RESUMO
In chronic myeloid leukemia, the identification of early molecular predictors of stable treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation is challenging. The predictive values of residual disease (BCR::ABL1 quantification) at month 3 and 6 and more recently, BCR::ABL1 transcript halving time (HT) have been described, but no study compared the predictive value of different early parameters. Using a real-world cohort of 408 patients, we compared the performance of the EUTOS long-term survival (ELTS) score, BCR::ABL1 HT, and residual disease at month 3 and 6 to predict the molecular response, achievement of the TKI discontinuation criteria, and TFR maintenance. The performances of BCR::ABL1 HT and residual disease at month 3 were similar. Residual disease at month 6 displayed the best performance for predicting the optimal response (area under the ROC curve between 0.81 and 0.92; cut-off values: 0.11% for MR4 at month 24 and 0.12% for MR4.5 at month 48). Conversely, no early parameter predicted reaching the TKI discontinuation criteria and TFR maintenance. We obtained similar results when patients were divided in subgroups by first-line treatment (imatinib vs. second-generation TKI [2G-TKI]). We identified a relationship between ELTS score, earlier milestones and TFR maintenance only in the 2G-TKI group. In conclusion, this first comparative study of early therapeutic response parameters showed that they are excellent indicators of TKI efficacy (BCR::ABL1 transcript reduction) and best responders. Conversely, they did not predict the achievement of the TKI discontinuation criteria and TFR maintenance, suggesting that other parameters are involved in TFR maintenance.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Neoplasia Residual , Inibidores de Proteínas Quinases , Indução de Remissão , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Neoplasia Residual/diagnóstico , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Prognóstico , Resultado do Tratamento , Idoso de 80 Anos ou mais , Adulto Jovem , Estudos de CoortesRESUMO
BACKGROUND: In the era of targeted therapies, the influence of aging on cancer management varies from one patient to another. Assessing individual frailty using geriatric tools has its limitations, and is not appropriate for all patients especially the youngest one. Thus, assessing the complementary value of a potential biomarker of individual aging is a promising field of investigation. The chronic myeloid leukemia model allows us to address this question with obvious advantages: longest experience in the use of tyrosine kinase inhibitors, standardization of therapeutic management and response with minimal residual disease and no effect on age-related diseases. Therefore, the aim of the BIO-TIMER study is to assess the biological age of chronic myeloid leukemia or non-malignant cells in patients treated with tyrosine kinase inhibitors and to determine its relevance, in association or not with individual frailty to optimize the personalised management of each patient. METHODS: The BIO-TIMER study is a multi-center, prospective, longitudinal study aiming to evaluate the value of combining biological age determination by DNA methylation profile with individual frailty assessment to personalize the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors. Blood samples will be collected at diagnosis, 3 months and 12 months after treatment initiation. Individual frailty and quality of life will be assess at diagnosis, 6 months after treatment initiation, and then annually for 3 years. Tolerance to tyrosine kinase inhibitors will also be assessed during the 3-year follow-up. The study plans to recruit 321 patients and recruitment started in November 2023. DISCUSSION: The assessment of individual frailty should make it possible to personalize the treatment and care of patients. The BIO-TIMER study will provide new data on the role of aging in the management of chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, which could influence clinical decision-making. TRIAL REGISTRATION: ClinicalTrials.gov , ID NCT06130787; registered on November 14, 2023.
