RESUMO
INTRODUCTION: The mechanism of EphB4/ephrinB2 in the resistance of chronic myelogenous leukemia to imatinib keeps unknown. METHODS: The imatinib resistant chronic myelogenous leukemia cell line-K562-R, was established. EphB4 receptor expression was detected in patients and resistant cells. Cell migration and drug sensitivity were tested in the EphB4 knockdown cells and mouse models. RESULTS: The EphB4 receptor was over-expressed in blast crisis patients compared to chronic phase patients. The level of EphB4 receptor expression was associated with a complete cytogenetic response within 12 months. Enhanced expression of the EphB4 receptor was detected in the K562-R cells. EphB4 knockdown inhibited cell migration ability and restored sensitivity to imatinib in vitro and in vivo. Restored sensitivity to imatinib was observed in K562-R cells, along with increased levels of phospho-EphB4 and decreased phosphorylation levels of RhoA, Rac1, and Cdc42. CONCLUSION: Our study illustrates that aberrant activation of EphB4/ephrinB2 may mediate chronic myeloid leukemia resistance involved in cytoskeletal proteins.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas do Citoesqueleto/metabolismo , Efrina-B2/metabolismo , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Receptor EphB4/metabolismo , Animais , Movimento Celular/genética , Movimento Celular/fisiologia , Proteínas do Citoesqueleto/genética , Resistencia a Medicamentos Antineoplásicos/genética , Efrina-B2/genética , Feminino , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Camundongos , Camundongos Nus , Fosforilação/genética , Fosforilação/fisiologia , Receptor EphB4/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismoRESUMO
OBJECTIVE: To analyze the relationship between serum cystatin C (CysC), ß2-microglobulin (ß2-MG) and the efficacy of demethylation therapy in patients with acute myeloid leukemia (AML). METHODS: A prospective cohort study was conducted on 98 AML patients admitted to the Affiliated Hospital of Inner Mongolia Medical University from February 2019 to January 2022. All patients were treated with decitabine (DAC) + HAG regimen, 28 days as a course and treated for 3-4 courses. At the end of each course of treatment, the treatment effect of the patients was evaluated, and the patients who achieved complete remission (CR) transferred to consolidation therapy, while the patients who did not reach CR at the end of the course of treatment were considered as treatment failure. The examination items before treatment include routine blood parameters, serum CysC, and ß2-MG, and general clinical data of the patients were collected. According to the statistical results, logistic regression model was used to analyze the relationship between serum CysC, ß2-MG and the efficacy of demethylation therapy in AML patients. The ROC curves were drawn, and the predictive efficacy of serum CysC, ß2-MG on demethylation therapy in AML patients was evaluated by the area under the curve (AUC). RESULTS: Of the 98 AML patients enrolled in the study, 5 cases were excluded during the treatment period, and 93 cases finally completed the chemotherapy courses. Among them, 23 patients achieved CR after the initial induction chemotherapy (course 1-2), and 11 patients achieved CR after the re-induction chemotherapy (course 3-4). The success rate of demethylation therapy was 36.56 % (34/93). Compared with the patients in treatment success group, patients in treatment failure group had a higher proportion of intermediate- and adverse-risk, lower levels of platelet (PLT) and hemoglobin (Hb), and higher expression levels of serum CysC and ß2-MG, all of which were statistically significant (P < 0.05). Logistic regression analysis showed that high expression of serum CysC, ß2-MG and adverse-risk were independent risk factors for failure of demethylation treatment in AML patients (OR >1, P < 0.05). The ROC curves showed that the AUC values of serum CysC, ß2-MG alone and combined in predicting the efficacy of demethylation therapy in AML patients were 0.788, 0.785 and 0.834, respectively. CONCLUSION: The failure of demethylation therapy in AML patients is related to the high expression of serum CysC and ß2-MG, and detection of serum CysC and ß2-MG before treatment can predict the risk of demethylation therapy failure in AML patients.
