RESUMEN
The CLL3 trial was designed to study intensive treatment including autologous stem cell transplantation (autoSCT) as part of first-line therapy in patients with chronic lymphocytic leukemia (CLL). Here, we present the long-term outcome of the trial with particular focus on the impact of genomic risk factors, and we provide a retrospective comparison with patients from the fludarabine-cyclophosphamide-rituximab (FCR) arm of the German CLL Study Group (GCLLSG) CLL8 trial. After a median observation time of 8.7 years (0.3-12.3 years), median progression-free survival (PFS), time to retreatment, and overall survival (OS) of 169 evaluable patients, including 38 patients who did not proceed to autoSCT, was 5.7, 7.3, and 11.3 years, respectively. PFS and OS were significantly reduced in the presence of 17p- and of an unfavorable immunoglobulin heavy variable chain mutational status, but not of 11q-. Five-year nonrelapse mortality was 6.5%. When 110 CLL3 patients were compared with 126 matched patients from the FCR arm of the CLL8 trial, 4-year time to retreatment (75% vs 77%) and OS (86% vs 90%) was similar despite a significant benefit for autoSCT in terms of PFS. In summary, early treatment intensification including autoSCT can provide very effective disease control in poor-risk CLL, although its clinical benefit in the FCR era remains uncertain. The trial has been registered with www.clinicaltrials.gov as NCT00275015.
Asunto(s)
Leucemia Linfocítica Crónica de Células B/terapia , Trasplante de Células Madre , Adolescente , Adulto , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Persona de Mediana Edad , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/métodos , Análisis de Supervivencia , Factores de Tiempo , Trasplante Autólogo , Adulto JovenRESUMEN
The transcriptional regulator GATA1 is crucially involved in megakaryocytopoiesis and erythropoiesis. Mutations of the gene which is located on the X chromosome have been associated with platelet and red blood cell abnormalities. We identified a family with a GATA1 (G208R) mutation in whom a low male birth rate and frequent miscarriages among heterozygous females suggested increased fetal death in male hemizygotes. Female mutation carriers had normal or near normal hemoglobin levels and platelet counts ranging from normal to severely reduced, probably reflecting skewed X chromosome inactivation. Platelets were dimorphous, and thrombocytopenia was associated with erythroblastosis. The only living male mutation carrier had severe macrothrombocytopenia with life-threatening bleeding episodes, moderate to severe anemia, eosinopenia, skeletal abnormalities, and abundant extramedullary hematopoiesis. Long-term sequelae in the 50-year-old patient included unilateral nephrectomy following misinterpretation of paraspinal hematopoiesis as renal cancer, spinal stenosis which was possibly favored by progressive bone marrow expansion, and severe secondary gout.
Asunto(s)
Anemia Diseritropoyética Congénita/genética , Eritropoyesis , Factor de Transcripción GATA1/genética , Mutación de Línea Germinal , Hematopoyesis Extramedular , Aborto Espontáneo/genética , Adolescente , Adulto , Anemia Diseritropoyética Congénita/sangre , Anemia Diseritropoyética Congénita/complicaciones , Anemia Diseritropoyética Congénita/fisiopatología , Anemia Diseritropoyética Congénita/terapia , Niño , Eritropoyesis/genética , Familia , Femenino , Factor de Transcripción GATA1/sangre , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/fisiopatología , Gota/etiología , Gota/fisiopatología , Hemicigoto , Heterocigoto , Humanos , Riñón/patología , Masculino , Persona de Mediana Edad , Paraparesia/etiología , Paraparesia/fisiopatología , Linaje , EmbarazoRESUMEN
Although chronic lymphocytic leukemia (CLL) is a disease of elderly patients, subjects older than 65 years are heavily underrepresented in clinical trials. The German CLL study group (GCLLSG) initiated a multicenter phase III trial for CLL patients older than 65 years comparing first-line therapy with fludarabine with chlorambucil. A total of 193 patients with a median age of 70 years were randomized to receive fludarabine (25 mg/m(2) for 5 days intravenously, every 28 days, for 6 courses) or chlorambucil (0.4 mg/kg body weight [BW] with an increase to 0.8 mg/kg, every 15 days, for 12 months). Fludarabine resulted in a significantly higher overall and complete remission rate (72% vs 51%, P = .003; 7% vs 0%, P = .011). Time to treatment failure was significantly shorter in the chlorambucil arm (11 vs 18 months; P = .004), but no difference in progression-free survival time was observed (19 months with fludarabine, 18 months with chlorambucil; P = .7). Moreover, fludarabine did not increase the overall survival time (46 months in the fludarabine vs 64 months in the chlorambucil arm; P = .15). Taken together, the results suggest that in elderly CLL patients the first-line therapy with fludarabine alone does not result in a major clinical benefit compared with chlorambucil. This trial is registered with www.isrctn.org under identifier ISRCTN 36294212.
