RESUMO
The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.
RESUMO
Although a growing body of evidence demonstrates that altered mtDNA content (mtDNAc) has clinical implications in several types of solid tumours, its prognostic relevance in acute promyelocytic leukaemia (APL) patients remains largely unknown. Here, we show that patients with higher-than-normal mtDNAc had better outcomes regardless of tumour burden. These results were more evident in patients with low-risk of relapse. The multivariate Cox proportional hazard model demonstrated that high mtDNAc was independently associated with a decreased cumulative incidence of relapse. Altogether, our data highlights the possible role of mitochondrial metabolism in APL patients treated with ATRA.
Assuntos
Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoína/uso terapêutico , DNA Mitocondrial/genética , Relevância Clínica , Recidiva Local de Neoplasia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resultado do TratamentoRESUMO
Stathmin 1 (STMN1) is a microtubule-destabilizing protein highly expressed in hematological malignancies and involved in proliferation and differentiation. Although a previous study found that the PML-RARα fusion protein, which contributes to the pathophysiology of acute promyelocytic leukemia (APL), positively regulates STMN1 at the transcription and protein activity levels, little is known about the role of STMN1 in APL. In this study, we aimed to investigate the STMN1 expression levels and their associations with laboratory, clinical, and genomic data in APL patients. We also assessed the dynamics of STMN1 expression during myeloid cell differentiation and cell cycle progression, and the cellular effects of STMN1 silencing and pharmacological effects of microtubule-stabilizing drugs on APL cells. We found that STMN1 transcripts were significantly increased in samples from APL patients compared with those of healthy donors (all p < 0.05). However, this had no effect on clinical outcomes. STMN1 expression was associated with proliferation- and metabolism-related gene signatures in APL. Our data confirmed that STMN1 was highly expressed in early hematopoietic progenitors and reduced during cell differentiation, including the ATRA-induced granulocytic differentiation model. STMN1 phosphorylation was predominant in a pool of mitosis-enriched APL cells. In NB4 and NB4-R2 cells, STMN1 knockdown decreased autonomous cell growth (all p < 0.05) but did not impact ATRA-induced apoptosis and differentiation. Finally, treatment with paclitaxel (as a single agent or combined with ATRA) induced microtubule stabilization, resulting in mitotic catastrophe with repercussions for cell viability, even in ATRA-resistant APL cells. This study provides new insights into the STMN1 functions and microtubule dynamics in APL.
Assuntos
Leucemia Promielocítica Aguda , Diferenciação Celular , Proliferação de Células , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Mitose , Proteínas de Fusão Oncogênica/genética , Paclitaxel , Estatmina/genéticaRESUMO
By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and ID1, BAALC, ERG, and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality (P < .001), remission (P = .004), overall survival (P < .001), cumulative incidence of relapse (P = .028), disease-free survival (P = .03), and event-free survival (P < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure.
Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA , Perfilação da Expressão Gênica , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/genética , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Farmacológicos/análise , Biomarcadores Tumorais/análise , Estudos de Coortes , Análise Mutacional de DNA/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/métodos , Mutação , Prognóstico , Sequências de Repetição em Tandem/genética , Transcriptoma , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.
Assuntos
Processamento Alternativo , Proteínas de Ligação a DNA/biossíntese , Regulação Leucêmica da Expressão Gênica , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/mortalidade , Modelos Biológicos , Proteínas Nucleares/biossíntese , Proteínas Supressoras de Tumor/biossíntese , Adolescente , Adulto , Idoso , Criança , Proteínas de Ligação a DNA/genética , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Modelos de Riscos Proporcionais , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/genética , Taxa de Sobrevida , Proteína Tumoral p73 , Proteínas Supressoras de Tumor/genéticaRESUMO
Thanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.
