RESUMEN
In this short opinion review we discuss recent aspects of T-lymphoma lymphoblastic adults, like the evolution of the knowledge of classification, prognostic factors and the patients management.
Nesta breve revisão os autores apresentam diversos aspectos de evolução dos conhecimentos na classificação e no manuseio dos pacientes portadores de linfoma linfoblástico-T em adultos.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Pronóstico , Trasplante Autólogo , Clasificación , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológicoRESUMEN
Adult T-lymphoblastic lymphoma is rare and has a poor prognosis. In the 80s, following the introduction of sequential, intensified chemotherapy, complete remissions in the order of 75 percent-95 percent of treated patients, were achieved. However, several patients, namely those with advanced disease, continued to relapse either in remission or during maintenance therapy. Moreover, all these early studies were not able to detect any valuable prognostic index to predict the outcome. In an attempt to reduce the relapse rate, upfront autologous stem cell transplantation in patients in complete remission was introduced. The results obtained with this approach were quite homogeneous, indicating a probability of disease-free survival of about 65 percent-75 percent and an overall survival rate of 60 percent. Successive therapies designed since 2000 were able to obtain complete remissions of above 90 percent, with a relapse rate in the order of 30 percent and an overall survival comparable to that obtained with the transplant procedure. Yet, these studies were also unable to detect valuable prognostic factors predictive of the outcome. Moreover, no study on the biologic profile of the disease has been developed. To improve the prognosis of T-lymphoblastic lymphoma it seems necessary to create national registries to collect both clinical and biological data of all lymphoblastic lymphoma patients. In this way it will be possible to reach critical numbers of data with which valid statistical analysis may be performed that is able to detect factors influencing the outcome. Moreover, subsets of patients needing intensified procedures such as stem cell transplant may be detected at diagnosis.
O linfoma linfoblástico de célula T é raro e com prognóstico ruim. Após introdução de terapêutica quimioterápica seqüencial e intensificada, remissões completas passaram a ser obtidas em 75 por cento-95 por cento dos pacientes. Entretanto, muitos pacientes, particularmente aqueles com a chamada doença avançada, continuaram a recair tanto durante a terapia de indução como na manutenção. Além disso, todos estes estudos iniciais não foram capazes de detectar qualquer índice prognóstico capaz de prever a evolução dos pacientes. No sentido de reduzir as taxas de recidiva, o transplante autólogo de célula progenitora hematopoética em pacientes em remissão completa foi introduzido. Os resultados obtidos com esta abordagem foram bastante homogêneos, indicando uma probabilidade de sobrevida livre de doença de 65 por cento-75 por cento e uma sobrevida global de 60 por cento. Sucessivos tratamentos desenhados já nos anos 2000, foram capazes de obter remissões completas acima de 90 por cento, com taxas de recidivas da ordem de 30 por cento e uma sobrevida global comparável à obtida com o transplante. Ainda, estes estudos também não foram capazes de detectar fatores prognósticos relacionados à evolução válidos. Mais ainda, qualquer estudo com perfil biológico foi desenvolvido. Para melhorar o prognóstico do LLB-T parece ser necessário esforço multicêntrico, de caráter nacional ou internacional, para coletar dados clínicos e biológicos. Nesta linha, é possível alcançar número crítico de dados com valor estatístico que poderiam ser capazes de detectar fatores com influência prognóstica. Finalmente, grupos de pacientes necessitam ser identificados para selecionar aqueles que poderiam se beneficiar do transplante de célula progenitora hematopoética detectados ao diagnóstico.
