RESUMEN
PURPOSE: Within families affected by parental cancer, open communication impacts the well-being of parents and their children; however, limited research exists on communication patterns in these families. This sub-study addresses this through the Family-SCOUT study, a multicenter, prospective, interventional, and non-randomized investigation with intervention (IG) and control group (CG). The purpose of this sub-study was to identify and compare the differences in communication patterns between the IG and CG as part of the process evaluation. The research question was addressed in both groups: What communication patterns do healthy parents perceive within their families? METHODS: Using a qualitative approach, the study involved interviewing healthy parents as surrogates for their families. The interviews were audio-recorded, transcribed, and coded using a template analysis. The resulting data were analyzed at the group level. RESULTS: Twenty-three interviews were conducted in the IG and 27 interviews in the CG. The analysis of themes centered on communication patterns as seen in the family structure. Both groups exhibited instances of open communication about fears and wishes as well as the use of child-friendly language when discussing cancer. Notable differences were observed: challenges in open communication with children were sorely reported in CG interviews, and "the illness is discussed when necessary" was sorely described in IG interviews. CONCLUSION: This study underscores the need to address and encourage open communication within families with parental cancer.
Asunto(s)
Comunicación , Neoplasias , Padres , Humanos , Neoplasias/psicología , Femenino , Masculino , Padres/psicología , Adulto , Estudios Prospectivos , Niño , Persona de Mediana Edad , Investigación Cualitativa , Entrevistas como Asunto , Hijo de Padres Discapacitados/psicologíaRESUMEN
BACKGROUND: Cancer patients with minor children but also their families suffer from significant psychological distress and comorbidity. Protective factors predicting successful coping are well known. Corresponding systematic interventions are rare and limited by access barriers. We developed a comprehensive family-centered intervention for cancer patients with at least one dependent minor. PATIENTS AND METHODS: Family-SCOUT represents a multicentric, prospective, interventional, and controlled study for families with parental cancer and their minor children. In the intervention group (IG), all family members were addressed using a care and case management approach for nine months. Families in the control group (CG) received standard of care. Participating parents were asked to complete the Hospital-Anxiety-Depression-Scale (HADS) questionnaire at enrolment (T0) and after 9 months (T2). The primary outcome was a clinically relevant reduction of distress in at least one parent per family, measured as minimal important difference (MID) of ≥1.6 in the HADS total score. The percentage of families achieving MID is compared between the IG and CG by exact Fisher's test, followed by multivariate confounder analyses. RESULTS: T0-questionnaire of at least one parent was available for 424 of 472 participating families, T2-questionnaire after 9 months was available for 331 families (IG n = 175, CG n = 156). At baseline, both parents showed high levels of distress (HADS total: sick parents IG: 18.7 ± 8.1; CG: 16.0 ± 7.2; healthy partners: IG: 19.1 ± 7.9; CG: 15.2 ± 7.7). The intervention was associated with a significant reduction in parental distress in the IG (MID 70.4% in at least one parent) compared with the CG (MID 55.8%; P = 0.008). Adjustment for group differences from specific confounders retained significance (P = 0.047). Bias from other confounders cannot be excluded. CONCLUSIONS: Parental cancer leads to a high psychosocial burden in affected families. Significant distress reduction can be achieved through an optimized and structured care approach directed at the family level such as family-SCOUT.
Asunto(s)
Neoplasias , Padres , Humanos , Femenino , Masculino , Neoplasias/psicología , Neoplasias/terapia , Estudios Prospectivos , Niño , Adulto , Padres/psicología , Adaptación Psicológica , Encuestas y Cuestionarios , Estrés Psicológico/etiología , Adolescente , Preescolar , Persona de Mediana EdadRESUMEN
PURPOSE OF THE STUDY: In the past years, high dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT)has more extensively been performed in elderly patients with multiple myeloma (MM). Several studies found a similar survival benefit compared to younger patients. The objective of our retrospective study is to analyse the tolerability of HDT + ASCT in elderly patients. PATIENTS AND METHODS: We compared 26 ASCT performed in MM patients ≥65 years to 127 ASCT in patients <65 years by evaluating treatment-tolerability, length of hospital stay and number of transfusions. RESULTS: There was no significant difference in the duration of hospitalisation (16 days (range 14-47) in the elderly vs. 17 days (range 14-71) days, P = 0.0903), median time of cytopenia (neutrophils<500/µl: 5 days (range 4-24) vs. 6 days (range 3-28) days, P = 0.1091; platelets<30 000/µl: 6 days (range 3-36) vs. 7 days (range 0-53) days, P = 0.274) or incidence of, or degree of complications between the two age-groups. Immediate and day 100 treatment related mortality (TRM) was comparable in both groups (3.85% vs. 1.58%, P = 0.4304). CONCLUSION: our findings support the concept that HDT + ASCT can be safely administered as first-line option for well-selected patients≥65 years.
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Envejecimiento/fisiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Mieloma Múltiple/terapia , Adulto , Factores de Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Terapia Combinada/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Alemania/epidemiología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/epidemiología , Terapia Neoadyuvante/efectos adversos , Selección de Paciente , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
In chronic-phase chronic myeloid leukaemia (CP-CML), residual BCR-ABL1+ leukaemia stem cells are responsible for disease persistence despite TKI. Based on in vitro data, CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) was an international, randomised phase II trial designed to study the safety and efficacy of imatinib (IM) and hydroxychloroquine (HCQ) compared with IM alone in CP-CML patients in major cytogenetic remission with residual disease detectable by qPCR. Sixty-two patients were randomly assigned to either arm. Treatment 'successes' was the primary end point, defined as ≥0.5 log reduction in 12-month qPCR level from trial entry. Selected secondary study end points were 24-month treatment 'successes', molecular response and progression at 12 and 24 months, comparison of IM levels, and achievement of blood HCQ levels >2000 ng/ml. At 12 months, there was no difference in 'success' rate (p = 0.58); MMR was achieved in 80% (IM) vs 92% (IM/HCQ) (p = 0.21). At 24 months, the 'success' rate was 20.8% higher with IM/HCQ (p = 0.059). No patients progressed. Seventeen serious adverse events, including four serious adverse reactions, were reported; diarrhoea occurred more frequently with combination. IM/HCQ is tolerable in CP-CML, with modest improvement in qPCR levels at 12 and 24 months, suggesting autophagy inhibition maybe of clinical value in CP-CML.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Análisis Citogenético/métodos , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Anciano , Femenino , Estudios de Seguimiento , Humanos , Hidroxicloroquina/administración & dosificación , Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The requirements for optimal biobanking from the point of view of the clinical partner can be highly variable. Depending on the material, processing, storage conditions, clinical data, and involvement of external partners, there will be special requirements for the participating clinician and specialist areas. What they all have in common is that the goal of any biobanking must be to improve clinical, translational, and basic research. While in the past biomaterials often had to be individually stored for each research project, modern biobanking offers decisive advantages: a comprehensive ethics vote fulfilling state-of-the-art data safety requirements, standardized processing and storage protocols, specialized biobank software for pseudonymization and localization, protection against power failures and defects of the equipment, centralized and sustainable storage, easy localization and return of samples, and their destruction or anonymization after completion of an individual project. In addition to this important pure storage function, central biobanking can provide a link to clinical data as well as the anonymous use of samples for project-independent research. Both biobank functions serve different purposes, are associated with specific requirements, and should be pursued in parallel. If successful, central biomaterial management can achieve a sustainable improvement of academic and non-academic biomedical research and the optimal use of resources. The close collaboration between clinicians and non-clinicians is a crucial prerequisite for this.
Asunto(s)
Bancos de Muestras Biológicas , Investigación Biomédica , HematologíaRESUMEN
Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities. As bosutinib is not currently indicated for newly diagnosed CML, toxicities associated with first-line treatment are not reviewed. Recognition and optimal management of these toxicities can facilitate patient compliance and affect treatment outcomes.
