RESUMO
By using the GRADE system, we updated the guidelines for management of follicular cell lymphoma issued in 2006 from SIE, SIES, and GITMO group. We confirmed our recommendation to frontline chemoimmunotherapy in patients with Stage III-IV disease and/or high tumor burden. Maintenance rituximab was also recommended in responding patients. In patients relapsing after an interval longer than 12 months from frontline therapy, we recommended chemoimmunotherapy with non cross-resistant regimens followed by rituximab maintenance. High dose chemotherapy followed by hematopoietic stem cell transplant was recommended for young fit patients who achieve a response after salvage chemoimmunotherapy.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Imunoterapia , Linfoma Folicular/terapia , Adulto , Anticorpos Monoclonais Murinos/farmacologia , Antineoplásicos/farmacologia , Gerenciamento Clínico , Esquema de Medicação , Feminino , Humanos , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Rituximab , Prevenção Secundária , Fatores de TempoRESUMO
BACKGROUND: The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has produced promising results in chronic lymphocytic leukemia and other lymphoproliferative disorders. The authors report the final results from a multicenter, prospective study examining FCR in Waldenstrom macroglobulinemia (WM). METHODS: Forty-three patients with symptomatic WM that was untreated or pretreated with 1 line of chemotherapy received rituximab 375 mg/m(2) intravenously on day 1 and fludarabine 25 mg/m(2) and cyclophosphamide 250 mg/m(2) intravenously on days 2 through 4. FCR was repeated every 28 days for up to 6 courses. RESULTS: The overall response rate was 79%, and the major response rate of 74.4%, including 11.6% complete remissions (CRs) and 20.9% very good partial remissions. An amelioration of the quality of responses was observed during follow-up, leading to 18.6% of CRs. No differences in terms of responses were observed among previously treated or untreated patients. Among the clinical and laboratory features that were considered, only the ß2-microglobulin level had a significant impact in terms of achieving a major response. The major toxicity reported was grade 3/4 neutropenia, which occurred in 45% of courses and was the main reason for treatment discontinuation. After the end of treatment, 19 patients (44%) had long-lasting episodes of neutropenia. Three patients developed myelodysplastic syndrome during follow-up. CONCLUSIONS: The FCR regimen was capable of neutralizing adverse prognostic factors and proved to be active in patients with WM, leading to rapid disease control and good-quality responses. Because myelosuppression was the main concern, further studies are warranted to optimize dosages and treatment duration.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Rituximab , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 x 10(9)/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.
Assuntos
Mielofibrose Primária/mortalidade , Fatores Etários , Idoso , Feminino , Hemoglobinas/metabolismo , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Estatísticos , Mielofibrose Primária/sangue , Mielofibrose Primária/terapia , Prognóstico , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
Within a cohort of 1,915 consecutive patients with myeloproliferative neoplasm followed for a median time of 5.2 years (range 0-33.3), we investigated the occurrence of lymphoid neoplasm with the aim of defining this risk and to investigate the role of genetic predisposing factors. We identified 22 patients with myeloproliferative neoplasm who developed lymphoid neoplasm over their lifetime. We found that the risk of developing lymphoid neoplasm was 2.79-fold higher (95% CI, 1.80-4.33; P<0.001) than that of the general Italian population. A tag SNP surrogate for JAK2 GGCC haplotype was used to clarify a potential correlation between lymphoid-myeloid neoplasm occurrence and this genetic predisposing factor. As we did not find any difference in GGCC haplotype frequency between patients with both myeloid and lymphoid neoplasm and patients with myeloid neoplasm, JAK2 GGCC haplotype should not be considered a genetic predisposing factor. No difference in familial clustering was observed between the two groups.