Assuntos
Redes Comunitárias/organização & administração , Países em Desenvolvimento , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/terapia , Melhoria de Qualidade/organização & administração , Adolescente , Adulto , Idoso , Brasil/epidemiologia , Chile/epidemiologia , Consenso , Países em Desenvolvimento/estatística & dados numéricos , Intervalo Livre de Doença , Feminino , Humanos , Internacionalidade , Leucemia Promielocítica Aguda/mortalidade , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Uruguai/epidemiologia , Adulto JovemRESUMO
Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Idoso , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Idarubicina/administração & dosagem , Leucemia Promielocítica Aguda/epidemiologia , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Fatores de Risco , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
The KMT2E (MLL5) gene encodes a histone methyltransferase implicated in the positive control of genes related to haematopoiesis. Its close relationship with retinoic acid-induced granulopoiesis suggests that the deregulated expression of KMT2E might lead acute promyelocytic leukaemia (APL) blasts to become less susceptible to the conventional treatment protocols. Here, we assessed the impact of KMT2E expression on the prognosis of 121 APL patients treated with ATRA and anthracycline-based chemotherapy. Univariate analysis showed that complete remission (P = 0·006), 2-year overall survival (OS) (P = 0·005) and 2-year disease-free survival (DFS) rates (P = 0·037) were significantly lower in patients with low KMT2E expression; additionally, the 2-year cumulative incidence of relapse was higher in patients with low KMT2E expression (P = 0·04). Multivariate analysis revealed that low KMT2E expression was independently associated with lower remission rate (odds ratio [OR]: 7·18, 95% confidence interval [CI]: 1·71-30·1; P = 0·007) and shorter OS (hazard ratio [HR]: 0·27, 95% CI: 0·08-0·87; P = 0·029). Evaluated as a continuous variable, KMT2E expression retained association with poor remission rate (OR: 10·3, 95% CI: 2·49-43·2; P = 0·001) and shorter survival (HR: 0·17, 95% IC: 0·05-0·53; P = 0·002), while the association with DFS was of marginal significance (HR: 1·01; 95% CI: 0·99-1·02; P = 0·06). In summary, low KMT2E expression may predict poor outcome in APL patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Ligação a DNA/metabolismo , Leucemia Promielocítica Aguda/tratamento farmacológico , Adolescente , Adulto , Antraciclinas/administração & dosagem , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemRESUMO
Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITD(positive) patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITD(negative) patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Promielocítica Aguda/genética , Proteínas de Neoplasias/genética , Sequências de Repetição em Tandem , Tirosina Quinase 3 Semelhante a fms/genética , Adolescente , Adulto , Idoso , Criança , DNA de Neoplasias/genética , Daunorrubicina/administração & dosagem , Intervalo Livre de Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Hemoglobinas/análise , Humanos , Idarubicina/administração & dosagem , Estimativa de Kaplan-Meier , América Latina/epidemiologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética , Resultado do Tratamento , Tretinoína/administração & dosagem , Adulto JovemAssuntos
Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/mortalidade , Adolescente , Adulto , Idoso , Criança , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Leucemia Promielocítica Aguda/terapia , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Neoplasia Residual , Taxa de SobrevidaRESUMO
The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
RESUMO
Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Leucemia Promielocítica Aguda/patologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Adolescente , Adulto , Idoso , Animais , Antraciclinas/farmacologia , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Intervalo Livre de Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Leucemia Promielocítica Aguda/sangue , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/mortalidade , Contagem de Leucócitos , Masculino , Microdomínios da Membrana/metabolismo , Camundongos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Adulto JovemRESUMO
Although overexpression of the brain and acute leukemia, cytoplasmic (BAALC) gene is associated with primary resistant disease and shorter relapse-free, disease-free, and overall survival in different subsets of acute myeloid leukemia (AML), little is known about its clinical impact in acute promyelocytic leukemia (APL). Using real-time reverse transcriptase polymerase chain reaction, we showed that BAALC expression is significantly lower in APL compared with other subsets of AML (P < .001). We also demonstrated that BAALC overexpression was associated with shorter disease-free survival (DFS) (hazard ratio [HR], 4.43; 95% confidence interval [CI], 1.29-15.2; P = .018) in 221 consecutive patients (median age, 35 years; range, 18-82 years) with newly diagnosed APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy. Cox proportional hazard modeling showed that BAALC overexpression was independently associated with shorter DFS in the total cohort (HR, 5.26; 95% CI, 1.52-18.2; P = .009) and in patients with high-risk disease (ie, those with initial leukocyte counts >10 × 109/L) (HR, 5.3; 95% CI, 1.14-24.5; P = .033). We conclude that BAALC expression could be useful for refining risk stratification in APL, although this needs to be confirmed in independent cohorts.