Assuntos
Cistatina C , Leucemia Mieloide Aguda , Microglobulina beta-2 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/sangue , Estudos Prospectivos , Microglobulina beta-2/sangue , Cistatina C/sangue , Desmetilação , Indução de Remissão , Decitabina , Masculino , Feminino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Expression profiling of microRNAs (miRNAs) in most diseases might be popular and provide the possibility for diagnostic implication, but few studies have accurately quantified the expression level of dysregulated miRNAs in acute myeloid leukemia (AML). In this study, we analyzed the peripheral blood mononuclear cells (PBMCs) from 10 AML patients (subtypes M1 to M5) and six normal controls by miRNA microarray and identified several differentially expressed miRNAs. Among them miR-29a and miR-142-3p were selectively encountered in Northern blot analysis and their significantly decreased expression in AML was further confirmed. Quantitative real-time PCR in 52 primarily diagnosed AML patients and 100 normal controls not only verified the expression properties of these 2 miRNAs, but also established that the expression level of miR-142-3p and miR-29a in PBMCs could be used as novel diagnostic markers. A better diagnostic outcome was achieved by combining miR-29a and miR-142-3p with about 90% sensitivity, 100% specificity, and an area under the ROC curve (AUC) of 0.97. Our results provide insights into the involvement of miRNAs in leukemogenesis, and offer candidates for AML diagnosis and therapeutic strategy.
Assuntos
Biomarcadores Tumorais/genética , Regulação Neoplásica da Expressão Gênica/genética , Leucemia Mieloide Aguda/genética , MicroRNAs/metabolismo , Área Sob a Curva , Northern Blotting , Perfilação da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/metabolismo , Leucócitos Mononucleares/metabolismo , Análise em Microsséries , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: C-reactive protein (CRP) has two natural isomers: C-reactive protein pentamer (pCRP) and C-reactive protein monomer (mCRP). The levels of CRP are significantly elevated in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). mCRP not only activates the endothelial cells, platelets, leukocytes, and complements, but also has a proinflammatory structural subtype that can localize and deposit in inflammatory tissues. Thus, it regulates a variety of clinical diseases, such as ischemia/reperfusion (I/R) injury, Alzheimer's disease, age-related macular degeneration, and cardiovascular disease. We hypothesized that plasma mCRP levels are related to cardiovascular disease in AAV. METHODS: In this cross-sectional study, 37 patients with AAV were assessed. Brain natriuretic peptide (BNP) and mCRP in plasma were assessed by enzyme-linked immunosorbent assay (ELISA). The acute ST-segment elevation myocardial infarction (STEMI) was diagnosed by coronary angiography, and the Gensini score calculated. Echocardiography evaluated the ejection fraction (EF%), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular mass index (LVMI). Estimated glomerular filtration rate (eGFR) was calculated based on serum creatinine, age, and gender. RESULTS: The plasma level of mCRP in AAV was significantly higher than that in healthy volunteers (P < 0.001). Then, mCRP and CRP levels were compared with and without STEMI complications in AAV. The plasma level of mCRP was higher, but that of CRP was lower in STEMI. The plasma level of mCRP was correlated with Birmingham vasculitis activity score (BVAS), eGFR, BNP, EF%, LVEDV, LVESV, LVMI, and STEMI complications' Gensini score in AAV; however, CRP did not correlate with BNP, EF%, LVEDV, LVESV, LVMI, and Gensini score. CONCLUSIONS: The plasma level of mCRP was related to cardiovascular diseases in AAV patients.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Doenças Cardiovasculares , Anticorpos Anticitoplasma de Neutrófilos , Biomarcadores , Estudos Transversais , Células Endoteliais , HumanosRESUMO