Asunto(s)
Humanos , Trasplante de Médula Ósea , Quimioterapia , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trasplante AutólogoRESUMEN
BACKGROUND: Randomized controlled trials (RCTs) reported conflicting results on the impact of high-dose chemotherapy (HDCT) and autologous stem cell transplantation in the first-line treatment of patients with aggressive non-Hodgkin lymphoma (NHL). METHODS: We performed a systematic meta-analysis to assess the efficacy HDCT compared to conventional chemotherapy in aggressive NHL patients with regard to complete response (CR), overall survival (OS), event-free survival (EFS), toxicity, and impact of the age-adjusted International Prognostic Index (aaIPI) risk factors. We searched the Cochrane Library, MEDLINE and other databases (1/1990 to 1/2005). Hazard ratio (HR), relative risks (RR) and 95% confidence intervals (CIs) were calculated using the fixed effect model. RESULTS: Fifteen RCTs including 2728 patients were identified. HDCT improved CR when compared to conventional chemotherapy (RR 1.11, CI 1.04-1.18). Overall, there was no evidence for HDCT to improve OS (HR 1.05, 95% CI 0.92-1.19) or EFS (HR 0.92, 95% CI 0.80-1.05) when compared with conventional chemotherapy. However, subgroup analysis indicated OS differences (p=0.032) between good (HR 1.46, 95% CI 1.02-2.09) and poor risk (HR 0.95, 95% CI 0.81-1.11) patients. Conflicting results were reported for poor risk patients, where some studies reported improved and others reduced OS and EFS after HDCT. CONCLUSION: There was no evidence that HDCT improved OS and EFS in good risk NHL patients. The evidence for poor risk patients is inconclusive. HDCT should not be further investigated in good risk patients with aggressive NHL but high quality studies in poor risk patients are warranted.
Asunto(s)
Antineoplásicos/administración & dosificación , Linfoma no Hodgkin/terapia , Trasplante de Células Madre , Terapia Combinada , Relación Dosis-Respuesta a Droga , Humanos , Linfoma no Hodgkin/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Análisis de Supervivencia , Trasplante AutólogoRESUMEN
O uso de quimioterapia em altas doses seguido do transplante autólogi de células-tronco hematopoéticas (TACTH) têm sido largamente empregado e é uma modalidade de tratamento eficaz na maioria dos tumores quimiossensíveis, particularmente os linfomas de Hodgkin e não Hodgkin. A aplicabilidade do TACTH tem aumentado com o uso de cálulas-tronco do sangue periférico, cuja administração é simples e factível e acarreta menos toxicidade e melhor relação custo-benefício do que o uso de células-tronco obtidas da medula óssea. Neste artigo revemos os mais recentes estudos sobre a toxicidade de regimes de tratamento que incorporam o TACTH, com atenção particular aos efeitos tardios observados em sobreviventes de longo prazo a regimes de resgate com TACTH.
High-dose chemotherapy with autologous stem cell transplantation (ASCT) is an effective treatment option for most chemo-sensitive tumors, particularly Hodgkin´s and non-Hodgkin´s lymphoma. The clinical applicability ASCT has been greatly extended by the use of peripheral blood progenitor cells, whose administration is simple and deasible, with lower toxicity and better cost-effectiveness than bone marrow transplantation. This review highlights the most recent studies on feasibility and main toxicities of ASCT-based programs, with particular attention to the late effects observed in subjects long long-term survivors after salvage with ASCT.
Asunto(s)
Humanos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Complicaciones Posoperatorias , Trasplante de Células Madre , Trasplante AutólogoRESUMEN
PURPOSE: In this multicenter, prospective, randomized clinical trial on advanced Hodgkin's lymphoma (HL), the efficacy and toxicity of two chemotherapy regimens, doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V) and mechlorethamine, vincristine, procarbazine, prednisone, epidoxirubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine (MOPPEBVCAD), were compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as standard therapy to select which regimen would best support a reduced radiotherapy program, which was limited to < or = two sites of either previous bulky or partially remitting disease (a modification of the original Stanford program). PATIENTS AND METHODS: Three hundred fifty-five patients with stage IIB, III, or IV HL were randomly assigned. Three hundred thirty-four patients were assessable for the study and received six cycles of ABVD (n = 122), three cycles of Stanford V (n = 107), or six cycles of MOPPEBVCAD (n = 106); radiotherapy was administered to 76, 71, and 50 patients in these three