Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Adulto , Idoso , Metilação de DNA/efeitos dos fármacos , Decitabina , Feminino , Humanos , Leucemia Mielomonocítica Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Análise de Sobrevida , Resultado do TratamentoRESUMO
After failure of erythropoiesis-stimulating agents (ESAs), lenalidomide (LEN) yields red blood cell (RBC) transfusion independence (TI) in 20-30% of lower-risk non-del5q myelodysplastic syndrome (MDS). Several observations suggest an additive effect of ESA and LEN in this situation. We performed a randomized phase III study in 131 RBC transfusion-dependent (TD, median transfusion requirement six RBC units per 8 weeks) lower-risk ESA-refractory non-del5q MDS. Patients received LEN alone, 10 mg per day, 21 days per 4 weeks (L arm) or LEN (same schedule) + erythropoietin (EPO) beta, 60,000 U per week (LE arm). In an intent-to-treat (ITT) analysis, erythroid response (HI-E, IWG 2006 criteria) after four treatment cycles (primary end point) was 23.1% (95% CI 13.5-35.2) in the L arm and 39.4% (95% CI 27.6-52.2) in the LE arm (P=0.044), while RBC-TI was reached in 13.8 and 24.2% of the patients in the L and LE arms, respectively (P=0.13). Median response duration was 18.1 and 15.1 months in the L and LE arms, respectively (P=0.47). Side effects were moderate and similar in the two arms. Low baseline serum EPO level and a G polymorphism of CRBN gene predicted HI-E. Combining LEN and EPO significantly improves erythroid response over LEN alone in lower-risk non-del5q MDS patients with anemia resistant to ESA.
Assuntos
Transfusão de Sangue , Deleção Cromossômica , Cromossomos Humanos Par 5/genética , Eritropoetina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Anemia/prevenção & controle , Inibidores da Angiogênese/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Lenalidomida , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Fatores de Risco , Talidomida/uso terapêuticoRESUMO
INTRODUCTION: Limited data is available on the feasibility of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (AHSCT) in elderly patients over 70 years of age with non-Hodgkin's lymphoma (NHL). MATERIALS AND METHODS: In the setting of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) group, we retrospectively analyzed 81 consecutive patients with NHL over 70 years of age who received AHSCT. RESULTS: The median age at AHSCT was 72.3 years [70-80]. Patients' were diagnosed with diffuse large B-cell lymphoma (n=40), follicular lymphoma (n=16), mantle cell lymphoma (n=15), T-cell lymphoma (n=5), and other (n=5). Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) was 0 in 73% of patients. Main conditionings were BEAM (Carmustine-Etoposide-Cytarabine-Melphalan, n=61) and melphalan alone (n=14). Median delays to reach 0.5×109/L neutrophils and 20 × 10(9)/L platelets were of 12 [9-76] days and 12 [0-143] days, respectively. One hundred day and one year cumulative incidence of NRM was 5.4% and 8.5%, respectively. The main cause of death remains relapse. CONCLUSION: In conclusion, this study revealed that AHSCT seemed to be acceptable in patients over 70 years of age with NHL. Patient age is not a limiting factor if clinical condition is adequate.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma não Hodgkin/terapia , Sociedades Médicas , Idoso , Idoso de 80 Anos ou mais , Transplante de Medula Óssea , Terapia Baseada em Transplante de Células e Tecidos , Intervalo Livre de Doença , Feminino , Seguimentos , França/epidemiologia , Humanos , Incidência , Linfoma não Hodgkin/epidemiologia , Masculino , Prevalência , Estudos Retrospectivos , Taxa de Sobrevida/tendênciasRESUMO
The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response.
