RESUMEN
BACKGROUND: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients. METHODS: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2â×â2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m2 and doxorubicin 70 mg/m2) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m2 and dexamethasone 4 mg/m2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m2 on day -7, intravenous cytarabine 200 mg/m2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m2 twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m2 on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018. FINDINGS: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group. INTERPRETATION: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis. FUNDING: Fondazione Italiana Linfomi.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso/terapia , Rituximab/administración & dosificación , Trasplante de Células Madre , Adulto , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carmustina/administración & dosificación , Quimioterapia de Consolidación , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Citarabina/administración & dosificación , Dexametasona/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Etopósido/administración & dosificación , Femenino , Estudios de Seguimiento , Enfermedades Hematológicas/inducido químicamente , Humanos , Quimioterapia de Inducción , Análisis de Intención de Tratar , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Prednisona/administración & dosificación , Prednisona/efectos adversos , Factores de Riesgo , Trasplante de Células Madre/efectos adversos , Tasa de Supervivencia , Trasplante Autólogo , Vincristina/administración & dosificación , Vincristina/efectos adversosRESUMEN
BACKGROUND: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). METHODS: We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months. RESULTS: The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group. CONCLUSIONS: Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bleomicina/efectos adversos , Bleomicina/uso terapéutico , Terapia Combinada , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Etopósido/efectos adversos , Etopósido/uso terapéutico , Femenino , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/mortalidad , Enfermedad de Hodgkin/radioterapia , Enfermedad de Hodgkin/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/efectos adversos , Prednisona/uso terapéutico , Procarbazina/efectos adversos , Procarbazina/uso terapéutico , Modelos de Riesgos Proporcionales , Inducción de Remisión , Terapia Recuperativa , Vinblastina/efectos adversos , Vinblastina/uso terapéutico , Vincristina/efectos adversos , Vincristina/uso terapéutico , Adulto JovenRESUMEN
Clinical trial results indicate that brentuximab vedotin brings considerable promise for the treatment of patients with relapsed or refractory Hodgkin's lymphoma. A retrospective multicenter study was conducted on 65 heavily pretreated patients who underwent therapy through a Named Patient Program in Italy (non trial-setting). The primary study endpoint was the objective response rate; secondary endpoints were safety, overall survival and progression-free survival. The best overall response rate (70.7%), including 21.5% complete responses, was observed at the first restaging after the third cycle of treatment. After a median follow up of 13.2 months, the overall survival rate at 20 months was 73.8% while the progression-free survival rate at 20 months was 24.2%. Globally nine patients are in continuous complete response with a median follow up of 14 months (range, 10-19 months). Four patients proceeded to autotransplantation and nine to allotransplantation. The most frequent extra-hematologic toxicity was peripheral neuropathy, observed in 21.5% of cases (9 patients with grade 1/2 and 5 patients with grade 3/4); neurological toxicity led to discontinuation of treatment in three patients and to dose reduction in four. In general the treatment was well tolerated and toxicities, both hematologic and extra-hematologic, were manageable. This report indicates and confirms that brentuximab vedotin as a single agent is effective and safe also when used in standard, everyday clinical practice outside a clinical trial. Best overall responses were recorded after three or four cycles and showed that brentuximab vedotin provides an effective bridge to further therapeutic interventions.
