RESUMO
BACKGROUND: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined. OBJECTIVE: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT. METHODS: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities. RESULTS: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT. CONCLUSION: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência , Transtornos Linfoproliferativos , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Classe I de Fosfatidilinositol 3-Quinases/imunologia , Intervalo Livre de Doença , Feminino , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/mortalidade , Síndromes de Imunodeficiência/patologia , Síndromes de Imunodeficiência/terapia , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/mortalidade , Transtornos Linfoproliferativos/patologia , Transtornos Linfoproliferativos/terapia , Masculino , Doenças da Imunodeficiência Primária , Taxa de SobrevidaRESUMO
Multiple myeloma (MM) is a uniformly fatal disorder of B cells characterized by the accumulation of abnormal plasma cells. Phosphoinositide 3-kinase (PI3K) signaling pathways play a critical regulatory role in MM pathology. Copanlisib, also known as BAY80-6946, is a potent PI3Kα and δ inhibitor. In this study, we investigated the efficacy of copanlisib and a proteasome inhibitor using MM cell lines and primary samples. The p110α and δ catalytic subunits of the class PI3K increased, and carfilzomib activity reduced in the presence of a supernatant from the feeder cell line, HS-5. Phosphorylation of Akt and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) partially reduced upon carfilzomib treatment in the presence of HS-5. Apoptosis also decreased. Copanlisib treatment for 72 h inhibited growth in MM cell lines and induced apoptosis. Combination treatment of MM cells with carfilzomib and copanlisib caused greater cytotoxicity than that caused by either drug alone and increased apoptosis. Caspase 3 activity increased while that of Akt decreased after combination treatment with copanlisib and carfilzomib. Further, copanlisib inhibited vascular endothelial growth factor (VEGF)-mediated angiogenesis in vitro and in vivo. It also inhibited C-X-C motif chemokine 12 (CXCL12)-mediated chemotaxis. The data suggest that administration of the PI3K inhibitor, copanlisib, may be a powerful strategy against stroma-associated drug resistance of MM cells and can enhance the cytotoxic effects of proteasome inhibitors in such residual MM cells.
Assuntos
Antineoplásicos/farmacologia , Mieloma Múltiplo/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Oligopeptídeos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Células 3T3 , Inibidores da Angiogênese/farmacologia , Animais , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Quimiocina CXCL12/antagonistas & inibidores , Quimiotaxia/efeitos dos fármacos , Sinergismo Farmacológico , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/enzimologia , Invasividade Neoplásica , Inibidores de Proteassoma/farmacologia , Células Estromais/efeitos dos fármacosRESUMO
Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos Clínicos , Leucemia Mieloide Aguda/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Masculino , Compostos de Fenilureia/administração & dosagem , Projetos de PesquisaRESUMO
Fatal events during treatment with ABL tyrosine kinase inhibitors (ABL TKIs) have been reported, and there have been concerns of high mortality rate in patients with chronic myeloid leukemia receiving ABL TKIs. The predictive factors of patients treated with ABL TKIs who are at risk of potentially fatal toxicities remain unknown. Although this scenario appears discouraging, the risk of severe toxicity might be predicted by investigating the effect of genetic variation on the disposition of ABL TKIs. Global genomic surveys should be conducted to identify factors contributing to an increased risk of toxicity using multivariable analyses with particular reference to ABL TKIs pharmacokinetics and baseline clinical characteristics.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/toxicidade , Análise Mutacional de DNA , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidadeRESUMO
A 53-year-old woman with a 27-year history of myeloproliferative neoplasms came to our hospital because of a marked white blood cell count increase and progressive anemia. Clinical examination demonstrated positivity for BCR-ABL1 and JAK2-V617F mutations. She was given a diagnosis of chronic myeloid leukemia. Using the international scale, a molecular response (MR) 4.5 was achieved after treatment with dasatinib, despite the persistence of marked splenomegaly. The pathological findings of myelofibrosis were demonstrated by bone marrow biopsy. After stopping dasatinib administration for 4 years and 5 months, treatment with ruxolitinib was started. Five months later, the size of her spleen was reduced. We speculated that translocation of BCR-ABL1 might have occurred in a sub-clone of the JAK2-V617F mutated tumor clone.
