RESUMO
The outcome of patients with relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after autologous stem cell transplantation (auto-SCT) is poor. Recently, the anti-CD30 monoclonal antibody-drug conjugate, brentuximab vedotin (BV), has shown remarkable activity in the setting of R/R cHL. In the pivotal phase II study, BV produced an overall response rate of 75% and a median progression-free survival of 6.7 months. Although these results have been reproduced by large registry studies, the impact of BV on the overall survival (OS) of patients with R/R cHL has not been addressed so far. The aim of this study was to examine the impact of BV on OS in the setting of post auto-SCT R/R cHL. Analysis was performed in a group of patients with R/R cHL after a previous auto-SCT reported in the Greek registry during the last 2 decades. By using a multivariate model and censoring patients at the time of subsequent allo-SCT or treatment with immune checkpoint inhibitors, we showed that treatment with BV in the posttransplant relapse setting has a positive impact on the outcome and results in significant improvement of OS. To our knowledge, this the first published study, addressing the impact of BV on the OS in the setting of posttransplant relapse.
Assuntos
Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Adolescente , Adulto , Idoso , Brentuximab Vedotin , Estudos de Coortes , Feminino , Doença de Hodgkin/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Salvação , Transplante de Células-Tronco , Taxa de Sobrevida , Adulto JovemRESUMO
This retrospective study aimed to describe the Hellenic experience on the use of brentuximab vedotin (BV) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) given within its indication. From June 2011 to April 2015, ninety-five patients with R/R HL, who received BV in 20 centers from Greece, were analyzed. Their median age was 33 years, and 62% were males. Sixty-seven patients received BV after autologous stem cell transplantation failure, whereas 28 patients were treated with BV without a prior autologous stem cell transplantation, due to advanced age/comorbidities or chemorefractory disease. The median number of prior treatments was 4 and 44% of the patients were refractory to their most recent therapy. The median number of BV cycles was 8 (range, 2-16), and the median time to best response was the fourth cycle. Fifty-seven patients achieved an objective response: twenty-two (23%), a complete response (CR), and 35 patients (37%), a partial, for an overall response rate of 60%. Twelve patients (13%) had stable disease, and the remaining twenty-six (27%) had progressive disease as their best response. At a median follow-up of 11.5 months, median progression-free survival and overall survival were 8 and 26.5 months, respectively. Multivariate analysis showed that chemosensitivity to treatment administered before BV was associated with a significantly increased probability of achieving response to BV (P = .005). Bulky disease (P = .01) and response to BV (P <.001) were significant for progression-free survival, while refractoriness to most recent treatment (P = .04), bulky disease (P = .005), and B-symptoms (P = .001) were unfavorable factors for overall survival. Among the 22 CRs, 5 remain in CR with no further treatment after BV at a median follow-up of 13 months. In conclusion, our data indicate that BV is an effective treatment for R/R HL patients even outside clinical trials. Whether BV can cure a fraction of patients remains to be seen.
Assuntos
Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Adulto , Brentuximab Vedotin , Feminino , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/farmacologia , Masculino , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Maximizing the response rate to first-line therapy in patients with multiple myeloma (MM) is important because it leads to improved outcome. Gene-expression studies have identified prognostic gene sets in patients receiving bortezomib-based therapy. Comparison of the lists of genes derived from two gene-expression-based models (GEP70, GEP80) showed that they overlap in three genes, namely PSMD4, BIRC5, and KIAA1754. An unanswered question is whether early gene-expression changes can be used as predictors of the response to first-line bortezomib. In this study we aimed to examine the predictive value of gene expression changes for the depth of response after bortezomib-based therapy in newly diagnosed MM. METHODS: We prospectively assessed the relation between early PSMD4, BIRC5, and KIAA1754 gene expression changes (before therapy and one week later) and the response rate after bortezomib-based therapy in 25 patients with newly diagnosed MM. Gene expression was studied by RT-PCR on CD138-selected plasma cells, and changes were recorded as upregulation, downregulation, or unchanged. RESULTS: Whereas baseline prognostic factors including genetic lesions and stage were not predictive of the response rate, we found that early BIRC5 and KIAA1754 gene-expression changes were significantly associated with the depth of response to bortezomib (p=0.001 and p<0.001, respectively). PSMD4 was not predictive of the depth of response. KIAA1754 upregulation was linked to complete remission (CR) or very good partial remission (VGPR). BIRC5 upregulation was linked to stable disease (SD) or progressive disease (PD). We also observed that BIRC5 upregulation was associated with worse progression-free survival (PFS). CONCLUSIONS: Our results suggest that BIRC5 and KIAA1754 gene-expression changes may predict the response to bortezomib-based therapy. These data may have relevance for the stratification and early adaptation of first-line treatment in patients with newly diagnosed MM.
Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Inibidoras de Apoptose/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Estudos Prospectivos , SurvivinaRESUMO
BACKGROUND: Primary bone lymphoma is a rare disease, representing less than 5% of all extra-nodal non-Hodgkin lymphomas. MATERIALS AND METHODS: We retrospectively searched the database of the lymphoma unit, Hematology/Lymphoma Department, Athens General Hospital 'Evangelismos' for primary bone lymphoma patients. Demographic and clinicopathologic data were collected and overall survival was analyzed. A log-rank test was used in a univariate analysis to identify factors affecting overall survival. RESULTS: We identified 24 and analyzed data from 22 patients. 12 were male (54.5%) and 10 female (45.4%) and their median age was 55 years (range: 19-83). Most patients had localized disease at the time of diagnosis (n = 19, 86.3%), the most common site was the spine (n = 11, 50%) and the most common histology was diffuse large B-cell lymphoma. 21 patients received chemotherapy as initial therapy and 16 received combined chemoradiation. 81.8% of the patients (n = 18) achieved complete remission. 5-year survival rate was 86.3% and overall survival was found to be affected by the patients' initial response to treatment. CONCLUSIONS: Primary bone lymphoma is usually associated with a good prognosis. Prospective studies are needed in order to clarify the effect of immunochemotherapy in overall survival.
Assuntos
Neoplasias Ósseas/mortalidade , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Grécia/epidemiologia , Humanos , Linfoma/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Estudos Retrospectivos , Rituximab , Vincristina/administração & dosagemRESUMO
The Hellenic experience regarding the efficacy of extracorporeal photopheresis (ECP) in the treatment of 58 patients with chronic graft-versus-host disease (cGVHD) is presented in this article. All 58, except one patient, had failed at least one line of immunosuppressive treatment including steroids. Thirty-three out of 58 patients showed an objective overall response to ECP in a median time of 10 weeks after the onset of treatment. The cumulative incidence of overall response was 65.1%. In multivariate analysis, the presence of severe chronic GVHD was the only parameter associated with a significantly lower probability of response to treatment (RR=0.4, CI 95% 0.2-0.9, p=0.03). Responders to treatment with ECP were more likely to discontinue immunosuppression, had a lower probability of non-relapse mortality (RR=0.2, CI 95% 0.1-0.5, p=0.002), and a higher probability of overall survival (RR=7.8, CI 95% 3-20, p<0.001) in comparison with non-responders. Eight out of 58 patients experienced relapse of the original disease. The cumulative incidence of relapse in the group of responders to ECP was 6%, while it was 25% in the group of non-responders to ECP. In multivariate analysis, response to treatment with ECP was the only parameter statistically associated with a significantly decreased hazard of relapse (RR=0.1, CI 95% 0.1-0.7, p=0.02). ECP should be tested as first-line treatment in patients with cGVHD with the aim to minimize the duration of immunosuppression and the rate of relapse of the malignant disease.
Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/terapia , Fotoferese/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Doença Crônica , Intervalo Livre de Doença , Feminino , Hematologia , Humanos , Terapia de Imunossupressão/métodos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/mortalidade , Neoplasias/terapia , Estudos Retrospectivos , Sociedades Médicas , Taxa de SobrevidaRESUMO
Extracorporeal photopheresis (ECP) has been established as an effective treatment modality for patients with chronic extensive graft-versus host disease (GVHD). In the present study, we evaluated the influence of ECP on the numbers of CD4+, CD8+, CD20+, CD56+ cells, and on T-regulatory (Tregs), as well as on the numbers of naïve, central memory (CM), and effector memory (EM) T-cells in patients treated for refractory chronic GVHD. Flow cytometric analysis of peripheral blood lymphocytes was performed for the calculation of the different T-cell subsets. Patients with GVHD had a higher percentage of EM-CD4+ cells in comparison with healthy donors (p=0.046). The percentages of naïve-CD8+, naïve-CD4+, CM-CD8+, CM-CD4+, EM-CD8+, and Tregs were not different between patients with GVHD and healthy donors. Similarly there was no statistical difference in the percentages of naïve, CM, and EM CD4+ and CD8+ cells before and after 3 months of treatment with ECP. However, in the subset of Tregs a statistically significant increase was observed after 3 months of treatment with ECP (p=0.015). Responders to ECP had statistically significantly higher absolute numbers of CD4+, and CD8+ cells, in comparison with non-responders. These data further support the concept that ECP does not cause immune-suppression, but should be better considered as an immune-modulating treatment.