Assuntos
Fragilidade , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Envelhecimento , Metilação de DNA , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Estudos Longitudinais , Terapia de Alvo Molecular , Medicina de Precisão/métodos , Estudos Prospectivos , Qualidade de Vida , /uso terapêuticoRESUMO
Superior rates of deep molecular response (DMR) have been reported with the combination of tyrosine kinase inhibitors and pegylated-interferon-alpha (Peg-IFN) in patients with newly diagnosed chronic phase-chronic myeloid leukaemia (CP-CML). In this setting, this study investigated the efficacy and safety of dasatinib combined to Peg-IFN-α2b (Dasa-PegIFN, NCT01872442). A total of 79 patients (age ≤65 years) started dasatinib; 61 were eligible for Peg-IFNα-2b add-on therapy at month 3 for a maximum 21-months duration. Dasatinib was continued thereafter. The primary endpoint was the cumulative rate of molecular response 4.5 log (MR4.5 ) by 12 months. The results are reported for the 5-year duration of the study. Grade 3 neutropenia was frequent with the combination but did not induce severe infection (one of grade 3). Other adverse events were generally low grade (4% of grade 3-4) and expected. Seventy-nine per cent and 61% of patients continued the Peg-IFN until months 12 and 24, respectively. Overall, at these time points, MR4.5 rates were 25% and 38%, respectively. Thereafter, 32% and 46% of patients achieved a sustained (≥2 years) MR4.5 or MR4 , respectively. This work established the feasibility and high rates of achievement of early and sustained DMR (a prerequisite for treatment-free-remission) with dasatinib and Peg-IFNα-2b combination as initial therapy.
Assuntos
Interferon-alfa , Leucemia Mieloide de Fase Crônica , Humanos , Idoso , Dasatinibe/efeitos adversos , Interferon-alfa/efeitos adversos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Polietilenoglicóis/efeitos adversos , Resultado do TratamentoRESUMO
Guidelines for tyrosine kinase inhibitor (TKI)-treated chronic phase-chronic myeloid leukemia (CML) management are essentially based on data from clinical research trials; however, real-world data should be valuable for optimizing such recommendations. Here, we analyzed the data collected in the French CML Observatory database, a multicenter real-world cohort (n = 646), using a first-line "intention-to-treat" analysis strategy. This cohort included patients treated with first-line imatinib (n = 484), nilotinib (n = 103), dasatinib (n = 17), imatinib and interferon (n = 9), or second-generation (2G)-TKIs and interferon (n = 29). The cumulative incidence of major molecular response (MMR), MR4, MR4.5 and MR5 confirmed the faster response kinetics with 2G-TKIs. Multivariate analysis identified being a woman and residual disease at month 6 as the main predictive factors of deep molecular response (DMR). Moreover, 30% of patients met the criteria for treatment discontinuation (5 years of treatment and ≥ 2 years of DMR), but only 38% of them stopped treatment. Among the 92 patients who actually discontinued treatment due to optimal response, 31.5% relapsed (48% of them after > 6 months of TKI discontinuation). Multivariate analysis identified age and TKI duration as factors positively correlated with treatment-free remission maintenance. Late (> 6 months) relapses were more frequent in patients with the e14a2 BCR::ABL transcript. Relapse rate was higher in patients who stopped TKI before than after 5 years of treatment (52.6% vs 26%; p = 0.040). These results advocate caution concerning early treatment withdrawal, including in patients receiving 2G-TKIs. This still recruiting database is a valuable source of information for the real-world follow-up of patients with CML.
Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide de Fase Crônica , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Mesilato de Imatinib/uso terapêutico , Interferons/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do TratamentoRESUMO
Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed or refractory Hodgkin lymphoma (HL). Although long-term disease control can be achieved, relapse is still frequent. The programmed cell death protein 1 (PD-1) pathway-blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in patients with relapsed or refractory HL who did not receive allo-HCT. However, PD-1 blocking strategy can increase the risk of graft-versus-host disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in 6 patients (30%) after nivolumab initiation. All 6 patients had prior history of acute GVHD. The patients with nivolumab-induced GVHD were managed by standard treatment for acute GVHD. Two patients died as a result of GVHD, 1 of progressive disease and 1 of complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, the 1-year progression-free survival rate was 58.2% (95% CI, 33.1%-76.7%) and the overall survival rate was 78.7% (95% CI, 52.4%-91.5%). Among 13 patients still in response, 6 received a single dose of nivolumab and 7 remain on nivolumab. Compared with standard options for this indication, our results show that nivolumab is effective with an acceptable safety profile.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Adulto , Aloenxertos , Anticorpos Monoclonais/efeitos adversos , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Doença de Hodgkin/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Nivolumabe , Taxa de SobrevidaRESUMO