Assuntos
Janus Quinase 2/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Mielofibrose Primária/etiologia , Antineoplásicos/uso terapêutico , Feminino , Proteínas de Fusão bcr-abl/análise , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Pessoa de Meia-IdadeRESUMO
Approximately 40% of chronic myeloid leukemia (CML) patients who discontinue imatinib (IM) therapy maintain undetectable minimal residual disease (UMRD) for more than one year (stopping IM (STOP-IM)). To determine a possible biomarker for STOP-IM CML, we examined plasma miRNA expression in CML patients who were able to discontinue IM. We first screened candidate miRNAs in unselected STOP-IM patients, who had sustained UMRD after discontinuing IM for more than six months, in comparison with healthy volunteers, by using a TaqMan low-density array for plasma or exosomes. Exosomal miR-215 and plasma miR-215 were downregulated in the STOP-IM group compared to the control, indicating that the biological relevance of the plasma miR-215 level is equivalent to that of the exosomal level. Next, we performed real-time quantitative RT-PCR in 20 STOP-IM patients, 32 patients with UMRD on continued IM therapy (IM group) and 28 healthy volunteers. The plasma miRNA-215 level was significantly downregulated in the STOP-IM group (p < 0.0001); we determined the cut-off level and divided the IM group patients into two groups according to whether the plasma miR-215 was downregulated or not. The IM group patients with a low plasma miR-215 level had a significantly higher total IM intake, compared to the patients with elevated miR-215 levels (p = 0.0229). Functional annotation of miR-215 target genes estimated by the Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatic tools involved cell cycle, mitosis, DNA repair and cell cycle checkpoint. Our study suggests a possible role of miR-215 in successful IM discontinuation.
Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , MicroRNAs/genética , Regulação para Baixo/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , MicroRNAs/sangueRESUMO
We conducted a questionnaire survey to assess the state of patients with CML after discontinuation of TKI therapy. Nine of 27 patients developed musculoskeletal pain after TKI discontinuation. One had discontinued nilotinib and eight had discontinued imatinib therapy. Median time to symptom development after discontinuation was 2 weeks. Four experienced grade 3 symptoms as per the CTCAE ver. 4.0. One had pain persisting over a period of 21 months. There was a significant difference between patients with and without symptoms as regards female gender and the probability of persistent MMR. Awareness of this withdrawal syndrome after TKI discontinuation is imperative.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Dor Musculoesquelética/etiologia , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Tirosina Quinases/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Inquéritos e Questionários , Resultado do TratamentoRESUMO
A 51-year-old man with chronic myeloid leukemia (CML) was treated with imatinib (IM). After 24 months of treatment, he achieved a complete molecular response (CMR), which he sustained for 3 years. However, 4 months after discontinuing IM treatment, the CML relapsed. The patient was treated again with IM and achieved CMR. A combination of IM and interferon-α (IFNα) was administered for the following year, and then discontinued. The patient has since sustained CMR without therapy for 24 months, to date. This patient was found to have a BCL2L11 (BIM) deletion polymorphism. CML patients with a BIM deletion polymorphism show a low response to IM, and we infer that the BIM deletion polymorphism is a negative factor for discontinuation of IM. IFNα treatment is expected to prevent relapse during immunological surveillance. Therefore, the combination of IM and IFNα might be a feasible approach for CML patients who experience difficulty with IM discontinuation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas Reguladoras de Apoptose/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Proteínas de Membrana/genética , Polimorfismo Genético , Proteínas Proto-Oncogênicas/genética , Proteína 11 Semelhante a Bcl-2 , Benzamidas/administração & dosagem , Terapia Combinada , Deleção de Genes , Humanos , Mesilato de Imatinib , Interferon-alfa/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Recidiva , Indução de Remissão/métodosRESUMO
