RESUMO
BACKGROUND: Commercial anti-CD19 chimeric antigen receptor T-cell therapies (CART19) are efficacious against advanced B-cell non-Hodgkin lymphoma (NHL); however, most patients ultimately relapse. Several mechanisms contribute to this failure, including CD19-negative escape and CAR T dysfunction. All four commercial CART19 products utilize the FMC63 single-chain variable fragment (scFv) specific to a CD19 membrane-distal epitope and characterized by slow association (on) and dissociation (off) rates. We hypothesized that a novel anti-CD19 scFv that engages an alternative CD19 membrane-proximal epitope independent of FMC63 and that is characterized by faster on- and off-rates could mitigate CART19 failure and improve clinical efficacy. METHODS: We developed an autologous CART19 product with 4-1BB co-stimulation using a novel humanized chicken antibody (h1218). This antibody is specific to a membrane-proximal CD19 epitope and harbors faster on/off rates compared to FMC63. We tested h1218-CART19 in vitro and in vivo using FMC63-CART19-resistant models. We conducted a first-in-human multi-center phase I clinical trial to test AT101 (clinical-grade h1218-CART19) in patients with relapsed or refractory (r/r) NHL. RESULTS: Preclinically, h1218- but not FMC63-CART19 were able to effectively eradicate lymphomas expressing CD19 point mutations (L174V and R163L) or co-expressing FMC63-CAR19 as found in patients relapsing after FMC63-CART19. Furthermore, h1218-CART19 exhibited enhanced killing of B-cell malignancies in vitro and in vivo compared with FMC63-CART19. Mechanistically, we found that h1218-CART19 had reduced activation-induced cell death (AICD) and enhanced expansion compared to FMC63-CART19 owing to faster on- and off-rates. Based on these preclinical results, we performed a phase I dose-escalation trial, testing three dose levels (DL) of AT101 (the GMP version of h1218) using a 3 + 3 design. In 12 treated patients (7 DLBCL, 3 FL, 1 MCL, and 1 MZL), AT101 showed a promising safety profile with 8.3% grade 3 CRS (n = 1) and 8.3% grade 4 ICANS (n = 1). In the whole cohort, the overall response rate was 91.7%, with a complete response rate of 75.0%, which improved to 100% in DL-2 and -3. AT101 expansion correlates with CR and B-cell aplasia. CONCLUSIONS: We developed a novel, safe, and potent CART19 product that recognizes a membrane-proximal domain of CD19 with fast on- and off-rates and showed significant efficacy and promising safety in patients with relapsed B-cell NHL. TRIAL REGISTRATION: NCT05338931; Date: 2022-04-01.
Assuntos
Linfoma não Hodgkin , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Humanos , Anticorpos , Antígenos CD19 , Epitopos/metabolismo , Imunoterapia Adotiva/efeitos adversos , Linfoma não Hodgkin/terapia , Linfoma não Hodgkin/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos de Linfócitos T/antagonistas & inibidoresRESUMO
Diffuse large B-cell lymphoma (DLBCL) is a prevalent and aggressive non-Hodgkin's lymphoma, and 40% of patients succumb to death. Despite numerous clinical trials aimed at developing treatment strategies beyond the conventional R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen, there have been no positive results thus far. Although the selective BCL2 inhibitor venetoclax has shown remarkable efficacy in chronic lymphocytic leukemia, its therapeutic effect in DLBCL was limited. We hypothesized that the limited therapeutic effect of venetoclax in DLBCL may be attributed to the complex expression and interactions of BCL2 family members, including BCL2. Therefore, we aimed to comprehensively analyze the expression patterns of BCL2 family members in DLBCL. We analyzed 157 patients with de novo DLBCL diagnosed at Asan Medical Center and Ajou University Hospital. The mRNA expression levels of BCL2 family members were quantified using the NanoString technology. BCL2 family members showed distinct heterogeneous expression patterns both intra- and inter-patient. Using unsupervised hierarchical cluster analysis, we were able to classify patients with similar BCL2 family expression pattern and select groups with clear prognostic features, C1 and C6. In the group with the best prognosis, C1, the expression of pro-apoptotic and pro-apoptotic BH3-only group gene expressions were increased, while anti-apoptotic group expression was significantly increased in both C1 and C6. Based on this, we generated the BCL2 signature score using the expression of pro-apoptotic genes BOK and BCL2L15, and anti-apoptotic gene BCL2. The BCL2 signature score 0 had the best prognosis, score 1/2 had intermediate prognosis, and score 3 had the worst prognosis (EFS, p = 0.0054; OS, p = 0.0011). Multivariate analysis, including COO and IPI, showed that increase in the BCL2 signature score was significantly associated with poor prognosis for EFS, independent of COO and IPI. The BCL2 signature score we proposed in this study provides information on BCL2 family deregulation based on the equilibrium of pro-versus anti-apoptotic BCL2 family, which can aid in the development of new treatment strategies for DLBCL in the future.
