RESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Luspatercept has high clinical activity in patients with transfusion-dependent lower-risk myelodysplastic syndromes (LR-MDS) and ring sideroblasts (RS) relapsed or refractory to erythropoietin. We report long-term luspatercept safety and efficacy in 108 patients with LR-MDS in the PACE-MDS study, including 44 non-RS and 34 non-transfusion-dependent or previously untreated patients. The primary end point was safety. Secondary end points included rates of hematologic improvement (HI) erythroid (HI-E), HI neutrophil, and HI platelet. Exploratory end points included erythropoiesis biomarker quantitation and mutation data. Median duration of luspatercept exposure was 315 days (range, 21-1,934 days). No new safety signals emerged. HI-E was observed in 53.7% of patients, including 36.4% of non-RS and 70.6% of non-transfusion-dependent patients. HI neutrophil and HI platelet were observed in 33.3% and 9.5% of patients, respectively. An almost three-fold increase in bone marrow late to early progenitor cell ratio accompanied HI-E response, irrespective of RS status. Lower baseline erythropoietin levels in non-RS patients (69.6 v 623.3 IU/L; P = .0077) and higher late to early erythroid progenitor cell ratio (10.44 v 4.48; P = .0106) in RS patients were associated with HI-E. This study highlights luspatercept's effects across LR-MDS subtypes, including untreated MDS-RS, serving as a platform for future trials.
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Anemia , Eritropoetina , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Receptores de Activinas Tipo II/uso terapêutico , Anemia/induzido quimicamente , Anemia/tratamento farmacológicoRESUMO
Chemoradiation is one of the therapeutic options in palliative treatment of locally advanced pancreatic adenocarcinoma, with a well-known safety profile. In this case report, we describe the treatment-related occurrence of an intrasplenic pancreatic pseudocyst which was successfully removed by gastrocystic drainage. This rare complication should be considered in the follow-up and clinical management of patients, particularly if left-sided complaints occur.
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BACKGROUND: Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF ß) superfamily inhibitors of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes. METHODS: In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13â000/µL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement-erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125-0·5 mg/kg vs 0·75-1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200-500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383. FINDINGS: Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125-1·75 mg/kg) and 31 patients in the expansion cohort (1·0-1·75 mg/kg). 32 (63% [95% CI 48-76]) of 51 patients receiving higher dose luspatercept concentrations (0·75-1·75 mg/kg) achieved HI-E versus two (22% [95% CI 3-60]) of nine receiving lower dose concentrations (0·125-0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one [2%]), increased blast cell count (one [2%]), and general physical health deterioration (one [2%]). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration. INTERPRETATION: Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing. FUNDING: Acceleron Pharma.
Assuntos
Ativinas/administração & dosagem , Anemia/tratamento farmacológico , Anemia/etiologia , Fragmentos Fc das Imunoglobulinas/administração & dosagem , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Proteínas Recombinantes de Fusão/administração & dosagem , Receptores de Activinas Tipo II , Ativinas/efeitos adversos , Adulto , Idoso , Anemia/mortalidade , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Alemanha , Humanos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Proteínas Recombinantes de Fusão/efeitos adversos , Medição de Risco , Índice de Gravidade de Doença , Análise de Sobrevida , Fatores de Tempo , Resultado do TratamentoRESUMO
The mammalian-target of rapamycin (also termed mechanistic target of rapamycin, mTOR) pathway integrates various pro-proliferative and anti-apoptotic stimuli and is involved in regulatory T-cell (TREG) development. As these processes contribute to the pathogenesis of myelodysplastic syndromes (MDS), we hypothesized that mTOR modulation with temsirolimus (TEM) might show activity in MDS. This prospective multicentre trial enrolled lower and higher risk MDS patients, provided that they were transfusion-dependent/neutropenic or relapsed/refractory to 5-azacitidine, respectively. All patients received TEM at a weekly dose of 25 mg. Of the 9 lower- and 11 higher-risk patients included, only 4 (20%) reached the response assessment after 4 months of treatment and showed stable disease without haematological improvement. The remaining patients discontinued TEM prematurely due to adverse events. Median overall survival (OS) was not reached in the lower-risk group and 296 days in the higher-risk group. We observed a significant decline of bone marrow (BM) vascularisation (P = 0·006) but were unable to demonstrate a significant impact of TEM on the balance between TREG and pro-inflammatory T-helper-cell subsets within the peripheral blood or BM. We conclude that mTOR-modulation with TEM at a dose of 25 mg per week is accompanied by considerable toxicity and has no beneficial effects in elderly MDS patients.
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Síndromes Mielodisplásicas/tratamento farmacológico , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Células Sanguíneas/patologia , Medula Óssea/irrigação sanguínea , Células da Medula Óssea/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Sirolimo/toxicidade , Taxa de Sobrevida , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Resultado do TratamentoRESUMO
PURPOSE: In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL). PATIENTS AND METHODS: Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week. RESULTS: Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF. CONCLUSION: Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Sirolimo/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Nervoso Central/mortalidade , Feminino , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Sirolimo/farmacocinética , Sirolimo/uso terapêuticoRESUMO
Chronic lymphocytic leukemia (CLL) is the most common subtype of adult leukemia in the western world. We here report a nationwide survey monitoring the treatment decisions concerning CLL patients in Germany in 2011 and compare treatment trends to sequential surveys performed previously during the last decade. The rate of patients diagnosed in early stages (Binet A/B) notably increased (2006: 66 %, 2009: 71 %, 2011: 77 %) over the years. From 2006 to 2009, the most frequent applied regime switched from chlorambucil to fludarabine containing regimes (2006 chlorambucil: 32 %, 2009: 14 %, fludarabine 2006: 23 %, 2009: 37 %). In 2011, the combination of rituximab with bendamustine (31 %) was most frequent used followed by the rituximab-fludarabine-cyclophosphamide (22 %) regime. Further, immune-chemotherapies were administered significantly more often over the observation period (2006: 15 %, 2011: 73 %). Taken together, this data reflects the change of treatment strategies over the last decade in clinical reality.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Pesquisas sobre Atenção à Saúde/tendências , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cloridrato de Bendamustina/administração & dosagem , Clorambucila/administração & dosagem , Feminino , Alemanha/epidemiologia , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Rituximab/administração & dosagem , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.
Assuntos
Sistema Nervoso Central/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Pirimidinas/administração & dosagem , Adolescente , Adulto , Benzamidas/administração & dosagem , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Piperazinas/administração & dosagem , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo/efeitos adversosRESUMO
BACKGROUND: Positron emission tomography (PET) with F-18-labeled fluorodeoxyglucose (FDG) provides remarkable accuracy in detection, treatment monitoring and follow-up of systemic malignant lymphoma. Its value in the management of patients with primary central nervous system lymphoma (PCNSL) is less clear. PATIENTS AND METHODS: In a prospective trial, 42 FDG-PET examinations were performed in ten immunocompetent patients with newly diagnosed or recurrent PCNSL before and repeatedly during and after the treatment. Brain and whole body FDG-PET were compared to brain MRI and extra-cerebral CT, respectively. RESULTS: Before the treatment, 6 of 10 patients had congruent findings on FDG-PET and MRI of the brain. Three patients had lesions on brain MRI, not detected by FDG-PET. One patient had additional FDG-PET positive lesions inconspicuous in MRI. The follow-up suggested FDG-PET to be false positive in these lesions. After the treatment, brain PET was in agreement with MRI in 6 of 8 patients. In the remaining 2 patients there were persistent lesions in brain MRI whereas FDG-uptake was reduced to normal values. In the long-term follow-up of 5 patients (63-169 weeks), 3 patients retained normal in both PET and MRI. In 2 patients a new focal pathologic FDG-uptake was detected 69 and 52 weeks after the end of the treatment. In one of these patients, recurrence was confirmed by MRI not until 9 weeks after PET. CONCLUSIONS: Brain FDG-PET may contribute valuable information for the management of PCNSL, particularly in the assessment of the treatment response. Integration of FDG-PET into prospective interventional trials is warranted to investigate prognostic and therapeutic implications.