Clonal chromosome abnormalities in Philadelphia-negative cells could concern chronic myeloid leukemia patients treated by tyrosine kinase inhibitors. The European LeukemiaNet distinguishes -7/del(7q) abnormalities as a "warning". However, the impact of clonal chromosome abnormalities, and specifically those of -7/del(7q), in Philadelphia-negative cells on clinical outcomes is unclear and based on case-reports showing morphological dysplasia and increased risk of acute myeloid leukemia, suggesting the coexistence of chronic myeloid leukemia and high-risk myelodysplastic syndrome. The aim of this study was to determine whether the impact of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells on the clinical outcome is different from that of other types of abnormalities, and we argue for an underlying associated high-risk myelodysplastic syndrome. Among 102 chronic myeloid leukemia patients with clonal chromosome abnormalities in Philadelphia-negative cells with more than a median of 6 years of follow up, patients with -7/del(7q) more frequently had signs of dysplasia, a lower cumulative incidence of deep molecular response and often needed further treatment lines, with the consequent impact on event-free and progression-free survival. Morphological features of dysplasia are associated with myelodysplastic syndrome/acute myeloid leukemia mutations and compromise the optimal response to tyrosine kinase inhibitors, irrespectively of the type of clonal chromosome abnormalities in Philadelphia-negative cells. However, mutation patterns determined by next-generation sequencing could not clearly explain the underlying high-risk disease. We hereby confirm the pejorative prognostic value of -7/del(7q) clonal chromosome abnormalities in Philadelphia-negative cells and suggest that myelodysplastic features constitute a warning signal that response to tyrosine kinase inhibitors may be less than optimal.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 7 , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/etiologia , Metáfase/genética , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Alelos , Deleção Cromossômica , Progressão da Doença , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/terapia , Prognóstico , Análise de SobrevidaRESUMO
To understand the complex interactions between hematopoietic stem cells and the bone marrow niche, a human experimental model is needed. Our hypothesis is that hematons are an appropriate ex vivo model of human bone marrow. We analyzed the hierarchical hematopoietic cell content and the tissue organization of single hematons from healthy donors. Most (>90%) hematons contained precursors of all cell lineages, myeloid progenitors, and LTC-ICs without preferential commitment. Approximately, half of the hematons could generate significant levels of lympho-myeloid hematopoiesis after transplantation in an NSG mouse model, despite the low absolute numbers of transplanted CD34+ cells. Mesenchymal STRO-1+ and/or CD271+ cells formed a critical network that preserved hematon cohesion, and STRO-1+ cells colocalized with most hematopoietic CD34+ cells (68%). We observed an influence of age and gender. These structures represent a particularly attractive model for studying the homeostasis of the bone marrow niche and pathological changes that occur during diseases.
Assuntos
Células da Medula Óssea/citologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Medula Óssea/fisiologia , Medula Óssea/ultraestrutura , Células da Medula Óssea/fisiologia , Células da Medula Óssea/ultraestrutura , Comunicação Celular/fisiologia , Feminino , Citometria de Fluxo , Voluntários Saudáveis , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/fisiologia , Células-Tronco Hematopoéticas/ultraestrutura , Humanos , Masculino , Camundongos , Microscopia Confocal , Microscopia Eletrônica , Pessoa de Meia-Idade , Transplante Heterólogo , Adulto JovemRESUMO
Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT) is often proposed for patients with comorbidities. To enhance engraftment and limit graft-versus-host disease (GVHD), antithymoglobulin (ATG) is usually used. However, the dose needed remains unclear unlike myeloablative conditioning. In order to clarify this point, we conducted a retrospective study on patients who received a reduced intensity conditioning allo-HSCT based on a 2-day fludarabine and busulfan treatment with either 1 or 2 days of ATG treatment. One hundred and eight patients received 2.5 mg/kg (ATG2.5) and another 60 patients 5 mg/kg (ATG5). The median follow-up was 36 months. The median overall survival was 39 months and the median disease-free survival 45 months. In multivariate analysis, overall nonrelapse mortality (NRM) was independently influenced by the acute GVHD grade III-IV (p < 0.001) and ATG dose (30 vs. 21% for ATG5; p = 0.008). Despite heterogeneity of populations, using proportional-hazard assumptions, we have been able to observe in multivariate analysis a lower NRM in the ATG5 group. This leads to a statistically higher overall survival for the ATG5 group. In conclusion, 2 days of ATG decrease NRM independently without increasing the risk of relapse or infectious disease.