OBJECTIVE: To determine the role and mechanism of EphB4 in dasatinib (DAS) resistance in advanced chronic myeloid leukemia (CML), we explored the EphB4-mediated apoptotic and matrix microenvironment pathway in human CML and K562 cell lines. METHOD: Heparinized bone marrow samples were obtained from enrolled five patients (identified as A to E and visits identified by number) at initial diagnosis (A1-E1) and in the DAS-resistance advanced phase (A2-E2). Meanwhile, highly DAS-resistant cells, named K562-R cells, were obtained from K562-W cells with increasing concentrations of DAS. Stable under-expressing EphB4 cells (K562-R-EphB4-sh) were obtained from K562-R cells by RNA interference. K562-W, K562-R and K562-R-EphB4-sh cells (108) were respectively injected subcutaneously on the dorsal surface of BALB/C female nude mice to establish the xenografts models. RESULT: The mRNA/protein of EphB4 was overexpressed in the DAS-resistant A2-E2 in comparison with the A1-E1 human cell lines. Further, compared with K562-R cells, the expressions of EphB4 and p-Rac1/Cdc42 protein/mRNA were significantly downregulated in K562-R-EphB4-sh cells (P<0.01). K562-R cells showed the highest DAS resistance (IC50 10.54±0.67µg/ml), but K562-R-EphB4-sh cells became sensitive to DAS (IC50 1.02±0.1µg/ml, P<0.01). The expression of EphB4/p-RhoA/MCL-1 protein was gradually increased in the stimulating of EphrinB2-Fc, which partly made K562-R-EphB4-sh cells restore sensitivity to DAS (4.18±0.30µg/ml). Meanwhile, the K562-R-EphB4-sh xenografts group had relatively good efficacy compared to K562-R xenografts nude mice receiving the same dose of DAS. The analysis of xenografts tissue also suggested parallel results with the overexpression of EphB4/RhoA/ROCK1/PTEN/MCL-1 in K562-R xenografts, which decreased in the A2-R-EphB4-sh xenografts (P<0.01). CONCLUSIONS: The present study found that a new DAS resistance pathway of EphB4 overexpression was triggered by EphrinB2-Fc, which induced the resistance to DAS by activating RhoA/ROCK1/PTEN/MCL-1 signaling.
Assuntos
Apoptose , Dasatinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Receptor EphB4/metabolismo , Adulto , Idoso , Animais , Antineoplásicos/farmacologia , Proliferação de Células , Feminino , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
OBJECTIVE: The open-label, prospective, observational study aimed to evaluate whether decitabine (DAC) plus thalidomide versus DAC monotherapy improved progression-free (PFS), overall survival (OS) and acute myeloid leukemia-free survival (AML-FS) for risk-tailored elderly patients with myelodysplastic syndromes (MDS). METHOD: Enrolled 107 patients (age: 65-82 years) received DAC (52/107) or DAC plus thalidomide (55/107) therapy for MDS. RESULTS: 35/52 patients (67.3%) with DAC therapy reached overall response (OR), compared with 36/55 patients (65.5%) in DAC+thalidomide regimen (P>0.05). DAC+thalidomide administered did not gain more profits of PFS and OS than DAC monotherapy. Risk-tailored analysis showed that DAC+thalidomide therapy did not enhance PFS (48.9% versus 42.8%, P>0.05) and OS (78.6% versus 71.2%, P>0.05) when compared with simple DAC regimen. Nevertheless, DAC+thalidomide markedly improved OS over DAC monotherapy (50.6% versus 40.2%, P<0.05) in high risk profile. Meanwhile, low risk group was superior to high risk group in AML-FS (57.2% versus 21.3%, P<0.01), but DAC+thalidomide still did not prolong 2-year AML-FS when compared with DAC (32.4% versus 27.8%, P<0.05). Moreover, thalidomide had a favorable toxicity profile as a single agent. In comparison with DAC monotherapy, the DAC+thalidomide regimen was relatively well tolerated. There was no severe non-hematological toxicity appearing in elderly patients with MDS. CONCLUSIONS: The study demonstrated that DAC+thalidomide improved 2-year OS for high risk patients. Thalidomide's proven activity and low toxicity profile made it an alternative treatment option for risk-tailored elderly patients with MDS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Idoso , Idoso de 80 Anos ou mais , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Decitabina , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida , Talidomida/administração & dosagemRESUMO
The purpose was to investigate the role of EphB4 in imatinib (IM) resistance and the mechanism responsible for homoharringtonine (HHT) contributing to imatinib sensitivity for a chronic myeloid leukemia (CML) cell lines. We established cell lines from a patient with CML at the time of first diagnosis and relapsed phase and designated them as NPhA1 and NPhA2, respectively. Stable underexpressing EphB4 cells (NPhA2-sh) were obtained. The activated signal proteins in cells were tested by Western blot. The EphB4 was overexpressed in IM-resistant NPhA2 in comparison with the NPhA1 cell line, but the expression of EphB4 mRNA and protein significantly decreased in knockdown NPhA2-EphB4-sh cells compared with NPhA2 and NPhA1 (P < 0.001) cell lines. NPhA2-EphB4-sh cells were sensitive to IM (IC50 0.93 mg/L), and NPhA2 showed IM resistance (IC50 5.45 mg/L) (P < 0.001). Meanwhile, phospho-Rac1/cdc42 was significantly increased in NPhA2 cells compared to NPhA2-EphB4-sh (P < 0.001). The apoptosis rate reached 58.71 ± 2.39 % with NPhA2 cells incubated with HHT + IM, which was higher than NPhA2 cells incubated with IM alone (P = 0.002). IC50 of NPhA2 cells incubated with IM was 5.45 mg/L. However, co-stimulation with HHT + IM decreased the IC50 of NPhA2 cells from 5.45 to 1.17 mg/L (P < 0.001). Furthermore, HHT blocked the expressions of EphB4/RhoA, but did not down-regulate the phospho-MEK/ERK in NPhA2 cells. The overexpression of EphB4 contributed to IM resistance in CML line cells. EphB4/RhoA may be a new marker of IM resistance. HHT + IM gained more treatment advantages than IM alone by blocking EphB4/RhoA pathways in CML cell lines.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Sinergismo Farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Receptor EphB4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Idoso , Apoptose/efeitos dos fármacos , Benzamidas/administração & dosagem , Western Blotting , Proliferação de Células/efeitos dos fármacos , Harringtoninas/administração & dosagem , Mepesuccinato de Omacetaxina , Humanos , Mesilato de Imatinib , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor EphB4/genética , Receptor EphB4/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais CultivadasRESUMO
The open-label, prospective study aimed to evaluate the efficacy and safety for standard intensive chemotherapy compared with attenuated therapy in elderly patients with acute myeloid leukemia (AML). A total of 297 patients between 65 and 82 years were enrolled in the study. The 141 patients received standard-dose therapy (daunorubicin 45 mg/m(2) × 3 days with cytarabine 100 mg/m(2) × 7 days for induction therapy, while post-induction therapy consisted of high-dose cytarabine 1.5 g/m(2) × 4 days), and the attenuated treatment (daunorubicin 30 mg/m(2) × 3 days with cytarabine 75 mg/m(2) × 7 days for induction therapy, while post-induction therapy consisted of attenuated high-dose Ara-C 1.0 g/m(2) × 3 days) was administered to the remaining 156 patients, based on a random number assigned. Total 168 patients (56.6%) achieved complete remission with an incomplete blood recovery (CR)/CRi. No significant differences were observed between the two treatments (P = 0.60). Attenuated chemotherapy improved overall survival (OS) and progression-free survival (PFS) compared to standard-dose therapy; 5-year OS values for these two groups were 39 and 24 months, respectively (P < 0.001), and the PFS values for these two groups were 35 versus 23 months (P < 0.001). In addition, the attenuated treatment with a poor risk profile overcame the negative impact and yielded OS and PFS values similar to those of the standard-dose chemotherapy with a better-to-intermediate risk profile. Five-year OS values for these two groups were 28 versus 28 months (P = 0.89), and the 5-year PFS values were 27 and 28 months, respectively (P = 0.89). The most common adverse drug effect for chemotherapy was agranulocytosis (98.3%). There was a significant difference in early mortality between the attenuated and standard-dose treatment groups (0.64% vs. 7.1%, respectively, P < 0.01). Standard intensive chemotherapy is less effective and far more toxic than attenuated induction and post-induction regimen in elderly patients with AML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Indução de Remissão , Taxa de SobrevidaRESUMO
The open-label, prospective, observational study aimed to evaluate whether the addition of maintenance rituximab (MR) improved progression-free survival (PFS) and overall survival (OS), after fludarabine, cyclophosphamide, and rituximab (FCR) for cytogenetic risk-tailored elderly patients with chronic lymphocytic leukemia (CLL). Enrolled 201 patients (ages 65-84 years) who received FCR and gained an overall response. One hundred and four of 201 patients were in the observation (OBS) arm while 97/201 patients continued to receive MR therapy. After FCR, no more benefits were provided by MR versus OBS in cytogenetic better intermediate-risk cohort. PFS at 10 years reached 68.6 versus 58.1 % (P > 0.05). Ten-year OS was 81.8 versus 74.6 % (P > 0.05). However, the improvement of PFS and OS were as dramatic as the improvements of being MR treating versus OBS mainly in the poor-risk cohort. PFS at 10 years reached 57.1 versus 22.7 % (P < 0.01), and 10-year OS was 71.2 versus 41.7 % (P < 0.01). Compared with OBS, no severe hematologic adverse events (AEs) (Grades 3-4) appeared in patients with MR; only some mild non-hematologic AEs incurred (nausea-vomiting 0.96 %, allergy 1.9 % and infection 1.9 %) during the maintenance treatment. The study showed that MR improved 10-year RFS and OS for cytogenetic poor-risk patients with CLL.
Assuntos
Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Murinos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Estudos Prospectivos , Fatores de Risco , Rituximab , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivadosRESUMO
This open-label, prospective, observational study aimed to evaluate disease-free survival (DFS), overall survival (OS), PML-RARα polymerase chain reaction (PCR) monitoring and safety in elderly patients with de novo acute promyelocytic leukemia (APL) who were treated with either arsenic trioxide (As2O3) or medium-dose cytosine arabinoside (MiDAC) as frontline consolidation regimens. A total of 167 patients (age≥65 years old) received all-trans retinoic acid + daunorubicin as induction therapy. Of these patients, 22 died before attaining complete remission; the remaining 145 subjects received MiDAC- or As2O3-based consolidation therapy. As2O3 was superior to MiDAC for improving DFS and OS. This benefit appeared to result from the longer 5-year DFS (92.0 vs. 69.1%, P<0.01) and OS (94.5 vs. 79.7%, P<0.05) of As2O3 compared to MiDAC. PCR monitoring demonstrated that As2O3 promoted a lower positive rate than MiDAC (21.7 vs. 4.5%, P<0.05), but this treatment had no advantage for maintaining a low positive rate in the high-risk group. The most common life-threatening adverse drug effects in patients with MiDAC were platelet counts<25×10(9)/L (85.7%), leukocyte counts<1.0×10(9)/L (81.4%) and severe infection (84.3%). In contrast, the As2O3 regimen rarely caused leukocyte counts<1.0×10(9)/L (22.7%, P<0.01), platelet counts<25×10(9)/L (37.3%, P<0.01) or severe infection (21.3%, P<0.01). These data confirm that MiDAC should not be added during the initial consolidation of patients with APL because this treatment is far less effective, particularly in patients with a low-risk profile, and far more toxic than As2O3.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Trióxido de Arsênio , Arsenicais/administração & dosagem , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Promielocítica Aguda/mortalidade , Leucemia Promielocítica Aguda/patologia , Masculino , Óxidos/administração & dosagem , Reação em Cadeia da Polimerase , Estudos Prospectivos , Taxa de Sobrevida , Tretinoína/administração & dosagemRESUMO
OBJECTIVE: This open-label, prospective, observational study aimed to evaluate treatment response, efficacy therapy and safety to IFN α-2b for the essential thrombocythemia (ET) and polycythemia vera (PV) with JAK2V617F positive mutation. METHOD: A total of 123 ET patients received IFNα-2b therapy with JAK2V617F positive or negative mutation; and 136 PV patients with JAK2V617F(+) received IFNα-2b or hydroxyurea (HU) therapy according to random number assignment (ages 18-65 years old). RESULT: ET patients receiving IFN α-2b with JAK2V617F(+) had a greater advantage in overall hematologic response (OHR) than JAK2V617F(-) (83.3% versus 61.4%, P<0.01). For PV patients with JAK2V617F(+), IFN had no OHR superiority to HU (70.3% versus 70.8%, P>0.05), but which gained a greater satisfactory molecular response than HU (54.7% versus 19.4%, P<0.01). IFN significantly decreased the phlebotomy rate, which was better than HU for MPDs patients with OHR than HU (3.6% versus 65.7%, P<0.01). Furthermore, ET patients with JAK2V617F(+) demonstrated a definite advantage over JAK2V617F(-) in five-year PFS (75.9% versus 47.6%, P<0.05). For PV patients with JAK2V617F(+), IFN α-2b was superior to HU in five-year PFS (66.3% versus 46.7%, P<0.01). Moreover, IFN α-2b also contributed to improved vasomotor symptoms in MPDs, and especially significantly decreased the incidence of distal paresthesias (14.1% versus 37.5%) and erythromelalgia (9.4% versus 29.2%) better than HU (P<0.01). Meanwhile, IFN did not observe the severe hematological adverse events in patients with PV or ET. CONCLUSION: The data confirmed that IFN α-2b benefited the patients with ET or PV, particularly for JAK2V617F(+) mutation.
Assuntos
Interferon-alfa/uso terapêutico , Janus Quinase 2/genética , Policitemia Vera/tratamento farmacológico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Hidroxiureia , Interferon alfa-2 , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Policitemia Vera/genética , Policitemia Vera/mortalidade , Proteínas Recombinantes/uso terapêutico , Trombocitemia Essencial/genética , Trombocitemia Essencial/mortalidadeRESUMO
BACKGROUND: This was an open-label, observational, prospective assessment. We conducted an analysis of the impact of bortezomib-based therapy (PAD: bortezomib, doxorubicin, high-dose dexamethasone vs. CBd: cyclophosphamide bortezomib, low-dose dexamethasone) on the survival rates and adverse events in elderly patients with newly diagnosed multiple myeloma (MM). METHODS: Out of 303 patients, 128 received the PAD regimen and the other 175 patients received the CBd induction therapy (age 65-89 years). Baseline patient characteristics between the two cohorts were balanced in age (P = 0.69), international staging system (ISS) prognostic stages (P = 0.90), serum calcium (P = 0.70), and serum creatinine (P = 0.52). RESULTS: Overall response (OS) after the induction chemotherapy was achieved in 214 of 303 patients (70.6 %), with no significant differences observed between the two treatment groups (71.9 vs. 69.7 %, P = 0.68). Patients with ISS stage 2 reached the same 5-year OS advantages compared to patients with ISS stage 1, because they received bortezomib-based PAD or CBd treatments. Patients receiving CBd protocol gained similar satisfactory progression-free survival (PFS) results when compared to the PAD regimen group: PFS at 5 years reached 58.2 versus 58.9 % (P = 0.85). Five-year OS in the CBd arm had significant advantages compared to the PAD group, 79.9 versus 49.9 % (P < 0.05). The overall safety profiles showed that 26 of 128 (20.3 %) patients died in the PAD arm, while 13 of 175 patients died (7.4 %) in the CBd group (P < 0.01). Similarly, the PAD arm had a higher serious infection rate than that of the CBd arm (39.2 vs. 13.1 %, P < 0.01). CONCLUSIONS: Bortezomib benefits elderly patients with newly diagnosed MM; they achieve satisfactory treatment responses and survival advantages. Further, patients treated with CBd have superior treatment advantages, with a predictable safety profile, when compared to the PAD regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Ácidos Borônicos/administração & dosagem , Bortezomib , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Pirazinas/administração & dosagem , Taxa de SobrevidaRESUMO
The purpose of the study was to compare the antitumor efficacy and safety profile of high-dose homoharringtonine as induction and post-induction therapy compared to either standard-dose homoharringtonine or daunorubicin in elderly patients with newly diagnosed acute myeloid leukemia. A total of 254 patients, age range 60-77 years received induction and post-induction therapy containing daunorubicin, standard-dose homoharringtonine, or high-dose homoharringtonine. After one course of induction therapy, the overall complete remission rate was similar between treatment arms (58.7%, P = .92). Among 161 patients with acute myeloid leukemia (non-M5 subtype), estimated median overall survival was 39, 29, and 37 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .53). In the 93 patients with acute myeloid leukemia-M5 subtype, there was a significant difference in estimated median overall survival: 24, 24, and 52 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .003). There was no significant difference in drug-related adverse events between treatment arms. High-dose homoharringtonine does not clearly increase the complete remission rate of elderly patients with acute myeloid leukemia. However, in the subset of elderly patients with acute monocytic leukemia, high-dose homoharringtonine as a first-line regimen prolonged overall survival with minimal toxicity.
Assuntos
Antineoplásicos/administração & dosagem , Harringtoninas/administração & dosagem , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Idoso , China , Daunorrubicina/uso terapêutico , Feminino , Harringtoninas/efeitos adversos , Mepesuccinato de Omacetaxina , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: In international prognostic index (IPI) risk-tailored adult patients with diffuse large B-cell lymphoma (DLBCL), it is still unclear whether the addition of maintenance rituximab (MR) improves progression-free (PFS) and overall survival (OS), after RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy. METHODS: In our study, 207 patients (age: 21-59 years) received six 14-day cycles of RCHOP and gained overall response. After RCHOP, 98 patients were enrolled in the observation (OBS) arm. 109 patients continued to receive MR therapy. RESULTS: In IPI risk <2 profile, PFS at 5 years reached 72.9% (MR arm) versus 56% (OBS arm) (P = 0.033). In IPI risk ≥2 profile, PFS estimation at 5 years was 44.9% (MR arm) versus 33.5% (OBS arm) (P = 0.006). It is noteworthy that patients with IPI ≥2 who received MR achieved PFS similar to that for patients in the OBS arm with the IPI <2, 44.9% versus 56% (P = 0.97). In patients with an IPI <2, OS at 5 years was 83.2% (MR arm) versus 81.2% (OBS arm) (P = 0.708). In patients with an IPI ≥2, 5-year OS estimation was 44.6% (MR arm) versus 40.5% (OBS arm) (P = 0.067). Subgroup analysis of patients with an IPI ≥3 risk profile shows a survival benefit for patients receiving MR. OS at 5 years was 62% (MR arm) versus 49% (OBS arm), (P = 0.033). CONCLUSIONS: In conclusion, maintenance rituximab after RCHOP improves progression-free survival. In addition, overall survival is improved for patients with an IPI ≥3 risk profile receiving MR.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Anticorpos Monoclonais Murinos/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Humanos , Quimioterapia de Manutenção , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Rituximab , Vincristina/administração & dosagem , Adulto JovemRESUMO
The purpose of the study was to evaluate event-free survival (EFS), overall survival (OS) and safety for early addition of arsenic trioxide (As(2)O(3)) as frontline consolidation therapy compared to high-dose arabinoside (HiDAC) in adult patients with de novo acute promyelocytic leukemia (APL). 271 patients (aged 17-65 years) received consolidation therapy containing As(2)O(3) (two 21-day courses) or HiDAC regimen. EFS at 5 years was 75% versus 54% (P < 0.001), and OS at 5 years was 83% versus 71% (P = 0.002) in As(2)O(3) and HiDAC treatment arms. 139 patients treated with As(2)O(3), EFS at 5 years reached 79% versus 56% (P = 0.014), but OS at 5 years was 77% versus 84% (P = 0.32) in low-risk (WBC ≤ 10 × 10(9)/L) and high-risk (WBC > 10 × 10(9)/L) cohorts. Further, patients treated with As(2)O(3) rarely incurred agranulocytosis (1.4%, P < 0.001), or severe infection (0.7%, P < 0.001). It is still very well tolerated compared to HiDAC. We confirmed that As(2)O(3) as a first-line consolidation regimen provided significant benefits of OS to patients with APL. The As(2)O(3) regimen made low-risk patients gain more EFS benefits than high-risk group. The high-risk cohort receiving As(2)O(3) overcame the negative impact, yielding OS similar to that for with the low-risk patients treated with As(2)O(3).
Assuntos
Antineoplásicos/uso terapêutico , Arsenicais/uso terapêutico , Quimioterapia de Consolidação/métodos , Citarabina/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Óxidos/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Trióxido de Arsênio , Arsenicais/efeitos adversos , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Promielocítica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Óxidos/efeitos adversos , Tretinoína/uso terapêutico , Adulto JovemRESUMO
OBJECTIVE: To assess the value of multiprobe fluorescence in situ hybridization (FISH) panel in the diagnosis of acute myeloid leukemia (AML). METHODS: The multiprobe AML/MDS panel comprising 8 different FISH probes for AML1/ETO transfusion gene, PML-RARα transfusion gene, CBFß/MYH11 transfusion gene, MLL breakapart, P53 deletion, Del(5q), -7/Del(7q), and Del(20q) was tested in 40 cases of AML, and the results were compared with those by conventional cytogenetic G-banding (CCG) test. RESULTS: With multiprobe FISH panel, 22 of the 40 AML cases were found to carry 7 types of cytogenetic abnormalities, namely AML1/ETO transfusion gene, PML-RARα transfusion gene, MLL breakapart, P53 deletion, Del(5q), -7/Del(7q) and trisomy 8. The positive ratio of the multiprobe FISH was 57.5%. CCG only identified 8 cases with the corresponding cytogenetic abnormalities and 3 cases with other cytogenetic abnormalities, and the positive ratio was only 27.50%. CONCLUSION: Mutiprobe FISH panel is more rapid, accurate and effective than CCG in the diagnosis of AML.
Assuntos
Sondas de DNA , Hibridização in Situ Fluorescente/métodos , Leucemia Mieloide Aguda/diagnóstico , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
High-dose arabinoside (HiDAC) and daunorubicin (DNR)-based chemotherapy are the primary consolidation treatment options for older adults (50-60 years old) with acute myeloid leukemia in China. We analyzed the event-free survival (EFS) and hospital treatment charges of older adult patients with different cytogenetic risk profiles. In patients with a better/intermediate risk profile, the average total treatment cost of HiDAC was similar to that of DNR (P = 0.11). A 5-year follow-up of patients with better/intermediate cytogenetic risk profiles revealed that the median EFS of patients who received HiDAC was significantly longer than for patients who received the DNR-based regimen (27 vs. 20 months, P = 0.03). Average cost per year of life saved was 18,746.84 USD for HiDAC, compared to 32,733.37 USD for DNR. In contrast, for patients with a poor cytogenetic risk profile, the average total treatment cost for HiDAC was higher than for DNR (P < 0.005). In addition, the median EFS in the HiDAC protocol group was significantly lower than in the DNR group (11 vs. 20 months, P = 0.003). Meanwhile, in this risk group, the average cost per year of life saved was 103,237.70 USD compared to 32,277.93 USD, respectively, in the HiDAC and DNR regimens. We conclude that HiDAC is a more efficacious and cost-effective consolidation treatment regimen in the better/intermediate risk group, while the DNR-based regimen is more cost-effective in the poor risk group.
Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Análise Custo-Benefício , Análise Citogenética , Feminino , Custos de Cuidados de Saúde , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-IdadeRESUMO
This study was purposed to investigate the relationship of expressions of gluthatione-S-transferase-pi (GST-pi), multidrug resistance protein-1 (MRP-1), lung resistance protein (LRP) with multidrug resistance of acute leukemia (AL), the correlation between 3 kinds protein expressions and the correlation of their protein expression with clinical features of AL patients. The S-P immunohistochemical staining method was used to determine the expressions of GST-pi, MRP1 and LRP proteins in 80 AL patients and 30 normal subjects. The results showed that there was the correlation between GST-pi, MRP1, LRP protein expression and chemotherapy resistance, meanwhile CR rates of patients with positive expression of those proteins were lower than that of patients with negative expression (P<0.05), so those protein expressions may be accounted for poor prognosis. There was the positive relationship between expression of GST-pi and MRP1 in refractory group (r=0.851, P<0.01). It is concluded that co-examination of GST-pi and MRP1 has greater significance than examination of one kind of protein in evaluating poor prognosis of leukemia patients. LRP protein expression increase obviously when WBC counts >or= 10 x 10(9)/L (63.6%, P<0.05), therefore LRP protein has great judging value for evaluating drug resistance and prognosis of acute leukemia patients whose peripheral blood WBC counts were high.