Assuntos
Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Humanos , Anticorpos Monoclonais Murinos/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/uso terapêutico , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Ciclofosfamida/uso terapêutico , Vincristina/uso terapêutico , Prednisona/uso terapêutico , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: The Khorana score (KS) has not been well studied in East Asian cancer patients, who have different genetic backgrounds for inherited thrombophilia, body metabolism, and cancer epidemiology. METHODS: By using the Common Data Model, we retrospectively collected deidentified data from 11,714 consecutive newly diagnosed cancer patients who underwent first-line chemotherapy from December 2015 to December 2021 at a single institution in Korea, and we applied the KS for cancer-associated thrombosis (CAT) prediction. Age at diagnosis, sex, and use of highly thrombogenic chemotherapeutics were additionally investigated as potential risk factors for CAT development. RESULTS: By 6 months after chemotherapy initiation, 207 patients (1.77%) experienced CAT. Only 0.4% had a body mass index (BMI) ≥ 35 kg/m2 and changing the cutoff to 25 kg/m2 improved the prediction of CAT. Age ≥ 65 years and the use of highly thrombogenic chemotherapeutics were independently associated with CAT development. KS values of 1 ~ 2 and ≥ 3 accounted for 52.3% and 7.6% of all patients, respectively, and the incidence of CAT in these groups was 2.16% and 4.16%, respectively, suggesting a lower incidence of CAT in the study population than in Westerners. The KS component regarding the site of cancer showed a good association with CAT development but needed some improvement. CONCLUSION: The KS was partially validated to predict CAT in Korean cancer patients undergoing modern chemotherapy. Modifying the BMI cutoff, adding other risk variables, and refining the use of cancer-site data for CAT risk prediction may improve the performance of the KS for CAT prediction in East Asian patients.
RESUMO
Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.
Assuntos
Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-bcl-2 , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Prednisona/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-myc/genética , Rituximab/uso terapêutico , Vincristina/uso terapêuticoRESUMO
Central venous catheters (CVCs) are generally required for chemotherapy in patients with acute leukemia, but catheter-related infection is one of the common causes of neutropenic fever. We investigated the in-hospital mortality according to early removal of CVCs and the factors influencing the mortality in patients with acute leukemia undergoing remission induction chemotherapy. This study retrospectively analyzed the hospital record data of 278 patients with acute leukemia treated with non-tunneled CVCs and remission induction chemotherapy in a single institution. Bloodstream infection was more common (p < 0.0001) and median peak C-reactive protein (CRP) levels after neutropenic fever were significantly higher (23.3 vs. 14.5 mg/dl, p = 0.003) in the group with early removal than in the group with maintenance of the CVC. Multivariate analysis of the patients revealed a significant decrease in the mortality with female gender (odds ratio (OR): 0.19, 95% confidence interval (CI): 0.06-0.54, p = 0.002) and a significant increase in the mortality according to the peak CRP (OR 1.12, 95% CI: 1.07-1.17, p < 0.0001). By contrast, early removal of the CVC had no significant effect on the mortality (OR = 1.16, 95% CI: 0.54-2.47, p = 0.706) in univariate analysis. Furthermore, subsequent bloodstream infection after clinical decision for maintenance or early removal of the CVC was confirmed more frequently in the group with early removal (early removal, 22.6%; maintenance, 7.6%, p < 0.0001). Early removal of the CVC had no benefit regarding the mortality and prophylaxis of bloodstream infection in patients with acute leukemia undergoing remission induction chemotherapy. Therefore, maintaining a CVC for as long as possible may be considered, if catheter-related bloodstream infection is not strongly suspected.
