RESUMO
Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.
Assuntos
Proliferação de Células , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mielomonocítica Crônica/metabolismo , Células-Tronco Multipotentes/metabolismo , Mutação , Transtornos Mieloproliferativos/metabolismo , Tirosina Quinase 3 Semelhante a fms/metabolismo , Animais , Diferenciação Celular , Sobrevivência Celular , Células Cultivadas , Éxons , Regulação Neoplásica da Expressão Gênica , Genótipo , Células-Tronco Hematopoéticas/patologia , Humanos , Estimativa de Kaplan-Meier , Leucemia Experimental/metabolismo , Leucemia Experimental/patologia , Leucemia Mielomonocítica Crônica/genética , Leucemia Mielomonocítica Crônica/mortalidade , Leucemia Mielomonocítica Crônica/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Multipotentes/patologia , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Fenótipo , Transdução de Sinais , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Disease alleles that activate signal transduction are common in myeloid malignancies; however, there are additional unidentified mutations that contribute to myeloid transformation. Based on the recent identification of TET2 mutations, we evaluated the mutational status of TET1, TET2, and TET3 in myeloproliferative neoplasms (MPNs), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML). Sequencing of TET2 in 408 paired tumor/normal samples distinguished between 68 somatic mutations and 6 novel single nucleotide polymorphisms and identified TET2 mutations in MPN (27 of 354, 7.6%), CMML (29 of 69, 42%), AML (11 of 91, 12%), and M7 AML (1 of 28, 3.6%) samples. We did not identify somatic TET1 or TET3 mutations or TET2 promoter hypermethylation in MPNs. TET2 mutations did not cluster in genetically defined MPN, CMML, or AML subsets but were associated with decreased overall survival in AML (P = .029). These data indicate that TET2 mutations are observed in different myeloid malignancies and may be important in AML prognosis.
Assuntos
Proteínas de Ligação a DNA/genética , Leucemia Mieloide Aguda/genética , Leucemia Mielomonocítica Crônica/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Estudos de Casos e Controles , Códon sem Sentido , Dioxigenases , Éxons , Mutação da Fase de Leitura , Humanos , Oxigenases de Função Mista , Mutação de Sentido Incorreto , Transtornos Mieloproliferativos/genética , Polimorfismo de Nucleotídeo Único , Prognóstico , Deleção de Sequência , Taxa de SobrevidaRESUMO
PURPOSE: To determine the safety and describe the antitumor activity of tipifarnib in patients with myelodysplastic syndrome (MDS) using an alternate-week schedule. EXPERIMENTAL DESIGN: Patients with MDS were given tipifarnib, escalating from 100 mg orally twice daily until the maximum tolerated dose for 8 weeks followed by maintenance therapy (same dose/schedule) for patients with stable disease or better. RESULTS: Sixty-three patients were treated. The most common toxicity was myelosuppression (60% of patients). Twenty percent of patients had no side effects. Nonhematologic toxicities included fatigue (20%), skin rash (9%), diarrhea (16%), increase in liver transaminases (14%) and bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib doses above 1,200 mg/d. Sixteen of 61 (26%) evaluable patients responded (3 complete remissions and 13 hematologic improvements) with major platelet responses being most common (11 of 16 responders). There was no obvious dose-response relationship. Four of the 16 responders (25%; including a complete responder) were treated at the lowest dose level (100 mg twice daily). Only one responder had a Ras mutation. Giving tipifarnib resulted in potent inhibition of farnesyl transferase (usually more than 75%) in peripheral blood mononuclear cells regardless of dose. Partial farnesyl transferase inhibition persisted during the week off. CONCLUSIONS: Alternate-week tipifarnib is active and well tolerated in patients with MDS at doses up to and including 600 mg orally twice daily. The biological activity of tipifarnib is not dependent on dose.