Assuntos
Janus Quinase 2/genética , Leucemia Linfoide/genética , Linfoma/genética , Transtornos Mieloproliferativos/genética , Análise por Conglomerados , Frequência do Gene , Predisposição Genética para Doença , Testes Genéticos , Haplótipos , Humanos , Itália , Leucemia Linfoide/enzimologia , Leucemia Linfoide/etiologia , Leucemia Linfoide/patologia , Linfoma/enzimologia , Linfoma/etiologia , Linfoma/patologia , Mutação , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/enzimologia , Transtornos Mieloproliferativos/patologia , Polimorfismo de Nucleotídeo Único , RiscoRESUMO
Risk stratification in primary myelofibrosis is currently based on two international prognostic scoring systems, neither of which takes into consideration red blood cell transfusion-dependency. In 288 consecutive patients with primary myelofibrosis, red blood cell transfusion-dependency at diagnosis affects survival independently of the International Prognostic Scoring System (P < 0.001). To evaluate the dynamic impact on survival of red blood cell transfusion-dependency, we performed a Cox's regression analysis with transfusion status as time-dependent covariate in 220 regularly followed patients with primary myelofibrosis. Patients who begin red blood cell transfusions anytime (n = 80, 36%) have a significantly worse survival compared to those who continue follow up without transfusions (HR: 7.8, 95%CI: 5.1-11.9; P < 0.001). Adjusting for Dynamic International Prognostic Scoring System in a multivariate analysis, red blood cell transfusion-dependency retained an independent prognostic impact on survival. This study suggests that red blood cell transfusion-dependency should be considered to improve risk stratification of primary myelofibrosis during follow up.
Assuntos
Transfusão de Eritrócitos/mortalidade , Mielofibrose Primária/mortalidade , Mielofibrose Primária/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Mielofibrose Primária/diagnóstico , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
The incidence of myelodysplastic syndromes increases with age and a high prevalence of co-morbid conditions has been reported in these patients. So far, risk assessment in myelodysplastic syndromes has been mainly based on disease status. We studied the prognostic impact of comorbidity on the natural history of myelodysplastic syndrome with the aim of developing novel tools for risk assessment. The study population included a learning cohort of 840 patients diagnosed with myelodysplastic syndrome in Pavia, Italy, and a validation cohort of 504 patients followed in Duesseldorf, Germany. Information on comorbidity was extracted from detailed review of the patients' medical charts and laboratory values at diagnosis and during the course of the disease. Univariable and multivariable survival analyses with both fixed and time-dependent covariates were performed using Cox's proportional hazards regression models. Comorbidity was present in 54% of patients in the learning cohort. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. In multivariable analysis, comorbidity had a significant impact on both non-leukemic death (P=0.01) and overall survival (P=0.02). Cardiac, liver, renal, pulmonary disease and solid tumors were found to independently affect the risk of non-leukemic death. A time-dependent myelodysplastic syndrome-specific comorbidity index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients which showed significantly different probabilities of non-leukemic death (P<0.001) and survival (P=0.005) also in the validation cohort. Landmark survival analyses at fixed time points from diagnosis showed that the MDS-CI can better define the life expectancy of patients with myelodysplastic syndrome stratified according to the WHO-classification based Prognostic Scoring System (WPSS).Comorbidities have a significant impact on the outcome of patients with myelodysplastic syndrome. Accounting for both disease status by means of the WPSS and comorbidity through the MDS-CI considerably improves risk stratification in myelodysplastic syndromes.