Promising outcomes have been reported in elder patients with acute myeloid leukemia (AML) using combined therapy of venetoclax (VEN) and azacytidine (AZA) in recent years. However, approximately one-third of patients appear to be refractory to this therapy. Vitamin K2 (VK2) shows apoptosis-inducing activity in AML cells, and daily oral VK2 (menaquinone-4, GlakayR) has been approved for patients with osteoporosis in Japan. We observed a high response rate to AZA plus VEN therapy, with no 8-week mortality in the newly diagnosed AML patients consuming daily VK2 in our hospital. The median age of the patients was 75.9 years (range 66-84) with high-risk features. Patients received AZA 75 mg/m2 on D1-7, VEN 400 mg on D1-28, and daily VK2 45 mg. The CR/CRi ratio was 94.7% (18/19), with a CR rate of 79%. Complete cytogenetic CR was achieved in 15 of 19 (79%) patients, and MRD negativity in 2 of 15 (13%) evaluable CR patients. Owing to the extremely high response rate in clinical settings, we further attempted to investigate the underlying mechanisms. The combination of VK2 and VEN synergistically induced apoptosis in all five AML cell lines tested. VK2, but not VEN, induced mitochondrial reactive oxygen species (ROS), leading to the transcriptional upregulation of NOXA, followed by MCL-1 repression. ROS scavengers repressed VK2 induced-NOXA expression and led to the cancellation of pronounced apoptosis and the downregulation of MCL-1 by VK2 plus VEN. Additionally, knockdown and knockout of NOXA resulted in abrogation of the MCL-1 repression as well as enhanced cytotoxicity by the two-drug combination, indicating that VK2 suppresses MCL-1 via ROS-mediated NOXA induction. These data suggest that the dual inhibition of BCL-2 by VEN and MCL-1 by VK2 is responsible for the remarkable clinical outcomes in our patients. Therefore, large-scale clinical trials are required.
Assuntos
Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Proteína de Sequência 1 de Leucemia de Células Mieloides , Proteínas Proto-Oncogênicas c-bcl-2 , Sulfonamidas , Vitamina K 2 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Idoso , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico , Vitamina K 2/farmacologia , Vitamina K 2/análogos & derivados , Vitamina K 2/uso terapêutico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Feminino , Masculino , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Sinergismo Farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Espécies Reativas de Oxigênio/metabolismo , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Treatment-free remission (TFR) is a new therapeutic goal for chronic myeloid leukemia in chronic phase (CML-CP). Deep molecular response (DMR) is a prerequite condition for TFR. The Japan Adult Leukemia Study Group (JALSG) conducted a multicentral prospective randomized phase 3 CML212 study for de novo CML-CP to compare the cumulative achievement of MR4.5 (international scale [IS] BCR::ABL1≤0.0032%) by 18 months between nilotinib and dasatinib as a primary endpoint. A total of 454 patients were randomly assigned to the nilotinib 300 mg, bid arm or dasatinib 100 mg, qd arm (both, n=227). BCR::ABL1 mRNA levels were monitored every three months. Study treatment was stopped if the patients were judged as failure by the European LekemiaNet (ELN) 2009 criteria or showed intolerance. The cumulative achievement rates of MR4.5 by 18 months were 32.6% (95% confidence interval [CI]: 26.5-39.1%) in the nilotinib arm and 30.8% (95% CI: 24.9-37.3%) in the dasatinib arm with no significant difference (p=0.66). Also, the cumulative achievement rates of early molecular response (EMR), complete cytogenetic response (CCyR) and major molecular response (MMR), MR4.0 by 12, 18, 24, and 36 months were almost the same between the two arms. At 36 months, 66.5% and 65.0% patients continued nilotinib and dasatinib, respectively (p=0.76). There was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two arms by log-rank tests (PFS, p=0.58; OS, p=0.64). These results suggest that nilotinib and dasatinib would be equally effective for de novo CML-CP patients with similar continuity. UMIN Clinical Trials Registry (#UMIN000007909).
RESUMO
A number of CML patients who achieve a sustained complete molecular response (CMR) for at least 2 years during imatinib (IM) therapy can discontinue IM without relapse. With the long-term goal of developing immunological criteria for managing IM therapy in CML patients, we compared the immunophenotypic profiles of three groups of CML patients: those who received IM and had a CMR for more than two consecutive years (CMR group); patients who received IM and did not have a sustained CMR but maintained a major molecular response for more than 2 years (fluctuating CMR group); and patients with a sustained CMR for more than 6 months after IM discontinuation (STOP-IM group), together with healthy controls. The percentages of effector populations of natural killer (NK) cells, such as interferon (IFN)-γ(+) CD3(-) CD56(+) cells, were significantly higher in the STOP-IM and CMR groups than in the fluctuating CMR and control groups. The elevated levels of these effector NK cells were sustained for more than 3 years after IM discontinuation. In contrast, the percentages of effector memory CD8(+) T cells, such as IFN-γ(+) CCR7(-) CD45RO(+) CD8(+) cells, were significantly higher in the STOP-IM and control groups than in the CMR and fluctuating CMR groups, possibly owing to IM intake. These results suggest that the immunological activation status of NK cells contributes to CMR maintenance. Higher activation levels of effector NK cells in CML patients being treated with IM might reflect minimization of BCR-ABL1 transcript levels and therefore could be additive information for determining whether to stop IM.
Assuntos
Benzamidas/uso terapêutico , Células Matadoras Naturais/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Feminino , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Resultado do Tratamento , Regulação para CimaRESUMO
Because a substantial number of patients with chronic myeloid leukemia acquire resistance to ABL tyrosine kinase inhibitors (TKIs), their management remains a challenge. Ponatinib, also known as AP24534, is an oral multi-targeted TKI. Ponatinib is currently being investigated in a pivotal phase 2 clinical trial. In the present study, we analyzed the molecular and functional consequences of ponatinib against imatinib- or nilotinib-resistant (R) K562 and Ba/F3 cells. The proliferation of imatinib- or nilotinib-resistant K562 cells did not decrease after treatment with imatinib or nilotinib. Src family kinase Lyn was activated. Point mutation Ba/F3 cells (E334V) were also highly resistant to imatinib and nilotinib. Treatment with ponatinib for 72h inhibited the growth of imatinib- and nilotinib-resistant cells. The phosphorylation of BCR-ABL, Lyn, and Crk-L was reduced. This study demonstrates that ponatinib has an anti-leukemia effect by reducing ABL and Lyn kinase activity and this information may be of therapeutic relevance.
Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Piridazinas/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismoRESUMO
BACKGROUND: The use of imatinib, an ABL tyrosine kinase inhibitor, has led to a dramatic change in the management of BCR-ABL-positive leukemia patients. However, resistance to imatinib mediated by mutations in the BCR-ABL domain has become a major problem in the treatment of these patients. METHODS: In the present study, we examined the activity of histone deacetylase (HDAC) inhibitors in combination with an Aurora kinase inhibitor in BCR-ABL-expressing cells. RESULTS: We found the HDAC inhibitors vorinostat and/or pracinostat (SB939) induced apoptosis in BCR-ABL-expressing cells. Additionally, HDAC inhibitors reduced levels of Aurora A and B protein. An Aurora kinase inhibitor, tozasertib (VX-680), inhibited growth, promoted pro-apoptotic activity, reduced the phosphorylation of BCR-ABL and Crk-L, and activated caspase-3 and poly (ADP-ribose) polymerase (PARP) in BCR-ABL-positive cells. Moreover, after treatment with tozasertib, HDAC protein expression was decreased. Combination of vorinostat or pracinostat with tozasertib had a synergistic inhibitory effect on the proliferation of T315I cells. Phosphorylation of Crk-L decreased, and PARP activation increased after treatment with vorinostat or pracinostat and tozasertib. Moreover, combination of vorinostat or pracinostat and tozasertib significantly increased the extent of apoptosis in primary chronic myeloid leukemia cells. CONCLUSIONS: This study demonstrated that combination of HDAC and Aurora inhibitors was highly effective against BCR-ABL-expressing cells.