RESUMO
OBJECTIVES: Several clinical trials conducted in Europe and US reported favorable outcomes of patients with APL treated with the combination of all trans retinoic acid (ATRA) and anthracyclines. Nevertheless, the results observed in developing countries with the same regimen was poorer, mainly due to high early mortality mainly due bleeding. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, Mexico and Uruguay. METHODS: The IC-APL treatment protocol is similar to the PETHEMA 2005, but changing idarubicin to daunorubicin. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. The immunofluorescence using an anti-PML antibody allowed a rapid confirmation of the diagnosis and, the importance of supportive measures was reinforced. RESULTS: The interim analysis of 97 patients enrolled in the IC-APL protocol showed that complete remission (CR) rate was 83% and the 2-year overall survival and disease-free survival were 80% and 90%, respectively. Of note, the early mortality rate was reduced to 7.5%. DISCUSSION: The results of IC-APL demonstrate the impact of educational programs and networking on the improvement of the leukemia treatment outcome in developing countries.
Assuntos
Antineoplásicos/uso terapêutico , Daunorrubicina/uso terapêutico , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Brasil , Comportamento Cooperativo , Países em Desenvolvimento , Intervalo Livre de Doença , Educação Médica , Humanos , Leucemia Promielocítica Aguda/diagnóstico , Leucemia Promielocítica Aguda/patologia , México , Indução de Remissão , Resultado do Tratamento , UruguaiRESUMO
Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two entire cohorts. Complete remission (CR) rate was significantly higher in the PETHEMA/HOVON (94 %) than in the IC-APL cohort (85 %) (P = 0.002). The distribution of causes of induction failure and the time to achieve CR were similar in both cohorts. Patients who achieved CR had comparable cumulative incidence of relapse and disease-free survival rates, but lower overall and event-free survivals were observed in the IC-APL cohort, which was mainly due to a higher death rate during induction therapy. A higher death rate during consolidation therapy was also observed in the IC-APL. These results show that daunorubicin and idarubicin have similar antileukaemic efficacy in terms of primary resistance, molecular persistence, as well as molecular and haematological relapse rates when combined with ATRA in treatment of APL. However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov](AU)
Assuntos
Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/terapia , Tretinoína/uso terapêutico , Antraciclinas/uso terapêutico , Citarabina/uso terapêutico , Bibliografia Nacional , UruguaiRESUMO
Activating internal tandem duplication (ITD) mutations in the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) are associated with poor outcome in acute myeloid leukemia, but their prognostic impact in acute promyelocytic leukemia (APL) remains controversial. Here, we screened for FLT3-ITD mutations in 171 APL patients, treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. We identified FLT3-ITD mutations in 35 patients (20 %). FLT3-ITD mutations were associated with higher white blood cell counts (P < 0.0001), relapse-risk score (P = 0.0007), higher hemoglobin levels (P = 0.0004), higher frequency of the microgranular morphology (M3v) subtype (P = 0.03), and the short PML/RARA (BCR3) isoform (P < 0.0001). After a median follow-up of 38 months, FLT3-ITDpositive patients had a lower 3-year overall survival rate (62 %) compared with FLT3-ITDnegative patients (82 %) (P = 0.006). The prognostic impact of FLT3-ITD on survival was retained in multivariable analysis (hazard ratio: 2.39, 95 % confidence interval [CI] 1.17-4.89; P = 0.017). Nevertheless, complete remission (P = 0.07), disease-free survival (P = 0.24), and the cumulative incidence of relapse (P = 0.94) rates were not significantly different between groups. We can conclude that FLT3-ITD mutations are associated with several hematologic features in APL, in particular with high white blood cell counts. In addition, FLT3-ITD may independently predict a shorter survival in patients with APL treated with ATRA and anthracycline-based chemotherapy(AU)