Assuntos
Síndromes Mielodisplásicas/epidemiologia , Adolescente , Adulto , Idoso , Comorbidade , Feminino , Alemanha , Cardiopatias/epidemiologia , Cardiopatias/patologia , Humanos , Itália , Nefropatias/epidemiologia , Nefropatias/patologia , Hepatopatias/epidemiologia , Hepatopatias/patologia , Pneumopatias/epidemiologia , Pneumopatias/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Neoplasias , Prognóstico , Medição de Risco/classificação , Índice de Gravidade de Doença , Análise de SobrevidaRESUMO
BACKGROUND: Anemia is an established negative prognostic factor in myelodysplastic syndromes but the relationship between its degree and clinical outcome is poorly defined. We, therefore, studied the relationship between severity of anemia and outcome in myelodysplastic syndrome patients. DESIGN AND METHODS: We studied 840 consecutive patients diagnosed with myelodysplastic syndromes at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, and 504 patients seen at the Heinrich-Heine-University Hospital, Düsseldorf, Germany. Hemoglobin levels were monitored longitudinally and analyzed by means of time-dependent Cox's proportional hazards regression models. RESULTS: Hemoglobin levels lower than 9 g/dL in males (HR 5.56, P=0.018) and 8 g/dL in females (HR=5.35, P=0.026) were independently related to reduced overall survival, higher risk of non-leukemic death and cardiac death (P<0.001). Severe anemia, defined as hemoglobin below these thresholds, was found to be as effective as transfusion-dependency in the prognostic assessment. After integrating this definition of severe anemia into the WHO classification-based Prognostic Scoring System, time-dependent regression and landmark analyses showed that the refined model was able to identify risk groups with different survivals at any time during follow up. CONCLUSIONS: Accounting for severity of anemia through the WHO classification-based Prognostic Scoring System provides an objective criterion for prognostic assessment and implementation of risk-adapted treatment strategies in myelodysplastic syndrome patients.
Assuntos
Anemia/complicações , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Cardiopatias/complicações , Cardiopatias/mortalidade , Humanos , Sobrecarga de Ferro/etiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Prognóstico , Reação Transfusional , Organização Mundial da Saúde , Adulto JovemRESUMO
The present study was designed to establish the incidence of cytogenetic evolution (CE), defined as the acquisition of chromosomal defects during the course of MDS, in order to correlate it with the WHO classification and IPSS score, and to assess its impact on overall survival (OS) and risk of MDS/AML evolution (progression-free interval, PFI) by means of Cox models for time-dependent covariates. Adjustments for known risk factors were achieved by performing a bivariable analysis. The study was carried out in 153 MDS patients who were followed for a median period of 45.2 months. Disease progression occurred in 42.4% of patients after a 65.2-month median PFI, while CE occurred in 30.7% of patients. Our study shows that (1) CE was more common in advanced than in early MDS, and advanced MDS presented secondary chromosomal defects distinct from those of early MDS; (2) CE significantly affected OS and PFI independently of other prognostic variables; (3) del(7)(q31q34) was the only secondary chromosomal defect which significantly affected PFI; trisomy 8 had only a moderate influence.
Assuntos
Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Idoso , Transformação Celular Neoplásica/genética , Aberrações Cromossômicas/estatística & dados numéricos , Análise Citogenética , Progressão da Doença , Evolução Molecular , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/epidemiologia , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Análise de SobrevidaRESUMO
Bone marrow (BM) examination is essential in the staging of non-Hodgkin's lymphoma (NHL) patients. Few studies have compared BM histologic findings with results of flow cytometric (FC) analysis. We analyzed the incidence and patterns of histologic BM involvement in a series of 753 patients with NHL. For 498 patients, a concurrent FC analysis on BM was available. Histologic involvement was detected at diagnosis in 311/753 (41%) patients. By FC, BM involvement was clearly detected in 150/498 (30%). After excluding 12 cases with equivocal histology, concordance between the two methods was detected in 411 (85%) cases (27% BMB+/FC+; 58% BMB-/FC-), while discordance was present in 75 (15%) (P < 0.001): 58 cases (12%) were BMB+/FC- and 17 (3%) were BMB-/FC+. Discordance was more frequent in FL and in lymphoplasmacytic lymphoma (LPL). These data demonstrate that the two methods are comparable in qualitative assessment of BM involvement in NHL, with the exception of FL and LPL. In FL, diffuse large B-cell lymphoma (DLBCL) and LPL, FC underestimates the extent of infiltrate with respect to histology.
