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The optimal treatment strategy for newly diagnosed primary central nervous system lymphoma (PCNSL) has yet to be established, especially in the elderly. In the current study, we conducted a phase II study to evaluate the efficacy and safety of rituximab plus high-dose MTX followed by rituximab plus cytarabine in patients aged ≥60 years newly diagnosed with PCNSL. Patients received an induction treatment of high-dose methotrexate plus rituximab followed by two cycles of a consolidation treatment of cytarabine plus rituximab. The primary end-point was a 2-year progression-free survival (PFS) rate. A total of 35 patients were recruited, and their median age was 73 (range: 60-81). After induction treatment, the complete and partial responses (PRs) were 56% and 20% respectively. Twenty-six patients proceeded to the consolidation treatment; the complete and PRs were 59% and 9% respectively. After a median follow-up duration of 36.0 months, the 2-year PFS rate was 58.7%. Treatment was generally well-tolerated as only three patients were withdrawn from the study due to toxicity, and no treatment-related mortality was reported. The 2-year overall survival rate was 77.9%. The current study may suggest the feasibility of administering high-dose MTX plus cytarabine in PCNSL patients aged ≥60 years and the potential role of additive rituximab.
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PURPOSE: We conducted a nationwide, multicenter, prospective registry study for newly diagnosed patients with peripheral T-cell lymphoma (PTCL) to better define the clinical characteristics, treatment patterns, survival outcomes, and the role of upfront autologous stem cell transplantation (ASCT) in these patients. Materials and Methods: Patients with PTCL receiving chemotherapy with curative intent were registered and prospectively monitored. All patients were pathologically diagnosed with PTCL. RESULTS: A total of 191 patients with PTCL were enrolled in this prospective registry study. PTCL, not otherwise specified (PTCL-NOS) was the most common pathologic subtype (n=80, 41.9%), followed by angioimmunoblastic T-cell lymphoma (AITL) (n=60, 31.4%). With a median follow-up duration of 3.9 years, the 3-year progression-free survival (PFS) and overall survival (OS) rates were 39.5% and 60.4%, respectively. The role of upfront ASCT was evaluated in patients who were considered transplant-eligible (n=59). ASCT was performed as an upfront consolidative treatment in 32 (54.2%) of these patients. There were no significant differences in PFS and OS between the ASCT and non-ASCT groups for all patients (n=59) and for patients with PTCL-NOS (n=26). However, in patients with AITL, the ASCT group was associated with significantly better PFS than the non-ASCT group, although there was no significant difference in OS. CONCLUSION: The current study demonstrated that the survival outcomes with the current treatment options remain poor for patients with PTCL-NOS. Upfront ASCT may provide a survival benefit for patients with AITL, but not PTCL-NOS.
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Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/patologia , Transplante Autólogo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , República da Coreia/epidemiologiaRESUMO
PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is the most common hematologic malignancy worldwide. Although substantial improvement has been achieved by the frontline rituximab-based chemoimmunotherapy, up to 40%-50% of patients will eventually have relapsed or refractory disease, whose prognosis is extremely dismal. MATERIALS AND METHODS: We have carried out two prospective cohort studies that include over 1,500 DLBCL patients treated with rituximab plus CHOP (#NCT01202448 and #NCT02474550). In the current report, we describe the outcomes of refractory DLBCL patients. Patients were defined to have refractory DLBCL if they met one of the followings, not achieving at least partial response after 4 or more cycles of R-CHOP; not achieving at least partial response after 2 or more cycles of salvage therapy; progressive disease within 12 months after autologous stem cell transplantation. RESULTS: Among 1,581 patients, a total of 260 patients met the criteria for the refractory disease after a median time to progression of 9.1 months. The objective response rate of salvage treatment was 26.4%, and the complete response rate was 9.6%. The median overall survival (OS) was 7.5 months (95% confidence interval, 6.4 to 8.6), and the 2-year survival rate was 22.1%±2.8%. The median OS for each refractory category was not significantly different (p=0.529). CONCLUSION: In line with the previous studies, the outcomes of refractory DLBCL patients were extremely poor, which necessitates novel approaches for this population.