RESUMO
A 68-year-old man was diagnosed with chronic lymphocytic leukemia (CLL) 3 years ago. His course was progressive, and he was complicated with autoimmune hemolytic anemia (AIHA). After the lack of efficacy of prednisone and cyclo-phosphamide, rituximab (375mg/m(2)) was administered based on the presence of CD20 positive leukemic cells by flow cytometric analysis of bone marrow. During 4 courses of rituximab administration, both anemia and hemolysis improved dramatically. Furthermore, the percentage of CLL cells in his peripheral blood was reduced. Rituximab may be one of the effective treatments for CLL associated AIHA in Japan as well as in foreign countries.
Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anticorpos Monoclonais Murinos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Idoso , Anemia Hemolítica Autoimune/diagnóstico , Anemia Hemolítica Autoimune/etiologia , Fator Estimulador de Colônias de Granulócitos/sangue , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/diagnóstico , Masculino , Rituximab , Resultado do TratamentoRESUMO
A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography-tandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival (OS) and event-free survival (EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400-mg group; n = 294), 270-359 mg (300-mg group; n = 90) and <270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Piperazinas/sangue , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Benzamidas , Progressão da Doença , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Masculino , Pessoa de Meia-Idade , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/uso terapêutico , Resultado do Tratamento , Adulto JovemAssuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Harringtoninas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Regulação Leucêmica da Expressão Gênica , Proteínas de Choque Térmico HSP90/genética , Proteínas de Choque Térmico HSP90/metabolismo , Mepesuccinato de Omacetaxina , Humanos , Imidazóis/farmacologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Cultura Primária de Células , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Piridazinas/farmacologia , Transdução de SinaisRESUMO
Aurora kinases play a pivotal role in the regulator of mitotic processes during cell division and Aurora kinases are overexpressed in a number of human cancers. In this study, we examined the intracellular signaling of Aurora kinases inhibitor, MK-0457 (VX-680), in BCR-ABL positive cell lines and in primary samples. MK-0457 induced apoptosis. Caspase 3 and poly (ADP-ribose) polymerase (PARP) were activated and heat shock proteins were reduced. A combination of MK-0457 and histone deacetylase inhibitor, vorinostat, increased apoptosis. Caspase 3 and PARP were activated and phosphorylation of BCR-ABL, Lyn, and Crk-L were reduced. BCR-ABL and Aurora A and B were reduced after vorinostat treatment. Moreover, combination of vorinostat and MK-0457 synergistically increased the extent of apoptosis in primary acute lymphoblastic leukemia cells with T315I mutation. Our study increases insight into how MK-0457 may mediate its effects on BCR-ABL positive leukemia cells with T315I mutation, and information of potential therapeutic relevance.
Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos , Piperazinas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Adulto , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Aurora Quinases , Linhagem Celular Tumoral , Proliferação de Células , Quimioterapia Combinada , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/farmacologia , Ácidos Hidroxâmicos/uso terapêutico , Piperazinas/farmacologia , Piperazinas/uso terapêutico , VorinostatRESUMO
To evaluate the effect of deferasirox in human myeloid leukemia cells, and to identify the molecular pathways responsible for antiproliferative effects on leukemia cells during chelation therapy, we performed gene expression profiling to focus on the pathway involved in the anticancer effect of deferasirox. The inhibitory concentration (IC50) of deferasirox was 17-50 microM in three human myeloid cell lines (K562, U937, and HL60), while those in fresh leukemia cells obtained from four patients it varied from 88 to 172 microM. Gene expression profiling using Affymerix GeneChips (U133 Plus 2.0) revealed up-regulation of cyclin-dependent kinase inhibitor 1A (CDKN1A) encoding p21CIP, genes regulating interferon (i.e. IFIT1). Pathways related to iron metabolism and hypoxia such as growth differentiation factor 15 (GDF-15) and Regulated in development and DNA damage response (REDD1) were also prominent. Based on the results obtained from gene expression profiling, we particularly focused on the REDD1/mTOR (mammalian target of rapamycin) pathway in deferasirox-treated K562 cells, and found an enhanced expression of REDD1 and its down-stream protein, tuberin (TSC2). Notably, S6 ribosomal protein as well as phosphorylated S6, which is known to be a target of mTOR, was significantly repressed in deferasirox-treated K562 cells, and REDD1 small interfering RNA restored phosphorylation of S6. Although iron chelation may affect multiple signaling pathways related to cell survival, our data support the conclusion that REDD1 functions up-stream of tuberin to down-regulate the mTOR pathway in response to deferasirox. Deferasirox might not only have benefit for iron chelation but also may be an antiproliferative agent in some myeloid leukemias, especially patients who need both iron chelation and reduction of leukemia cells.