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OBJECTIVE: To assess the outcome of elderly patients with primary CNS lymphoma (PCNSL) treated within the G-PCNSL-SG-1 trial. METHODS: We reviewed response, toxicity, and survival of patients with PCNSL aged 70 or more enrolled in the G-PCNSL-SG-1 trial. RESULTS: A total of 126 of the 526 eligible patients (24%) and 66 of 318 patients (21%) in the per protocol population were aged 70 or more. Among all eligible patients, the rate of complete and partial responses (CR+PR) to HD-MTX-based chemotherapy was 44% in the elderly vs 57% in the younger patients (p = 0.016). Toxicity was age-independent except for a higher rate of grade III/IV leukopenia in the elderly (34% vs 21%, p = 0.007). Death on therapy was more frequent (18% vs 11%; p = 0.027), and progression-free survival (PFS) (4.0 vs 7.7 months, p = 0.014) and overall survival (12.5 vs 26.2 months, p < 0.001) inferior, in the elderly. A striking difference between younger and elderly patients was the PFS of CR patients of 35.0 in the younger vs 16.1 in the elderly patients (p = 0.024). Elderly patients were treated less often and less aggressively at salvage. However, age was not associated with survival from salvage whole brain radiotherapy in patients progressing during primary HD-MTX-based chemotherapy (p = 0.633). CONCLUSIONS: Lower response rate and higher mortality on HD-MTX-based chemotherapy as well as lower PFS of CR patients and less salvage therapy contribute to the poor prognosis of elderly patients with PCNSL.
Assuntos
Antimetabólitos/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Linfoma/terapia , Metotrexato/uso terapêutico , Fatores Etários , Idoso , Antimetabólitos/administração & dosagem , Antimetabólitos/efeitos adversos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/radioterapia , Terapia Combinada , Intervalos de Confiança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucopenia/induzido quimicamente , Leucopenia/epidemiologia , Linfoma/tratamento farmacológico , Linfoma/radioterapia , Masculino , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Terapia de Salvação , Análise de Sobrevida , Conduta ExpectanteRESUMO
The prognosis of patients with CNS involvement of solid tumors is poor. In these patients, systemic chemotherapy has a theoretical advantage of concurrent treatment of systemic disease and reduced risk of neurotoxicity. Here, we report on the efficacy and toxicity of topotecan/ifosfamide (TOPO/IFO) combination chemotherapy in patients treated for CNS involvement of different solid malignancies. Fourteen patients with CNS manifestations (seven with brain metastases, two meningeal carcinomatosis, and five both) of solid tumors (seven with breast cancer, six lung cancer, and one unknown primary cancer) received TOPO/IFO treatment. Eleven patients each were pretreated with 1-6 systemic therapy regimens and whole-brain irradiation. Patients received a total of 34 (median 2) TOPO/IFO cycles. TOPO dosage was 3.6 mg/m(2) (1.2 mg/m(2), days 1-3) and IFO dosage 3,000 mg/m(2) (1,500 mg/m(2), days 1-2) per cycle. Of 12 patients with brain metastases, one patient had partial remission, three stable disease, two progressed, and six had no radiologic CNS response evaluation. Response of meningeal carcinomatosis was found in two and progressive disease in two (three patients not evaluated). Neurologic improvement or stabilization was observed in six of twelve evaluable patients. No systemic tumor response was seen in seven evaluated patients. Grade 3/4 toxicities in eleven evaluable patients were leukopenia (n = 9), infection (n = 6), and thrombopenia (n = 5). Median time to treatment failure was 43 days and median overall survival 107 days. Symptom control was frequently achieved with TOPO/IFO systemic chemotherapy despite a low objective response rate. The feasibility of this treatment is impaired by severe hematotoxicity.
