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1.
Haematologica ; 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31278207

RESUMO

Iron overload due to red blood cell transfusions is associated with morbidity and mortality in lower-risk myelodysplastic syndrome patients. Many studies suggested improved survival after iron chelation therapy, but valid data are limited. The aim of this study was to assess the effect of iron chelation on overall survival and hematological improvement in lower-risk myelodysplastic syndrome patients in the European MDS registry. We compared chelated patients with a contemporary, non-chelated control group within the European MDS registry, that met the eligibility criteria for starting iron chelation. A Cox proportional hazards model was used to assess overall survival, treating receipt of chelation as a time-varying variable. Additionally, chelated and non-chelated patients were compared using a propensity-score matched model. Of 2200 patients, 224 received iron chelation. The hazard ratio and 95% confidence interval for overall survival for chelated patients, adjusted for age, sex, comorbidity, performance status, cumulative red blood cell transfusions, IPSS-R, and presence of ringed sideroblasts was 0.50 (0.34-0.74). The propensity-score analysis, matched for age, sex, country, red blood cell transfusion intensity, ferritin level, comorbidity, performance status, and IPSS-R and additionally corrected for cumulative red blood cell transfusions and presence of ringed sideroblasts, demonstrated a significantly improved overall survival for chelated patients with a hazard ratio of 0.42 (0.27-0.63) compared to non-chelated patients. Up to 39% of chelated patients reached an erythroid response. In conclusion, our results suggest that iron chelation may improve overall survival and hematopoiesis in transfused lower-risk myelodysplastic syndrome patients. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

2.
Br J Haematol ; 2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31271217

RESUMO

The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO-SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO-SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02-2·74)] with a 93-month cut-off time, and history of osteoarticular symptoms [RR = 1·84 (1·04-3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre-existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.

3.
Clin Cancer Res ; 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31292142

RESUMO

Purpose: Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.Patients and Methods: We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.Results: A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1-64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%-59%] at 6 months, and 50% (95% CI, 43%-57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415-0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360-0.858), respectively.Conclusions: We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML.

4.
Haematologica ; 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171638

RESUMO

Progression-free survival of lower-risk myelodysplastic syndromes patients treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals of newly diagnosed lower-risk myelodysplastic syndromes patients from 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk myelodysplastic syndromes /acute myeloid leukemia as events. Of the 1267 patients included in the analyses, 317 patients died without progression, in 162 patients the disease had progressed. Progression-free survival was significantly associated with age, EQ-5D index, baseline WHO classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with progression-free survival (p<1x10-4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoietin agents, lenalidomide and/or iron chelators. Conclusion: the negative effect of transfusion treatment on progression-free survival already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior progression-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

5.
Cancer Med ; 8(6): 3296-3304, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31038849

RESUMO

BACKGROUND: Data on Chronic Myeloid Leukemia (CML) prevalence are scarce. Here we provide an estimation of the prevalence of CML in France for the year 2014 using French national health insurance data. METHODS: We selected patients claiming reimbursement for tyrosine kinase inhibitors (TKI) or with hospital discharge diagnoses for CML, BCR/ABL-positive or with full reimbursement of health care expenses for myeloid leukemia. We built an algorithm which we validated on a random sample of 100 potential CML patients by comparing the results obtained using the algorithm and the opinion of two hematologists who reviewed the patient demographics and sequence of care abstracted from claims data (internal validity). For external validity, we compared the number of incident CML patients identified using the algorithm with those recorded in French population-based cancer registries in departments covered by such a registry. RESULTS: We identified 10 789 prevalent CML patients in 2014, corresponding to a crude prevalence rate of 16.3 per 100 000 inhabitants [95% confidence interval (CI) 16.0-16.6]: 18.5 in men [18.0-19.0] and 14.2 in women [13.8-14.6]. The crude CML prevalence was less than 1.6 per 100 000 [1.2-2.0] under age 20, increasing to a maximum of 48.2 [45.4-51.2) at ages 75-79. It varied from 10.2 to 23.8 per 100 000 across French departments. The algorithm showed high internal and external validity. Concordance rate between the algorithm and the hematologists was 96%, and the numbers of incident CML patients identified using the algorithm and the registries were 162 and 150, respectively. CONCLUSION: We built and validated an algorithm to identify CML patients in administrative healthcare databases. In addition to prevalence estimation, the algorithm could be used for future economic evaluations or pharmaco-epidemiological studies in this population.