Assuntos
Linfócitos T CD8-Positivos , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/terapia , Fotoferese/métodos , Linfócitos T Reguladores , Estudos de Coortes , Feminino , Hematologia , Humanos , Contagem de Linfócitos , Masculino , Sociedades Médicas , Fatores de TempoRESUMO
Among various laboratory and clinical features megakaryocytopoiesis and platelet (PLT) counts have been previously insufficiently evaluated for their prognostic significance in acute myelogenous leukaemia (AML). We studied several clinical and laboratory features of 108 first diagnosed AML patients in relation with their prognosis. Patients with favourable prognostic features were excluded from the study. This study focused on the prognostic impact of PLT counts and related molecular biology in AML patients at initial diagnosis. In particular, the PLT counts were correlated with the endogenous production of thrombopoietin (TPO), c-mpl expression, CD34+ leukemic blast cell proportion, cytogenetics, and a prognostic correlation was established. We found that the most favorable prognosis appeared in the AML patient group with PLTs <25x10(9)/l and correlated to cytogenetic findings (normal or abnormal karyotypes), while by far the most unfavorable prognosis was found in the patient group with PLTs > or =130x10(9)/l independent of the corresponding cytogenetics. It was demonstrated that AML patients with normal or elevated PLT counts at first presentation, may constitute a distinct patient group with particular characteristics such as higher levels of endogenous TPO production, high expression of CD34+ leukemic blast cells, higher expression of c-mpl and consequently low response to chemotherapy and a very poor prognosis. These correlations between PLTs production (megakaryothrombopoiesis), TPO serum levels and TPO receptor (c-mpl) expression may help in the determination of risk-adapted AML patient groups and of targeted therapeutic strategies.
Assuntos
Plaquetas/fisiologia , Leucemia Mieloide Aguda/sangue , Adolescente , Adulto , Idoso , Aberrações Cromossômicas , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Prognóstico , Trombopoetina/sangueRESUMO
OBJECTIVE: To describe a patient with Bcr-abl(+) acute lymphoblastic leukemia who developed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) while being treated with high-dose imatinib. CASE SUMMARY: A 29-year-old woman was diagnosed with Bcr-abl(+) acute lymphoblastic leukemia, and treatment was initiated with chemotherapy and imatinib 800 mg daily. Following imatinib initiation, a gradual decrease in serum sodium level was noticed. Prolonged aplasia and neutropenic fever prompted discontinuation of therapy for 4 weeks. Following the patient's recovery, complete remission was achieved and monotherapy with imatinib 800 mg daily was restarted; however, hyponatremia recurred a few days later. The clinical findings and laboratory workup were compatible with the diagnosis of SIADH, which was attributed to high-dose imatinib. Fluid restriction and imatinib dosage reduction (to 600 mg/day) restored sodium levels. According to the Naranjo probability scale, this adverse reaction was probably associated with imatinib. DISCUSSION: Imatinib emerged as the first tyrosine kinase inhibitor to enter everyday clinical practice for the treatment of Ph(+) leukemias. Due to its molecular specificity, imatinib lacks the broad cytotoxicity of conventional chemotherapy. Inhibition of kinases in normal tissues accounts for many of imatinib's adverse reactions. To our knowledge, this is the first reported case of imatinib-induced SIADH. CONCLUSIONS: We recommend monitoring for SIADH if a patient receiving high-dose imatinib develops hyponatremia.
Assuntos
Síndrome de Secreção Inadequada de HAD/induzido quimicamente , Piperazinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Adulto , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Benzamidas , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Hiponatremia/induzido quimicamente , Mesilato de Imatinib , Piperazinas/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagemRESUMO
BACKGROUND AND OBJECTIVES: Although most patients with classical Hodgkin's lymphoma (CHL) are cured, a significant minority are refractory to treatment. The investigation of biological markers could improve the predictive capacity of clinical staging systems. The aim of our study was to detect B-cell differentiation markers and transcription factors in CHL in order to define subgroups with different histogeneses and prognoses. DESIGN AND METHODS: We evaluated 107 cases of CHL for BCL6, CD79a, MUM1/IRF4 and B-cell transcription factors BOB.1, OCT.2 expression by immunohistochemistry. Statistical analysis was performed using Fisher's exact test, the Mann-Whitney test, the Kaplan-Meier method and the log rank test. Univariate and multivariate regression analyses were performed to identify variables with a significant effect on survival. RESULTS: CD79a was expressed in 5.8%, BCL6 in 14.7%, MUM1/IRF4 in 92.3%, BOB.1 in 53.4% and OCT.2 in 12.6% of cases. There was no significant association between CD79a or BCL6 expression and clinical characteristics. Univariate analysis showed that age of 45 or more, stage III and IV disease and MUM/IRF4 negative status were associated with significantly shorter time to progression (TTP) and overall survival (OS). On multivariate analysis the lack of MUM/IRF4 expression was associated with significantly shorter TTP while age of 45 or more and the presence of extralymphatic sites of disease were associated with significantly shorter OS. INTERPRETATION AND CONCLUSIONS: Our study has confirmed that MUM1/IRF4 is expressed in most cases of CHL and shows that lack of this expression in a minority of cases may be a potential adverse prognostic factor.
