwide population-based registers. For each case, individuals from the general population were selected and matched with a maximum ratio of 1:5 based on age, sex, calendar year, and county. RESULTS: 846 patients newly diagnosed with AL amyloidosis and 4227 demographically matched individuals were identified. From 2011 to 2019, annual AL amyloidosis incidence increased from 10.5 to 15.1 cases per million. At baseline, patients with AL amyloidosis had a significantly higher disease burden including higher rates of cardiac and renal failure relative to the comparison group. Among patients with AL amyloidosis, 21.5% had incident heart failure and 17.1% had incident renal failure after initial diagnosis. Median OS for patients with AL amyloidosis was 56 months versus not reached in the matched general population comparison group. CONCLUSION: The incidence of newly diagnosed AL amyloidosis in Sweden increased over time with AL amyloidosis being associated with a higher risk of cardiac/renal failure and all-cause mortality compared with the general population.
Asunto(s)
Amiloidosis , Insuficiencia Cardíaca , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas , Insuficiencia Renal , Humanos , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/diagnóstico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/epidemiología , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/terapia , Suecia/epidemiología , Amiloidosis/diagnóstico , Amiloidosis/epidemiología , Amiloidosis/terapia , Insuficiencia Cardíaca/complicaciones , Insuficiencia Renal/complicaciones , Estudios RetrospectivosRESUMEN
This prospective Phase II study is the first to assess the feasibility and efficacy of maintenance 5-azacytidine for older patients with high-risk myelodysplastic syndrome (MDS), chronic myelomonocytic leukaemia and MDS-acute myeloid leukaemia syndromes in complete remission (CR) after induction chemotherapy. Sixty patients were enrolled and treated by standard induction chemotherapy. Patients that reached CR started maintenance therapy with subcutaneous azacytidine, 5/28 d until relapse. Promoter-methylation status of CDKN2B (P15 ink4b), CDH1 and HIC1 was examined pre-induction, in CR and 6, 12 and 24 months post CR. Twenty-four (40%) patients achieved CR after induction chemotherapy and 23 started maintenance treatment with azacytidine. Median CR duration was 13.5 months, >24 months in 17% of the patients, and 18-30.5 months in the four patients with trisomy 8. CR duration was not associated with CDKN2B methylation status or karyotype. Median overall survival was 20 months. Hypermethylation of CDH1 was significantly associated with low CR rate, early relapse, and short overall survival (P = 0.003). 5-azacytidine treatment, at a dose of 60 mg/m(2) was well tolerated. Grade III-IV thrombocytopenia and neutropenia occurred after 9.5 and 30% of the cycles, respectively, while haemoglobin levels increased during treatment. 5-azacytidine treatment is safe, feasible and may be of benefit in a subset of patients.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Azacitidina/efectos adversos , Metilación de ADN , ADN de Neoplasias/metabolismo , Esquema de Medicación , Métodos Epidemiológicos , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Neutropenia/inducido químicamente , Reacción en Cadena de la Polimerasa/métodos , Regiones Promotoras Genéticas , Inducción de Remisión , Trombocitopenia/inducido químicamente , Resultado del TratamientoRESUMEN
PURPOSE: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy. EXPERIMENTAL DESIGN: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-beta-d-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15(ink4b) (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment. RESULTS: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile. CONCLUSIONS: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Metilación de ADN , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/genética , Factores de Edad , Anciano , Anciano de 80 o más Años , Antígenos CD34/biosíntesis , Células de la Médula Ósea/inmunología , Cadherinas/genética , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Citidina/administración & dosificación , Daunorrubicina/administración & dosificación , Femenino , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Leucemia Mielomonocítica Crónica/inmunología , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/inmunología , Estudios Prospectivos , Inducción de Remisión , Resultado del TratamientoRESUMEN
Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median ß-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.