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Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Humanos , Rituximab/uso terapêutico , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Transplante Autólogo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , República da CoreiaRESUMO
FLT3 mutations are the most common genomic alteration detected in acute myeloid leukemia (AML) with a worse clinical prognosis. The highly frequent FLT3 mutations, together with the side effects associated with clinical prognosis, make FLT3 promising treatment targets and have provoked the advancement of FLT3 inhibitors. Recently, numerous FLT3 inhibitors were actively developed, and thus the outcomes of this aggressive subtype of AML were significantly improved. Recently, midostaurin and gilteritinib were approved as frontline treatment of AML and as therapeutic agents in the recurred disease by the United States Food and Drug Administration. Recently, numerous promising clinical trials attempted to seek appropriate management in frontline settings, in relapsed/refractory disease, or after stem cell transplantation in AML. This review follows numerous clinical trials about the usefulness of FLT3 inhibitors as frontline therapy, as relapsed/refractory conditioning, and as maintenance therapy of stem cell transplantation. The cumulative data of FLT3 inhibitors would be important clinical evidence for further management with FLT3 inhibitors in AML patients with FLT3 mutations.
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Antineoplásicos , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Compostos de Anilina/farmacologia , Mutação , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
PURPOSE: Febrile neutropenia (FN) can cause suboptimal treatment and treatment-related mortality (TRM) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP). MATERIALS AND METHODS: We conducted a prospective cohort study to evaluate the effectiveness of pegfilgrastim prophylaxis in DLBCL patients receiving R-CHOP, and we compared them with the PROCESS cohort (n=485). RESULTS: Since January 2015, 986 patients with DLBCL were enrolled. Pegfilgrastim was administered at least once in 930 patients (94.3%), covering 90.3% of all cycles. FN developed in 137 patients (13.9%) in this cohort (23.7% in the PROCESS cohort, p<0.001), and 4.2% of all cycles (10.2% in the PROCESS cohort, p<0.001). Dose delay was less common (≥3 days: 18.1% vs. 23.7%, p=0.015; ≥5 days: 12.0% vs. 18.3%, p=0.023) in this cohort than in the PROCESS cohort. The incidence of TRM (3.2% vs. 5.6%, p=0.047) and infection-related death (1.8% vs. 4.5%, p=0.004) was lower in this cohort than in the PROCESS cohort. The 4-year overall survival (OS) and progression-free survival (PFS) rates of the two cohorts were not different (OS: 73.0% vs. 71.9%, p=0.545; PFS: 69.5% vs. 68.8%, p=0.616). However, in patients aged ≥75 years, the 4-year OS and PFS rates were higher in this cohort than in the PROCESS cohort (OS: 49.6% vs. 33.7%, p=0.032; PFS: 44.2% vs. 30.3% p=0.047). CONCLUSION: Pegfilgrastim prophylaxis is effective in the prevention of FN and infection-related death in DLBCL patients receiving R-CHOP, and it also improves OS in patients aged ≥75 years.
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Neutropenia Febril , Linfoma Difuso de Grandes Células B , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/prevenção & controle , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/patologia , Polietilenoglicóis , Prednisolona/uso terapêutico , Prednisona/efeitos adversos , Estudos Prospectivos , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.
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Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Sulfonamidas/uso terapêutico , Estados Unidos , United States Food and Drug AdministrationRESUMO
Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.