Assuntos
Farnesiltranstransferase/metabolismo , Síndromes Mielodisplásicas/tratamento farmacológico , Quinolonas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Esquema de Medicação , Farnesiltranstransferase/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/enzimologia , Síndromes Mielodisplásicas/imunologia , Quinolonas/efeitos adversos , Quinolonas/uso terapêuticoRESUMO
The initial success of the first synthetic bcr-abl kinase inhibitor imatinib has been dampened by the emergence of imatinib-resistant disease in blast crisis chronic myeloid leukemia. Here, we report that the novel triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-diene-28-oate (CDDO-Me) potently induced cytotoxicity in imatinib-resistant KBM5 cells expressing the T315I mutation of bcr-abl (24-h EC50, 540 nmol/L). In long-term culture, CDDO-Me abrogated the growth of human parental KBM5 and KBM5-STI cells with 96-h IC50 of 205 and 221 nmol/L, respectively. In addition, CDDO-Me rapidly decreased the viability of murine lymphoid Ba/F3 cells expressing wild-type p210 as well as the imatinib-resistant E255K and T315I mutations of bcr-abl. The low-dose effects of CDDO-Me are associated with inhibition of mitochondrial oxygen consumption, whereas the cytotoxic effects appear to be mediated by a rapid and selective depletion of mitochondrial glutathione that accompanies the increased generation of reactive oxygen species and mitochondrial dysfunction. Interestingly, the mitochondriotoxic effects of CDDO-Me are followed by the rapid autophagocytosis of intracellular organelles or the externalization of phosphatidylserine in different cell types. We conclude that alterations in mitochondrial function by CDDO-Me can result in autophagy or apoptosis of chronic myeloid leukemia cells regardless of the mutational status of bcr-abl. CDDO-Me is in clinical trials and shows signs of clinical activity, with minimal side effects and complete lack of cardiotoxicity. Studies in leukemias are in preparation.
Assuntos
Antineoplásicos/farmacologia , Apoptose , Autofagia , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Mitocôndrias/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , Benzamidas , Relação Dose-Resposta a Droga , 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/patologia , Mitocôndrias/metabolismo , Ácido Oleanólico/farmacologia , Oxirredução , Oxigênio/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Chronic myelomonocytic leukemia continues to be a poorly understood disease, defined by clinical rather than biological features, with no consensus on optimal therapy. In the past, patients were often assessed for risk using scoring systems developed for other diseases, notably the International Prognostic Scoring System commonly used for myelodysplastic syndrome. The M.D. Anderson Prognostic Scoring System, using hemoglobin, absolute lymphocyte count, peripheral blood immature cells, and bone marrow blasts, was developed specifically for CMML; it was based on retrospective analysis of 213 patients. This report re-examines the validity of this scoring system based on follow-up of the initial cohort and prospectively examines its validity in 250 new patients. Both the original MDAPS system and a modified version derived from data of the initial cohort after extended follow-up (substituting lactate dehydrogenase for bone marrow blasts) effectively stratify both patient cohorts by survival and provide a useful risk assessment tool and additional guidance during treatment decisions.