Assuntos
Soro Antilinfocitário/uso terapêutico , Agonistas Mieloablativos/uso terapêutico , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Estudos Retrospectivos , Condicionamento Pré-Transplante , Transplante Homólogo , Vidarabina/uso terapêuticoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Terapia de Salvação , Adolescente , Adulto , Idoso , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Intervalo Livre de Doença , Feminino , Gemtuzumab , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Recidiva , Resultado do Tratamento , Adulto JovemRESUMO
One of the essential parameters of targeted therapy efficiency in cancer treatment is the amount of drug reaching the therapeutic target area. Imatinib (IM) was the first specifically targeted drug to be developed and has revolutionized the treatment of patients with chronic myeloid leukemia (CML). To evaluate cellular uptake of IM, we developed a method based on the chemical structure of the molecule and using the natural UV fluorescence that we quantified by flow cytometry. In two CML cell lines, we obtained a satisfactory relationship between intracellular IM (ICIM) levels and media concentrations, and we found a strong correlation between ICIM at 1 h and IM efficacy at 24 h, demonstrating that ICIM at 1 h might be a relevant predictive parameter of cell sensitivity. Our method was more sensitive than the standard physicochemical method. We applied our method to primary cells and found cell morphology-dependent IM accumulation. Moreover, in CML cells from patients at diagnosis, IM accumulation was heterogeneous. In all cases, ICIM at the single-cell level was much higher than in culture media arguing in favor of a predominantly active uptake process. We developed a simple method directly applicable to primary cells that has shown two major advantages: only a small number of cells are required, and cell subsets can be identified according to morphological criteria and/or the presence of particular antigenic sites. This method provides a new tool to assess CML cell sensitivity to IM, and ICIM levels in native CML cells could be used to monitor therapeutic response.
Assuntos
Citometria de Fluxo/métodos , Leucemia Mielogênica Crônica BCR-ABL Positiva/metabolismo , Piperazinas/farmacocinética , Pirimidinas/farmacocinética , Antineoplásicos/farmacocinética , Benzamidas , Forma Celular , Meios de Cultura/metabolismo , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Fluorescência , Humanos , Mesilato de Imatinib , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Piperazinas/sangue , Pirimidinas/sangue , Sensibilidade e Especificidade , Raios UltravioletaRESUMO
From COVID pandemic spread until now, many HSCT unrelated donor registries recommend as a precaution a systematic COVID-19 testing for all donors during the precollection time. Literature is quite poor to support this systematic attitude. We report one sibling allogeneic HSCT which we proceeded despite a positive COVID test on related asymptomatic donor and summarize the all seven cases reported until now. We suggest to question this systematic COVID testing, two years after pandemic began, when there is no systematic testing on other blood products received during all the haematological malignancies treatment process.
RESUMO
Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients' response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.
Assuntos
Antígenos CD34/imunologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica , Pirimidinas/farmacologia , Humanos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Células Tumorais CultivadasRESUMO
Disease recurrence and graft dysfunction after allogeneic hematopoietic stem cell transplantation (allo-HSCT) currently remain among the major causes of treatment failure in malignant and non-malignant hematological diseases. A second allo-HSCT is a valuable therapeutic option to salvage those situations. During the 8th annual harmonization workshops of the french Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines on feasibility, indications, donor choice and conditioning in the case of a second allo-HSCT. In case of relapse, a second allo-HSCT with reduced intensity or non-myeloablative conditioning is a reasonable option, particularly in patients with a good performance status (Karnofsky/Lansky>80%), low co-morbidity score (EBMT score≤3), a longer remission duration after the first allo-HSCT (>6 months), and who present low disease burden at the time of second allo-HSCT. Matched related donors tend to be associated with better outcomes. In the presence of graft dysfunction (primary and secondary graft rejection), an immunoablative conditioning regimen is recommended. A donor change remains a valid option, especially in the absence of graft-versus-host disease after the first allo-HSCT.