Asunto(s)
Compuestos de Anilina/efectos adversos , Antineoplásicos/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Nitrilos/efectos adversos , Quinolinas/efectos adversos , Humanos , Terapia Recuperativa/efectos adversos , Terapia Recuperativa/métodosRESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics. The overall lesional spectrum of T-PLL is mainly annotated to axes of DNA damage responses, T-cell receptor/cytokine signaling, and histone modulation. We formulate a multi-dimensional model of T-PLL pathogenesis centered around a unique combination of TCL1 overexpression with damaging ATM aberrations as initiating core lesions. The effects imposed by TCL1 cooperate with compromised ATM toward a leukemogenic phenotype of impaired DNA damage processing. Dysfunctional ATM appears inefficient in alleviating elevated redox burdens and telomere attrition and in evoking a p53-dependent apoptotic response to genotoxic insults. As non-genotoxic strategies, synergistic combinations of p53 reactivators and deacetylase inhibitors reinstate such cell death execution.
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Proteínas de la Ataxia Telangiectasia Mutada/genética , Daño del ADN , Epigénesis Genética , Leucemia Prolinfocítica de Células T/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Anciano , Animales , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica/métodos , Células HEK293 , Humanos , Estimación de Kaplan-Meier , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas/metabolismoRESUMEN
This corrects the article DOI: 10.1038/leu.2017.9.
RESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.
Asunto(s)
Antineoplásicos/farmacología , Biomarcadores de Tumor , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Ensayos Analíticos de Alto Rendimiento , Leucemia Prolinfocítica de Células T/genética , Mutación , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Ciclo Celular/genética , Línea Celular Tumoral , Aberraciones Cromosómicas , Femenino , Expresión Génica , Perfilación de la Expresión Génica , Humanos , Quinasas Janus/metabolismo , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Oxazoles/farmacología , Fenotipo , Inhibidores de Proteínas Quinasas/farmacología , Factores de Transcripción STAT/metabolismo , Tiazoles/farmacologíaRESUMEN
Allogeneic hematopoietic cell transplantation is part of the standard of care for many hematological diseases. Over the last decades, significant advances in patient and donor selection, conditioning regimens as well as supportive care of patients undergoing allogeneic hematopoietic cell transplantation leading to improved overall survival have been made. In view of many new treatment options in cellular and molecular targeted therapies, the place of allogeneic transplantation in therapy concepts must be reviewed. Most aspects of hematopoietic cell transplantation are well standardized by national guidelines or laws as well as by certification labels such as FACT-JACIE. However, the requirements for the construction and layout of a unit treating patients during the acute phase of the transplantation procedure or at readmission for different complications are not well defined. In addition, the infrastructure of such a unit may be decisive for optimized care of these fragile patients. Here we describe the process of planning a transplant unit in order to open a discussion that could lead to more precise guidelines in the field of infrastructural requirements for hospitals caring for people with severe immunosuppression.
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Instituciones de Atención Ambulatoria/organización & administración , Arquitectura y Construcción de Instituciones de Salud , Trasplante de Células Madre Hematopoyéticas , Unidades Hospitalarias/organización & administración , Acreditación/métodos , Acreditación/organización & administración , Acreditación/normas , Instituciones de Atención Ambulatoria/normas , Certificación , Arquitectura y Construcción de Instituciones de Salud/métodos , Arquitectura y Construcción de Instituciones de Salud/normas , Necesidades y Demandas de Servicios de Salud/estadística & datos numéricos , Trasplante de Células Madre Hematopoyéticas/normas , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Capacidad de Camas en Hospitales/normas , Capacidad de Camas en Hospitales/estadística & datos numéricos , Unidades Hospitalarias/normas , Unidades Hospitalarias/estadística & datos numéricos , Humanos , Licencia Hospitalaria/organización & administración , Licencia Hospitalaria/normas , Guías de Práctica Clínica como Asunto , Medicina Regenerativa/organización & administración , Medicina Regenerativa/normas , Medicina Regenerativa/estadística & datos numéricos , Recolección de Tejidos y Órganos/métodos , Recolección de Tejidos y Órganos/normas , Medicina Transfusional/organización & administración , Medicina Transfusional/normas , Medicina Transfusional/estadística & datos numéricos , Trasplante Homólogo/métodos , Trasplante Homólogo/normasRESUMEN
Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.