Assuntos
Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/etiologia , Leucemia Mielomonocítica Crônica/patologia , Estadiamento de Neoplasias/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Projetos de Pesquisa , Medição de Risco , Fatores de Risco , Análise de SobrevidaRESUMO
PURPOSE: The efficacy, toxicity, and tolerability of chemoimmunotherapy with the combination of fludarabine, cyclophosphamide, and rituximab (FCR) were evaluated in previously treated patients with chronic lymphocytic leukemia (CLL). The purpose of this study was to improve the complete remission (CR) rate for previously treated patients and evaluate the quality of bone marrow response. PATIENTS AND METHODS: One hundred seventy-seven previously treated patients with CLL were evaluated. Treatment consisted of rituximab 375 mg/m(2) day 1 of course 1 and 500 mg/m(2) day 1 of courses 2 to 6; fludarabine 25 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6; and cyclophosphamide 250 mg/m(2)/d days 2 to 4 of course 1 and days 1 to 3 of courses 2 to 6. Courses were repeated every 4 weeks. RESULTS: CR was achieved in 25% of 177 patients, and nodular partial remission and partial remission were achieved in 16% and 32% of patients, respectively; the overall response rate was 73%. Twelve (32%) of 37 complete responders tested achieved molecular remission in bone marrow. Univariate and multivariate analyses were used to identify pretreatment patient characteristics associated with CR and overall remission, longer time to progression, and overall survival. CONCLUSION: The FCR regimen was an active and well-tolerated treatment for previously treated patients with CLL. Myelosuppression was the most common toxicity. FCR induced the highest CR rate reported in a clinical trial of previously treated patients with CLL. Furthermore, molecular remissions were achieved in a third of patients achieving CR.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Vidarabina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Murinos , Distribuição de Qui-Quadrado , Ciclofosfamida/administração & dosagem , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Recidiva , Indução de Remissão , Rituximab , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagemRESUMO
PURPOSE: To investigate the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of BMS-214662, a farnesyl transferase (FTase) inhibitor, in patients with acute leukemias and high-risk myelodysplastic syndromes (MDS). PATIENTS AND METHODS: Patients with relapsed or refractory acute leukemias or MDS, or previously untreated but poor candidates for chemotherapy, were included in this phase I study with a 3 + 3 dose escalation design. BMS-214662 was administered as a 1-hour bolus once weekly at doses of 42 to 157 mg/m2. Once the MTD was identified, the schedule was changed to a 24-hour continuous infusion once weekly (starting dose, 300 mg/m2). RESULTS: Thirty patients were treated at a dose of 42 (n = 1), 56 (n = 3), 84 (n = 3), 118 (n = 13), 157 (n = 6) or 300 mg/m2 (n = 4). DLT occurred in 3 patients at 157 mg/m2, including nausea, vomiting, diarrhea, hypokalemia and cardiovascular problems. No DLT occurred with 24-hour continuous infusion. MTD with a 1-hour infusion was 118 mg/m2, with no MTD identified with the 24-hour infusion. Plasma concentrations of BMS-214662 correlated with the dose. Inhibition of FTase activity of approximately 60% occurred after the infusion with recovery to near baseline after 24 hours. Five patients had evidence of antileukemia activity, including two with complete remission with incomplete platelet recovery, one with hematologic improvement, and two with morphologic leukemia-free state. CONCLUSION: BMS-214662 is well tolerated at doses of up to 118 mg/m2 as a 1-hour infusion. The toxicity profile and efficacy may be improved with prolonged exposure. Further investigation of this agent in leukemia is warranted.
Assuntos
Benzodiazepinas/efeitos adversos , Benzodiazepinas/uso terapêutico , Imidazóis/efeitos adversos , Imidazóis/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Benzodiazepinas/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Imidazóis/administração & dosagem , Infusões Intravenosas , Leucemia Mieloide/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologiaRESUMO
AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.
Assuntos
Inibidores da Angiogênese/administração & dosagem , Antineoplásicos/administração & dosagem , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Doença Aguda , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/efeitos adversos , Inibidores da Angiogênese/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Axitinibe , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Imidazóis/efeitos adversos , Imidazóis/farmacocinética , Imuno-Histoquímica , Indazóis/efeitos adversos , Indazóis/farmacocinética , Leucemia Mieloide/diagnóstico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Fator de Crescimento Placentário , Valor Preditivo dos Testes , Proteínas da Gravidez/antagonistas & inibidores , Proteínas da Gravidez/sangue , Prognóstico , Proteínas Proto-Oncogênicas c-kit/sangue , Proteínas Proto-Oncogênicas c-kit/efeitos dos fármacos , Resultado do Tratamento , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
We determined mutations and promoter methylation status of NPM1 using pyrosequencing in 199 samples of myeloid neoplasia including myeloproliferative disorders (MPD). The mutations were present in 4% of chronic myelomonocytic leukemia, but not in other MPD or myelodysplastic syndromes. Promoter methylation was rare, and was found in only three samples of MPD.