Assuntos
Humanos , Leucemia Promielocítica Aguda/tratamento farmacológico , Tretinoína/uso terapêutico , Bibliografia Nacional , UruguaiRESUMO
Dentre as doenças cardiovasculares, a trombose venosa (TV) destaca-se pela associação entre fatores de riscos adquiridos e fatores genéticos. A resistência hereditária à proteína C ativada tem sido identificada como a principal causa dos casos de trombose venosa, sendo frequentemente associada à mutação fator V Leiden (G1694A). Em indivíduos homozigotos, o risco de trombose venosa é 50 a 100 vezes maior que em pacientes homozigotos normais, enquanto em pacientes heterozigotos o risco é de 5 a 10 vezes. Baseado na necessidade de avaliação e acompanhamento de pacientes com casos de trombose venosa e prevenção de seus respectivos familiares, foi desenvolvido um método simples de discriminação alélica do fator V da coagulação utilizando PCR em tempo real. Foram selecionados 67 pacientes com histórico de TV e 51 indivíduos sem histórico de TV. Primeiramente, a discriminação alélica do fator V foi realizada através de PCR convencional seguida de digestão enzimática (Mnl). Posteriormente, o diagnóstico foi realizado por PCR em tempo real. Ambos os métodos foram baseados no polimorfismo G1691A, sendo no segundo utilizado fluoróforos VIC e FAM para marcar os nucleotídeos G e A, respectivamente. A técnica de PCR-RFLP foi utilizada para diagnosticar 95 indivíduos homozigotos normais, 21 heterozigotos e 2 homozigotos FVL. Utilizando PCR em tempo real foram obtidos os mesmos resultados. A máxima similaridade entre os resultados obtidos por PCR em tempo real e PCR-RFLP indicou precisão significativa do novo método de discriminação e visualização alélica do fator V.
Among cardiovascular diseases, venous thrombosis is important due to the association between acquired and genetic risks factors. Hereditary resistance to activated protein C has been identified as the main cause of venous thrombosis, and is frequently associated to the factor V Leiden mutation (G1694A). In homozygotic individuals, the risk of venous thrombosis is 50 to 100 times higher that in normal patients, while in heterozygotic patients the risk is 5 to 10 times higher. Based on the need of evaluation and follow up of patients with venous thrombosis and prevention in their respective families, a simple method of allelic discrimination of coagulation V factor was developed using real time PCR. Sixty-seven patients with a history of venous thrombosis and 51 individuals without venous thrombosis were selected for this study. First, identification of the factor V allele was achieved through conventional PCR followed by enzymatic digestion (Mnl). Subsequently, diagnosis was attained by real time PCR. Both the methods investigated the G1691A polymorphism using VIC and FAM fluorophores to mark nucleotides G and A, respectively. By PCR-RFLP, 95 individuals were diagnosed as normal homozygotes, 21 as heterozygotes and 2 as homozygotic factor V Leiden individuals. The same results were obtained using real time PCR. Maximum similarity between the results of real time PCR and PCR-RFLP indicates high precision of the new method for allelic identification and visualization of factor V Leiden.