Assuntos
Rejeição de Enxerto/terapia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/normas , Retratamento/normas , Condicionamento Pré-Transplante/normas , Fatores Etários , Transplante de Medula Óssea , Terapia Baseada em Transplante de Células e Tecidos , Seleção do Doador , Rejeição de Enxerto/imunologia , Histocompatibilidade , Humanos , Recidiva , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodosRESUMO
INTRODUCTION: Malnutrition is common after allogeneic hematopoietic stem cell transplantation (allo-HSCT), and is a well-known prognostic factor for survival. The nutritional status of patients in a long term after allo-HSCT is less well documented. The main objective of this study was to evaluate the prevalence of malnutrition in adult patients who underwent allo-HSCT more than one year ago. Secondary objectives were to assess body composition, muscle strength, and factors associated with malnutrition. PATIENTS & METHODS: All allo-HSCT patients admitted into the University Hospital of Clermont-Ferrand between 1st January 1985 and 31st December 2012 were screened. Clinical and biological nutritional assessments included anthropometric measurements, serum nutritional proteins, body composition assessed by bioelectrical impedance, and upper-limb muscle strength (MS) measured by dynamometry. Hematological and nutritional data during and after hospital stay for allo-HSCT were retrospectively collected. RESULTS: Eighty four allo-HSCT patients (52% men; mean age 54.4 ± 12.5 years) were enrolled. Average follow-up after allo-HSCT was 56.4 ± 47.5 months. Prevalence of malnutrition at the end of follow-up was 20%. Compared to well-nourished patients (WN group), undernourished patients (UN group) at the end of follow-up were significantly more likely to be undernourished (50% vs. 21%, p = 0.04) at hospital admission, and to have a Nutritional Risk Index of <97.5 (47% vs. 20%, p = 0.004). Compared to a reference population, mid-arm muscle circumference and MS were significantly more likely to be decreased in the UN group than in the WN group (35.3% vs. 8.9%, p = 0.017; 24% vs. 3%, p = 0.005, respectively); fat-free mass index and appendicular skeletal muscle mass index were decreased in 30.5% and 36.6% of all patients, respectively, with no difference between UN and WN groups. Chronic graft-versus-host disease was more frequent, although not significantly in the UN group (76% vs. 52%, p = 0.071). In multivariate analyses, the presence of malnutrition at hospital admission for allo-HSCT trended towards an increased risk of longer-term malnutrition (OR = 3.60 [0.95; 13.67], p = 0.06). CONCLUSION: Malnutrition is a frequent consequence of allo-HSCT, and may occur several months or years after allo-HSCT, particularly if malnutrition existed before allo-HSCT. Our findings support the need for specialized nutritional care for both before and after allo-HSCT. Furthermore, assessment of muscle mass may be a pertinent parameter of malnutrition in this instance.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Desnutrição/epidemiologia , Avaliação Nutricional , Complicações Pós-Operatórias/epidemiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Desnutrição/diagnóstico , Pessoa de Meia-Idade , Estado Nutricional , Complicações Pós-Operatórias/diagnóstico , PrevalênciaRESUMO
Despite the high efficiency of tyrosine kinase inhibitors (TKI), some patients with chronic myeloid leukemia (CML) will display residual disease that can become resistant to treatment, indicating intraclonal heterogeneity in chronic-phase CML (CP-CML). To determine the basis of this heterogeneity, we conducted the first exhaustive characterization of the DNA methylation pattern of sorted CP-CML CD34+ CD15- (immature) and CD34- CD15+ (mature) cells at diagnosis (prior to any treatment) and compared it to that of CD34+ CD15- and CD34- CD15+ cells isolated from healthy donors (HD). In both cell types, we identified several hundreds of differentially methylated regions (DMRs) showing DNA methylation changes between CP-CML and HD samples, with only a subset of them in common between CD34+ CD15- and CD34- CD15+ cells. This suggested DNA methylation variability within the same CML clone. We also identified 70 genes that could be aberrantly repressed upon hypermethylation and 171 genes that could be aberrantly expressed upon hypomethylation of some of these DMRs in CP-CML cells, among which 18 and 81, respectively, were in CP-CML CD34+ CD15- cells only. We then validated the DNA methylation and expression defects of selected candidate genes. Specifically, we identified GAS2, a candidate oncogene, as a new example of gene the hypomethylation of which is associated with robust overexpression in CP-CML cells. Altogether, we demonstrated that DNA methylation abnormalities exist at early stages of CML and can affect the transcriptional landscape of malignant cells. These observations could lead to the development of combination treatments with epigenetic drugs and TKI for CP-CML.