Assuntos
Autofagia , Proliferação de Células , Ciclina G2/metabolismo , Regulação Leucêmica da Expressão Gênica , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Complexo Repressor Polycomb 1/metabolismo , Apoptose , Western Blotting , Imunoprecipitação da Cromatina , Ciclina G2/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Células Tumorais CultivadasRESUMO
In chronic myeloid leukemia (CML), evidence is supporting the role of VEGF in growth, and survival of leukemia cells. The evaluation of plasma VEGF levels in 403 CML patients randomized within SPIRIT study to received imatinib-400mg versus imatinib+cytarabine versus imatinib+interferon (IFN) versus imatinib-600mg demonstrated that VEGF is an independent factor of BCR-ABL burden. VEGF low levels at diagnosis were associated with a progression-free survival of 100% at 48 months. Under treatment, significant lowest levels were observed in imatinib+IFN arm. These results support the use of VEGF as a parameter to predict CML evolution and let us to speculate about antiangiogenic properties of IFN.
Assuntos
Benzamidas/administração & dosagem , Interferons/administração & dosagem , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazinas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
INTRODUCTION: POEMS syndrome (polyneuropathy, organomegaly, endocrynopathy, M-protein, and skin changes) is a rare multisystem disease associated with plasma cell dyscrasia. The efficacy of autologous peripheral blood stem cell transplantation (auto-PBSCT) reported in case series has been mainly based on hematologic criteria and clinical recovery of peripheral neuropathy dysfunctions but has not been specifically evaluated. This retrospective study aimed to analyze the efficacy of auto-PBSCT on disability and electrophysiological patterns in patients with POEMS syndrome. METHODS: Five patients presenting with POEMS syndrome received auto-PBSCT. Disability was evaluated before treatment and at 6 and 12 months using the Overall Neuropathy Limitation Scale (ONLS) and MRC sumscore of 28 muscles. Nerve conduction studies were performed before and one year after treatment, on median, ulnar, fibular and tibial nerves. RESULTS: Mean age was 60.6 years (49-70). Disease duration between first symptoms and auto-PBSCT was 15.4 months (2-33). Before auto-PBSCT, mean ONLS score was 4.2 (1-10) and mean MRC sumscore 115.8/140 (74-140). At M6, mean ONLS score decreased and mean MRC sumscore increased; both were improved in all patients at M12: mean ONLS score 3 (range 0-8) at M6 and 2.2 (range 0-7) at M12; mean MRC sumscore 118/140 (77-140) at M6 and 122.4/140 (80-140) at M12. Significant recovery in electrophysiological patterns was observed in all patients on ulnar and median nerves: before-after treatment differences were observed for motor conduction velocities (34.41 vs. 45.47 m/s; P<0.001), distal CMAP amplitudes (5.04 vs. 5.96 mV; P=0.004), and sensory conduction velocities (43.20 vs. 49.20 m/s; P=0.001). Distal CMAP amplitude remained low in fibular and tibial nerves (0.41 vs. 0.17 mV). CONCLUSIONS: Clinical and electrophysiological improvement is obvious in POEMS syndrome peripheral neuropathy within one year after treatment with auto-PBSCT, undoubtedly resulting from extensive remyelinisation and axonal regeneration. Further studies are required to examine long-term outcome in patients with POEMS syndrome given auto-PBSCT.
Assuntos
Síndrome POEMS/terapia , Transplante de Células-Tronco de Sangue Periférico , Doenças do Sistema Nervoso Periférico/terapia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome POEMS/complicações , Doenças do Sistema Nervoso Periférico/etiologia , Transplante Autólogo , Resultado do TratamentoRESUMO
Darbepoetin (DAR), with or without granulocyte colony-stimulating factor (G-CSF), has proved effective in treating anemia in patients with lower-risk myelodysplastic syndrome (MDS), but its effects on quality of life (QoL) and exercise functioning are less well established. In this phase II study (no. NCT00443339), lower-risk MDS patients with anemia and endogenous erythropoietin (EPO) level <500 IU/L received DAR 500 µg once every 2 weeks for 12 weeks, with G-CSF added at week 12 in non-responders. Physical performance was assessed with the 6-min walking test and, for fit patients, maximal oxygen consumption (VO2max). QoL was evaluated using SF-36 and FACT-An tests. In 99 patients, erythroid response rate according to IWG 2006 criteria was 48 and 56 % at 12 and 24 weeks, respectively. Addition of G-CSF rescued 22 % of non-responders. In 48 % of the responders, interval between darbepoetin injections could be increased for maintenance treatment. Serum EPO level was the only independent predictive factor of response at 12 weeks, and its most discriminant cutoff value was 100 IU/L. QoL and VO2max showed improvement over time in responders, compared with non-responders. With a median follow-up of 52 months, median response duration was not reached, and 3-year cumulative incidence of acute myeloid leukemia and overall survival (OS) was 14.5 and 70 %, respectively. Baseline transfusion dependence, International Prognostic Score System (IPSS), and Revised IPSS accurately predicted OS from treatment onset. Tolerance of darbepoetin was good. In conclusion, this regimen of darbepoetin every 2 weeks yielded high response rates and prolonged response duration. Objective improvement in exercise testing and in patient-reported QoL confirms the clinical relevance of anemia correction with erythropoiesis-stimulating agents.
Assuntos
Eritropoetina/análogos & derivados , Tolerância ao Exercício/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Qualidade de Vida , Idoso , Anemia/complicações , Anemia/tratamento farmacológico , Anemia/mortalidade , Anemia/fisiopatologia , Darbepoetina alfa , Eritropoetina/administração & dosagem , Eritropoetina/efeitos adversos , Exercício Físico/fisiologia , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Hematínicos/administração & dosagem , Hematínicos/efeitos adversos , Humanos , Masculino , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/fisiopatologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Risco , Análise de Sobrevida , Resultado do TratamentoRESUMO
Imatinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML). Indication was based on the STI571 0109 study, in which imatinib favorably compared to historical treatments in patients failing prior therapies. The relevance of these results to currently newly diagnosed AP-CML patients remains unknown. We evaluated the benefit of imatinib in 42 newly diagnosed AP-CML patients. In all, 16 patients had hematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome (ACAs; HEM-AP), 16 solely had ACAs (ACA-AP) and 10 had hematological acceleration plus ACAs (HEM-AP + ACA). Major cytogenetic responses were achieved in 93.7% of HEM-AP patients, 75% of patients with ACA-AP (P=NS) and 40% of patients with HEM-AP + ACA (P=0.0053). The 24-month failure-free survival rate was 87.5% in HEM-AP patients, 43.8% in ACA-AP patients and 15% in HEM-AP + ACA patients (P=0.022). The 24-month estimate of progression-free survival was 100% in HEM-AP patients, 92.8% in ACA-AP patients and 58.3% in HEM-AP + ACA patients (P=0.0052). In conclusion, frontline imatinib allows favorable outcomes in HEM-AP and ACA-AP patients but appears insufficient for patients with HEM-AP + ACA. Broader-target and/or more potent BCR-ABL tyrosine kinase inhibitors alone or in combination may be considered in this setting.
Assuntos
Antineoplásicos/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Leucemia Mieloide de Fase Acelerada/tratamento farmacológico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Benzamidas , Feminino , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Acelerada/mortalidade , Masculino , Pessoa de Meia-IdadeRESUMO
We studied a retrospective cohort of 282 higher-risk MDS treated with azacitidine, including 32 patients who concomitantly received an ESA for a median of 5.8 months after azacitidine onset. Forty-four percent of ESA and 29% of no-ESA patients reached HI-E (p=0.07); 48% and 20% achieved transfusion independence (p=0.01). Median OS was 19.6 months in the ESA and 11.9 months in the no-ESA groups (p=0.04). Addition of an ESA significantly improved OS (p=0.03) independently of azacitidine schedule and duration, and of our proposed azacitidine risk score (Blood 2011;117:403-11). Adding an ESA to azacitidine in higher-risk MDS should be studied prospectively.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Hematínicos/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Resultado do TratamentoRESUMO
Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts <10% and either previous ESA failure or relapse, endogenous EPO >500 U/l or other cytopenia(s) (absolute neutrophilic count <1.0 G/l or platelets <50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO >500 U/l (n=18): 11 and 19%; patients transfused >2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.