Asunto(s)
Medicina General , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/epidemiología , Inmunoconjugados/uso terapéutico , Adolescente , Adulto , Anciano , Brentuximab Vedotina , Niño , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Medicina General/métodos , Enfermedad de Hodgkin/diagnóstico , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Prevención Secundaria , Adulto JovenRESUMEN
BACKGROUND: Preclinical studies have highlighted the activity of lenalidomide in mantle cell lymphoma and its anti-proliferative synergy with dexamethasone. DESIGN AND METHODS: In this prospective, multicenter, phase II study, patients with relapsed/refractory mantle cell lymphoma who were not eligible for, or had relapsed after, intensive treatments received lenalidomide 25 mg/day (days 1-21 of each 28-day cycle) and dexamethasone (40 mg/day on days 1, 8, 15, and 22) for up to 12 months. RESULTS: The primary end-points, overall and complete response rates, were achieved by 17 of 33 (52%; 95% confidence interval [CI], 35-68%) and 8 of 33 patients (24%; 95% CI, 13-41%), respectively, by the end of treatment. Fifteen patients (45%) discontinued treatment prematurely, 13 due to lack of response. The median progression-free and overall survival were 12 months (95% CI, 5-19 months) and 20 months (95% CI, 12 months to not estimable), respectively. Treatment resulted in a significant increase in microvessel density (P=0.033) and non-significant increases in macrophage and natural killer cell counts, while serum levels of neoangiogenic factors did not change significantly. Grade 3/4 adverse events were neutropenia (53%), leukopenia (25%), thrombocytopenia (22%), infections (12%), and febrile neutropenia (12%). CONCLUSIONS: These results confirm a favorable safety and activity profile of lenalidomide in relapsed/refractory mantle cell lymphoma. The contribution of dexamethasone in achieving these results is unclear because of its possible detrimental effect on the immune activation generated by lenalidomide and a higher risk of developing infectious complications. (clinicaltrials.gov identifier: NCT00786851).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células del Manto/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Terapia Recuperativa , Microambiente Tumoral/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Dexametasona/administración & dosificación , Femenino , Humanos , Lenalidomida , Linfoma de Células del Manto/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del TratamientoRESUMEN
We studied 160 Hepatitis C virus (HCV)-positive patients with NHL (59 indolent NHL, 101 aggressive). Median age was 67 years. HCV-RNA was present in 146. HBsAg was positive in seven patients. At diagnosis, ALT value was above UNL in 67 patients. One hundred and twenty patients received an anthracycline-based therapy, alkylators, 28 received chemotherapy plus rituximab. Cytotoxic drugs dose was reduced in 63 patients. Among 93 patients with normal ALT at presentation, 16 patients developed WHO grade II-III liver toxicity. Among 67 patients with abnormal ALT, eight patients had a 3.5 times elevation during treatment. Among 28 patients treated with rituximab and chemotherapy, five patients (18%) developed liver toxicity. Thirty four patients (21%) did not complete treatment (eight for liver toxicity). Median progression-free survival (PFS) for patients who experienced liver toxicity is significantly shorter than median PFS of patients without toxicity (respectively, 2 years and 3.7 years, P = 0.03). After a median F-UP of 2 years, 32 patients died (three for hepatic failure). A significant proportion of patients with HCV+ NHL develop liver toxicity often leading to interruption of treatment. This could be a limit to the application of immunochemotherapy programs. HCV+ lymphomas represent a distinct clinical subset of NHL that deserves specific clinical approach to limit liver toxicity and ameliorate survival.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/virología , Citotoxinas/efectos adversos , Hepatitis C Crónica/complicaciones , Linfoma no Hodgkin/complicaciones , Linfoma no Hodgkin/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antraciclinas/administración & dosificación , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Antineoplásicos Alquilantes/administración & dosificación , Factores Biológicos/administración & dosificación , Citotoxinas/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , RituximabAsunto(s)
Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/tratamiento farmacológico , Compuestos de Mostaza Nitrogenada/uso terapéutico , Adulto , Clorhidrato de Bendamustina , Evaluación de Medicamentos/métodos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Terapia Recuperativa/métodos , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