Assuntos
Antígenos CD34/metabolismo , Metilação de DNA/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Antígenos CD15/metabolismo , Transcrição Gênica , Adulto , Idoso , Idoso de 80 Anos ou mais , Ilhas de CpG/genética , Feminino , Regulação Leucêmica da Expressão Gênica , Estudos de Associação Genética , Células-Tronco Embrionárias Humanas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Adulto JovemRESUMO
Ponatinib represents a remarkable progress in the treatment of heavily pretreated chronic myelogenous leukemia (CML) and de novo Philadelphia chromosome-positive ALL patients despite significant toxicity in clinical trials. To date, "real-life" data remain few and the use of ponatinib in this setting and its consequences remain mostly unknown. We report, within a national observational study, the use of ponatinib in unselected CML patients who had previously failed ≥2 lines of tyrosine kinase inhibitor (TKI) therapy (or one line if an Abelson (ABL)T315I mutation was identified), in real-life conditions (2013-2014) in a compassionate program. Our analysis has been focused on 48 chronic phase CML patients recorded. With a median follow-up of 26.5 months since ponatinib initiation, the overall survival (OS) rates (80.5% at 3 years) and cumulative incidence of major molecular response (81.8% at 18 months) were similar to those of the phase II study, with no influence of BCR-ABL mutations nor the reason of ponatinib prescription. A specific subanalysis of the preexisting cardiovascular risk factors and events occurring on ponatinib is described. These events occurred after a median time on ponatinib of 5.8 months (excluding hypertension) and were observed in 29/48 patients (47%), even in those already on anti-aggregants/coagulants. The majority were not severe and resolved, but two cases were fatal. Other hematological or nonhematological nonvascular adverse events were similar to those previously described in trials. This observational study reports similar rates of survival, molecular responses, and a slight increase in the cardiovascular toxicity of ponatinib in real-life conditions, prompting improved control of cardiovascular risk factors and selection of patients.
Assuntos
Antineoplásicos/uso terapêutico , Imidazóis/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Terapia de Salvação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Ensaios de Uso Compassivo , Resistencia a Medicamentos Antineoplásicos , Feminino , Genes abl , Humanos , Imidazóis/efeitos adversos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Ensaios Clínicos Pragmáticos como Assunto , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Análise de Sobrevida , Falha de Tratamento , Adulto JovemRESUMO
The French society of bone marrow transplantation and cell therapy (SFGM-TC) organizes annually workshops in the attempt to harmonize clinical practices between different francophone transplantation center. Here, we report our recommendations regarding the management of Epstein Barr virus reactivation and lymphoproliferative disorders, cytomegalovirus (CMV) and human herpes virus 6 (HHV6) after allogeneic stem cell transplantation.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus/fisiologia , Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/fisiologia , Herpesvirus Humano 6/fisiologia , Infecções por Roseolovirus , Ativação Viral , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/terapia , Infecções por Citomegalovirus/virologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/terapia , Infecções por Vírus Epstein-Barr/virologia , França , Humanos , Transtornos Linfoproliferativos/tratamento farmacológico , Infecções por Roseolovirus/diagnóstico , Infecções por Roseolovirus/terapia , Infecções por Roseolovirus/virologia , Sociedades Médicas , Transplante Homólogo , Carga ViralRESUMO
To harmonize clinical practice in hematopoietic stem cell transplantation, the Francophone Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the sixth annual series of workshops which brought together practitioners from all member centers and took place in September 2015 in Lille. The main aim of this session was to describe the impact, evaluation and treatment of post-transplant iron overload.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/terapia , Flebotomia/métodos , Transfusão de Eritrócitos/estatística & dados numéricos , França , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/prevenção & controle , Sociedades MédicasRESUMO
Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients.