RESUMO
Biosimilar medicinal products (biosimilars) have been available in Europe for 10 years, allowing a wide use particularly in oncology. Biosimilars are being developed and approved by means of scientifically sound principles to assure close similarity with the reference products with regard to quality, efficacy, and safety. The scientific principles for establishing biosimilarity are the same as those for demonstrating comparability after a change in the manufacturing process of an already licensed biological. Nevertheless, many clinicians voiced concerns about biosimilars related to their pharmaceutical quality, efficacy (particularly in extrapolated indications), safety (especially immunogenicity), and interchangeability with the originator product. The availability of biosimilars would strengthen the economic competition on the pharmaceutical market, provide opportunities to improve healthcare access, and contribute to the financial sustainability of European healthcare systems. Biosimilars can be considered therapeutic alternatives to the reference product. To date, no data has been published revealing any disadvantages of the biosimilars' use. This article aims to acquaint clinicians, particularly oncologists and haematologists, with the biosimilar concept as they are going to be confronted with a constantly increasing number of biosimilars due to patent expirations in the near future. Furthermore, it provides information on scientific principles guiding biosimilar development and regulatory requirements. This should minimise unfounded fears and concerns among clinicians. Additionally, we provide information on the interchangeability between originator products and biosimilars to assist clinicians in making evidence-based, appropriate, and cost-effective treatment choices for their patients.
Assuntos
Antineoplásicos/administração & dosagem , Medicamentos Biossimilares/administração & dosagem , Aprovação de Drogas/métodos , Substituição de Medicamentos/tendências , Neoplasias Gastrointestinais/tratamento farmacológico , Antineoplásicos/efeitos adversos , Medicamentos Biossimilares/efeitos adversos , União Europeia , Medicina Baseada em Evidências , Neoplasias Gastrointestinais/diagnóstico , Humanos , Equivalência Terapêutica , Resultado do TratamentoRESUMO
We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.
Assuntos
Leucemia Mieloide Aguda/tratamento farmacológico , Adulto , Aminoglutetimida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citarabina/uso terapêutico , Danazol/uso terapêutico , Intervalo Livre de Doença , Fator Estimulador de Colônias de Granulócitos , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Transplante de Células-Tronco , Taxa de Sobrevida , Tamoxifeno/uso terapêutico , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Between 1981 and 2000, 6 609 children (<18 years of age) were treated in 5 consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria, and Switzerland. Probability of 10-year event-free survival (survival) improved from 65% (77%) in study ALL-BFM 81-78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: 1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk ALL patients and eliminated in non-high-risk non-T-ALL patients, if it was replaced by high-dose and intrathecal methotrexate; 2) omission of delayed reintensification severely impaired outcome of low-risk patients; 3) 6 months less maintenance therapy caused an increase in systemic relapses; 4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; 5) condensed induction therapy resulted in a significant improvement of outcome; 6) the daunorubicin dose in induction could be safely reduced in low-risk patients; 7) intensification of consolidation/reintensification treatment led to considerable improvement of outcome in high-risk patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/história , Oncologia/história , Pediatria/história , Leucemia-Linfoma Linfoblástico de Células Precursoras/história , Ensaios Clínicos Controlados Aleatórios como Assunto/história , Asparaginase/história , Criança , Ciclofosfamida/história , Citarabina/história , Daunorrubicina/história , Europa (Continente) , Alemanha , História do Século XX , História do Século XXI , Humanos , Mercaptopurina/história , Metotrexato/história , Prednisona/história , Vincristina/históriaRESUMO