Assuntos
Metilação de DNA , Mutação , Transtornos Mieloproliferativos/genética , Proteínas Nucleares/genética , Regiões Promotoras Genéticas , Sequência de Bases , Primers do DNA , Variação Genética , Humanos , Leucemia Mieloide/genética , Nucleofosmina , Reação em Cadeia da PolimeraseRESUMO
Based on clinical and pathological findings, chronic myelomonocytic leukemia (CMML) differs from other myeloproliferative/myelodysplastic disorders by its hallmark, monocytosis. It is unknown whether the presence of monocytosis and the diagnosis of CMML carry a prognostic significance. The present study aimed to determine whether the survival of patients with CMML differs from that of patients with BCR/ABL-negative CML or Ph(1-), BCR/ABL-unknown CML, once other potentially prognostic variables have been accounted for. The records of 485 patients with myeloproliferative/myelodysplastic disorders [CMML, n = 304; BCR/ABL-negative CML, n = 107; Ph(1-), BCR/ABL unknown, n = 74] were analysed. Of the covariates found to be significantly (P < 0.01) associated with survival in univariate and multivariate analyses, the following remained predictive and adversely associated with survival, after accounting for the influence of other covariates: increasing age, white blood cell count, platelets, bone marrow blasts and cellularity, decreasing hemoglobin, abnormal karyotype, and diagnosis of CMML. The diagnosis of CMML is prognostically significant and independently associated with a shorter survival and a higher risk of death than BCR/ABL-negative CML or Ph(1-) BCR/ABL-unknown CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/complicações , Leucemia Mielomonocítica Crônica/complicações , Leucocitose/complicações , Monócitos/patologia , Síndromes Mielodisplásicas/complicações , Transtornos Mieloproliferativos/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Diagnóstico Diferencial , Feminino , Genes abl , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Leucemia Mielomonocítica Crônica/diagnóstico , Leucemia Mielomonocítica Crônica/patologia , Contagem de Leucócitos , Leucocitose/diagnóstico , Leucocitose/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia , Cromossomo Filadélfia , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Resistance to or intolerance of imatinib in patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) has encouraged the development of more potent Bcr-Abl inhibitors. AMN107 is a novel, orally bioavailable ATP-competitive inhibitor of Bcr-Abl. The effects of AMN107 were compared with those of imatinib on imatinib-sensitive (KBM5 and KBM7) and imatinib-resistant CML cell lines (KBM5-STI571R1.0 and KBM7-STI571R1.0). Compared with the antiproliferative activity of imatinib, AMN107 was 43 times more potent in KBM5 (IC50 of 11.3 versus 480.5 nmol/L) and 60 times more potent in KBM7 (IC50 of 4.3 versus 259.0 nmol/L) cells. IC50 for AMN107 and imatinib were 2,418.3 and 6,361.4 nmol/L, respectively, in KBM5-STI571R1.0, and 97.2 and 2,497.3 nmol/L, respectively, in KBM7-STI571R1.0 cells. AMN107 inhibited autophosphorylation of Bcr-Abl kinase more effectively than imatinib in all cell lines. They had similar effects on cell cycle progression and apoptotic response in these cell lines. Among severe combined immunodeficient mice bearing KBM5 cells, mean survival times of groups treated with 10, 20, and 30 mg/kg/d of AMN107, starting day 20 after leukemic cell grafting and continuing for 20 days, were 144%, 159%, and 182%, respectively, compared with controls. These results strongly support investigation of the clinical efficacy of AMN107 in patients with CML.
