RESUMEN
BACKGROUND: Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS: The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS: At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS: Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Síndromes Mielodisplásicos , Antimetabolitos Antineoplásicos , Azacitidina , Humanos , Síndromes Mielodisplásicos/terapia , América del Norte , Resultado del TratamientoRESUMEN
BACKGROUND: Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well-established clinical risk classification: the International Prognostic Scoring System (IPSS). METHODS: A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). RESULTS: A new prognostic index was developed: the FA-IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients. CONCLUSIONS: The FA-IPSS(h) is a novel patient-centered prognostic index that includes patients' self-reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2018;124:1251-9. © 2017 American Cancer Society.
Asunto(s)
Síndromes Mielodisplásicos/mortalidad , Medición de Resultados Informados por el Paciente , Calidad de Vida , Autoinforme , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Agencias Internacionales , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Tasa de SupervivenciaAsunto(s)
Deferasirox/uso terapéutico , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Síndromes Mielodisplásicos/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Transfusión Sanguínea , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion-dependent patients with myelodysplastic syndromes (MDS), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted. METHODS: The safety and efficacy of deferasirox was examined in a prospective, open-label, single-arm, multicenter trial of transfusion-dependent patients with International Prognostic Scoring System low- or intermediate-1-risk MDS and evidence of transfusion-related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined. RESULTS: Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10-20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event (AE). Fourteen treatment-related grade 3 AEs occurred in 11 patients, whereas no grade 4 or 5 drug-related AEs were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher MDS-Specific Comorbidity Index, and a shorter diagnosis-enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL (P < 0.0001). The cumulative incidence of transfusion independence, adjusted for death and disease progression, was 2.6%, 12.3%, and 15.5% after 6, 9, and 12 months, respectively. CONCLUSIONS: Deferasirox therapy in transfusion-dependent patients with MDS was moderately well tolerated and effectively lowered serum ferritin levels. Positive hematological responses were observed, and a subset of patients achieved transfusion independence.
Asunto(s)
Benzoatos/uso terapéutico , Transfusión Sanguínea , Quelantes del Hierro/uso terapéutico , Sobrecarga de Hierro/tratamiento farmacológico , Sobrecarga de Hierro/etiología , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/terapia , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Benzoatos/efectos adversos , Deferasirox , Femenino , Ferritinas/sangre , Humanos , Quelantes del Hierro/efectos adversos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Reacción a la Transfusión , Resultado del Tratamiento , Triazoles/efectos adversos , Adulto JovenAsunto(s)
Anemia Hemolítica/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Talasemia/tratamiento farmacológico , Talidomida/uso terapéutico , Anciano , Anemia Hemolítica/sangre , Anemia Hemolítica/inmunología , Anemia Hemolítica/patología , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Transfusión Sanguínea , Femenino , Hemólisis/efectos de los fármacos , Humanos , Alotipos de Inmunoglobulinas/sangre , Factores Inmunológicos/uso terapéutico , Persona de Mediana Edad , Rituximab , Talasemia/sangre , Talasemia/inmunología , Talasemia/patología , Resultado del TratamientoRESUMEN
Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value =6.3 ms). Only patients with severe hepatic iron overload (T2* <1.4 ms) showed cardiac T2* value indicative of dangerous myocardial iron deposition. Serum ferritin was not significantly correlated with cardiac T2* (p=0.24). Gradient echo T2* magnetic resonance imaging provides a rapid and reproducible method for detecting myocardial iron overload which developed after a heavy transfusion burden equal to or greater than 290 mL/kg of packed red blood cell units.
Asunto(s)
Anemia/terapia , Sobrecarga de Hierro/patología , Hierro/administración & dosificación , Reacción a la Transfusión , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hígado/metabolismo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana EdadRESUMEN
Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 (p = 1.16 × 10-12), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 × 10-6 and 3.34 × 10-6, are situated in the methylene tetrahydrofolate reductase (MTHFR) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.
Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Inmunomodulación/genética , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Alelos , Biología Computacional/métodos , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Metaanálisis como Asunto , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: The primary objective of this study was to evaluate the health-related quality of life (HRQOL) in lower-risk, transfusion-dependent patients with myelodysplastic syndromes (MDS) treated with deferasirox. A secondary objective was to investigate the relationship between HRQOL, serum ferritin levels and transfusion dependency. PATIENTS AND METHODS: This was a prospective multicentre study enrolling 159 patients, of whom 152 received at least one dose of deferasirox. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline and then at 3, 6, 9 and 12â months. Primary analysis was performed estimating mean HRQOL scores over time by a linear mixed model on selected scales. RESULTS: The median age of treated patients was 72â years (range 24-87â years). No statistically significant changes over time were found in mean scores for global health status/quality of life (p=0.564), physical functioning (p=0.409) and fatigue (p=0.471) scales. Also, no significant changes were found for constipation (p=0.292), diarrhoea (p=0.815) and nausea and vomiting (p=0.643). Serum ferritin levels were not associated with HRQOL outcomes. A higher patient-reported baseline pain severity was an independent predictive factor of an earlier achievement of transfusion independence with a HR of 1.032 (99% CI 1.004 to 1.060; p=0.003). CONCLUSIONS: HRQOL of transfusion-dependent patients with MDS receiving deferasirox therapy remains stable over time. HRQOL assessment might also provide important predictive information on treatment outcomes. TRIAL REGISTRATION NUMBER: NCT00469560.
Asunto(s)
Benzoatos/uso terapéutico , Quelantes del Hierro/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/psicología , Calidad de Vida , Reacción a la Transfusión , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Benzoatos/administración & dosificación , Deferasirox , Femenino , Humanos , Quelantes del Hierro/administración & dosificación , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/metabolismo , Estudios Prospectivos , Resultado del Tratamiento , Triazoles/administración & dosificación , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Monocítica Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Aguda/tratamiento farmacológico , Infiltración Leucémica/prevención & control , Meninges/patología , Adulto , Trasplante de Médula Ósea , Terapia Combinada , Citarabina/administración & dosificación , Daunorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Idarrubicina/administración & dosificación , Inyecciones Espinales , Leucemia Monocítica Aguda/patología , Leucemia Monocítica Aguda/cirugía , Leucemia Mieloide Aguda/patología , Leucemia Mielomonocítica Aguda/patología , Infiltración Leucémica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Testículo/patología , Adulto JovenRESUMEN
Until the beginning of the current millennium, few concrete therapeutic possibilities were available for myelodysplastic syndrome (MDS) patients. This situation has dramatically changed in the last decade when new knowledge, new drugs and new opportunities have become available for physicians and their MDS patients. A correct diagnostic and prognostic assessment of all MDS patients wherever they are first seen in a hematology or internal medicine department is mandatory to identify the best therapeutic option and the most appropriate resources allocation. This article will review modern diagnostic criteria and classification together with correlated new therapeutic opportunities.
Asunto(s)
Hematología/métodos , Hematología/tendencias , Medicina Interna/métodos , Medicina Interna/tendencias , Síndromes Mielodisplásicos/diagnóstico , Humanos , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/terapia , Pronóstico , Factores de RiesgoRESUMEN
Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not receive chelation therapy due to short-life expectancy and the difficulties associated with the administration of the current reference standard chelator, deferoxamine. There have, however, been some reports of reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion requirement, ultimately resulting in long-lasting transfusion-free survival.