Assuntos
Exame de Medula Óssea/métodos , Medula Óssea/patologia , Linfoma não Hodgkin/patologia , Citometria de Fluxo , Técnicas Histológicas , Humanos , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Estudos Retrospectivos , Macroglobulinemia de WaldenstromRESUMO
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.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/virologia , Citotoxinas/efeitos adversos , Hepatite C Crônica/complicações , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Antineoplásicos Alquilantes/administração & dosagem , Fatores Biológicos/administração & dosagem , Citotoxinas/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , RituximabRESUMO
Immunoglobulin gene usage and somatic mutation patterns were studied in 59 patients with splenic marginal zone lymphoma and were correlated with clinical characteristics. Fifty-nine IGHV rearrangements were amplified. IGHV1, IGHV3, and IGHV4 subgroups accounted for 30%, 56%, and 14% of sequences, respectively. IGHV genes most frequently used were IGHV1-2 (n=12), IGHV3-23 (n=15), IGHV3-30 (n=7) and IGHV4-34 (n=5). IGHV was unmutated in 25%. Villous lymphocytes >10% were detected in 50% of patients belonging to the IGHV1-2 group, in 21% of the IGHV3-23 group, and in no patient of the IGHV3-30 group (p=0.05). Liver involvement was present in 50% of the IGHV3-30 group, in 9% of the IGHV3-23 group, and in no patient of the IGHV1-2 group (p=0.04). HCV-serology was positive in 50% of the IGHV3-30 group, in 7% of the IGHV3-23 group, and in 17% of the IGHV1-2 group (p=0.04). The proportion of intermediate and high risk patients according to the SMZL score was higher in the unmutated respect to the mutated group (69% vs 32%, p=0.05). In conclusion, IGHV rearrangement analysis in splenic marginal zone B-cell lymphoma reveals a non-random preference for use of IGHV1-2, IGHV3-23 and IGHV3-30 genes, whose presence differs according to clinical features and prognostic category.
Assuntos
Rearranjo Gênico de Cadeia Pesada de Linfócito B , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise por Conglomerados , Feminino , Humanos , Linfoma de Zona Marginal Tipo Células B/imunologia , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Prognóstico , Risco , Neoplasias Esplênicas/imunologia , Neoplasias Esplênicas/mortalidade , Neoplasias Esplênicas/patologia , Análise de SobrevidaRESUMO
OBJECTIVES: Bortezomib has proven to be effective as single agent in myeloma patients. Aim of this study was to evaluate the efficacy and toxicity of bortezomib in combination with dexamethasone in a cohort of multiple myeloma (MM) relapsed/refractory patients treated in a single center. PATIENTS AND METHODS: In this single center study, 70 patients were treated with bortezomib alone (9) or in combination with dexamethasone (61). RESULTS: Forty-one patients (59%) achieved at least a partial response (PR), including 7% complete response (CR), 36% very good partial response (VGPR) reaching the best response within four cycles. The duration of response was significantly longer for patients achieving CR/VGPR than for those achieving PR (7.3 vs. 3.8 months, P = 0.03). Likewise, time to progression, time to alternative treatment, and treatment free interval were significantly better for patients obtaining CR/VGPR (6.8, 9.4, 6.5 months respectively) as compared with PR (4.9, 6.3, 2 months respectively). The only dose-limiting toxicity was peripheral neuropathy (PN), which occurred in 38/70 patients (55%) and was of grade 3-4 in 12 (17%). PN led to a dose reduction or treatment discontinuation in 17 (24%) patients. Complete resolution or improvement of PN occurred in 29/38 (76%) after a median time of 100 d (range: 17-202). CONCLUSIONS: Bortezomib in combination with dexamethasone is highly effective in relapsed/refractory MM producing an impressive rate of CR/VGPR, but responses are short-lived.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/prevenção & controle , Adulto , Idoso , Ácidos Borônicos/administração & dosagem , Bortezomib , Dexametasona/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Pirazinas/administração & dosagem , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de TempoRESUMO
Blast phase (BP) may occur as a late event in essential thrombocythemia (ET). This study includes 19 patients with post-ET BP diagnosed and followed in a single institution. At BP, 63% of patients had leukocytosis (white blood cell count >10 x 10(9)/L), 74% had anemia (hemoglobin value <10 g/dL), 74% had thrombocytopenia (platelet count <100 x 10(9)/L), and 84% were over 65 years of age. Cytogenetic analysis was available in 10 patients: six had karyotype aberrations. According to cytogenetic-based risk stratification of de novo acute leukemia (AL), all patients had an unfavorable profile. JAK2 (V617F) mutational status was evaluated in five patients. In two of them, the JAK2 mutation was undetectable in blast cells (one with JAK2-positive ET), whereas in three both granulocytes and blast cells displayed the mutation. Treatment of BP was patient-based according to the performance status and co-morbidities and consisted of palliation in 14 patients, and of induction of remission in five. Median survival was 2.3 months (range 0.2-22.3), irrespective of the treatment received. In conclusion, this study indicates that AL evolved from ET has unfavorable clinical and biological features. JAK2 (V617F)-positive ET may evolve in few instances into JAK2-negative leukemia. The outcome of patients is poor whatever the treatment used.