Assuntos
Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/farmacologia , Pirimidinas/farmacologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Benzamidas , Western Blotting , Caspase 3 , Caspases/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Camundongos , Camundongos SCID , Modelos Moleculares , Fosforilação/efeitos dos fármacos , Piperazinas/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêutico , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
The major mechanism of action of STI571 is a competitive interference with the ATP-binding site of the Bcr/Abl tyrosine kinase. In the BCR/ABL-positive cell line KBM5, we studied cellular events associated with the in vitro acquisition of resistance to STI571. The emergence of the STI571-resistant phenotype was accompanied by only a marginal increase in the number of copies of the BCR/ABL gene and its level of expression. The activity of the Bcr/Abl kinase (level of autophosphorylation) in resistant cells was, however, incompletely inhibited by STI571, and the acquisition of the high degree of resistance was associated with a single-point mutation leading to a substitution of a threonine-to-isoleucine at position 315 of Abl. In the resistant KBM5-STI571(R1.0) cells, 20% of the BCR/ABL transcripts and 10% of BCR/ABL gene copies on the DNA level were mutated. The mutation was present in all 10 STI571-resistant clones derived from low density clonogenic assay, confirming its presence in all colony-forming cells but only in a fraction of the BCR/ABL gene copies in each cell. The contribution of this mutation to STI571-resistant phenotype remains unknown. Preliminary data showing partial reversibility of resistance in these cells suggest that resistance may be multifactorial. No other mutations were identified in the kinase domain of the BCR/ABL gene.
Assuntos
Antineoplásicos/farmacologia , Genes abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação , Piperazinas/farmacologia , Proteínas Tirosina Quinases/genética , Pirimidinas/farmacologia , Trifosfato de Adenosina/metabolismo , Benzamidas , Sítios de Ligação , Análise Mutacional de DNA , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/biossíntese , 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/enzimologia , Fosforilação/efeitos dos fármacos , Proteínas Tirosina Quinases/metabolismo , Células Tumorais CultivadasRESUMO
Myelodysplastic syndromes (MDS) are comprised of a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis and susceptibility to transform to acute myeloid leukemia. The molecular pathways underlying disease initiation and evolution are still largely unknown. We recently demonstrated that acquired mutations in PTPN11 are a major event in JMML and occur with variable prevalence in children with other hematologic malignancies, including MDS. Here, we investigated contribution of PTPN11 mutations to adult MDS and CMML pathogenesis. Our results indicate that PTPN11 lesions might play a role in adult MDS/CMML pathogenesis but do not represent a major molecular event.
Assuntos
Leucemia Mielomonocítica Crônica/genética , Mutação , Síndromes Mielodisplásicas/genética , Proteínas Tirosina Fosfatases/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 11RESUMO
PURPOSE: In this Phase I, dose-seeking study, we investigated the dose-limiting toxicities (DLTs) and maximal tolerated dose (MTD) of oral topotecan in patients with hematological malignancies. EXPERIMENTAL DESIGN: Patients with myelodysplastic syndromes, myeloproliferative disorders, or relapsed acute myelogenous leukemia were treated with 0.6-1.9 mg/m(2)/day oral topotecan for 5 consecutive days on and 2 days off, for 3 weeks (15 doses/course) followed by 2-4 weeks of rest. The DLTs occurring during the first course of treatment were considered for defining the MTD. Preliminary results of antitumor activity were assessed by examining bone marrow status and peripheral blood cell counts. RESULTS: All 26 patients enrolled in the study were evaluable for toxicity, and 24 patients were evaluable for response. A total of 54 courses were administered. The most frequently reported nonhematological toxicities (percentage of courses) were diarrhea (57%), nausea/vomiting (50%), fatigue (24%), and mucositis (9%). DLTs included grade 3 or 4 nausea/vomiting and diarrhea at 1.9 mg/m(2)/day. The MTD for oral topotecan in patients with hematological malignancies was defined at 1.4 mg/m(2)/day. Hematological toxicity was noted in all 26 patients and with all courses but was not considered dose-limiting. Four (17%) patients achieved a complete response, and six (25%) patients experienced hematological improvement. CONCLUSIONS: Protracted administration of oral topotecan is safe and well tolerated in patients with hematological malignancies. At the dose-schedule used, single-agent oral topotecan has a definite activity in patients with myelodysplastic syndrome and acute myelogenous leukemia and warrants further investigation alone or in combination with other agents.
Assuntos
Antineoplásicos/toxicidade , Neoplasias Hematológicas/tratamento farmacológico , Topotecan/toxicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Humanos , Contagem de Leucócitos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Contagem de Plaquetas , Topotecan/administração & dosagem , Topotecan/farmacocinéticaRESUMO
PURPOSE: VNP40101M is a novel sulfonylhydrazine alkylating agent with broad antitumor activity in animal models. As alkylating agents are important antileukemia drugs, a Phase I and pharmacokinetic study of VNP40101M was conducted in patients with refractory or relapsed leukemias or poor-risk myelodysplastic syndromes (MDS). EXPERIMENTAL DESIGN: VNP40101M was given as a single i.v. infusion over 15-70 min on day 1. Courses were repeated every 4 weeks according to antileukemic activity. The starting dose of 220 mg/m(2) was escalated by approximately 33% in cohorts of 3-6 patients until a maximum-tolerated dose was established. One additional cohort was treated with the maximum-tolerated dose divided over days 1 and 8. RESULTS: Thirty-eight patients, including 28 with acute myeloid leukemia and 5 with MDS, received 52 courses of treatment. Nondose-limiting, reversible infusion-related toxicities were the most frequent adverse event, occurring in 24 (63%) patients on the first course. Dose escalation was terminated at 708 mg/m(2) for prolonged myelosuppression in 1 of 7 patients, and 600 mg/m(2) was selected as the recommended Phase II dose, with no significant extramedullary toxicity at this dose level. Two patients, 1 with MDS treated with 300 mg/m(2) and 1 with acute myeloid leukemia treated with 600 mg/m(2), achieved complete remission. CONCLUSIONS: VNP40101M had significant antileukemic activity and minimal extramedullary toxicity in patients with relapsed or refractory disease.
Assuntos
Alquilantes/uso terapêutico , Hidrazinas/uso terapêutico , Leucemia Mieloide/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Sulfonamidas/uso terapêutico , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alquilantes/efeitos adversos , Alquilantes/farmacocinética , Área Sob a Curva , Humanos , Hidrazinas/sangue , Hidrazinas/farmacocinética , Leucemia Mieloide/metabolismo , Leucemia Mieloide/patologia , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Náusea/induzido quimicamente , Sulfonamidas/sangue , Sulfonamidas/farmacocinética , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Resultado do Tratamento , Vômito/induzido quimicamenteRESUMO
In previous studies, we demonstrated that the diphtheria toxin-urokinase fusion protein DTAT was selectively toxic to acute myeloid leukemia (AML) cell lines overexpressing the CD87 urokinase receptor. In the present study, we analyzed the sensitivity of patient leukemic progenitors to DTAT and correlated the sensitivity with CD87 expression. We isolated leukemic blasts by density gradient centrifugation and performed immunophenotyping by flow cytometry and blast sensitivity measurements by inhibition of cell proliferation and colony formation in semisolid media. We found CD87 overexpression in 18 (25%) of 71 patient leukemic blast samples, including 18 (28%) of 64 myeloid malignancies and 0 (0%) of 7 lymphoid malignancies. DTAT was toxic to patient leukemic blasts by both proliferation inhibition (IC50
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Antineoplásicos/farmacologia , Toxina Diftérica/farmacologia , Leucemia Mieloide/patologia , Proteínas de Neoplasias/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Receptores de Superfície Celular/efeitos dos fármacos , Ativador de Plasminogênio Tipo Uroquinase/farmacologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Divisão Celular/efeitos dos fármacos , Toxina Diftérica/genética , Sistemas de Liberação de Medicamentos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptores de Ativador de Plasminogênio Tipo Uroquinase , Proteínas Recombinantes de Fusão/farmacologia , Ensaio Tumoral de Célula-TroncoRESUMO
Two hundred and thirty-five consecutive patients presenting to a single center with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after breast cancer treatment were compared with matched patients with de novo AML or MDS. There was no significant difference in median overall survival (OS) times between patients with therapy-related AML and those with de novo AML (8.7 months vs.10.2 months; p = 0.17). Patients with therapy-related MDS had slightly lower median baseline platelet counts and a higher frequency of poor cytogenetics than those with de novo MDS, but the two groups had similar OS times (13.6 months vs. 18.9 months; p = 0.06). Multivariate analysis revealed that cytogenetic risk, baseline white blood cell count, age and performance status were predictive for OS time in AML and that cytogenetic risk and performance status were predictive for OS time in MDS. Having therapy-related disease is not an independent risk factor in patients with myeloid neoplasms and with a history of breast cancer. Clinical trials should be designed to serve both populations.