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Antineoplásicos Alquilantes/uso terapêutico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ifosfamida/uso terapêutico , Carcinomatose Meníngea/tratamento farmacológico , Inibidores da Topoisomerase I/uso terapêutico , Topotecan/uso terapêutico , Idoso , Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/secundário , Feminino , Humanos , Avaliação de Estado de Karnofsky , Masculino , Carcinomatose Meníngea/secundário , Pessoa de Meia-IdadeAssuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Sirolimo/análogos & derivados , Adulto , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Prednisolona/uso terapêutico , Indução de Remissão , Sirolimo/uso terapêutico , Neoplasias da Língua/tratamento farmacológico , Falha de Tratamento , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
PURPOSE: The aim of this study was to examine the penetration of ifosfamide (IFO) and 4-hydroxy-ifosfamide (4-OH-IFO) into the CSF of human adults and to evaluate the influence of blood-CSF barrier (BCB) function. METHODS: In 12 adult patients with a malignant CNS disease treated with IFO 1,300-2,000 mg/m(2)/d as a 3-hour intravenous infusion, 17 CSF samples were collected within 10 min after the end of IFO infusion. In 8 of these patients, the CSF was obtained in up to 5 sequential 2-ml portions to detect a potential caudocranial concentration gradient. Additionally, blood was collected before treatment and immediately following IFO infusion. RESULTS: IFO was detected in all 17 CSF samples at a median concentration of 79.24 µmol/l (39.27-176.73) and a median CSF/plasma ratio of 0.38 (0.18-0.72). 4-OH-IFO was detected in 11 CSF samples from 7 patients at a median concentration of 4.1 µmol/l (2.44-36.03) and a median CSF/plasma ratio of 3.07 (0.62-29.12). 4-OH-IFO was undetectable in 6 CSF samples from 5 patients and in one plasma sample. Both CSF drug concentrations and their CSF/plasma quotients neither correlated with steroid comedication nor with albumin quotients (QAlb). CONCLUSIONS: Both IFO and 4-OH-IFO can penetrate into the CSF of human adults without a correlation to CSF turnover. In contrast to IFO, 4-OH-IFO CSF penetration is not reliable with levels ranging between undetectable and exceeding those in the corresponding plasma.
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Antineoplásicos Alquilantes/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ifosfamida/análogos & derivados , Ifosfamida/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/farmacocinética , Barreira Hematoencefálica/metabolismo , Feminino , Humanos , Ifosfamida/farmacocinética , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , PermeabilidadeRESUMO
The frequency of meningeal dissemination (MD) in primary CNS lymphoma (PCNSL), its prognostic impact, and optimal management have not been defined thus far. In 69 of 92 (75%) immunocompetent patients, primarily diagnosed with PCNSL at our institution between January 1994 and February 2007, cerebrospinal fluid was analyzed for MD. MD was found by cytomorphology in 7/63 (11%), by immunophenotyping in 1/32 (3%), and by PCR of the IgH CDR III region in 6/37 (16%). Neuroradiologic examination revealed MD in 3 of 69 patients (4%). Median event-free survival (EFS) of patients with MD diagnosed by any of the methods was 26 months, of those without MD 34.1 months (P = .24); median overall survival (OAS) of these two patients' groups was 45.5 and 42.5 months, respectively (P = .34). Patients with cytomorphologic proof of MD had a median EFS of 15.4 months and OAS of 18.5 months, those without MD 34.3 and 45 months (P = .018 and .017, respectively). We found a low frequency of MD despite the use of putatively sensitive diagnostic methods. No impact on outcome was seen for MD, diagnosed by any of the methods used; however, patients with cytomorphologic proof of MD had a significantly shorter median EFS and OAS.