Assuntos
Infecções Relacionadas a Cateter/prevenção & controle , Cateteres Venosos Centrais/efeitos adversos , Remoção de Dispositivo , Mortalidade Hospitalar , Leucemia Mieloide Aguda/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Adolescente , Adulto , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bacteriemia/epidemiologia , Bacteriemia/etiologia , Bacteriemia/prevenção & controle , Infecções Relacionadas a Cateter/etiologia , Neutropenia Febril/etiologia , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Although combination chemotherapy (CC) is generally recommended in recurrent or primary metastatic gastric cancer (RPMGC), the results of randomized trials are conflicting. METHODS: A retrospective review was conducted on 687 RPMGC patients who received palliative chemotherapy. We compared the overall survival (OS) between CC and single-agent chemotherapy (SC) among these patients, and we analyzed the clinicopathological characteristics affecting outcome including neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). RESULTS: Although 521 patients (75.8%) underwent CC, SC was more frequently performed in elderly patients (57.6%) and ECOG performance status (PS) 2 or 3 (65.8%) patients (p < 0.0001, in each case). The median OS of patients who received CC was significantly longer than that of patients who received SC (11 vs. 8 months, p < 0.0001). No difference in OS between CC and SC was observed in elderly patients (p = 0.583), poor PS (p = 0.810), signet ring cell (p = 0.347), palliative surgical resection (p = 0.307), and high PLR (p = 0.120), with a significant interaction between age and type of regimen (p = 0.012). Moreover, there was no difference in OS between CC and SC after propensity score matching (p = 0.322). Multivariate analysis revealed that palliative resection and ≥ second-line chemotherapy were independently associated with favorable OS (p < 0.0001, in each case), whereas poor PS (p = 0.004), signet ring cell (p < 0.0001), peritoneal metastasis (p = 0.04), high NLR (p = 0.001), and high PLR (p = 0.033) were independent prognostic factors of poor OS. CONCLUSIONS: Although CC is the standard of care in RPMGC, SC can be considered a reasonable option in certain subgroups, such as elderly patients.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cuidados Paliativos/métodos , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Contagem de Plaquetas , Estudos Retrospectivos , Neoplasias Gástricas/sangue , Análise de Sobrevida , Adulto JovemRESUMO
Natural killer (NK)/T cell lymphoid malignancy comprises extranodal NK/T cell lymphoma (ENKTL) and aggressive NK cell leukemia (ANKL), and the outcomes for advanced or relapsed/refractory ENKTL and ANKL remain poor. Allogeneic stem cell transplantation (SCT) can be used as a frontline consolidation treatment to prevent the relapse of advanced disease or as salvage treatment after chemotherapy for relapsed sensitive disease. We retrospectively analyzed 36 patients (ENKTL, nâ¯=â¯26; ANKL, nâ¯=â¯10) who underwent upfront (nâ¯=â¯19) and salvage allogeneic SCT (nâ¯=â¯17) at 6 hospitals. Patients received myeloablative (nâ¯=â¯25) or reduced-intensity (n =11) conditioning regimens depending on the institute's policy. The median age at the time of allogeneic SCT was 37 years (range, 17 to 62), and more patients with ANKL (8/10) received upfront allogeneic SCT than ENKTL patients (11/26). Disease status before allogeneic SCT, conditioning regimen, and donor source did not differ between upfront and salvage allogeneic SCT groups. Febrile neutropenia (nâ¯=â¯20) and acute graft-versus-host disease (nâ¯=â¯16) were common adverse events. The median overall survival (OS) and progression-free survival (PFS) after allogeneic SCT were 11.8 months and 10.0 months, respectively. Twelve patients died from disease relapse and 12 from nondisease-related causes. Ten deaths occurred within 100 days after allogeneic SCT (10/24); these were mostly related to disease relapse (nâ¯=â¯8). The OS after allogeneic SCT did not differ between ENKTL and ANKL (Pâ¯=â¯.550) or between upfront and salvage SCT (Pâ¯=â¯.862). Complete chimerism was significantly associated with better PFS (P < .001). No significant differences in PFS were observed based on the conditioning regimen or source of stem cells (P > .05). Allogeneic SCT may be beneficial for patients with ENKTL and ANKL given that some patients were able to maintain their remission after allogeneic SCT. However, allogeneic SCT should only be performed in highly selected patients because the risks of disease relapse and nondisease-related mortality remain high.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Linfoide/terapia , Células T Matadoras Naturais/metabolismo , Terapia de Salvação/métodos , Transplante Homólogo/métodos , Adolescente , Adulto , Feminino , Humanos , Leucemia Linfoide/patologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/patologia , Adulto JovemRESUMO