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Antineoplásicos/uso terapéutico , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Análisis de Supervivencia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana Edad , Adulto JovenAsunto(s)
Proteínas de Microfilamentos/genética , Proteínas de Microfilamentos/metabolismo , Mutación/genética , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Animales , Células Madre Embrionarias/metabolismo , Células Madre Hematopoyéticas/metabolismo , Linfoma/metabolismo , Ratones , Ratones NoqueadosRESUMEN
Philadelphia-negative myeloproliferative neoplasms (MPN) comprise a heterogeneous group of chronic hematological malignancies with significant variations in clinical characteristics. Due to the long survival and the feasibility of oral or subcutaneous therapy, these patients are frequently treated outside of larger academic centers. This analysis was performed to elucidate differences in MPN patients in three different health care settings: university hospitals (UH), community hospitals (CH), and office-based physicians (OBP). The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences were used. Besides a different distribution of MPN subtypes between the settings, patients contributed by UH showed an impaired medical condition, a higher comorbidity burden, and more vascular complications. In the risk group analyses, the majority of polycythemia vera (PV) and essential thrombocythemia (ET) patients from UH were classified into the high-risk category due to previous vascular events, while for PV and ET patients in the CH and OBP settings, age was the major parameter for a high-risk categorization. Regarding MPN-directed therapy, PV patients from the UH setting were more likely to receive ruxolitinib within the framework of a clinical trial. In summary, the characteristics and management of patients differed significantly between the three health care settings with a higher burden of vascular events and comorbidities in patients contributed by UH. These differences need to be taken into account for further analyses and design of clinical trials.
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Atención a la Salud/estadística & datos numéricos , Trastornos Mieloproliferativos/terapia , Índice de Severidad de la Enfermedad , Evaluación de Síntomas/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Atención a la Salud/métodos , Femenino , Hospitales Comunitarios/estadística & datos numéricos , Hospitales Universitarios/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Cromosoma Filadelfia , Médicos/estadística & datos numéricos , Consultorios Médicos/estadística & datos numéricos , Estudios Prospectivos , Sistema de Registros/estadística & datos numéricos , Factores de Riesgo , Evaluación de Síntomas/métodosRESUMEN
BACKGROUND: Patients with Ph-negative myeloproliferative neoplasms (MPN), such as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), are at increased risk for thrombosis/thromboembolism and major bleeding. Due to the morbidity and mortality of these events, antiplatelet and/or anticoagulant agents are commonly employed as primary and/or secondary prophylaxis. On the other hand, disease-related bleeding complications (i.e., from esophageal varices) are common in patients with MPN. This analysis was performed to define the frequency of such events, identify risk factors, and assess antiplatelet/anticoagulant therapy in a cohort of patients with MPN. METHODS: The MPN registry of the Study Alliance Leukemia is a non-interventional prospective study including adult patients with an MPN according to WHO criteria (2008). For statistical analysis, descriptive methods and tests for significant differences as well as contingency tables were used to identify the odds of potential risk factors for vascular events. RESULTS: MPN subgroups significantly differed in sex distribution, age at diagnosis, blood counts, LDH levels, JAK2V617F positivity, and spleen size (length). While most thromboembolic events occurred around the time of MPN diagnosis, one third of these events occurred after that date. Splanchnic vein thrombosis was most frequent in post-PV-MF and MPN-U patients. The chance of developing a thromboembolic event was significantly elevated if patients suffered from post-PV-MF (OR 3.43; 95% CI = 1.39-8.48) and splenomegaly (OR 1.76; 95% CI = 1.15-2.71). Significant odds for major bleeding were previous thromboembolic events (OR = 2.71; 95% CI = 1.36-5.40), splenomegaly (OR = 2.22; 95% CI 1.01-4.89), and the administration of heparin (OR = 5.64; 95% CI = 1.84-17.34). Major bleeding episodes were significantly less frequent in ET patients compared to other MPN subgroups. CONCLUSIONS: Together, this report on an unselected "real-world" cohort of German MPN patients reveals important data on the prevalence, diagnosis, and treatment of thromboembolic and major bleeding complications of MPN.