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Neoplasias do Sistema Nervoso Central/mortalidade , Neoplasias do Sistema Nervoso Central/patologia , Linfoma não Hodgkin/mortalidade , Linfoma não Hodgkin/patologia , Neoplasias Meníngeas/mortalidade , Neoplasias Meníngeas/secundário , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/terapia , Terapia Combinada , Feminino , Humanos , Linfoma não Hodgkin/terapia , Masculino , Neoplasias Meníngeas/terapia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Indução de Remissão , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemAssuntos
Vértebras Cervicais , Doenças do Esôfago/diagnóstico , Doenças do Esôfago/microbiologia , Granuloma/diagnóstico , Tuberculose da Coluna Vertebral/diagnóstico , Tuberculose/diagnóstico , Idoso , Antituberculosos/uso terapêutico , Transtornos de Deglutição/etiologia , Doenças do Esôfago/complicações , Esôfago/microbiologia , Esôfago/patologia , Feminino , República da Geórgia , Granuloma/complicações , Humanos , Mycobacterium tuberculosis/isolamento & purificação , Necrose , Sons Respiratórios/etiologia , Tuberculose/complicações , Tuberculose/tratamento farmacológico , Tuberculose da Coluna Vertebral/complicaçõesRESUMO
An isolated CNS relapse is rarely seen in acute myeloid leukemia. However, it has a potentially fatal clinical outcome. We herein present the case of a 39-year-old man, who presented to our emergency room with horizontal diplopic images, vertigo, bilateral deafness, and progressing somnolence. Cerebral imaging revealed cerebral and cerebellar edema and a diffuse leukoencephalopathy. With the one-year-old history of an initially successfully treated FAB-M0 acute myeloid leukemia (AML) in mind, a lumbar puncture was carried out that showed a vast number of myeloid blasts in the morphologic analysis of the cerebrospinal fluid. In conjunction with normal findings in the peripheral blood-count with differential and the bone marrow examination a diagnosis of an isolated CNS relapse of the AML was made. Cytarabine chemotherapy was initiated and the symptoms resolved rapidly. To our surprise, cerebral imaging in the course of the treatment not only showed a resolution of the brain edema but also of the leukoencephalopathy, pointing to a direct infiltration of brain parenchyma by leukemic blasts. The case highlights the relevance of the CNS as a pharmacologic "sanctuary" for tumor cells in patients that on prior treatments have not received intrathecal chemotherapy or chemotherapeutics that cross the blood-brain barrier.
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Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/diagnóstico , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/etiologia , Imageamento por Ressonância Magnética , Adulto , Humanos , Masculino , RecidivaRESUMO
PURPOSE: Homing of malignant lymphocytes to the central nervous system (CNS) may play a role in the pathogenesis of CNS lymphoma. In this study, we evaluated the chemokines CXCL12 and CXCL13 in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma. EXPERIMENTAL DESIGN: Samples from 30 patients with CNS lymphoma (23 with primary and 7 with secondary CNS lymphoma; all B-cell lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood-brain barrier disruption was estimated by the CSF/serum albumin ratio. RESULTS: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were significantly higher in CNS lymphoma patients as compared with controls (P < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma, CXCL13 concentration in CSF correlated with the degree of blood-brain barrier disruption (R = 0.66; P = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients during therapy decreased in five patients who responded to chemotherapy and increased in two with lymphoma progression. CONCLUSIONS: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients, which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies.