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Neoplasias da Mama/terapia , Leucemia Mieloide Aguda/diagnóstico , Síndromes Mielodisplásicas/diagnóstico , Sobreviventes/estatística & dados numéricos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/etiologia , Mastectomia/efeitos adversos , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/etiologia , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de SobrevidaRESUMO
The prognostic impact of FLT3 mutations on the outcome of patients with diploid AML, treated with intensive chemotherapy, was analyzed. In 176 patients, the frequency of single ITD was 30% (<61 years: 37%, >60 years: 23%), single D835 mutation 2.3%, and both 2.3%. There was no association between ITD and CR rate. ITD-positive patients <61 years had a higher frequency of resistant disease. ITD was adversely associated with CR duration and survival in both younger and elderly patients treated with comparable chemotherapy but the effect was less in the elderly. Presence of both ITD and D835 heralded the least favorable outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Sequências de Repetição em Tandem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diploide , Feminino , Humanos , Cariotipagem , Leucemia Mieloide Aguda/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fmsRESUMO
Clonal expansion of leukemic cells is thought to be due to proliferation in excess of apoptosis. To define and compare proliferation and apoptosis between various leukemias and myelodysplastic syndrome (MDS), we measured proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation as surrogate markers for proliferation and caspase 3 activity and annexin V surface binding as surrogate markers for activation of the apoptotic cascade in patients with MDS, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). We found high proliferation in bone marrow cells from MDS and CMML as measured by PCNA and BrdU incorporation. The lowest level of proliferation was found in CLL. Apoptosis was also highest in MDS and CMML as measured by annexin V and caspase 3 activity. Unexpectedly, we found no significant difference in proliferation in bone marrow CD34+ cells from various leukemias or MDS. Apoptosis was significantly higher in bone marrow CD34+ cells from MDS and CML in chronic phase as compared to CD34+ cells from AML patients. Our results illustrate differences in proliferation and apoptosis between acute and chronic leukemias and MDS. These differences may have diagnostic and therapeutic implications.
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Leucemia/patologia , Síndromes Mielodisplásicas/patologia , Doença Aguda , Anexina A5/metabolismo , Antígenos CD34/análise , Apoptose/fisiologia , Biomarcadores/análise , Células da Medula Óssea/patologia , Bromodesoxiuridina/análise , Bromodesoxiuridina/farmacocinética , Estudos de Casos e Controles , Caspase 3 , Caspases/metabolismo , Divisão Celular/fisiologia , Doença Crônica , Humanos , Leucemia/fisiopatologia , Síndromes Mielodisplásicas/fisiopatologia , Antígeno Nuclear de Célula em Proliferação/análise , Estudos ProspectivosRESUMO
As fludarabine, topotecan and cytarabine (ara-C) are effective in acute myeloid leukemia (AML), a pilot study of these three agents combined (FTA) was conducted. FTA consisted of topotecan 1.25 mg/m2 by CIV days 1-5, fludarabine 15 mg/m2 and ara-C 0.5 g/m2 IV, BID, on days 2-6. Seventeen patients (6 primary resistant, 11 relapsed) with AML received 33 courses of FTA. Six patients (35%) achieved complete remission. Seven patients (41%) developed grade 3 or 4 diarrhea. FTA was effective and warrants further study in patients with refractory AML.