Assuntos
Diferenciação Celular , Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Fatores Reguladores de Interferon/metabolismo , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Fatores de Transcrição/metabolismo , Adolescente , Adulto , Idoso , Biomarcadores , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de SobrevidaRESUMO
BACKGROUND: Primary Sjögren's syndrome (pSs) is an autoimmune rheumatic disease that may express in a small number of patients a spectrum of lymphoproliferative diseases. The aim of this study was to describe clinical, imaging and pathology features of the extranodal marginal zone B-cell lymphoma (MZCL) of the lung of mucosa-associated lymphoid tissue (MALT) type in patients with pSs. METHODS: All patients (N=10) with biopsy proven MZCL of the lung of MALT type diagnosed in a tertiary teaching hospital during the last 7 years were studied. RESULTS: Seven patients had pSs. Almost all patients presented an indolent clinical course, contrasting strongly with the spectacular radiological findings in both chest roentgenograms and computed tomography. Pathology infiltration patterns observed were either nodular, peribronchial-perivascular, alveolar, or interstitial. Immunohistochemical study in all cases showed B cell phenotypes. Immunoglobulin light chain restriction was demonstrated in all patients. Monoclonal IgM(kappa) was evident in 5/7, IgM(lambda) in 1/7 and IgG (kappa) in 1/7 of patients. CONCLUSIONS: Lung MZCL associated with pSs are characterized by an important dissociation between clinical expression and radiological pattern. Clinical presentation and imaging features are not specific. Therefore, histologic documentation is mandatory to ensure diagnosis. Various chemotherapeutic agents in combination with rituximab lead to partial or complete remission in the majority of patients.
Assuntos
Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Células B/complicações , Linfócitos B/patologia , Biomarcadores/análise , Linfócitos T CD4-Positivos/patologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Queratinas/análise , Pulmão/diagnóstico por imagem , Pulmão/patologia , Linfoma de Células B/diagnóstico por imagem , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico por imagem , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico por imagem , Síndrome de Sjogren/patologia , Tomografia Computadorizada por Raios XAssuntos
Hipergamaglobulinemia/patologia , Doenças Linfáticas/patologia , Linfocitose/patologia , Plasmócitos/patologia , Adulto , Humanos , Hipergamaglobulinemia/complicações , Hipergamaglobulinemia/imunologia , Linfonodos/patologia , Doenças Linfáticas/complicações , Doenças Linfáticas/imunologia , Linfocitose/complicações , Linfocitose/imunologia , MasculinoAssuntos
Antibacterianos/uso terapêutico , Antifúngicos/uso terapêutico , Fungemia/tratamento farmacológico , Fusarium , Leucemia Mieloide Aguda/complicações , Micoses/tratamento farmacológico , Peptídeos Cíclicos , Peptídeos , Idoso , Caspofungina , Equinocandinas , Fungemia/etiologia , Fungemia/microbiologia , Fusarium/efeitos dos fármacos , Humanos , Lipopeptídeos , Masculino , Micoses/etiologiaRESUMO
PURPOSE: Activation of phosphatidylinositol 3'-kinase pathway is implicated in the pathogenesis of mantle cell lymphoma (MCL). The genetic change in phosphatidylinositol 3'-kinase catalytic subunit alpha (PIK3CA) in MCL has not been identified. EXPERIMENTAL DESIGN: Thirty-five primary MCL cases and 2 MCL cell lines (GRANTA-519 and Rec-1) were used to investigate somatic mutation and gene copy number of PIK3CA. Gene copy number was determined using quantitative real-time PCR and fluorescence in situ hybridization. We used quantitative real-time reverse transcription-PCR to measure PIK3CA transcription levels. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and phoshorylated AKT protein levels were analyzed using Western blotting and immunohistochemistry. Flow cytometry was used to assess apoptosis after treatment of MCL cell lines and one control cell line with LY294002, a specific inhibitor of PI3KCA. RESULTS: Fifteen of 22 (68%) MCL cases and the MCL cell lines harbored a gain (> or =3) of PIK3CA gene copy number. In addition, cases with increased PIK3CA gene copy number had elevated PIK3CA mRNA levels. Furthermore, amplification of PIK3CA correlated with the status of AKT phosphorylation in 7 of 12 (58%) primary MCL cases. Inhibition of PIK3CA induced increased apoptosis in the MCL cell lines. PTEN protein expression was present in all 14 primary MCL cases and cell lines by Western blotting, whereas 5 of 33 (15%) cases tested by immunohistochemistry had loss of PTEN expression. CONCLUSIONS: We conclude that a gain of gene copy number of PIK3CA is frequent genetic alteration that contributes to MCL progression. PIK3CA is a promising therapeutic target in MCL.