Asunto(s)
Coagulación Sanguínea/fisiología , Hemorragia/fisiopatología , Trastornos Mieloproliferativos/fisiopatología , Sistema de Registros/estadística & datos numéricos , Trombosis/fisiopatología , Adulto , Anciano , Anciano de 80 o más Años , Anticoagulantes/uso terapéutico , Coagulación Sanguínea/efectos de los fármacos , Femenino , Alemania/epidemiología , Hemorragia/diagnóstico , Hemorragia/prevención & control , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/tratamiento farmacológico , Trastornos Mieloproliferativos/epidemiología , Prevalencia , Estudios Prospectivos , Esplenomegalia/diagnóstico , Esplenomegalia/fisiopatología , Trombosis/diagnóstico , Trombosis/prevención & controlRESUMEN
Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of â¼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.
Asunto(s)
Mesilato de Imatinib/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Neoplasias Primarias Secundarias/inducido químicamente , Inhibidores de Proteínas Quinasas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/inducido químicamente , Femenino , Estudios de Seguimiento , Humanos , Mesilato de Imatinib/uso terapéutico , Incidencia , Interferón-alfa/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Linfoma no Hodgkin/inducido químicamente , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/uso terapéutico , Factores SexualesRESUMEN
The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Masculino , Persona de Mediana Edad , Pirimidinas/efectos adversosRESUMEN
DNA methylation changes are a constant feature of acute myeloid leukemia. Hypomethylating drugs such as azacitidine are active in acute myeloid leukemia (AML) as monotherapy. Azacitidine monotherapy is not curative. The AML-AZA trial tested the hypothesis that DNA methyltransferase inhibitors such as azacitidine can improve chemotherapy outcome in AML. This randomized, controlled trial compared the efficacy of azacitidine applied before each cycle of intensive chemotherapy with chemotherapy alone in older patients with untreated AML. Event-free survival (EFS) was the primary end point. In total, 214 patients with a median age of 70 years were randomized to azacitidine/chemotherapy (arm-A) or chemotherapy (arm-B). More arm-A patients (39/105; 37%) than arm-B (25/109; 23%) showed adverse cytogenetics (P=0.057). Adverse events were more frequent in arm-A (15.44) versus 13.52 in arm-B, (P=0.26), but early death rates did not differ significantly (30-day mortality: 6% versus 5%, P=0.76). Median EFS was 6 months in both arms (P=0.96). Median overall survival was 15 months for patients in arm-A compared with 21 months in arm-B (P=0.35). Azacitidine added to standard chemotherapy increases toxicity in older patients with AML, but provides no additional benefit for unselected patients.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/uso terapéutico , Quimioterapia de Inducción/métodos , Leucemia Mieloide Aguda/tratamiento farmacológico , Anciano , Citarabina/uso terapéutico , Análisis Citogenético , Daunorrubicina/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Inducción de Remisión , Análisis de SupervivenciaRESUMEN
Chronic myeloid leukemia (CML) is driven by malignant stem cells that can persist despite therapy. We have identified Metastasis suppressor 1 (Mtss1/MIM) to be downregulated in hematopoietic stem and progenitor cells from leukemic transgenic SCLtTA/Bcr-Abl mice and in patients with CML at diagnosis, and Mtss1 was restored when patients achieved complete remission. Forced expression of Mtss1 decreased clonogenic capacity and motility of murine myeloid progenitor cells and reduced tumor growth. Viral transduction of Mtss1 into lineage-depleted SCLtTA/Bcr-Abl bone marrow cells decreased leukemic cell burden in recipients, and leukemogenesis was reduced upon injection of Mtss1-overexpressing murine myeloid 32D cells. Tyrosine kinase inhibitor (TKI) therapy and reversion of Bcr-Abl expression increased Mtss1 expression but failed to restore it to control levels. CML patient samples revealed higher DNA methylation of specific Mtss1 promoter CpG sites that contain binding sites for Kaiso and Rest transcription factors. In summary, we identified a novel tumor suppressor in CML stem cells that is downregulated by both Bcr-Abl kinase-dependent and -independent mechanisms. Restored Mtss1 expression markedly inhibits primitive leukemic cell biology in vivo, providing a therapeutic rationale for the Bcr-Abl-Mtss1 axis to target TKI-resistant CML stem cells in patients.