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Linfócitos B/imunologia , Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Imunoterapia Adotiva/métodos , Antígenos CD19/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Epitopos de Linfócito B , Humanos , Leucemia Linfocítica Crônica de Células B , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologiaRESUMO
This trial was designed to investigate the efficacy and toxicity of bendamustine, carboplatin, and dexamethasone (BCD) for relapsed or refractory peripheral T-cell lymphomas (PTCLs), which would be expected to exhibit more promising clinical outcomes compared with bendamustine therapy alone. After treatments with BCD, eight patients exhibited a complete response (CR; 29%) and seven exhibited a partial response (PR; 25%). The overall response rate (ORR) was 54%. Five patients proceeded to ASCT and three patients finally achieved CR. The median progression-free survival (PFS) was 4.4 months (2.8-6.0, 95% CI). For a total of 85 cycles of BCD, grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in 17.6, 38.8, and 16.5% of cycles, respectively. Only one patient experienced febrile neutropenia. BCD was a considerable salvage regimen for relapsed or refractory PTCLs with acceptable toxicity; AITL or ASCT eligible patients were more effective to BCD.ClinicalTrials.gov Identifier:NCT02424045.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Linfoma de Células T Periférico/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação/métodos , Adulto , Idoso , Anemia/induzido quimicamente , Anemia/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Intervalo Livre de Progressão , Terapia de Salvação/efeitos adversos , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Adulto JovemRESUMO
In tumor microenvironment, the programmed death 1 (PD-1) immune checkpoint has a crucial role of mechanism of T cell exhaustion leading to tumor evasion. Ligands of PD-1, programmed death ligand 1/2 (PD-L1/L2) are over-expressed in tumor cells and participate in prolonged tumor progression and survivals. Recently, clinical trials for patients who failed to obtain an optimal response prior to standardized chemotherapy in several solid cancers have been focused on targeting therapy against PD-1 to reduce disease progression rates and prolonged survivals. Since various inhibitors targeting the immune checkpoint in PD-1/PD-L1 pathway in solid cancers have been introduced, promising approach using anti-PD-1 antibodies were attempted in several types of hematologic malignances. In diffuse large B cell lymphoma (DLBCL) as the most common and aggressive B cell type of non-Hodgkin's lymphoma, anti-PD-1 and anti-PD-L1 antibodies were studies in various clinical trials. In this review, we summarized the results of several studies associated with PD-1/PD-L1 pathway as an immune evasion mechanism and described clinical trials about targeting therapy against PD-1/PD-L1 pathway in DLBCL.
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Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/imunologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/análise , Antígeno B7-H1/antagonistas & inibidores , Humanos , Imunoterapia/métodos , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Terapia de Alvo Molecular/métodos , Receptor de Morte Celular Programada 1/análise , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
Both-side synchronous involvement has been reported to account for 7-24% of ocular adnexal marginal zone lymphoma (OAML). We conducted a retrospective analysis to identify the clinical features and treatment outcomes of synchronous bilateral OAML (SB-OAML) by treatment modality. We analyzed patients with a histologic diagnosis of SB-OAML, excluding metachronous bilateral involved OAML. We enrolled a total of 95 patients for this analysis, 36 males and 59 females; the median patient age was 42 years (range 16-77 years). Eleven (11.6%) patients had been treated with chemotherapy or chemo-immunotherapy (eight R-CVP, two CVP, and one R-CHOP). The median number of treatments was 6 (range 6-8); there were 9 complete responses (CRs; 81.8%) and 2 partial responses (PRs; 18.2%). Nearly all patients (88.4%) received radiotherapy in both eyes, and the median radiation dose was 27 Gy (range 20-40 Gy) to each eye; 68 CRs (80.9%) and 14 PRs (16.7%) were achieved. Ten-year progression-free survival (PFS) and overall survival (OS) rates were 79.8 and 91.1%, respectively. Radiotherapy continued to be an independent prognostic marker, with the hazard of progression (P = 0.036). Eleven patients (13.1%) had surgery for cataract treatment during follow-up, and patients who received low-dose radiation (< 30.3 Gy) experienced fewer cataract operations. SB-OAML was predominantly observed in young females, and they had good response and prognosis regardless of treatment modalities. Low-dose radiotherapy to both eyes showed a tendency of longer PFS than did chemotherapy and could decrease cataract operations.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Oculares/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Neoplasias Primárias Múltiplas/tratamento farmacológico , Adolescente , Adulto , Idoso , Catarata/etiologia , Terapia Combinada , Gerenciamento Clínico , Intervalo Livre de Doença , Neoplasias Oculares/diagnóstico por imagem , Neoplasias Oculares/radioterapia , Feminino , Humanos , Imunoterapia , Estimativa de Kaplan-Meier , Linfoma de Zona Marginal Tipo Células B/diagnóstico por imagem , Linfoma de Zona Marginal Tipo Células B/mortalidade , Linfoma de Zona Marginal Tipo Células B/radioterapia , Masculino , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Neoplasias Primárias Múltiplas/mortalidade , Neoplasias Primárias Múltiplas/radioterapia , Curva ROC , Radioterapia/efeitos adversos , República da Coreia/epidemiologia , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Myelofibrosis (MF) is a clinical manifestation of chronic BCR-ABL1-negative chronic myeloproliferative neoplasms. Splenomegaly is one of the major clinical manifestations of MF and is directly linked to splenic extramedullary hematopoiesis (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells due to the dysregulated bone marrow (BM) microenvironment leading to progressive splenomegaly. Several recent data have emphasized the role of several cytokines for splenic EMH. Alteration of CXCL12/CXCR4 pathway could also lead to splenic EMH by migrated clonal hematopoietic cells from BM to the spleen. Moreover, low Gata1 expression was found to be significantly associated with the EMH. Several gene mutations were found to be associated with significant splenomegaly in MF. In recent data, JAK2V617F homozygous mutation was associated with a larger spleen size. In other data, CALR mutations in MF were signigicantly associated with longer larger splenomegaly-free survivals than others. In addition, MF patients with ≥1 mutations in AZXL1, EZH1 or IDH1/2 had significantly low spleen reduction response in ruxolitinib treatment. Developments of JAK inhibitors, such as ruxolitinib, pacritinib, momelotinib, and febratinib enabled the effective management in MF patients. Especially, significant spleen reduction responses of the drugs were demonstrated in several randomized clinical studies, although those could not eradicate allele burdens of MF.
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Hematopoese Extramedular/fisiologia , Janus Quinases/genética , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Esplenomegalia/genética , Medula Óssea/patologia , Movimento Celular , Quimiocina CXCL12/metabolismo , Hematopoese Extramedular/efeitos dos fármacos , Humanos , Inibidores de Janus Quinases/farmacologia , Inibidores de Janus Quinases/uso terapêutico , Mutação , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores CXCR4/metabolismo , Baço/patologia , Esplenomegalia/tratamento farmacológico , Esplenomegalia/fisiopatologiaRESUMO
PURPOSE: The treatment strategy for elderly patients older than 80 years with diffuse large B-cell lymphoma (DLBCL) has not been established because of poor treatment tolerability and lack of data. MATERIALS AND METHODS: This multicenter retrospective study was conducted to investigate clinical characteristics, treatment patterns and outcomes of patients older than 80 years who were diagnosed with DLBCL at 19 institutions in Korea between 2005 and 2016. RESULTS: A total of 194 patients were identified (median age, 83.3 years). Of these, 114 patients had an age-adjusted International Prognostic Index (aaIPI) score of 2-3 and 48 had a Charlson index score of 4 or more. R-CHOP was given in 124 cases, R-CVP in 13 cases, other chemotherapy in 17 cases, radiation alone in nine cases, and surgery alone in two cases. Twenty-nine patients did not undergo any treatment. The median number of chemotherapy cycles was three. Only 37 patients completed the planned treatment cycles. The overall response rate from 105 evaluable patientswas 90.5% (complete response, 41.9%). Twentynine patients died due to treatment-related toxicities (TRT). Thirteen patients died due to TRT after the first cycle. Median overall survival was 14.0 months. The main causes of death were disease progression (30.8%) and TRT (27.1%). In multivariate analysis, overall survival was affected by aaIPI, hypoalbuminemia, elevated creatinine, and treatment. CONCLUSION: Age itself should not be a contraindication to treatment. However, since elderly patients show higher rates of TRT due to infection, careful monitoring and dose modification of chemotherapeutic agents is needed.
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Linfoma Difuso de Grandes Células B/terapia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , República da Coreia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
KML001 (sodium metaarsenite;NaAs2O3) is known to have antitumor activity against a variety of cancers. In this study, we examined its effect on multiple myeloma (MM). KML001 reduced the growth of all MM cell lines examined with an IC50 of 5x108 M. Exposure to KML001 (5x108 M) decreased levels of cyclins A/B1/D1/E1, CDK2/4/6 in U266 cells and increased the p21 and p27 levels. Furthermore, p21 became bound to CDK2/4/6, resulting in a reduction of CDK2/4/6 kinase activity. The cleaved forms of Bcl-2, and caspases3, 8 and 9 were detected, and the anti-apoptotic molecule, Bax, also increased. Activation of STAT1/3, NF-κB (p65 and p50 subunits), pAKT and pERK decreased, and pPTEN increased. There was also a significant reduction of hTERT at 12 h and upregulation of γ-H2AX and CHK1/2 molecules at 24 h. Thus, KML001 appears to have antitumor activity against MM by inhibiting various oncogenic signaling pathways. It may be useful for treating MM.
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Arsenitos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Compostos de Sódio/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Processos de Crescimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quinases Ciclina-Dependentes/antagonistas & inibidores , Quinases Ciclina-Dependentes/metabolismo , Dano ao DNA , Relação Dose-Resposta a Droga , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Transdução de Sinais/efeitos dos fármacos , Telomerase/biossíntese , Telomerase/genética , Telômero/genética , Telômero/metabolismoRESUMO
BACKGROUND: To assess whether the rotation of dexamethasone to methylprednisolone decreases the intensity of dexamethasone-induced hiccup (DIH) in cancer patients treated with chemotherapy. MATERIALS AND METHODS: Adult patients who experienced DIH within 3 days after the administration of dexamethasone as an antiemetic were screened. Eligible patients were randomly assigned to receive dexamethasone (n = 33) or methylprednisolone (n = 32) as an antiemetic (randomization phase). In the next cycle of chemotherapy, the dexamethasone group received methylprednisolone and vice versa in the methylprednisolone group (crossover phase). The primary endpoint was the difference in hiccup intensity as measured using the numeric rating scale (NRS) between two groups. RESULTS: No female patients were enrolled, although the study did not exclude them. At the randomization phase, hiccup frequency was 28/33 (84.8%) in the dexamethasone group versus 20/32 (62.5%) in the methylprednisolone group (p = .04). Intensity of hiccup was significantly higher in the dexamethasone group than that in the methylprednisolone group (mean NRS, 3.5 vs. 1.4, p < .001). At the crossover phase, hiccup intensity was further decreased after the rotation of dexamethasone to methylprednisolone in the dexamethasone group (mean NRS, 3.5 to 0.9, p < .001), while it was increased by rotating methylprednisolone to dexamethasone in the methylprednisolone group (mean NRS, 1.4 to 3.3, p = .025). There were no differences in emesis intensity between the two groups at either the randomization or crossover phases. Clinicaltrials.gov identifier: NCT01974024. CONCLUSION: Dexamethasone-induced hiccup is a male-predominant phenomenon that can be ameliorated by rotating dexamethasone to methylprednisolone without compromising the antiemetic efficacy. IMPLICATIONS FOR PRACTICE: In this randomized, multicenter, phase III trial, hiccup intensity was significantly lower when the antiemetic corticosteroid was rotated from dexamethasone to methylprednisolone without a change in emesis intensity than that when dexamethasone was maintained. At the crossover phase, hiccup intensity was increased again if dexamethasone was readministered instead of methylprednisolone. The present study demonstrated that dexamethasone-induced hiccup can be improved by rotating from dexamethasone to methylprednisolone without compromising its antiemetic efficacy.
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Corticosteroides/administração & dosagem , Dexametasona/administração & dosagem , Metilprednisolona/administração & dosagem , Neoplasias/tratamento farmacológico , Corticosteroides/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Antieméticos/administração & dosagem , Antieméticos/efeitos adversos , Dexametasona/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Soluço/induzido quimicamente , Soluço/prevenção & controle , Humanos , Masculino , Metilprednisolona/efeitos adversos , Pessoa de Meia-Idade , Neoplasias/complicações , Vômito/tratamento farmacológico , Vômito/patologiaRESUMO
BACKGROUND: To investigate the efficacy, safety, and tolerability of weekly docetaxel treatment in advanced non-small cell lung cancer (NSCLC) patients in Korea. METHODS: This prospective observational study included Korean advanced NSCLC patients with Eastern Cooperative Oncology Group performance status <2 who received weekly monotherapy of docetaxel at a dose determined by the physician. Efficacy measurements included tumor response rate, overall survival (OS), progression-free survival, and one-year survival rate. Safety was analyzed through recorded incidences of adverse events (AEs), serious adverse events (SAEs), deaths, and other related safety parameters, along with their toxicity grades. RESULTS: Of 274 patients analyzed, one patient achieved a complete response and 42 partial responses; thus, the overall response rate was 15.7%. The OS rate at baseline and at one-year follow-up was 38.3% and 33.8%, respectively. AEs were reported in 229 (83.6%) patients. The most frequently reported hematologic AE of grade ≥3 was a decrease in neutrophils, with 6.6% of the patients developing neutropenia. In non-hematologic AEs of grade ≥3, the most common were infection with unknown absolute neutrophil count and death not associated with Common Terminology Criteria for Adverse Events (CTCAE) (4.7% each). The most common SAE reported was death, not associated with CTCAE (7.3%). CONCLUSIONS: In Korean patients, the weekly regimen of docetaxel monotherapy was safe and efficacious against advanced NSCLC.
RESUMO
BACKGROUND: Iron is a crucial element for cell proliferation, growth, and metabolism. However, excess iron and altered iron metabolism are both associated with tumor initiation and tumor growth. Deferasirox is an oral iron chelator. Although some studies have indicated that deferasirox is a promising candidate for anti-cancer therapies, its effectiveness against gastric cancer has not yet been determined. This study was conducted to determine whether deferasirox exerts anti-tumor effects in gastric cancer cell lines and whether deferasirox and cisplatin act synergistically. METHODS: Four human gastric cancer cell lines (AGS, MKN-28, SNU-484, and SNU-638) were treated with various concentrations of deferasirox to determine the IC50 for each cell line. The effects of deferasirox on the cell cycle were evaluated by flow cytometry, and the effects of deferasirox on iron metabolism, the cell cycle, and apoptosis were assessed by Western blotting. To determine whether deferasirox enhances the effect of cisplatin, AGS cells were cultured in the presence and absence of cisplatin. RESULTS: Deferasirox inhibited the proliferation of all gastric cancer cell lines as assessed by MTT assays. Since the IC50 of deferasirox was the lowest (below 10 µM) in AGS cells, subsequent experiments were performed in this line. Deferasirox upregulated transferrin receptor 1 expression and decreased ferroportin expression. Moreover, deferasirox induced G1 arrest; upregulated p21, p27, and p53 expression; and downregulated cyclin D1, cyclin B, and CDK4 expression. Furthermore, deferasirox induced apoptosis, upregulated N-myc downstream regulated gene 1 (NDRG1), and downregulated p-mTOR and c-myc expression. It was also found to act synergistically with cisplatin. CONCLUSIONS: Our results suggest that deferasirox may exert anti-tumor effects in the context of gastric cancer. Deferasirox affects a number of different pathways and molecules; for instance, deferasirox upregulates NDRG1 expression, inhibits the cell cycle, downregulates mTOR and c-myc expression, and induces apoptosis. In addition, deferasirox appears to potentiate the anti-cancer effects of cisplatin. Although the efficacy of deferasirox remains to be tested in future studies, the results presented here indicate that deferasirox is a promising novel anti-cancer therapeutic agent.
Assuntos
Apoptose/efeitos dos fármacos , Benzoatos/farmacologia , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Neoplasias Gástricas/tratamento farmacológico , Triazóis/farmacologia , Antineoplásicos/farmacologia , Western Blotting , Cisplatino/farmacologia , Deferasirox , Sinergismo Farmacológico , Humanos , Neoplasias Gástricas/patologia , Células Tumorais CultivadasRESUMO
Arsenic compounds have been used in traditional medicine for several centuries. KML001 (sodium metaarsenite; NaAsO2) is an orally bio-available arsenic compound with potential anti-cancer activity. However, the effect of KML001 has not been studied in lymphoid neoplasms. The aim of this study is to evaluate the anti-proliferative effect of KML001 in non-Hodgkin's lymphoma and to compare its efficacy with As2O3. KML001 inhibited cellular proliferation in all tested lymphoma cell lines as well as JurkatR cells (adriamycin-resistant Jurkat cells) in a dose-dependent manner, while As2O3 was not effective. Cell cycle regulatory protein studies have suggested that KML001 induces G1 arrest via p27-induced inhibition of the kinase activities of CDK2, 4, and 6. Treatment of KML001 induced apoptosis in Jurkat and JurkatR cells. The apoptotic process was associated with down-regulation of Bcl-2 (antiapoptotic molecule), up-regulation of Bax (proapoptotic molecule), and inhibition of caspase-3, -8, and -9. In addition, cell signaling including the STAT, PI3K/Akt, MAPK, and NF-κB signal pathways were inhibited in KML001-treated Jurkat and JurkatR cells. Furthermore, targeting the telomere by KML001 was observed in the Jurkat and JurkatR cells. The In vivo anti-tumoral activity of KML001 was confirmed in a xenograft murine model. Interestingly, partial responses were seen in two lymphoma patients treated with 10 mg/day (follicular lymphoma for 16 weeks and mantle cell lymphoma for 24 weeks) without severe toxicities. These findings suggest that KML001 may be a candidate agent for the treatment of de novo, refractory, and relapsed non-Hodgkin's lymphoma patients.