BACKGROUND: Flow cytometry immunophenotyping (FCM) is an undispensable tool for the diagnosis and for the treatment stratification of childhood acute lymphoblastic leukemia. The correlation of the EGIL-classification with prognostically relevant parameters like age, prednisone response and risk group is analyzed. PATIENTS: Between March 2000 and June 2009 12 patients less than 1 year of age, 1 836 patients with 1 to less than 6 years, 620 patients with 6 to less than 10 years, 615 patients with 10 to less than 15 years and 275 patients with 15 to less than 19 years were analyzed with a comprehensive 4-color antibody panel and classified according to the EGIL recommendations. METHODS: Bone marrow or peripheral blood mononuclear cells were isolated by ficoll gradient centrifugation, washed and stained with fluorochrome-conjugated antigen-specific monoclonal antibodies. Cell preparations were acquired and analyzed on a flow cytometer. RESULTS: Centralized FCM was performed for 2 775 patients (82.6%) with B-cell precursor acute lymphoblastic leukemia, 493 patients (14.7%) with T-cell acute lymphoblastic leukemia and 90 patients (2,7%) with biphenotypic acute leukemia. There was a slight overall predominance of male (56.1%) over female (43.9%) patients. Patients with B-cell precursor ALL had a slightly more favourable outcome with a 10 y pEFS of 78 ± 1.0%, compared to patients with a T-ALL or BAL (biphenotypic acute leukemia) phenotype with a 10 y pEFS of 74 ± 1.8% (n.s.) or 69 ± 9.0% (p<0.009), respectively. CONCLUSIONS: FCM according to the EGIL recommendations not only provides diagnostic lineage determination and subclassification but also enables an initial prognostic orientation before MRD (minimal residual disease)-based risk stratification becomes available.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem da Célula/genética , Leucemia Aguda Bifenotípica/tratamento farmacológico , Leucemia Aguda Bifenotípica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Daunorrubicina/efeitos adversos , Daunorrubicina/uso terapêutico , Feminino , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Leucemia Aguda Bifenotípica/classificação , Leucemia Aguda Bifenotípica/mortalidade , Masculino , Mercaptopurina/efeitos adversos , Mercaptopurina/uso terapêutico , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Neoplasia Residual/classificação , Neoplasia Residual/tratamento farmacológico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/classificação , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidade , Leucemia-Linfoma Linfoblástico de Células T Precursoras/classificação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prognóstico , Análise de Sobrevida , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
The off-label use of approved pharmaceuticals outside the authorized status is implemented in pharmacotherapy of many diseases, especially for rare diseases and in cases of therapy resistance. The German regulations are presented and analyzed and the relative literature is discussed.
Assuntos
Seguro de Serviços Farmacêuticos/economia , Seguro de Serviços Farmacêuticos/legislação & jurisprudência , Programas Nacionais de Saúde/economia , Programas Nacionais de Saúde/legislação & jurisprudência , Uso Off-Label/economia , Uso Off-Label/legislação & jurisprudência , Doenças Raras/tratamento farmacológico , Mecanismo de Reembolso/economia , Mecanismo de Reembolso/legislação & jurisprudência , Adulto , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/economia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Bevacizumab , Criança , Análise Custo-Benefício/economia , Análise Custo-Benefício/legislação & jurisprudência , Aprovação de Drogas/economia , Aprovação de Drogas/legislação & jurisprudência , Resistência a Medicamentos , Medicina Baseada em Evidências/economia , Medicina Baseada em Evidências/legislação & jurisprudência , Alemanha , Fidelidade a Diretrizes/economia , Fidelidade a Diretrizes/legislação & jurisprudência , Humanos , Produção de Droga sem Interesse Comercial/economia , Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Papel do Médico , Ranibizumab , Doenças Raras/economia , Resultado do TratamentoRESUMO
The t(10;11)(p12;q14) is a recurring chromosomal translocation that gives rise to the CALM/AF10 fusion gene, which is found in acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma. We analyzed the fusion transcripts in 20 new cases of CALM/AF10-positive leukemias, and compared the gene expression profile of 10 of these to 125 patients with other types of leukemia and 10 normal bone marrow samples. Based on gene set enrichment analyses, the CALM/AF10-positive samples showed significant upregulation of genes involved in chromatin assembly and maintenance and DNA repair process, and downregulation of angiogenesis and cell communication genes. Interestingly, we observed a striking upregulation of four genes located immediately centromeric to the break point of the t(10;11)(p12;q14) on 10p12 (COMMD3 (COMM domain containing 3), BMI1 (B lymphoma Mo-MLV insertion region 1 homolog), DNAJC1 (DnaJ (Hsp40) homolog subfamily C member 1) and SPAG6 (sperm associated antigen 6)). We also conducted semiquantitative reverse transcriptase-PCR analysis on leukemic blasts from a murine CALM/AF10 transplantation model that does not have the translocation. Commd3, Bmi1 and Dnajc1, but not Spag6 were upregulated in these samples. These results strongly indicate that the differential regulation of these three genes is not due to the break point effect but as a consequence of the CALM/AF10 fusion gene expression, though the mechanism of regulation is not well understood.
Assuntos
Montagem e Desmontagem da Cromatina/genética , Sítios Frágeis do Cromossomo , Cromossomos Humanos Par 10 , Reparo do DNA/genética , Leucemia/genética , Proteínas Monoméricas de Montagem de Clatrina/genética , Fatores de Transcrição/genética , Regulação para Cima , Animais , Humanos , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Translocação GenéticaRESUMO
Precursor T-cell acute lymphoblastic leukemia (T-ALL) remains an important challenge in pediatric oncology. Because of the particularly poor prognosis of relapses, it is vital to identify molecular risk factors allowing early and effective treatment stratification. Activating NOTCH1 mutations signify a favorable prognosis in patients treated on ALL-BFM protocols. We have now tested if NOTCH pathway activation at different steps has similar clinical effects and if multiple mutations in this pathway function synergistically. Analysis of a validation set of 151 T-ALL patients and of the total cohort of 301 patients confirms the low relapse rate generally and the overall favorable effect of activating NOTCH1 mutations. Subgroup analysis shows that the NOTCH1 effect in ALL-BFM is restricted to patients with rapid early treatment response. Inactivation of the ubiquitin ligase FBXW7 is associated with rapid early treatment response and synergizes with NOTCH1 receptor activation. However, the effect of FBXW7 inactivation is separable from NOTCH1 activation by not synergizing with NOTCH1 mutations in predicting favorable long-term outcome, which can probably be explained by the interaction of FBXW7 with other clients. Finally, the comparison with other European protocols suggests that the NOTCH effect is treatment dependent generally and may depend on the intensity of central nervous system-directed therapy specifically.
Assuntos
Proteínas de Ciclo Celular/genética , Proteínas F-Box/genética , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prednisona/uso terapêutico , Receptor Notch1/genética , Ubiquitina-Proteína Ligases/genética , Proteínas de Ciclo Celular/fisiologia , Criança , Proteínas F-Box/fisiologia , Proteína 7 com Repetições F-Box-WD , Humanos , Resultado do Tratamento , Ubiquitina-Proteína Ligases/fisiologiaAssuntos
Proteínas de Homeodomínio/genética , Leucemia Mieloide Aguda/genética , Proteína de Leucina Linfoide-Mieloide/genética , Fatores de Transcrição/genética , Sequência de Bases , Primers do DNA , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Cariotipagem , Reação em Cadeia da PolimeraseRESUMO
The production of hematopoietic cells is under the tight control of distinct growth factors. As therapeutic agents, granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), and thrombopoiesis-stimulating agents (TSA) are in routine clinical use. Granulocyte colony-stimulating factor is used to prevent febrile neutropenia or to increase dose-density in chemotherapy regimens. Despite a reduced duration of neutropenia, randomized controlled trials have documented only a modest clinical benefit. A clinical advantage of dose-dense chemotherapy has been shown only in specific chemotherapy regimens. Clinical practice guidelines recommend the use of G-CSF for patients with a high risk of adverse outcome of febrile neutropenia. Erythropoiesis-stimulating agents (ESAs) are used as an alternative to blood transfusion in patients with chemotherapy-induced anemia. However, recent meta-analyses of clinical studies suggest that their use was associated with an increased risk of all-cause mortality and serious adverse events. Thrombopoiesis-stimulating agents have been introduced recently into the market for patients with immune thrombocytopenic purpura. Prior to the use of TSA in other conditions such as chemotherapy-induced thrombocytopenia the lessons learned with G-CSF and ESAs should be taken into account.