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is an independent prognostic marker in solid and hematological cancers. While the derived NLR (dNLR) was shown to be non-inferior to the NLR in large cohorts of patients with different cancer types, it has not been validated as a prognostic marker for multiple myeloma (MM) to date. METHODS: Between May 22, 2011 and May 29, 2014, 176 patients with MM from 38 centers who were ineligible for autologous stem cell transplantation were analyzed. The dNLR was calculated using complete blood count differential data. The optimal dNLR cut-off value according to receiver operating characteristic analysis of overall survival (OS) was 1.51. All patients were treated with melphalan and prednisone combined with bortezomib. RESULTS: The complete response rate was lower in the high dNLR group compared to the low dNLR group (7 vs. 26.1%, respectively; p = 0.0148); the corresponding 2-year OS rates were 72.2 and 84.7%, respectively (p = 0.0354). A high dNLR was an independent poor prognostic factor for OS (hazard ratio 2.217, 95% CI 1.015-4.842; p = 0.0458). CONCLUSION: The dNLR is a readily available and cheaply obtained parameter in clinical studies, and shows considerable potential as a new prognostic marker for transplantation-ineligible patients with MM.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfócitos/citologia , Mieloma Múltiplo/terapia , Neutrófilos/citologia , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Área Sob a Curva , Intervalo Livre de Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Transplante AutólogoRESUMO
BACKGROUND: The clinical outcome of extranodal natural killer T-cell lymphoma (ENKTL) has improved substantially as a result of new treatment strategies with non-anthracycline-based chemotherapies and upfront use of concurrent chemoradiotherapy or radiotherapy. A new prognostic model based on the outcomes obtained with these contemporary treatments was warranted. METHODS: We did a retrospective study of patients with newly diagnosed ENKTL without any previous treatment history for the disease who were given non-anthracycline-based chemotherapies with or without upfront concurrent chemoradiotherapy or radiotherapy with curative intent. A prognostic model to predict overall survival and progression-free survival on the basis of pretreatment clinical and laboratory characteristics was developed by filling a multivariable model on the basis of the dataset with complete data for the selected risk factors for an unbiased prediction model. The final model was applied to the patients who had complete data for the selected risk factors. We did a validation analysis of the prognostic model in an independent cohort. FINDINGS: We did multivariate analyses of 527 patients who were included from 38 hospitals in 11 countries in the training cohort. Analyses showed that age greater than 60 years, stage III or IV disease, distant lymph-node involvement, and non-nasal type disease were significantly associated with overall survival and progression-free survival. We used these data as the basis for the prognostic index of natural killer lymphoma (PINK), in which patients are stratified into low-risk (no risk factors), intermediate-risk (one risk factor), or high-risk (two or more risk factors) groups, which were associated with 3-year overall survival of 81% (95% CI 75-86), 62% (55-70), and 25% (20-34), respectively. In the 328 patients with data for Epstein-Barr virus DNA, a detectable viral DNA titre was an independent prognostic factor for overall survival. When these data were added to PINK as the basis for another prognostic index (PINK-E)-which had similar low-risk (zero or one risk factor), intermediate-risk (two risk factors), and high-risk (three or more risk factors) categories-significant associations with overall survival were noted (81% [95% CI 75-87%], 55% (44-66), and 28% (18-40%), respectively). These results were validated and confirmed in an independent cohort, although the PINK-E model was only significantly associated with the high-risk group compared with the low-risk group. INTERPRETATION: PINK and PINK-E are new prognostic models that can be used to develop risk-adapted treatment approaches for patients with ENKTL being treated in the contemporary era of non-anthracycline-based therapy. FUNDING: Samsung Biomedical Research Institute.
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Quimiorradioterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/terapia , Adulto , Idoso , Antraciclinas , Antineoplásicos/administração & dosagem , Estudos de Coortes , Terapia Combinada , Intervalos de Confiança , Intervalo Livre de Doença , Feminino , Humanos , Células Matadoras Naturais/patologia , Linfoma Extranodal de Células T-NK/diagnóstico , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Prognóstico , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
Micafungin, a clinically important echinocandin antifungal drug, needs to be investigated as empirical therapy in febrile neutropenia in comparison with azole compounds. A prospective randomized study was conducted to compare clinical outcomes between micafungin and intravenous itraconazole as an empirical therapy for febrile neutropenia in hematological malignancies. The antifungal drug (micafungin 100 mg or itraconazole 200 mg IV once daily) was given for high fever that was sustained despite the administration of appropriate antibiotics. Treatment success was determined by composite end points based on breakthrough invasive fungal infection (IFI), survival, premature discontinuation, defervescence, and treatment of baseline fungal infection. Duration of fever, hospital stay, and overall survival (OS) were studied. A total of 153 patients were randomized to receive micafungin or itraconazole. The overall success rate was 7.1 % point higher in the micafungin group (64.4 vs. 57.3 %, p = 0.404), satisfying the statistical criteria for the non-inferiority of micafungin. The duration of fever and hospital stay were significantly shorter in the micafungin group (6 vs. 7 days, p = 0.014; 22 vs. 27 days, p = 0.033, respectively). Grade 3 adverse events including hyperbilirubinemia (2 vs. 7), elevation of transaminase levels (2 vs. 4), electrolyte imbalance (1 vs. 2), atrial fibrillation (1 vs. 0), and anaphylaxis (1 vs. 0) occurred in 7 and 13 patients in the micafungin (10.4 %) and itraconazole (18.8 %) groups, respectively. Micafungin, when compared with itraconazole, had favorably comparable success rate and toxicity profiles on febrile neutropenia in patients with hematological malignancies. In addition, it showed superior effect on shortening the hospital stay.
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Antifúngicos/administração & dosagem , Equinocandinas/administração & dosagem , Neutropenia Febril/tratamento farmacológico , Neoplasias Hematológicas/tratamento farmacológico , Itraconazol/administração & dosagem , Lipopeptídeos/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Equinocandinas/efeitos adversos , Pesquisa Empírica , Neutropenia Febril/diagnóstico , Neutropenia Febril/epidemiologia , Feminino , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/epidemiologia , Humanos , Itraconazol/efeitos adversos , Tempo de Internação/tendências , Lipopeptídeos/efeitos adversos , Masculino , Micafungina , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVES: We assessed the clinical significance of FDG uptake in cervical lymph nodes after treatment of patients with DLBCL. METHODS: In total, 87 patients with DLBCL were enrolled. All patients had newly appeared FDG uptake in cervical lymph nodes on PET/CT during follow-up after cessation of therapy. Cervical lymph nodes were finally diagnosed as benign or malignant according to histopathological findings or follow-up PET. Clinical characteristics and PET findings were compared between groups and factors associated with malignant lesions were evaluated. RESULTS: Only 8 (9.2 %) patients with cervical lymph nodes with FDG uptake ultimately had malignancy. FDG uptake lymph nodes appeared significantly earlier in the malignant group than in patients with benign FDG uptake (p = 0.013). Primary nodal lymphoma was more frequent in patients with cancer spread than in those with benign FDG uptake in lymph nodes (p < 0.001). CONCLUSION: Most cervical lymph nodes with FDG uptake (about 91 %) appearing after treatment of malignant DLBCL were ultimately benign. The elapsed time between the end of therapy and the appearance of cervical lymph nodes with FDG uptake and the primary sites of lymphomas are helpful clues in determining which cases are malignant. KEY POINTS: ⢠About 91 % appearing after treatment of DLBCL were benign. ⢠Elapsed time between therapy and FDG uptake was associated with malignancy. ⢠Primary sites of lymphoma are helpful clues to determine malignancy.
Assuntos
Fluordesoxiglucose F18/farmacocinética , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/terapia , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Idoso , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Pescoço , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos RetrospectivosRESUMO
The hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen has been widely used for lymphoblastic lymphoma (LBL) as a primary treatment. However, there is few data about its treatment outcome in Asian patients. Thus, we conducted this study to evaluate the efficacy of hyper-CVAD induction and stem cell transplantation (SCT) consolidation in LBL patients. The treatment responses of 49 patients treated with the hyper-CVAD regimen were retrospectively analyzed in 13 institutions. Given 24 patients who responded to hyper-CVAD underwent consolidation treatment with SCT, overall survival (OS) and progression-free survival (PFS) of patients who received SCT were compared with patients who did not. The overall response rate was 79 %: 73 % (36/49) complete responses, 6 % (3/49) partial responses, and 4 % (2/49) induction deaths. The major limitation for the delivery of the planned hyper-CVAD cycles was hematological toxicity. Among 39 responders, 24 patients underwent autologous (n = 16) and allogeneic SCT (n = 8) consolidation. Their 3-year OS and PFS rates were 76 and 78 %, respectively, and there was no difference in survival outcomes between autologous and allogeneic SCT. However, 15 patients without SCT consolidation showed poorer PFS even though they all achieved complete response. Thus, only seven patients maintained their response at the time of analysis. In conclusion, the hyper-CVAD regimen is effective for remission induction in LBL, and SCT consolidation after hyper-CVAD induction produced better clinical outcomes than did continuation of hyper-CVAD.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Quimioterapia de Indução/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Adulto , Terapia Combinada , Ciclofosfamida/uso terapêutico , Dexametasona/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Vincristina/uso terapêutico , Adulto JovemRESUMO
For decades, maintenance chemotherapy has failed to improve the cure rate or prolong the survival of patients with acute myeloid leukemia (AML), other than those with acute promyelocytic leukemia. Immediately after the first complete remission following consolidation therapy was obtained, oral maintenance chemotherapy (daily 6-mercaptopurine and weekly methotrexate) was given and continued for two years in transplant-ineligible AML patients. Leukemia-free survival (LFS) and overall survival (OS) were studied and compared between these patients and the historical control group who did not receive maintenance therapy. Consecutive 52 transplant-ineligible AML patients were analyzed. Among these patients, 27 received oral maintenance chemotherapy. No significant difference was found in the patients' characteristics between the maintenance and the control groups. The median OS was 43 (95% CI, 19-67) and 19 (95% CI, 8-30) months in the maintenance and the control groups, respectively (P = 0.202). In the multivariate analysis, the presence of maintenance therapy was an independent prognostic factor for better OS (P = 0.021) and LFS (P = 0.024). Clinical benefit from maintenance chemotherapy was remarkable in older patients (≥ 60 yr) (P = 0.035), those with intermediate or unfavorable cytogenetics (P = 0.006), those with initial low blast count in peripheral blood (P = 0.044), and those receiving less than two cycles of consolidation therapy (P = 0.017). Maintenance oral chemotherapy as a post-remission therapy can prolong the survival of patients with AML who are not eligible for transplantation, particularly older patients, those with intermediate or unfavorable cytogenetics, those with initial low blast count, and those receiving less than two cycles of consolidation therapy.
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Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Mercaptopurina/uso terapêutico , Metotrexato/uso terapêutico , Adolescente , Adulto , Idoso , Citarabina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Radotinib (IY5511HCL), a novel and selective BCR-ABL1 tyrosine kinase inhibitor, has shown pre-clinical and phase I activity and safety in chronic myeloid leukemia. This phase II study investigated the efficacy and safety of radotinib in Philadelphia chromosome-positive chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors. Patients received radotinib 400 mg twice daily for 12 cycles based on results from the phase I trial. The primary end point was rate of major cytogenetic response by 12 months. A total of 77 patients were enrolled. Major cytogenetic response was achieved in 50 (65%; cumulative 75%) patients, including 36 (47%) patients with complete cytogenetic response by 12 months. Median time to major cytogenetic response and complete cytogenetic response were 85 days and 256 days, respectively. Major cytogenetic response and complete cytogenetic response rates were similar between imatinib-resistant and imatinib-intolerant patients, but were higher in patients without BCR-ABL1 mutations. Overall and progression-free survival rates at 12 months were 96.1% and 86.3%, respectively. All newly-occurring or worsening grade 3/4 hematologic abnormalities included thrombocytopenia (24.7%) and anemia (5.2%); grade 3/4 drug-related non-hematologic adverse events included fatigue (3.9%), asthenia (3.9%), and nausea (2.6%). The most common biochemistry abnormality was hyperbilirubinemia (grade 3/4 23.4%), and 12 of 18 cases were managed with dose modification. Study findings suggest radotinib is effective and well tolerated in chronic phase-chronic myeloid leukemia patients with resistance and/or intolerance to BCR-ABL1 tyrosine kinase inhibitors and may represent a promising alternative for these patients. (clinicaltrials.gov identifier: 01602952).