Assuntos
Benzoatos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Quelantes de Ferro/farmacologia , Leucemia Mieloide/metabolismo , Proteínas Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzoatos/administração & dosagem , Linhagem Celular Tumoral , Deferasirox , Progressão da Doença , Perfilação da Expressão Gênica , Humanos , Quelantes de Ferro/administração & dosagem , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Camundongos , Camundongos Nus , Proteína S6 Ribossômica/metabolismo , Serina-Treonina Quinases TOR , Fatores de Transcrição/genética , Triazóis/administração & dosagem , Regulação para Cima , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Mutation in the ABL kinase domain is the principal mechanism of imatinib resistance. MK-0457 is a small molecule inhibitor of the Aurora kinase family, but the mechanism of MK-0457 has not been evaluated. In this study, the gene expression profiles and intracellular signaling of chronic myeloid leukemia (CML) cell line K562 exposed to imatinib or MK-0457. MK-0457 induced cell growth inhibition in K562 cells. In gene expression profiles, there was an increase of 938 genes in imatinib and 895 genes in MK-0457 and 638 genes overlapped. In contrast, there was a decrease of 597 genes in imatinib and 582 genes in MK-0457 and 406 genes overlapped. These down-regulated genes include heat shock proteins (HSPs). These results indicate that MK-0457 is effective in CML cells by the down-regulation of HSPs which may relate to BCR-ABL stability, and offer new information regarding the molecular basis of strategy against to CML.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/metabolismo , Apoptose , Benzamidas , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proteínas de Fusão bcr-abl , Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP90/genética , Humanos , Mesilato de Imatinib , Pirimidinas/farmacologia , Transcrição Gênica/efeitos dos fármacosRESUMO
PURPOSE: Although dual src-family kinase/BCR/ABL inhibitor, dasatinib (BMS-354825), provides therapeutic advantages to imatinib-resistant cells, the mechanism of dasatinib resistance was not fully known. EXPERIMENTAL DESIGN: We used TF-1 BCR/ABL cells, by introducing the BCR/ABL gene into a leukemia cell line, TF-1 and K562, and established dasatinib- (BMS-R) and imatinib-resistant (IM-R) cells. We characterized chronic myelogenous leukemia drug-resistant cells and examined intracellular signaling. RESULTS: The IC(50) of dasatinib was 0.75 nmol/L (TF-1 BCR/ABL), 1 nmol/L (K562), 7.5 nmol/L (TF-1 BCR/ABL IM-R), 10 nmol/L (K562 IM-R), 15 micromol/L (TF-1 BCR/ABL BMS-R), and 25 micromol/L (K562 BMS-R). The number of BCR/ABL copies in resistant cell lines was the same as the parental cell line by fluorescence in situ hybridization analysis. There was no mutation in Abl kinase. We found that protein levels of BCR/ABL were reduced in dasatinib-resistant cell lines. BCR/ABL protein was increased by treatment of an ubiquitin inhibitor. The Src kinase, Lck, as well as mitogen-activated protein kinase and Akt were activated, but p21(WAF), phosphatase and tensin homologue was reduced in K562 BMS-R cells. Removal of dasatinib from the culture medium of K562 BMS-R cells led to apoptosis, and activated caspase 3 and poly (ADP-ribose) polymerase. CONCLUSION: These results suggest that the expression and protein activation signatures identified in this study provide insight into the mechanism of resistance to dasatinib and imatinib and may be of therapeutic chronic myelogenous leukemia value clinically.