The Italian Society of Hematology (SIE), the Italian Society of Experimental Haematology (SIES) and the Italian Group for Bone Marrow Transplantation (GITMO) commissioned a project to develop practice guidelines for the initial work-up, therapy and follow-up of classical Hodgkin's lymphoma. Key questions to the clinical evaluation and treatment of this disease were formulated by an Advisory Committee, discussed and approved by an Expert Panel (EP) composed of senior hematologists and one radiotherapist. After a comprehensive and systematic literature review, the EP recommendations were graded according to their supporting evidence. An explicit approach to consensus methodologies was used for evidence interpretation and for producing recommendations in the absence of a strong evidence. The EP decided that the target domain of the guidelines should include only classical Hodgkin's lymphoma, as defined by the WHO classification, and exclude lymphocyte predominant histology. Distinct recommendations were produced for initial work-up, first-line therapy of early and advanced stage disease, monitoring procedures and salvage therapy, including hemopoietic stem cell transplant. Separate recommendations were formulated for elderly patients. Pre-treatment volumetric CT scan of the neck, thorax, abdomen, and pelvis is mandatory, while FDG-PET is recommended. As to the therapy of early stage disease, a combined modality approach is still recommended with ABVD followed by involved-field radiotherapy; the number of courses of ABVD will depend on the patient risk category (favorable or unfavorable). Full-term chemotherapy with ABVD is recommended in advanced stage disease; adjuvant radiotherapy in patients without initial bulk who achieved a complete remission is not recommended. In the elderly, chemotherapy regimens more intensive than ABVD are not recommended. Early evaluation of response with FDG-PET scan is suggested. Relapsed or refractory patients should receive high-dose chemotherapy and autologous hemopoietic stem cells transplant. Allogeneic transplant is recommended in patients relapsing after autologous transplant. All fertile patients should be informed of the possible effects of therapy on gonadal function and fertility preservation measures should be taken before the initiation of therapy.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad de Hodgkin/terapia , Clasificación , Enfermedad de Hodgkin/clasificación , Enfermedad de Hodgkin/diagnóstico , Humanos , Italia , Tomografía de Emisión de Positrones/métodos , Terapia Recuperativa/métodos , Sociedades Médicas , Organización Mundial de la SaludRESUMEN
Febrile neutropenia (FN) is a potentially life-threatening complication of myelosuppressive chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) guidelines recommend use of primary granulocyte colony-stimulating factor (G-CSF) prophylaxis if the overall FN risk to a patient is >or=20%, or if a reduction in chemotherapy dose intensity correlates with a poorer outcome. Many of the regimens used for treatment of lymphoma, including R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine and prednisolone), are associated with an FN risk of approximately 20% or higher. Individual patient factors that may increase the risk of FN such as advanced age or advanced disease should be taken into account when assessing the need for G-CSF support. Predictive models are being developed to facilitate individual risk assessment. Additional anti-infective prophylaxis may be indicated in some settings. There is now much evidence for the benefits of G-CSF in reducing the incidence of FN and facilitating delivery of chemotherapy, including dose-escalated and dose-dense (interval-reduced) regimens. If given according to guidelines, G-CSF has the potential to reduce FN and related morbidity. Furthermore, by facilitating delivery of planned chemotherapy, use of G-CSF may potentially influence survival in the curative setting. Implementation of the EORTC guidelines will lead to a greater proportion of patients receiving G-CSFs, but the costs involved should be at least partly offset by a reduction in FN and its associated costs, including those of hospitalization.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Fiebre/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Linfoma/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Química Farmacéutica/normas , Europa (Continente) , Fiebre/inducido químicamente , Factor Estimulante de Colonias de Granulocitos/economía , Humanos , Neutropenia/inducido químicamente , Neutropenia/prevención & control , Factores de RiesgoRESUMEN
BACKGROUND: Essential thrombocythemia is a chronic myeloproliferative disorder; patients with this disorder have a propensity to develop thrombosis, myelofibrosis, and leukemia. DESIGN AND METHODS: We studied 605 patients with essential thrombocythemia (follow-up 4596 person-years) with the aim of defining prognostic factors for thrombosis, myelofibrosis, and leukemia during follow-up. RESULTS: Sixty-six patients (11%) developed thrombosis with a 10-year risk of 14%. Age >60 years (p<0.001) and a history of thrombosis (p=0.03) were independent risk factors for thrombosis. Progression to myelofibrosis occurred in 17 patients (2.8%) with a 10-year risk of 3.9%. Anemia at diagnosis of essential thrombocythemia was significantly correlated (p<0.001) with progression to myelofibrosis. Leukemia occurred in 14 patients (2.3%) at a median time of 11 years after the diagnosis of essential thrombocythemia; the risk was 2.6% at 10 years. Age >60 years (p=0.02) was significantly correlated with the development of leukemia. Cytotoxic treatment did not imply a higher risk of leukemia. At the time of the analysis, 64 of the 605 patients (10.6%) had died. The 10-year probability of survival was 88%, with a median survival of 22.3 years. Age >60 years (p<0.001) and history of thrombosis (p=0.001) were independent risk factors for survival. CONCLUSIONS: The findings from this study on a large series of patients treated according to current clinical practice provide reassurance that essential thrombocythemia is an indolent disorder and affected patients have a long survival. The main risk is thrombosis, while myelofibrosis and leukemia are rare and late complications.
Asunto(s)
Leucemia/fisiopatología , Trastornos Mieloproliferativos/genética , Mielofibrosis Primaria/fisiopatología , Trombocitemia Esencial/complicaciones , Trombosis/fisiopatología , Anciano , Progresión de la Enfermedad , Estudios de Seguimiento , Humanos , Janus Quinasa 2/genética , Leucemia/epidemiología , Leucemia/etiología , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/epidemiología , Mielofibrosis Primaria/etiología , Pronóstico , Factores de Riesgo , Trombosis/epidemiología , Trombosis/etiología , Factores de TiempoRESUMEN
PURPOSE: The aim of this study was to define the risk of second cancer in nongastric marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). EXPERIMENTAL DESIGN: We considered for the analysis 157 patients with a confirmed histology of marginal zone B-cell lymphoma of MALT, presenting with a clinically prevalent extranodal site of disease, except for stomach. All patients came from two hematologic institutions of Northern Italy. We compared the occurrence of second cancer with respect to the general population by calculating the standardized incidence ratio, with the age- and sex-specific incidence rates of a cancer registry of Northern Italy (Lombardia) as a reference. RESULTS: A history of solid neoplasia was present in 29 (18%) patients for a total number of 30 neoplasms: 25 solid tumors, 2 hematologic diseases (1 Hodgkin's lymphoma and 1 essential thrombocythemia), and 3 nonmelanoma in situ skin cancers. In 4 patients, the site of cancer and lymphoma was the same. In 21 cases the solid tumor preceded the MALToma, in 3 the neoplasm was concomitant, whereas in 6 it was subsequent. For the entire group, the standardized incidence ratio of an additional malignancy was 0.8 [95% confidence interval (95% CI), 0.55-1.17; P = 0.2]. After excluding nonmelanoma skin cancer, the standardized incidence ratio of a second tumor was 0.75 (95% CI, 0.5-1.12; P = 0.2). After excluding all previous malignancies, the standardized incidence ratio of a second cancer was 1.32 (95% CI, 0.69-2.55; P = 0.4). The comparison of risks between males and females was not significant in each group analysis. CONCLUSIONS: Patients with nongastric MALT lymphomas are not at increased risk for other neoplasms compared with the general population of the same geographic area.
Asunto(s)
Mucosa Gástrica/patología , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B/patología , Neoplasias Primarias Secundarias , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
The field of treatment of diffuse large B-cell lymphoma has been in a continuous flux over the last 10-15 years owing to the introduction of new therapeutic approaches such as dose-dense chemotherapy, monoclonal antibodies and high-dose chemotherapy followed by autologous peripheral blood stem cell transplant. The use of clinical prognostic factors has improved our ability to predict the outcome of these lymphomas; moreover, the gene and protein expression pattern has been shown, at least in the pre-rituximab era, to be an independent and powerful prognostic indicator. This review will focus on results obtained in the last decade by large clinical trials evaluating the first-line therapy in nonlocalized diffuse large B-cell lymphoma; special emphasis will be placed on more mature results that can be indicated as 'standard' therapy. Ongoing studies addressing as yet unanswered or controversial questions will be analyzed, and preliminary data will be critically reviewed.
Asunto(s)
Antineoplásicos/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales de Origen Murino , Ensayos Clínicos como Asunto , Perfilación de la Expresión Génica , Humanos , Inmunoquímica , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/terapia , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Pronóstico , Rituximab , Trasplante de Células MadreRESUMEN
PURPOSE: To report on long-term events after short doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy and adjuvant radiotherapy in favorable early-stage Hodgkin's lymphoma. EXPERIMENTAL DESIGN: We monitored late events and causes of death over 15 years (median follow-up, 120 months) in 120 patients with nonbulky stage IA-IIA Hodgkin's lymphoma, treated with four cycles of ABVD and limited radiotherapy. Pulmonary and cardiac function tests were done throughout the follow-up. Outcome measures included cause-specific mortality, standardized mortality ratio, and standardized incidence ratio for secondary neoplasia. RESULTS: Projected 15-year event-free and overall survival were 78% and 86%, and tumor mortality was 3%. Standardized mortality ratio was significantly higher than 1 for both males (2.8; P=0.029) and females (9.4; P=0.003). The risk of cardiovascular events at 5 and 12 years was 5.5% and 14%, with a median latent time of 67 months (range: 23-179 months) from the end of radiotherapy. Pulmonary toxicity developed in 8% of patients; all had received mediastinal irradiation and the median time from radiotherapy to pulmonary sequelae was 76 weeks (range: 50-123 weeks). The risk of secondary neoplasia at 5 and 12 years was 4% and 8%, respectively, with no cases of leukemia. Fertility was preserved. CONCLUSIONS: Long-term events were mostly related to radiotherapy; the role of short ABVD chemotherapy was very limited, as documented by fertility preservation and lack of secondary myelodysplasia/leukemia. A proportion of patients died from causes unrelated to disease progression and the excess mortality risk was mostly due to the occurrence of secondary neoplasms and cardiovascular diseases. A moderate dose reduction of radiotherapy from 40-44 Gy to 30-36 Gy did not decrease the risk of late complications; abolishing radiotherapy in nonbulky early-stage Hodgkin's lymphoma is being evaluated.
Asunto(s)
Enfermedades Cardiovasculares/etiología , Enfermedad de Hodgkin/terapia , Enfermedades Pulmonares/etiología , Neoplasias Inducidas por Radiación/etiología , Neoplasias Primarias Secundarias/etiología , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bleomicina/efectos adversos , Bleomicina/uso terapéutico , Enfermedades Cardiovasculares/epidemiología , Dacarbazina/efectos adversos , Dacarbazina/uso terapéutico , Supervivencia sin Enfermedad , Doxorrubicina/efectos adversos , Doxorrubicina/uso terapéutico , Femenino , Fertilidad/efectos de los fármacos , Fertilidad/efectos de la radiación , Estudios de Seguimiento , Enfermedad de Hodgkin/mortalidad , Humanos , Enfermedades Pulmonares/epidemiología , Masculino , Persona de Mediana Edad , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Primarias Secundarias/epidemiología , Embarazo , Radioterapia Adyuvante , Análisis de Supervivencia , Vinblastina/efectos adversos , Vinblastina/uso terapéuticoRESUMEN
OBJECTIVES: Follicular lymphoma (FL) is generally considered an indolent disorder but a significant subset of patients shows a worse outcome. Aim of this study was to validate the FLIPI score in an independent series of follicular lymphoma patients and to correlate prognostic categories with the period of diagnosis and the use of anthracycline. METHODS: We evaluated the clinical characteristics, prognostic stratification, and outcome of 338 patients with follicular lymphoma consecutively diagnosed and followed at our Institution between 1975 and 2002. RESULTS: The distribution of patients within the prognostic categories of the IPI and FLIPI score, while confirming the indolent outcome of follicular lymphoma, shows that a subset of patients has a worse prognosis. With the IPI score, 62% of patients are in the low risk, 26% in the low-intermediate, and 12% in the high (high-intermediate+high) risk group. With the FLIPI score, 48% of patients are categorized as low risk, 31% as intermediate risk, and 21% as poor risk. With the IPI score, median OS is 17.3 years for the low risk; 6.3 for the intermediate risk, and 5.2 years for the high risk group (p=0.0004). With the FLIPI system, median OS is 15.5 years for the low risk, 8.3 years for the intermediate risk, and 5.2 for the poor risk group (p=0.0002). Prognostic scores were calculated also after dividing patients according to the time of diagnosis: in three periods (before 1987, between 1988 and 1997, and from 1998), as well as in two periods (before and after 1998). In all the periods studied survival of patients classified according to IPI and FLIPI categories was significantly different. CONCLUSION: This study shows in an independent series that the FLIPI score is a reproducible prognostic index of clinical utility for the initial assessment of patients with follicular lymphoma.