arms, respectively. RESULTS: The complete response rates for ABVD, Stanford V, and MOPPEBVCAD were 89%, 76% and 94%, respectively; 5-year failure-free survival (FFS) and progression-free survival rates were 78%, 54%, 81% and 85%, 73%, and 94%, respectively (P < .01 for comparison of Stanford V with the other two regimens). Corresponding 5-year overall survival rates were 90%, 82%, and 89% for ABVD, Stanford V, and MOPPEBVCAD, respectively. Stanford V was more myelotoxic than ABVD but less myelotoxic than MOPPEBVCAD, which had larger reductions in the prescribed drug doses. CONCLUSION: When associated with conditioned and limited (not adjuvant) radiotherapy, ABVD and MOPPEBVCAD were superior to Stanford V chemotherapy in terms of response rate and FFS and progression-free survival. Patients were irradiated less often after MOPPEBVCAD, but this regimen was more toxic. ABVD is still the best choice when it is combined with optional, limited irradiation.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/radioterapia , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bleomicina/administración & dosificación , Terapia Combinada , Dacarbazina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Etopósido/administración & dosificación , Femenino , Enfermedad de Hodgkin/patología , Humanos , Lomustina/administración & dosificación , Masculino , Mecloretamina/administración & dosificación , Melfalán/administración & dosificación , Persona de Mediana Edad , Prednisona/administración & dosificación , Procarbazina/administración & dosificación , Resultado del Tratamiento , Vinblastina/administración & dosificación , Vincristina/administración & dosificación , Vindesina/administración & dosificaciónRESUMEN
The aim of the study was to determine the safety and efficacy of the combination of fludarabine (FLU), cyclophosphamide (CY) and mitoxantrone (FLU/CY/MITO) in untreated follicular lymphomas (FL), Sixty patients with newly diagnosed stage II bulky to IV FL, median age 59 years (range 36-70), received FLU/CY/MITO regimen (FLU 25 mg/m2 days 1-3, CY 300 mg/m2 days 1-3, Mito 10 mg/m2 day 1). Patients received antibiotic oral prophylaxis during all treatments, and growth factors (G-CSF) when grade III granulocytopenia (WHO) occurred. The overall response rate was 87%: 46 patients achieved complete response (CR) (77%), 6 a partial response (10%) and 8 were non-responders. Fifty patients are surviving with a median observation time of 31 months. The 4-year estimated probability of overall survival and failure-free survival were 78.2% and 45% respectively. Thirty-five patients (58%) are still in CR. Sixty percent of patients experienced grade III-IV granulocytopenia. Two patients suffered grade III pulmonary infection and one grade III liver toxicity. In a subset of 46 patients, bcl-2 translocation was positive in bone marrow (BM) and/or peripheral blood (PB) of 36 patients. At the end of treatment, 25 of these patients had CR and 19 (76%) converted to polymerase chain reaction (PCR) negativity. FLU/CY/MITO regimen showed a high level of activity in follicular lymphoma. Toxicity, mainly hematological, was acceptable and the treatment was made feasible by the use of antibiotic prophylaxis and G-CSF. Significant non-hematological toxicities were seen, but no patients died. The conversion of bcl-2 from positive to negative by PCR in BM and/or PB suggests a possible role for this treatment in clearing minimal residual disease and improving patients' outcome.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Folicular/tratamiento farmacológico , Vidarabina/análogos & derivados , Adulto , Anciano , Médula Ósea , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Linfoma Folicular/mortalidad , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Neoplasia Residual/tratamiento farmacológico , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Seguridad , Tasa de Supervivencia , Resultado del Tratamiento , Vidarabina/administración & dosificaciónRESUMEN
To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years (P=.0002), equal to or more than 2 extranodal sites (P=.0002), lactic dehydrogenase (LDH) value at normal levels or above (P<.0001), performance status (PS) equal to or more than 2 (P< or =.0001), stage III or higher (P=.0001), and bone marrow involvement (P=.0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P<.0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P<.0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P<.0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P=.026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4, 3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively (P< or =.0001; log-rank, 66.79).