Assuntos
Anemia/etiologia , Anemia/prevenção & controle , Antineoplásicos/efeitos adversos , Fatores de Crescimento de Células Hematopoéticas/administração & dosagem , Neutropenia/tratamento farmacológico , Neutropenia/prevenção & controle , Humanos , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neutropenia/induzido quimicamenteRESUMO
Between 1981 and 2000, 6609 children (<18 years of age) were treated in five consecutive trials of the Berlin-Frankfurt-Münster (BFM) study group for childhood acute lymphoblastic leukemia (ALL). Patients were treated in up to 82 centers in Germany, Austria and Switzerland. Probability of 10-year event-free survival (EFS) (survival) improved from 65% (77%) in study ALL-BFM 81 to 78% (85%) in ALL-BFM 95. In parallel to relapse reduction, major efforts focused on reducing acute and late toxicity through advanced risk adaptation of treatment. The major findings derived from these ALL-BFM trials were as follows: (1) preventive cranial radiotherapy could be safely reduced to 12 Gy in T-ALL and high-risk (HR) ALL patients, and eliminated in non- HR non-T-ALL patients, if it was replaced by high-dose and intrathecal (IT) MTX; (2) omission of delayed re-intensification severely impaired outcome of low-risk patients; (3) 6-month-less maintenance therapy caused an increase in systemic relapses; (4) slow response to an initial 7-day prednisone window was identified as adverse prognostic factor; (5) condensed induction therapy resulted in significant improvement of outcome; (6) the daunorubicin dose in induction could be safely reduced in low-risk patients and (7) intensification of consolidation/re-intensification treatment led to considerable improvement of outcome in HR patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Irradiação Craniana , Recidiva Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante de Células-Tronco , Adolescente , Criança , Pré-Escolar , Terapia Combinada , Feminino , Seguimentos , Humanos , Imunofenotipagem , Lactente , Masculino , Recidiva Local de Neoplasia/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Prognóstico , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
The objective of this study for newly diagnosed acute promyelocytic leukemia (APL) was to evaluate the efficacy of an intensified double induction chemotherapy including high dose ara-C (HD) and all-trans retinoic acid (ATRA) followed by consolidation and 3 years maintenance therapy. In contrast to APL studies stratifying therapy according to pretreatment white blood cell (WBC) count < and > or =10 x 10(9)/l (low/intermediate and high risk according to the Sanz score), our patients received uniform therapy. From 1994 to 2005, 142 patients (age, 16-60 years) were enrolled. In the low/intermediate (n=105) vs high (n=37) WBC group, the rates of complete remission were 95.2 vs 83.8%, of induction death were 4.8 vs 16.2% (P=0.05) and of molecular remission were 87.5 vs 91.3% (P=1). Long-term overall survival was 84.4 vs 73.0% (P=0.12), event free survival was 78.3 vs 67.3% (P=0.11), relapse free survival was 82.1 vs 80.0% (P=0.83) and the cumulative incidence of relapse was 7.4 vs 11.4% (P=0.46). No relapse or death occurred after 4.7 years. ATRA and intensified chemotherapy including HD ara-C followed by prolonged maintenance therapy reduced the relapse risk in high risk patients. Pretreatment WBC count > or =10 x 10(9)/l count was no relevant prognostic factor for relapse.
Assuntos
Citarabina/administração & dosagem , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Alemanha , Humanos , Leucemia Promielocítica Aguda/mortalidade , Estudos Longitudinais , Contagem de Linfócitos , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Análise de Sobrevida , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
The problem of inhalation of Aspergillus spores outside rooms with high-efficiency particulate air (HEPA) filtration has not been resolved as yet. Well-fitting masks are used in industrial and health care settings to protect from inhaling particles of 0.3-0.5 mum size. To investigate the efficacy and tolerability of well-fitting masks in high-risk patients, we conducted a prospective, randomised, multicentre study comparing standard hospital hygiene procedures with or without wearing masks in adults undergoing chemotherapy for acute leukaemia or allogeneic haematopoietic stem-cell transplantation (aHSCT). Forty-one patients were randomly assigned to wearing masks and 39 to the control group. In all, 76% of patients were treated in laminar airflow or HEPA-filtered rooms, 84% received oral polyenes, and three aHSCT recipients were given fluconazole. Duration of neutropenia was similar in both treatment groups. Invasive fungal infections were diagnosed in eight patients in either study arm. One patient in each arm died from proven invasive aspergillosis. There was no difference in the use of systemic antifungals. Of patients in the mask group, 65% described the comfort as acceptable, 26% as unpleasant, and 9% as intolerable. This first randomised study on the use of well-fitting masks failed to show a reduction of invasive fungal infections.