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Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crônica/genética , Leucemia Mieloide de Fase Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/efeitos adversos , Pirazinas/uso terapêutico , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
Febrile neutropenia (FN) is the major toxicity of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen in the treatment of diffuse large B-cell lymphoma (DLBCL). The prediction of neutropenia and FN is mandatory to continue the planned R-CHOP therapy resulting in successful anti-cancer treatment. The clinical features and patterns of neutropenia and FN from 181 DLBCL patients treated with R-CHOP were analyzed retrospectively. Sixty percent (60.2%) of patients experienced at least one episode of grade 4 neutropenia. Among them, 42.2% of episodes progressed to FN. Forty-eight percent (48.8%) of patients with FN was experienced their first FN during the first cycle of R-CHOP. All those patients never experienced FN again during the rest cycles of R-CHOP. Female, higher stage, international prognostic index (IPI), age ≥65 yr, comorbidities, bone marrow involvement, and baseline serum albumin ≤3.5 mg/dL were significant risk factors for FN by univariate analysis. Among these variables, comorbidities (P=0.009), bone marrow involvement (P=0.006), and female gender (P=0.024) were independent risk factors for FN based on multivariate analysis. On observing the patterns of neutropenia and FN, primary prophylaxis of granulocyte colony-stimulating factor (G-CSF) and antibiotics should be considered particularly in female patients, patients with comorbidities, or when there is bone marrow involvement of disease.
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Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neutropenia Febril Induzida por Quimioterapia/etiologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Demografia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutropenia/etiologia , Neutropenia/patologia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Rituximab , Fatores Sexuais , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico , Adulto JovemRESUMO
Purpose: This multicenter, open-label, phase II trial evaluated the efficacy and safety of bortezomib combined with dexamethasone for the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) in previously treated patients across 14 institutions in South Korea. Patients and Methods: Between September 2017 and July 2020, 29 patients with histologically confirmed CTCL received treatment, consisting of eight 4-week cycles of induction therapy followed by maintenance therapy, contingent upon response, for up to one year. The primary endpoint was the proportion of patients achieving an objective global response. Results: Thirteen (44.8%) of the 29 patients achieved an objective global response, including two complete responses. The median progression-free survival (PFS) was 5.8 months, with responders showing a median PFS of 14.0 months. Treatment-emergent adverse events were generally mild, with a low incidence of peripheral neuropathy and hematologic toxicities. Despite the trend toward shorter PFS in patients with higher mutation burdens, genomic profiling before and after treatment showed no significant emergence of new mutations indicative of disease progression. Conclusion: This study supports the use of bortezomib and dexamethasone as a viable and safe treatment option for previously treated CTCL, demonstrating substantial efficacy and manageability in adverse effects. Further research with a larger cohort is suggested to validate these findings and explore the prognostic value of mutation profiles.
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BACKGROUND/AIMS: Optimal risk stratification based on simplified geriatric assessment to predict treatment-related toxicity and survival needs to be clarified in older patients with diffuse large B-cell lymphoma (DLBCL). METHODS: This multicenter prospective cohort study enrolled newly diagnosed patients with DLBCL (≥ 65 yr) between September 2015 and April 2018. A simplified geriatric assessment was performed at baseline using Activities of Daily Living (ADL), Instrumental ADL (IADL), and Charlson's Comorbidity Index (CCI). The primary endpoint was event-free survival (EFS). RESULTS: The study included 249 patients, the median age was 74 years (range, 65-88), and 125 (50.2%) were female. In multivariable Cox analysis, ADL, IADL, CCI, and age were independent factors for EFS; an integrated geriatric score was derived and the patients stratified into three geriatric categories: fit (n = 162, 65.1%), intermediate-fit (n = 25, 10.0%), and frail (n = 62, 24.9%). The established geriatric model was significantly associated with EFS (fit vs. intermediate-fit, HR 2.61, p < 0.001; fit vs. frail, HR 4.61, p < 0.001) and outperformed each covariate alone or in combination. In 87 intermediate-fit or frail patients, the relative doxorubicin dose intensity (RDDI) ≥ 62.4% was significantly associated with worse EFS (HR, 2.15, 95% CI 1.30-3.53, p = 0.002). It was related with a higher incidence of grade ≥ 3 symptomatic non-hematologic toxicities (63.2% vs. 27.8%, p < 0.001) and earlier treatment discontinuation (34.5% vs. 8.0%, p < 0.001) in patients with RDDI ≥ 62.4% than in those with RDDI < 62.4%. CONCLUSION: This model integrating simplified geriatric assessment can risk-stratify older patients with DLBCL and identify those who are highly vulnerable to standard dose-intensity chemoimmunotherapy.