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Arsenitos/farmacologia , Linfoma não Hodgkin/tratamento farmacológico , Compostos de Sódio/farmacologia , Idoso , Animais , Antineoplásicos/administração & dosagem , Trióxido de Arsênio , Arsenicais/farmacologia , Arsenitos/administração & dosagem , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Células Jurkat , Linfoma não Hodgkin/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Óxidos/farmacologia , Projetos Piloto , Transdução de Sinais/efeitos dos fármacos , Compostos de Sódio/administração & dosagem , Regulação para Cima/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Among the currently available prognostic models for diffuse large B-cell lymphoma (DLBCL), we investigated to determine which is most adoptable for DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) followed by upfront autologous stem cell transplantation (auto-SCT). METHODS: We retrospectively evaluated survival differences among risk groups based on the International Prognostic Index (IPI), the age-adjusted IPI (aaIPI), the revised IPI (R-IPI), and the National Comprehensive Cancer Network IPI (NCCN-IPI) at diagnosis in 63 CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT. RESULTS: At the time of auto-SCT, 74.6% and 25.4% of patients had achieved complete remission and partial remission after R-CHOP, respectively. As a whole, the 5-year overall (OS) and progression-free survival (PFS) rates were 78.8% and 74.2%, respectively. The 5-year OS and PFS rates according to the IPI, aaIPI, R-IPI, and NCCN-IPI did not significantly differ among the risk groups for each prognostic model (P-values for OS: 0.255, 0.337, 0.881, and 0.803, respectively; P-values for PFS: 0.177, 0.904, 0.295, and 0.609, respectively). CONCLUSION: There was no ideal prognostic model among those currently available for CD20-positive DLBCL patients treated with R-CHOP followed by upfront auto-SCT.
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There is no standard salvage chemotherapy for relapsed or refractory peripheral T-cell lymphomas (PTCLs). Gemcitabine combined with cisplatin has been known as an effective regimen for lymphoma treatment in the salvage setting. We investigated the efficacy and toxicity of gemcitabine, dexamethasone, and cisplatin (GDP) for relapsed or refractory PTCLs in search of a more effective and less toxic therapy. Patients with relapsed or refractory PTCLs with more than one previous regimen were eligible. Treatment consisted of gemcitabine 1000 mg/m(2) intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1-4, and cisplatin 70 mg/m(2) i.v. on day 1, and then every 21 days. Patients could proceed to autologous stem cell transplantation (ASCT) after four cycles of GDP or receive up to six treatment cycles. Twenty-five eligible patients were evaluated for toxicity and response. The diagnoses of participants included 14 cases of PTCL-not otherwise specified (NOS) (56 %) and four cases of angioimmunoblastic T-cell lymphoma (16 %) among others. The median age of the patients was 59 years (range 20-75 years). After treatments with GDP, which delivered a median of four GDP cycles, there were 12 patients with complete responses (CR; 48 %) and six with partial responses (PR; 24 %). The overall response rate (RR) was 72 %. Four patients preceded to ASCT, and three patients finally achieved CR. The median progression free survival was 9.3 months (95 % confidence interval (CI); 4.1-14.6) with a median follow-up duration of 27.1 months. In a total of 86 cycles of GDP, grade 3 or 4 neutropenia and thrombocytopenia occurred in 16.3 and 12.8 % of cycles, respectively. Three patients (3.3 %) experienced febrile neutropenia. GDP is a highly effective and optimal salvage regimen for relapsed or refractory PTCLs and can be administered with acceptable toxicity.