Asunto(s)
Linfoma de Células T/terapia , Antineoplásicos/uso terapéutico , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Lupus Eritematoso Sistémico/complicaciones , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/mortalidad , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Selección de Paciente , Pronóstico , Estudios Retrospectivos , Trasplante de Células Madre , Análisis de Supervivencia , Factores de TiempoRESUMEN
BACKGROUND: The objective of the current study was to evaluate in a multicenter setting the feasibility and efficacy of a high-dose sequential (HDS) chemotherapy regimen that combined intensive debulking and high-dose therapy (HDT) with peripheral blood progenitor cell (PBPC) autografting in patients with refractory or recurrent Hodgkin lymphoma (HL). METHODS: Data were collected from 102 patients with HL who were treated with the HDS regimen at 14 centers associated with the Intergruppo Italiano Linfomi. Twenty-four patients had primary refractory HL, 59 patients had their first recurrence of HL (within 1 year in 32 patients and > 1 year in 27 patients), and 19 patients had multiple disease recurrences. The HDS regimen included the sequential delivery of high-dose (hd) cyclophosphamide with PBPC harvesting, methotrexate, etoposide, then HDT (usually hd mitoxantrone plus L-phenylalanine mustard) with PBPC autografting. In addition, radiotherapy was delivered to 36 patients at sites of bulky or persistent disease. RESULTS: Ninety-two patients (90%) completed the HDS program. There were five toxic deaths (treatment-related mortality rate, 4.9%) and six secondary malignan cies (five patients developed myelodysplastic syndrome/acute myelogenous leukemia, and one patient developed colorectal carcinoma). At a median follow-up of 5 years, the 5-year overall survival (OS) and event-free survival (EFS) projections were 64% (95% confidence interval [95% CI], 54-74%) and 53% (95% CI, 43-63%), respectively. Patients with their first recurrence had the most favorable outcome, with 5-year OS and EFS projections of 77% (95% CI, 66-88%) and 63% (95% CI, 50-76%), respectively. There were no significant differences between patients with early first recurrence and late first recurrence. The poorest outcome was observed in patients with refractory HL, with 5-year OS and EFS projections of 36% (95% CI, 16-55%) and 33% (95% CI, 14-52%), respectively. Patients who received HDS chemotherapy after multiple recurrences had an intermediate outcome. Multivariate analysis showed that refractory disease and systemic symptoms at the time of initial presentation were associated significantly associated with poor OS and EFS. CONCLUSIONS: The use of HDS chemotherapy for patients with refractory and/or recurrent HL is feasible at the multicenter level. The combination of intensive debulking and HDT with PBPC autografting offers a good chance of prolonged disease free survival for patients with their first recurrence of HL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/terapia , Adolescente , Adulto , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Etopósido/administración & dosificación , Femenino , Enfermedad de Hodgkin/mortalidad , Humanos , Masculino , Melfalán/administración & dosificación , Metotrexato/administración & dosificación , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Pronóstico , Trasplante Autólogo , Resultado del TratamientoRESUMEN
Apoptosis is critical to the progression of human immunodeficiency virus-1 (HIV-1) infection. It appears reasonable that antiretroviral therapies may not achieve a full control of the infection in the absence of an impact on apoptosis. We assigned 20 asymptomatic HIV-infected subjects with advanced immunodeficiency to receive either zidovudine (AZT), and didanosine (DDI) or the same regimen plus L-carnitine, a known antiapoptotic drug, for 7 months. Immunologic and virologic parameters were measured at baseline and after 15, 60, 120, and 210 days of treatment. We assessed on each time point the following: (a) the frequency of peripheral blood apoptotic CD4 and CD8 lymphocytes, CD4 and CD8 cells with disrupted mitochondrial membrane potential, and CD4 and CD8 cells undergoing oxidant stress; (b) the expression of the molecular markers of apoptosis Fas and caspase-1; and (c) the expression of p35/cdk-5 regulatory subunit that is involved in regulating cell survival and apoptosis. Absolute CD4 and CD8 counts and plasma viremia were also measured. Apoptotic CD4 and CD8 cells, lymphocytes with disrupted mitochondrial membrane potential, and lymphocytes undergoing oxidant stress were greatly reduced in subjects treated with AZT and DDI plus L-carnitine compared with those who did not receive L-carnitine. Fas and caspase-1 were down-expressed and p35 over-expressed in lymphocytes from patients of the L-carnitine group. No difference was found in CD4 and CD8 counts and viremia between the groups. No toxicity of L-carnitine was recognized. The addition of L-carnitine is safe and allows apoptosis and oxidant stress to be greatly reduced in lymphocytes from subjects treated with AZT and DDI.
Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Apoptosis/fisiología , Carnitina/uso terapéutico , Didanosina/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Estrés Oxidativo , Linfocitos T/metabolismo , Zidovudina/uso terapéutico , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Carnitina/administración & dosificación , Carnitina/efectos adversos , Quimioterapia Combinada , Citometría de Flujo , Infecciones por VIH/inmunología , Infecciones por VIH/fisiopatología , VIH-1/inmunología , VIH-1/metabolismo , Humanos , Peróxido de Hidrógeno/metabolismo , Masculino , Potenciales de la Membrana/fisiología , Mitocondrias/metabolismo , Oxidantes/metabolismo , Fenotipo , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Superóxidos/metabolismo , Receptor fas/metabolismoRESUMEN
Single-center experiences have shown that intensified treatments with autologous transplantation are a promising therapeutic strategy for patients with high-risk follicle-center lymphoma (FCL) at diagnosis, whereas data from prospective multicenter trials are still lacking. This paper describes the results of a prospective multicenter study of an intensified purging-free high-dose sequential (i-HDS) chemotherapy schedule with peripheral blood progenitor cell (PBPC) autografting. The main feature of this program is harvesting stem cells after intensified chemotherapeutic debulking, with no ex vivo manipulation of PBPCs. Ninety-two previously untreated patients aged 60 or younger with advanced-stage FCL were enrolled by 20 Italian centers and evaluated on an intention-to-treat basis. i-HDS proved feasible with limited toxicity (87% patients completed the planned treatment schedule). i-HDS led to a complete remission rate of 88%. The projected overall survival and disease-free survival (DFS) were, respectively, 84% and 67% at 4 years. Centralized molecular analysis showed that polymerase chain reaction-negative harvests could be collected in 47% of cases. Following autograft, 65% of molecularly evaluable patients achieved clinical and molecular remission. The projected DFS at 4 years of this subgroup is 85%. This result emphasizes the importance of achieving maximal tumor reduction in these patients. In conclusion, our data show that highly effective intensified treatments can now be routinely offered to young patients with poor-risk FCL even at small institutions, with no need for sophisticated and expensive cell manipulation procedures.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Linfoma Folicular/terapia , Adulto , Terapia Combinada , Femenino , Humanos , Italia , Linfoma Folicular/mortalidad , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Inducción de Remisión , Análisis de Supervivencia , Trasplante AutólogoRESUMEN
Oxidative stress is involved in the pathogenesis of a wide spectrum of diseases, implicating that strategies directed at counterbalancing oxidative processes could have a role in clinical medicine. There is also an evidence that oxidative stress acts as a major determinant of apoptotic cell death. Many studies have reported favourable effects of antioxidant formulas on several parameters of the oxidant-antioxidant balance, but none of them has focused whether antioxidant formulas could modulate apoptosis. We investigated in 20 healthy individuals the effect of supplementation with a formula containing alpha-tocopherol, alpha-lipoic acid, coenzyme Q(10), carnitines, and selenomethionine, on plasma oxidant status and peroxide levels, erythrocyte antioxidant enzymes, lymphocyte apoptosis, and generation of ROS at the mitochondrial level. Control subjects received only carnitines or an incomplete formula with alpha-tocopherol, alpha-lipoic acid, coenzyme Q(10), and selenomethionine. Supplementation with the complete formula resulted in a significant increase in the plasma antioxidant status that was mirrored by a decrease in blood peroxide levels and a reduced generation of ROS at the mitochondrial level. This was associated with a significant decrease in the frequency of peripheral blood lymphocytes, with either CD4 or CD8 phenotype, undergoing apoptosis. Less consistent results were found when either incomplete formula was used. Our study suggests that supplementation with antioxidant formulas can modulate the process of apoptosis under in vivo conditions. The clinical potential of this strategy in the treatment of diseases with an elevated commitment to apoptosis should be explored.
Asunto(s)
Antioxidantes/farmacología , Apoptosis , Linfocitos/efectos de los fármacos , Ubiquinona/análogos & derivados , Adulto , Antioxidantes/efectos adversos , Antioxidantes/farmacocinética , Carnitina/efectos adversos , Carnitina/sangre , Carnitina/farmacología , Coenzimas , Eritrocitos/enzimología , Femenino , Humanos , Linfocitos/citología , Masculino , Oxidación-Reducción/efectos de los fármacos , Peróxidos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Selenometionina/efectos adversos , Selenometionina/sangre , Selenometionina/farmacología , Ubiquinona/efectos adversos , Ubiquinona/sangre , Ubiquinona/farmacología , Vitamina E/efectos adversos , Vitamina E/sangre , Vitamina E/farmacologíaRESUMEN
Dentro das perspectivas futuras do tratamento dos linfomas näo Hodgkin (LMH) está aquela de melhorar os resultados com os denominados linfomas de baixo grau de malignidade. Dentro do estado-da-arte atual, este grupo de linfomas pode ser considerado incurável. Desde o observar-e-esperar até o transplante alogênico de medula óssea, muitas dúvidas existem e devem ser esclarecidas. O objetivo desta revisäo é de apresentar e discutir a utilizaçäo da Fludarabina, isolada ou associada à antraciclínicos e alquilantes no tratamento dos linfomas näo Hodgkin de baixo grau de malignidade (LBG).