Assuntos
Neoplasias do Sistema Nervoso Central/sangue , Neoplasias do Sistema Nervoso Central/líquido cefalorraquidiano , Quimiocina CXCL12 , Quimiocina CXCL13 , Linfoma/sangue , Linfoma/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/líquido cefalorraquidiano , Estudos de Casos e Controles , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Quimiocina CXCL12/sangue , Quimiocina CXCL12/líquido cefalorraquidiano , Quimiocina CXCL13/sangue , Quimiocina CXCL13/líquido cefalorraquidiano , Progressão da Doença , Feminino , Humanos , Ifosfamida/administração & dosagem , Linfoma/diagnóstico , Linfoma/tratamento farmacológico , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , PrognósticoRESUMO
Catumaxomab is a trifunctional monoclonal antibody consisting of a mouse immunoglobulin G2a part and a rat immunoglobulin G2b part with 2 different antigen binding sites binding the epithelial cell adhesion molecule antigen on tumor cells and CD3 on T lymphocytes. The intact Fc region provides a third functional binding site, binding and activating selectively Fcgamma receptor I, IIa, and III-positive accessory cells. These binding properties lead to specific tumor cell killing. As catumaxomab demonstrated efficacy in patients with malignant ascites, we performed this phase 1/2 trial in patients with malignant pleural effusion (MPE). We investigated a series of 3 escalating doses of 5 to 200 microg catumaxomab administered intrapleurally to patients with MPE containing epithelial cell adhesion molecule -positive cells. Primary objectives were determination of dose-limiting toxicity, safety, and tolerability. Secondary objectives were efficacy and pharmacodynamics. Twenty-four patients were treated with catumaxomab. Most frequent adverse events were pyrexia, elevated liver enzymes, nausea, and decreased lymphocytes. Dose-limiting toxicities were observed in 2 patients: One had pleural empyema and fatal sepsis and 1 had grade 3 erythema and hepatobiliary disorder. Five patients with breast cancer out of 7 evaluable patients had a response to treatment. Intrapleural administration of catumaxomab is feasible although the substantial number of drop-outs and deaths in short proximity to study treatment raise questions whether MPE is the right indication for catumaxomab or whether the patient population should be defined different. Safety profile was as expected reflecting catumaxomab's mode of action. Preliminary efficacy showed a suggestion of improvement in some patients.
Assuntos
Anticorpos Biespecíficos/uso terapêutico , Derrame Pleural Maligno/terapia , Adulto , Idoso , Animais , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Neoplasias/complicações , Derrame Pleural Maligno/etiologia , Ratos , Resultado do TratamentoRESUMO
Immunotherapy is a growing field of interest in the treatment of malignant diseases, such as colorectal cancer (CRC). The induction or enhancement of T-cell responses against tumor-associated antigens is particularly important in tumor vaccination strategies. Successful immunization relies on an intact immune system. Both chemotherapy and the tumor itself are known to potentially inhibit immune responses. In this study we analyzed T cells directed against antigens of cytomegalovirus (CMV) and influenza virus in 39 HLA-A2-positive CRC patients and 29 HLA-A2-positive healthy donors using the tetramer technology. We found no difference between CRC patients and the healthy control group for either the proportion of samples with detection of virus specific T cells or the magnitude of these specific T cells. Although we cannot draw a firm conclusion on T-cell induction in cancer patients during vaccination therapy, our results show that CRC patients retain their antiviral T cells, suggesting a potential susceptibility to immunotherapy. The quantity of adaptive immunity acquired earlier in life seems not to be affected by the presence of CRC.
Assuntos
Anticorpos Antivirais/sangue , Neoplasias Colorretais/imunologia , Linfócitos T/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Contagem de Células , Neoplasias Colorretais/sangue , Citomegalovirus/imunologia , Feminino , Humanos , Imunidade Celular/imunologia , Masculino , Pessoa de Meia-Idade , Orthomyxoviridae/imunologia , Linfócitos T/citologia , Adulto JovemRESUMO
Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m(2) of MTX (4 h infusion on day 1) and 1.5-2 g/m(2)/day of IFO (3 h infusion on days 3-5). The study included 20 patients with a median age of 65 years (range, 30-83) and CNS relapse of a malignant lymphoma. Seventeen patients had been pretreated with up to two chemotherapy regimens. The objective response rate was 90% with 12 complete or unconfirmed complete (CR and CRu) and six partial remissions. All patients had at least stabilization of their neurological symptoms. Myelosuppression was the most common toxicity. The median follow-up time was 14.9 months. The median time to neurological progression was 8.9 months. Twelve patients received subsequent therapy, including high-dose chemotherapy with autologous stem cell transplantation in five cases. The median overall survival was not reached. Systemic chemotherapy with HDMTX/IFO is a feasible and promising treatment modality for CNS relapse of a malignant lymphoma.