Asunto(s)
Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Linfoma Folicular/diagnóstico , Linfoma Folicular/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Proyectos de Investigación , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the feasibility and toxicity of CHOP-14, with rituximab (R-CHOP-14), supported by pegfilgrastim, in untreated diffuse large B-cell lymphoma (DLBCL). DESIGN AND METHODS: This study included 50 patients with DLBCL with a median age of 55 years (range: 22-70). Sixty-two percent had an International Prognostic Index score >1, 40% had bulky disease and 52% had stage IV disease. CHOP was administered every 14 days, preceded on day 1 by rituximab (375 mg/m2) and followed on day 3 by pegfilgrastim (6 mg per cycle). Toxicity was calculated over 277 cycles administered; feasibility was calculated over 227, since the first cycle in each patient was not susceptible to delay or dose-reduction. RESULTS: Therapy was delivered on time in 92% of cycles, with the relative dose intensity being 95% for doxorubicin and cyclophosphamide. Grade 4 neutropenia developed in 19% of cycles and neutropenic fever in 4% of cycles (16% of patients), with a median duration of 3 days (range: 2-10). The program was completed in 40 of 50 patients (80%); reasons for withdrawal included progression in three patients, interstitial pneumonia in four, prolonged severe neutropenia in two and septic shock in one patient. Severe adverse events occurred on 12 occasions (4% of cycles), involving 11 patients (22% of total); the most frequent severe adverse event was interstitial pneumonia which occurred in seven patients (14% of total). In three cases, Pneumocystis carinii pneumonia was documented; no cotrimoxazole prophylaxis had been given and a correlation with hypogammaglobulinemia was observed. The complete remission rate was 74%; the 2-year event-free and overall survival rates were 72% and 68%, respectively. INTERPRETATION AND CONCLUSIONS: A single dose of pegfilgrastim per cycle of R-CHOP allowed on-time delivery of this chemotherapy in DLBCL, with a low incidence of febrile neutropenia; the risk of P. carinii pneumonia makes cotrimoxazole prophylaxis essential in this setting.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales/toxicidad , Anticuerpos Monoclonales de Origen Murino , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Ciclofosfamida/administración & dosificación , Ciclofosfamida/toxicidad , Doxorrubicina/administración & dosificación , Doxorrubicina/toxicidad , Filgrastim , Humanos , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/mortalidad , Persona de Mediana Edad , Polietilenglicoles , Prednisona/administración & dosificación , Prednisona/toxicidad , Proteínas Recombinantes , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificación , Vincristina/toxicidadRESUMEN
This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m(2)) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%; p = 0.002) and OS (two-year OS: 100% vs 76%; p < 0.001). Toxicity was overall similar with the two regimens. The addition of bortezomib to IGEV does not improve response in relapsed/refractory HL patients. However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/patología , Enfermedad de Hodgkin/terapia , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/administración & dosificación , Terapia Combinada , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Resistencia a Antineoplásicos , Femenino , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/mortalidad , Humanos , Ifosfamida/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Recurrencia , Inducción de Remisión , Análisis de Supervivencia , Trasplante Autólogo , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vinblastina/análogos & derivados , Vinorelbina , Adulto Joven , GemcitabinaRESUMEN
PURPOSE: The clinical impact of positron emission tomography (PET) evaluation performed early during first-line therapy in patients with advanced-stage Hodgkin lymphoma, in terms of providing a rationale to shift patients who respond poorly onto a more intensive regimen (PET response-adapted therapy), remains to be confirmed. PATIENTS AND METHODS: The phase II part of the multicenter HD0801 study involved 519 patients with advanced-stage de novo Hodgkin lymphoma who received an initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and who underwent an early ifosfamide-containing salvage treatment followed by stem-cell transplantation if they showed a positive PET evaluation after two cycles of chemotherapy (PET2). The primary end point was 2-year progression-free survival calculated for both PET2-negative patients (who completed a full six cycles of ABVD treatment) and PET2-positive patients. Overall survival was a secondary end point. RESULTS: In all, 103 of the 512 evaluable patients were PET2 positive. Among them, 81 received the scheduled salvage regimen with transplantation, 15 remained on ABVD (physician's decision, mostly because of minimally positive PET2), five received an alternative treatment, and two were excluded because of diagnostic error. On intention-to-treat analysis, the 2-year progression-free survival was 76% for PET2-positive patients (regardless of the salvage treatment they received) and 81% for PET2-negative patients. CONCLUSION: Patients with advanced-stage Hodgkin lymphoma for whom treatment was at high risk of failing appear to benefit from early treatment intensification with autologous transplantation, as indicated by the possibility of successful salvage treatment in more than 70% of PET2-positive patients through obtaining the same 2-year progression-free survival as the PET2-negative subgroup.