Assuntos
Eritropoetina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Tretinoína/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Neutropenia/tratamento farmacológico , Neutrófilos , Contagem de Plaquetas , Proteínas Recombinantes , Trombocitopenia/tratamento farmacológico , Resultado do Tratamento , Adulto JovemAssuntos
Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/biossíntese , Proteínas de Fusão bcr-abl/genética , Regulação Leucêmica da Expressão Gênica , Harringtoninas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Mutação , Piperazinas/farmacologia , Pirimidinas/farmacologia , Antineoplásicos/uso terapêutico , Benzamidas , Medula Óssea/metabolismo , Mepesuccinato de Omacetaxina , Humanos , Mesilato de Imatinib , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
An open-label, phase II non-randomised trial was conducted with darbepoetin (DAR), an erythropoiesis-stimulating factor with prolonged half-life, at a weekly dose of 300 mug subcutaneously in 62 anaemic patients with myelodysplastic syndrome (MDS) with an endogenous erythropoietin (EPO) level <500 mU/ml. Most of the patients were classified as low or intermediate 1 according to the International Prognostic Scoring System. After 12 weeks, 44 (71%) patients had an erythroid response (34 major and 10 minor), including eight of 13 patients who were previous non-responders to conventional EPO. Two additional responses (one minor and one major) occurred, in 10 non-responders, after the addition of granulocyte colony-stimulating factor (G-CSF). Thirty-six of the 46 total responders (31/35 major and 5/11 minor) continued to respond on maintenance DAR after a median of 40 weeks (range 4-84). Median dose of DAR required to maintain response was 300 microg every 14 d. The only prognostic factors of favourable response were low endogenous EPO level and low or absent red blood cell transfusion requirement. Those results suggest that high-dose DAR alone yields high erythroid response rates in anaemia of lower risk MDS, possibly equivalent to those obtained with conventional EPO + G-CSF, although this will need to be confirmed in larger and randomised trials.
Assuntos
Anemia/tratamento farmacológico , Eritropoetina/análogos & derivados , Síndromes Mielodisplásicas/complicações , Idoso , Idoso de 80 Anos ou mais , Anemia/complicações , Darbepoetina alfa , Esquema de Medicação , Quimioterapia Combinada , Eritropoese/efeitos dos fármacos , Eritropoetina/administração & dosagem , Eritropoetina/efeitos adversos , Eritropoetina/uso terapêutico , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Fatores de Risco , Resultado do TratamentoRESUMO
Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Crise Blástica/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Dexametasona/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Humanos , Mesilato de Imatinib , Projetos Piloto , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Vincristina/administração & dosagemRESUMO
The K562 cell line serves as a model to study the molecular mechanisms associated with leukemia differentiation. We show here that cotreatment of K562 cells with PMA and low doses of SB202190 (SB), an inhibitor of the p38 MAPK pathway, induced a majority of cells to differentiate towards the megakaryocytic lineage. Electronic microscopy analysis showed that K562 cells treated with PMA+SB exhibited characteristic features of physiological megakaryocytic differentiation including the presence of vacuoles and demarcation membranes. Differentiation was also accompanied by a net increase in megakaryocytic markers and a reduction of erythroid markers, especially when both effectors were present. PMA effect was selectively mediated by new PKC isoforms. Differentiation of K562 cells by the combination of PMA and SB required Erk1/2 activation, a threshold of JNK activation and p38 MAPK inhibition. Interestingly, higher concentrations of SB, which drastically activated JNK, blocked megakaryocytic differentiation, and considerably increased cell death in the presence of PMA. c-DNA microarray membranes and PCR analysis allow us to identify a set of genes modulated during PMA-induced K562 cell differentiation. Several gene families identified in our screening, including ephrins receptors and some angiogenic factors, had never been reported so far to be regulated during megakaryocytic differentiation.