RESUMO
As tromboses são eventos de etiopatogênese multifatorial resultantes da interação de fatores genéticos e ambientais, constituindo na atualidade uma das causas mais comuns de morbimortalidade. Uma mutação de ponto no fator V da coagulação, o fator V Leiden (FVL), constitui o defeito genético mais comum associado com trombofilia. No Brasil, o estudo deste fator de risco é relativamente recente e se dispõe de poucos dados na literatura especializada. Este trabalho teve como objetivo determinar a freqüência da mutação do fator V Leiden em 292 indivíduos sob investigação de trombofilia no Hemocentro de Pernambuco. A técnica molecular utilizada foi a RE/PCR (Enzima de Restrição/Reação em Cadeia da Polimerase), usando primers específicos e a enzima MnlI. A freqüência do FVL encontrada foi de 13,3 por cento, sendo 36 heterozigotos e 3 homozigotos. A presença da mutação foi semelhante em indivíduos com idade tanto inferior quanto superior a 45 anos. Os resultados da pesquisa mostraram que a freqüência do FVL na população estudada é semelhante à descrita na literatura científica para indivíduos selecionados com tromboembolismo e confirmam a importância do estudo molecular nas diferentes faixas etárias.
Thrombosis is a multifactorial disease involving genetic and environmental factors and constitutes one of the most common causes of morbimortality. A point mutation in coagulation factor V - factor V Leiden (FVL), constitutes the most prevalent genetic defect associated with thrombophilias. The study of this risk factor is relatively recent in Brazil and only a few reports have been published to date. The aim of this study was to determine the frequency of FVL in 292 individuals being investigated for thrombophilia at the Pernambuco State Blood Center. The molecular biology technique used was RE/PCR (Restriction Enzyme / Polymerase Chain Reaction), using specific primers and the MnlI enzyme. The frequency of FVL was 13.3 percent including 36 heterozygous and 3 homozygous individuals. The presence of the mutation was similar among individuals under and over 45 years old. Our findings are similar to results published for selected patients who suffered from thromboembolism and they confirm the importance of molecular testing at different ages.
Assuntos
Humanos , Masculino , Feminino , Fator V , Tromboembolia , TrombofiliaRESUMO
O tratamento da leucemia promielocítica aguda (LPA) com antrciclínicos e ácido trans-retinóico (ATRA) tem sido amplamente empregado e resultou em taxas de sobrevida a longo prazo de 80% a 90% em diferentes ensaios clínicos. A despeito da alta prevalência de LPA na América Latina, a efetividade de regimes de tratamento com ATRA e antraciclínicos não é conhecida. No Brasil, mais de 20% das leucemias mielóides agudas são do subtipo LPA. Neste estudo descrevemos uma análise retrospectiva de 157 pacientes brasileiros com LPA. Comparado com pacientes de países desenvolvidos, observamos uma alta prevalência de pacientes de alto risco e ma sobrevida e três anos de 49,9%. A taxa de mortalidade precoce foi de 28%, principalmente devido a sangramento (88,6%), com 45,2% dos pacientes apresentando evidências laboratoriais de coagulação intravascular disseminada ao diagnóstio. A despeito do fato de que nõ foram excluídos pacientes com base na idade ou no performance status, esta alta taxa de óbito mostra que é necessária uma melhora urgente no acesso dos pacientes a centros médicos especializados.
Therapy based on anthracyclines and all-trans-retinoic acid (ATRA) hás been widely used for acute promyelocytic leukemia (APL) and result in long term survival rates of 80% to 90% in different clinical trials. Despite the higher incidence of APL in Latin America, the effectiveness of ATRA + anthracyclines treatment is not known. In Brazil, more than 20% of acute myeloid leukemia are of the APL subtype. We describe a retrospective analysis including 157 Brazilian APL patients. Compared to developed countries, a higher incidence of higher incidence of high risk patients was observed and the overwall survival in three years was only 49.9%. Early mortality was 28%, mainly due to bleeding (88.6%), and laboratorial evidence of disseminated intravascular coagulation at diagnosis was present in 45.2% of the patients. Despite the fact that no patient was excluded based on age and performance status, the high death rates shows that urgent improvement in acess to specialized medical care is necessary in Brazil. Aiming to improve the outcome of APL patients in developing countries, the American Society of Hematology launched the International Consortium on APL, an educational iniative based on the use of an unified simplified treatment protocol, on line discussion tools and centralized laboratory diagnosis.