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Avaliação Geriátrica , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/mortalidade , Feminino , Idoso , Masculino , Estudos Prospectivos , Idoso de 80 Anos ou mais , Medição de Risco , Fatores de Risco , Fatores Etários , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Progressão , Atividades Cotidianas , Valor Preditivo dos Testes , Fatores de Tempo , Técnicas de Apoio para a Decisão , Doxorrubicina/efeitos adversos , Doxorrubicina/administração & dosagem , Idoso Fragilizado , Fragilidade/diagnóstico , Fragilidade/epidemiologia , Comorbidade , República da Coreia/epidemiologiaRESUMO
Although recent studies have suggested that cessation of imatinib (IM) in chronic myeloid leukemia patients can be associated with sustained response, further validation is needed to explore predictive factors. In a prospective, multicenter study, chronic phase patients were eligible for cessation of IM therapy after more than 3 years if they had no detectable BCR-ABL1 transcript for at least 2 years. A total of 48 patients with a median age of 47 years (19-74 years) were enrolled. Twenty patients received IM for post-transplant relapse. After a median follow-up of 15.8 months (1.4-28.2 months) after IM discontinuation, nine of the non-transplant group lost undetectable molecular residual disease (UMRD) and major molecular response (MMR), whereas none of the 20 patients in the transplant group experienced UMRD loss. Probabilities for sustained MMR and UMRD were 64.4% and 66.3% in the non-transplant group, respectively. Of nine patients re-treated with IM, eight patients re-achieved MMR at a median of 1.7 months (0.9-2.8 months). Seven of these patients re-achieved UMRD at a median of 5.6 months (2.8-12.1 months). Previous transplantation, IM duration, and UMRD duration were significantly associated with sustained molecular responses. Our data strongly suggest that immunological control contributes to sustained suppression of residual leukemia cell expansion and that IM can be safely discontinued in patients with post-transplant relapse.
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Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Feminino , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Despite the small but significant survival benefit of adjuvant chemotherapy in locally advanced gastric cancer (LAGC), the optimal regimen remains to be determined. We conducted a randomized trial comparing oral (PO) chemoimmunotherapy (CITX) with intravenous (IV) CITX in LAGC patients (stages IB-IIIB) with curative resection (≥ D2 dissection). METHODS: The patients were randomized to the IV (5-fluorouracil 500 mg/m(2) weekly for 24 weeks, mitomycin-C 8 mg/m(2) every 6 weeks × 4) or the PO (uracil-ftorafur (UFT) 400-600 mg/day for 12 months) group. Patients in both groups received PO polysaccharide-K (3 g/day for 4 months). The planned number of patients was 368 for proving the non-inferiority of PO CITX compared to IV CITX for overall survival. RESULTS: The trial was closed prematurely after enrolling 82 patients (44 in the IV group, 38 in the PO group). With a median follow-up of 82 months, there were no significant differences in the 5-year disease-free survival (73% vs. 55%, p = 0.358) and overall survival (77% vs. 66%, p = 0.159) between the 2 groups. The IV group demonstrated a higher incidence of grade 2 or 3 neutropenia, thrombocytopenia, and vomiting. CONCLUSIONS: PO CITX with UFT appeared to be at least non-inferior to 5-fluorouracil and mitomycin-C CITX, with lower toxicity in the adjuvant treatment for LAGC.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteoglicanas/administração & dosagem , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Adulto , Idoso , Quimioterapia Adjuvante/mortalidade , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Humanos , Imunoterapia/mortalidade , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Prevalência , República da Coreia/epidemiologia , Fatores de Risco , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida , Tegafur/administração & dosagem , Resultado do Tratamento , Uracila/administração & dosagemRESUMO
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.