Assuntos
Crise Blástica/etiologia , Trombocitemia Essencial/complicações , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Crise Blástica/sangue , Crise Blástica/tratamento farmacológico , Crise Blástica/epidemiologia , Plaquetas/citologia , Intervalo Livre de Doença , Feminino , Hemoglobinas/análise , Humanos , Janus Quinase 2/genética , Contagem de Leucócitos , Leucócitos/citologia , Masculino , Pessoa de Meia-Idade , Mutação , Contagem de Plaquetas , Fatores de Risco , Trombocitemia Essencial/sangue , Trombocitemia Essencial/epidemiologia , Trombocitemia Essencial/genéticaRESUMO
Philadelphia-negative chronic myeloproliferative disorders (CMD) include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Angiogenesis is critical in the pathogenesis of PMF. We studied angiogenesis in 115 patients with CMD (23 PV, 24 ET, 46 PMF, 12 post-PV and 10 post-ET myelofibrosis) by assessment of microvessel density (MVD) in bone marrow (BM). Kruskall-Wallis analysis of variance showed that patients with PMF had significantly higher values of MVD than those with PV (P < 0.001), ET (P < 0.001) and controls (P < 0.001). Mann-Whitney U-test demonstrated that patients with PMF at the prefibrotic stage had significantly higher MVD values than those with ET (P = 0.02). Patients with post-PV myelofibrosis showed significantly higher MVD values than those with PV (P < 0.001), as did patients with post-ET myelofibrosis compared with ET (P < 0.001). In patients with CMD, the multivariate generalized linear regression model showed that the JAK2 (V617F) mutational burden (P = 0.01), serum lactate dehydrogenase level (P = 0.003), and anaemia (P < 0.001) independently correlated with MVD. In summary, this study indicates that assessment of BM angiogenesis, as measured by MVD, may be a useful additional tool in the histopathological definition of CMD.
Assuntos
Medula Óssea/irrigação sanguínea , Transtornos Mieloproliferativos/patologia , Neovascularização Patológica/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Doença Crônica , Feminino , Humanos , Janus Quinase 2/genética , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/complicações , Transtornos Mieloproliferativos/genética , Policitemia Vera/genética , Policitemia Vera/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Trombocitemia Essencial/genética , Trombocitemia Essencial/patologiaRESUMO
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.