Assuntos
Hospedeiro Imunocomprometido , Aspergilose Pulmonar Invasiva/imunologia , Aspergilose Pulmonar Invasiva/prevenção & controle , Dispositivos de Proteção Respiratória , Adolescente , Adulto , Idoso , Antifúngicos/uso terapêutico , Antineoplásicos/efeitos adversos , Infecção Hospitalar/imunologia , Infecção Hospitalar/prevenção & controle , Feminino , Humanos , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Fatores de Risco , Adulto JovemRESUMO
Treatment response is a strong outcome predictor for childhood acute lymphoblastic leukemia (ALL). Here, we evaluated the predictive impact of flow cytometric blast quantification assays (absolute blast count, BC, and blast reduction rate, BRR) in peripheral blood (pB) and/or bone marrow (BM) at early time points of induction therapy (days 0, 8 and 15) on the remission status in the AIEOP-BFM-ALL 2000 protocol. At the single parameter level (905 patients), the strongest predictive parameter for the remission status as a dichotomous minimal residual disease (MRD) parameter (positive/negative) has been provided by the BC at day 15 in BM (cutoff: 17 blasts/microl; 50 vs 15%; odds ratio: 5.6; 95% confidence interval: 4.1-7.6, P<0.001), followed by the BRR at day 15 in BM and by the BC at day 8 in pB (odds ratios: 3.8 and 2.6, respectively). In the multiple regression analysis (440 patients), BC in pB (d0 and d8) and in BM (d15) as well as BRR at day 8 in pB provided significantly contributing variables with an overall correct prediction rate of 74.8%. These data show that the quantitative assessment of early response parameters, especially absolute BCs at day 15 in BM, has a predictive impact on the remission status after induction therapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Citometria de Fluxo/métodos , Imunofenotipagem/métodos , Células-Tronco Neoplásicas/patologia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Área Sob a Curva , Células Sanguíneas/patologia , Medula Óssea/patologia , Contagem de Células , Criança , Pré-Escolar , Ensaios Clínicos como Assunto/estatística & dados numéricos , Monitoramento de Medicamentos , Feminino , Humanos , Lactente , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Prognóstico , Curva ROC , Indução de Remissão , Resultado do TratamentoRESUMO
There is a wide variety of conjunctival tumors. A good diagnosis can be reached by discussing the case history with the patient in conjunction with a slit-lamp examination. Presented here is the case of a 39-year-old patient with a rapidly growing conjunctival tumor on his left eye. After tumor resection and histological analysis, a plasmacytoma was found. The completed hemato-oncological analysis gave no further suspicious pathological results, leading to the diagnosis of a solitary extramedullary plasmacytoma. Percutaneous radiotherapy was carried out.
Assuntos
Túnica Conjuntiva/patologia , Neoplasias da Túnica Conjuntiva/diagnóstico , Neoplasias da Túnica Conjuntiva/radioterapia , Plasmocitoma/diagnóstico , Plasmocitoma/radioterapia , Adulto , Humanos , Masculino , Resultado do TratamentoRESUMO
Lymphoplasmacytic lymphoma (LPL) is an indolent lymphoma with moderate sensitivity to conventional chemotherapy. This study investigated whether the addition of rituximab to standard chemotherapy improves treatment outcome in LPL and the subgroup of LPL patients fulfilling the criteria of Waldenstroem's macroglobulinemia (WM). A total of 69 patients with previously untreated LPL were enrolled into the trial; 64 patients were evaluable for treatment outcome. In all, 48 of the 64 LPL patients fulfilled the criteria of WM. Patients were randomly assigned to R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, n=34) or CHOP (n=30). R-CHOP resulted in significantly higher overall response (OR) rate (94 vs 67%, P=0.0085) in the LPL patients and in the WM subgroup (91 vs 60%, P=0.0188). With a median observation time of 42 months, R-CHOP induced a significantly longer time to treatment failure (TTF) with a median of 63 months for R-CHOP vs 22 months in the CHOP arm in the LPL patients (P=0.0033) and in the WM subgroup (P=0.0241). There was no major difference of treatment-associated toxicity between both treatment groups. These data indicate that the addition of rituximab to front-line chemotherapy improves treatment outcome in patients with LPL or WM.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/toxicidade , Anticorpos Monoclonais Murinos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Humanos , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Indução de Remissão , Rituximab , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
Despite several recommendations for standardization of multiparameter flow cytometry (MFC) the number, specificity and combinations of reagents used by diagnostic laboratories for the diagnosis and classification of acute leukemias (AL) are still very diverse. Furthermore, the current diagnostic interpretation of flow cytometry readouts is influenced arbitrarily by individual experience and knowledge. We determined the potential value of a minimal four-color combination panel of 13 monoclonal antibodies (mAbs) with a CD45/sideward light scatter-gating strategy for a standardized MFC immunophenotyping of the clinically most relevant subgroups of AL. Bone marrow samples from 155 patients with acute myeloid leukemia (AML, n=79), B-cell precursor acute lymphoblastic leukemia (BCP-ALL, n=29), T-cell precursor acute lymphoblastic leukemia (T-ALL, n=12) and normal bone marrow donors (NBMD, n=35) were analyzed. A knowledge-based learning algorithm was generated by comparing the results of the minimal panel with the actual diagnosis, using discriminative function analysis. Correct classification of the test sample according to lineage, that is, BCP-ALL, T-ALL, AML and differentiation of NBMD was achieved in 97.2% of all cases with only six of the originally applied 13 mAbs of the panel. This provides evidence that discriminant function analysis can be utilized as a decision support system for interpretation of flow cytometry readouts.
Assuntos
Diagnóstico por Computador/métodos , Citometria de Fluxo/métodos , Leucemia/diagnóstico , Doença Aguda , Algoritmos , Anticorpos Monoclonais , Medula Óssea/patologia , Linhagem da Célula , Cor , Diagnóstico por Computador/instrumentação , Diagnóstico por Computador/normas , Citometria de Fluxo/normas , Humanos , Imunofenotipagem , Padrões de ReferênciaRESUMO
In childhood acute lymphoblastic leukemia (ALL), persistence of leukemic blasts during therapy is of crucial prognostic significance. In the present study, we address molecular and cell biologic features of blasts persisting after 1 week of induction glucocorticoid therapy. Genome-wide gene expression analysis of leukemic samples from precursor B-cell ALL patients (n=18) identified a set of genes differentially expressed in blasts at diagnosis day 0 (d0) and persisting on day 8 (d8). Expression changes indicate a shift towards mature B cells, inhibition of cell cycling and increased expression of adhesion (CD11b/ITGAM) and cytokine (CD119/IFNGR1) receptors. A direct comparison with normal B cells, which are largely therapy resistant, confirmed the differentiation shift at the mRNA (n=10) and protein (n=109) levels. Flow cytometric analysis in independent cohorts of patients confirmed both a decreased proliferative activity (n=13) and the upregulation of CD11b and CD119 (n=29) in d8 blasts. The differentiation shift and low proliferative activity in d8 blasts may account for the persistence of blasts during therapy and affect their sensitivity to further therapeutic treatment. CD11b and CD119 are potential specific markers for d8 blast persistence and detection of minimal residual disease, which warrant further investigation.
Assuntos
Linfócitos B/metabolismo , Crise Blástica/metabolismo , Perfilação da Expressão Gênica , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Adolescente , Antígeno CD11b/análise , Ciclo Celular , Proliferação de Células , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Prednisona/uso terapêutico , Receptores de Interferon/análise , Receptor de Interferon gamaRESUMO
Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Linfoma de Célula do Manto/tratamento farmacológico , Adulto , Idoso , Carmustina/uso terapêutico , Clorambucila/uso terapêutico , Ciclofosfamida/uso terapêutico , Citarabina/uso terapêutico , Dexametasona/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Alemanha/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Prednisolona/uso terapêutico , Prednisona/uso terapêutico , Estudos Prospectivos , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
Deletions of chromosome 6q have been reported in several hematological malignancies, but data are not conclusive regarding their biological and prognostic impact. Therefore, we focused on pediatric patients diagnosed with T-cell lymphoblastic lymphoma (T-LBL) treated uniformly according to the NHL-BFM95 protocol. We used loss-of-heterozygosity (LOH) analysis of 25 microsatellite markers located on chromosome 6q14-q24. Fragment-length analysis was performed on ABI-PRISM3100 Genetic-Analyzer. Eligibility criterion was > or =3 informative markers. Between April 1995 and March 2003, 185 T-LBL patients were treated according to the NHL-BFM95 protocol. Five-year event-free (EFS) and disease-free survival (DFS) were 79+/-3 and 87+/-3% (median follow-up 4.7 [1.2-10.1] years). Sixty-one patients were evaluable for LOH analysis, including 18 out of 23 patients with relapse. EFS and DFS were 67+/-6 and 69+/-6% for these 61 patients. Testing of 853 markers in the 61 patients identified the presence of LOH in 19 patients (31%): 13 of the 18 relapse patients and five of the 41 in complete remission (odds ratio 18.7, 95% confidence interval 4.7-75.3). One LOH-positive patient died from treatment-related toxicity. We conclude that LOH on chromosome 6q14-q24 may have conferred a high risk of relapse on our group of children with T-LBL treated according to the NHL-BFM95 protocol.