Asunto(s)
Antineoplásicos Alquilantes/administración & dosificación , Clorambucilo/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Vidarabina/análogos & derivados , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Inducción de Remisión , Tasa de Supervivencia , Vidarabina/administración & dosificaciónRESUMEN
PURPOSE: Mantle cell lymphomas (MCLs) represent a clinically aggressive lymphoma subtype with a poor prognosis. To explore a potential progress in outcome a historical comparison was performed using data from the Kiel Lymphoma Study Group (KLSG; 1975 to 1986) and the German Low Grade Lymphoma Study Group (GLSG; 1996 to 2004). PATIENTS AND METHODS: All patients with the histologically confirmed diagnosis of advanced-stage nonblastoid MCL were eligible. To minimize the potential heterogeneity of different risk profiles frequency matching was pursued. In addition, we adjusted for potential confounding variables by multiple Cox regression. RESULTS: A total of 520 patients were assessable, 150 from KLSG and 370 from GLSG studies. The median overall survival was 2.7 years for KLSG patients as compared with 4.8 years for GLSG patients (P < .0001). The 5-year survival rates were 22% in the KLSG group (95% CI, 13% to 31%) as compared with 47% for GLSG treated patients (95% CI, 38% to 55%). The hazard ratio adjusted for performance status, lactate dehydrogenase, and age was 0.44 for GLSG patients (95% CI, 0.32 to 0.59). CONCLUSION: Median overall survival of patients with advanced nonblastoid MCL almost doubled during the past 30 years. Potential reasons for this apparent improvement in overall survival include the application of anthracycline-containing regimens and new approaches, such as antilymphoma antibodies or stem cell transplantation. Advances in general supportive care, new diagnostic tools, and general improvement of life span might have also reinforced this effect. However, our results are questioning the validity of historical comparisons which had been frequently applied in previous trials.
Asunto(s)
Linfoma de Células del Manto/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
Combination chemotherapy with fludarabine plus cyclophosphamide (FC) was compared with the standard regimen of fludarabine monotherapy in first-line treatment of younger patients with chronic lymphocytic leukemia (CLL). Between 1999 and 2003, a total of 375 patients younger than 66 years who predominantly had advanced CLL were randomly assigned to receive either fludarabine (25 mg/m(2) for 5 days intravenously, repeated every 28 days) or FC combination therapy (fludarabine 30 mg/m(2) plus cyclophosphamide 250 mg/m(2) for 3 days intravenously, repeated every 28 days). Both regimens were administered to a maximum of 6 courses. FC combination chemotherapy resulted in significantly higher complete remission rate (24%) and overall response rate (94%) compared with fludarabine alone (7% and 83%; P < .001 and P = .001). FC treatment also resulted in longer median progression-free survival (48 vs 20 months; P = .001) and longer treatment-free survival (37 vs 25 months; P < .001). Thus far, no difference in median overall survival has been observed. FC caused significantly more thrombocytopenia and leukocytopenia but did not increase the number of severe infections. In summary, first-line treatment with FC increases the response rates and the treatment-free interval in younger patients with advanced CLL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Factores de Edad , Anciano , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Infecciones/etiología , Infusiones Intravenosas , Leucemia Linfocítica Crónica de Células B/complicaciones , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Trombocitopenia/inducido químicamente , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
Mantle cell lymphoma (MCL) is an aggressive lymphoma with accepted risk factors such as proliferation markers. To date, the different follicular dendritic cell (FDC) patterns have never been analyzed in comparison with the overall survival time. Lymph node biopsy specimens from 96 patients were analyzed by conventional morphology and immunohistochemistry with antibodies against cluster differentiation (CD)20, CD5, CD23, cyclin D1, and FDC (Ki-M4P). Two groups can be distinguished with different FDC patterns: a nodular pattern in 79 cases and a diffuse pattern in 17 cases. A Kaplan-Meier analysis revealed significantly better survival for the nodular group (p=0.0312). This group was subdivided into a group with a nodular FDC pattern similar to the FDC distribution in primary follicles (PF-nodular in 72 cases) and one with a nodular FDC pattern resembling the colonization of germinal centers (GCs) by tumor cells (GC-nodular in seven cases). A Kaplan-Meier analysis showed that patients with MCL with a PF-nodular FDC pattern had a significantly better clinical outcome than patients with the other two patterns (p=0.0033). If only cases with classical cytology (n=79) were analyzed (blastoid types excluded), patients with a PF-nodular FDC pattern had a better clinical outcome (p=0.0008). The distribution of FDC in MCL is a diagnostic tool for identifying patients with a better clinical prognosis.
Asunto(s)
Proliferación Celular , Células Dendríticas Foliculares/patología , Linfoma de Células del Manto/patología , Antígenos CD20/análisis , Complejo CD3/análisis , Antígenos CD5/análisis , Células Dendríticas Foliculares/metabolismo , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Antígeno Ki-67/análisis , Linfoma de Células del Manto/metabolismo , Masculino , Persona de Mediana Edad , Receptores de IgE/análisisRESUMEN
OBJECTIVES: Proliferation indices are important prognostic factors for the clinical outcome of patients with mantle cell lymphoma (MCL). We investigated whether the expression of repp86 (restrictedly expressed proliferation-associated protein 86 kDa), a new proliferation specific marker expressed in the cell cycle phases G(2), S and M, but not in G(1), correlates with the clinical course in patients with MCL. PATIENTS AND METHODS: Biopsy specimens from 94 untreated patients enrolled in two multicenter trials were investigated immunohistochemically with monoclonal antibodies against CD20, CD5, CD3, CD23, cyclin D1, and repp86 (Ki-S2). RESULTS: Patients with 0-1% repp86 expression had a median overall survival time of 71.0 months, compared with 38.2 months for patients with 1-5% positive cells and 25.4 months for patients with 5-10% positive tumor cells. Patients with repp86 expression of more than 10% showed the shortest survival (median: 15.0 months). Kaplan-Meier analysis revealed a significant difference in the overall survival time between patients with very high (>10%) and very low (0-1%) repp86 expression (P < 0.0001) in the tumor cells. The multivariate analysis revealed repp86 expression to be superior to other clinical characteristics as a prognostic factor (P = 0.0016). CONCLUSION: Based on these findings, repp86 expression is a new important prognostic factor in MCL.