Assuntos
Leucemia/fisiopatologia , Transtornos Mieloproliferativos/genética , Mielofibrose Primária/fisiopatologia , Trombocitemia Essencial/complicações , Trombose/fisiopatologia , Idoso , Progressão da Doença , Seguimentos , Humanos , Janus Quinase 2/genética , Leucemia/epidemiologia , Leucemia/etiologia , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/epidemiologia , Mielofibrose Primária/etiologia , Prognóstico , Fatores de Risco , Trombose/epidemiologia , Trombose/etiologia , Fatores de TempoRESUMO
BACKGROUND: Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics. METHODS: Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 mug/kg, beginning 24 hours after induction and consolidation chemotherapy. RESULTS: The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim. CONCLUSION: These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics. TRIAL REGISTRATION: Clinicaltrials.gov NCT00114764.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Neutropenia/tratamento farmacológico , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Adulto , Idoso , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Método Duplo-Cego , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Neutropenia/sangue , Neutropenia/induzido quimicamente , Neutropenia/patologia , Neutrófilos/imunologia , Polietilenoglicóis , Proteínas Recombinantes , Recuperação de Função Fisiológica/imunologia , Indução de RemissãoRESUMO
OBJECTIVE: Bortezomib is a new chemotherapeutic drug available for the treatment of lymphoid disorders, including multiple myeloma. Although its primary mechanism of action is proteasome inhibition, other mechanisms can contribute to the therapeutic effects, including modulation of inflammatory cytokines and immune response. One of the main toxic effects of bortezomib is peripheral neuropathy, usually occurring in the form of a painful, sensory axonal neuropathy. The mechanisms of peripheral damage, however, are still unclear. We here report a series of patients treated with bortezomib, who developed a peripheral damage possibly related to immuno-mediated, rather than toxic, mechanisms. METHODS: Five patients who developed a peripheral neuropathy with severe motor involvement under bortezomib treatment underwent CSF, electrophysiological, and spinal cord MRI examinations. RESULTS: Peripheral damage was characterized by: demyelinating or mixed axonal-demyelinating neuropathy, with prominent motor involvement; albumin-cytological dissociation; lumbar root enhancement on MRI in 2/5 patients; favourable outcome in 4/5 patients after immune treatments, either steroids (2 patients) or IVIg (2 patients). CONCLUSIONS: In some instances, the peripheral damage associated with bortezomib may recognize immuno-mediated mechanisms. SIGNIFICANCE: This form of bortezomib-associated neuropathy needs to be recognized as treatable condition, as it may respond to immune therapies. Unexplained worsening of neurological dysfunction despite bortezomib discontinuation, with prominent motor involvement and CSF signs of inflammation, may be the clues to this complication.
Assuntos
Antineoplásicos/uso terapêutico , Ácidos Borônicos/efeitos adversos , Mieloma Múltiplo/tratamento farmacológico , Polineuropatias/induzido quimicamente , Polineuropatias/imunologia , Pirazinas/efeitos adversos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Potenciais de Ação/efeitos da radiação , Idoso , Bortezomib , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Condução Nervosa/efeitos dos fármacos , Polineuropatias/etiologia , Tempo de Reação/efeitos dos fármacosRESUMO
BACKGROUND: Mutations involving KIT and FLT3 genes, encoding tyrosine kinase (TK) membrane receptors, are detected in core-binding factor leukaemia (CBFL) patients. PDFGRA and PDGFRB encode class III TK receptors and are involved both in physiological processes and in the pathogenesis of haematological and solid tumours. The aim of this study was to investigate if PDGFR mutations are involved in CBFL. PATIENTS AND METHODS: In order to detect PDGFR mutations in CBFL, 35 patients without KIT or FLT3 mutations patients were screened by rapid and sensitive single-strand conformation polymorphism (SSCP) analysis. Sequence analysis was performed in polymerase chain reaction (PCR) products showing altered mobility in SSCP analysis in order to determine the nucleotide changes. RESULTS: Three types of single-nucleotide polymorphism (SNP) were detected in the PDGFRA gene (exon 12, exon 13 and exon 18) while no mutation of PDGFRB was detected in the tested CBFLs. CONCLUSION: These data showed that no pathogenic mutations in PDGFRA and PDGFRB were detected in the context of CBFL without KIT and FLT3 mutations. Thus, PDGFR genes do not seem to be involved in CBFL and future studies are needed to establish the genetic causes of the disease in these particular patients.
Assuntos
Leucemia Mieloide/genética , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Tirosina Quinase 3 Semelhante a fms/genética , Doença Aguda , Adulto , Idoso , Fatores de Ligação ao Core/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo Conformacional de Fita SimplesRESUMO
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.
Assuntos
Mucosa Gástrica/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma de Células B/patologia , Segunda Neoplasia Primária , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.