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sustitución de Medicamentos , Enfermedad de Hodgkin/terapia , Tomografía de Emisión de Positrones , Trasplante de Células Madre , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Enfermedad de Hodgkin/diagnóstico por imagen , Enfermedad de Hodgkin/mortalidad , Humanos , Italia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Valor Predictivo de las Pruebas , Medición de Riesgo , Factores de Riesgo , Terapia Recuperativa , Trasplante de Células Madre/efectos adversos , Trasplante de Células Madre/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
This paper critically reviews an experience of health cooperation in an hospital of a rural area of Ivory Coast. This particular situation is analysed in the more general frame of health problems in low-income countries and may suggest priorities for international health cooperation. The analysis of the main causes of avoidable death in poor countries does indicate targets and tools of intervention. In this case, the target was the reduction of infant mortality from anaemia of different origin and from HIV-1 mother-to-infant transmission. The major tool for intervention was the partnership between an Italian teaching and research hospital and the African hospital, with the catalyst of a non-governmental organisation. This paper analyses the different levels at which cooperation developed in this project, from sheer economic support to the implementation of disease-oriented twinning programs that can improve health care and strengthen research capacity on both sides. Besides, medical, ethical and social implications of the ongoing cooperation program are discussed, with particular reference to the problems of preventing mortality from severe anaemia (diet fortification in children and pregnancy and transfusional guidelines in severe malaria) and of preventing mother-to-child neonatal transmission of HIV-1 infection (counselling and testing pregnant women for HIV-1, nevirapine administering to the mother and the baby and breast-feeding).
Asunto(s)
Países en Desarrollo , Cooperación Internacional , Servicios de Salud Rural , Adulto , Causas de Muerte , Côte d'Ivoire , Femenino , Salud Global , Humanos , Recién Nacido , Enfermedades del Recién Nacido , Masculino , Pobreza , Organización Mundial de la SaludRESUMEN
PURPOSE: To assess life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. METHODS: The study sample consisted of 831 consecutive patients with polycythemia vera (n = 396; 4184 person-years of follow-up) or essential thrombocythemia (n = 435; 4304 person-years of follow-up). Mortality in each group was compared with the Italian population using the standardized mortality ratio (SMR) based on life expectancy data obtained from the Italian Institute of Statistics. RESULTS: The 15-year survival was 65% in patients with polycythemia and 73% in those with thrombocythemia. By Cox regression analysis, the independent predictors of death were a history of thrombosis for polycythemia (hazard ratio [HR] = 2.2; P = 0.0002) and thrombocythemia (HR = 2; P = 0.01), and male sex (HR = 1.8; P = 0.03) for thrombocythemia. Mortality compared with the general population was 1.6-fold higher (P <0.001) in patients with polycythemia but was not increased in those with thrombocythemia (SMR = 1; P = 0.8). CONCLUSION: Life expectancy of patients with polycythemia vera (especially if younger than 50 years) was reduced compared with the general population, whereas life expectancy of patients with essential thrombocythemia was not affected significantly by the disease, reflecting the more indolent nature of the proliferation. History of thrombosis was the main predictor of death in both diseases.
Asunto(s)
Esperanza de Vida , Policitemia Vera/mortalidad , Trombocitemia Esencial/mortalidad , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Policitemia Vera/complicaciones , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Análisis de Supervivencia , Trombocitemia Esencial/complicacionesRESUMEN
Optimal treatment for splenic marginal zone lymphoma (MZL) is not clearly established. Splenectomy has been proposed as the treatment of choice in patients with cytopenias and/or symptoms caused by an enlarged spleen. Splenic MZL, which expresses the CD20 antigen on tumor cell surfaces, is a disease entity candidate to treatment with anti-CD20 monoclonal antibodies. We employed an immunochemotherapy regimen with rituximab/cyclophosphamide/vincristine in 3 patients with splenic MZL who had only a partial response following CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) or CHOP-like therapy. The immunochemotherapy regimen was well tolerated and all patients exhibited complete remission. To our knowledge, this is the first report of splenic MZL showing response to a combination of rituximab with chemotherapy.