7.
Exp Hematol ; 67: 41-48, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30195076

RESUMO

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.

8.
Blood Adv ; 2(16): 2079-2089, 2018 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-30126931

RESUMO

Prognosis of lower-risk (International Prognostic Scoring System [IPSS] low/intermediate-1) myelodysplastic syndrome (MDS) is heterogeneous and relies on steady-state assessment of cytopenias. We analyzed relative drops in neutrophil and platelet counts during the first 6 months of follow-up of lower-risk MDS patients. We performed a landmark analysis of overall survival (OS) of lower-risk MDS patients prospectively included in the European LeukaemiaNet MDS registry having a visit at 6 ± 1 month from inclusion to assess the prognostic relevance of relative drops in neutrophils and platelets, defined as (count at landmark - count at inclusion)/count at inclusion. Of 2102 patients, 807 were eligible for the stringent 6-month landmark analysis. Median age was 73 years. Revised IPSS was very low, low, and intermediate/higher in 26%, 43%, and 31% of patients, respectively. A relative drop in platelets >25% at landmark predicted shorter OS (5-year OS, 21.9% vs 48.6% with platelet drop ≤25%, P < 10-4), regardless of baseline IPSS-revised or absolute platelet counts. Relative neutrophil drop >25% had no significant impact on OS. We built a classifier based on red blood cell transfusion dependence (RBC-TD) and relative platelet drop >25% at landmark. Patients with none (62%), either (27%), or both criteria (11%) had 5-year OS of 53.3%, 32.7%, and 9.0%, respectively (P < 10-4). This classifier was validated in an independent cohort of 335 patients. Combining relative platelet drop >25% and RBC-TD at 6 months from diagnosis provides an inexpensive and noninvasive way to predict outcome in lower-risk MDS. This study was registered at www.clinicaltrials.gov as #NCT00600860.

9.
Med Sci (Paris) ; 34(6-7): 540-546, 2018 Jun-Jul.
Artigo em Francês | MEDLINE | ID: mdl-30067206

RESUMO

Convincing clinical and experimental evidence is converging on the essential role of NK (Natural Killer) cells in the recognition and eradication of tumors. Recent studies emphasized the role of NK cells in the immune control of chronic myeloid leukemia (CML), a malignancy arising from hematopoietic stem cells, and the treatment of which has been revolutionized by the use of tyrosine kinase inhibitors (TKI). Three major findings are emerging: 1) the impairment of the numbers and function of NK cells at diagnosis, 2) the restoration of the NK cell function and numbers during remissions induced with TKI therapies and 3) the potential role of the more mature NK CD56dim cell population in maintaining relapse-free survival after stopping TKI therapy. Immunological control of CML by NK cells which has been suspected for several decades is thus a new field of investigation for future therapies.

10.
Haematologica ; 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30026341

RESUMO

In standard risk acute promyelocytic leukemia, recent results have shown that ATRA + Arsenic trioxide combinations were at least as effective as classical ATRA + anthracycline based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher risk acute promyelocytic leukemia, and access to arsenic remains limited for frontline treatment of standard risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared for consolidation treatment (after ATRA-Chemotherapy induction treatment) arsenic, ATRA and the classical AraC in standard risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher risk APL. Newly diagnosed acute promyelocytic leukemia patients with white blood cells < 10 G/L, after an induction treatment consisting of ATRA plus Idarubicin-AraC, received consolidation chemotherapy with Idarubicin and AraC, arsenic or ATRA. Patients with white blood cells >10G received consolidation chemotherapy with arsenic or without arsenic.795 acute promyelocytic leukemia patients were enrolled in this trial. In Standard risk APL (n= 581), 5-year EFS from randomization was 88.7%, 95.7% and 85.4% in the AraC, arsenic and ATRA consolidation groups, respectively (p=0.0067) and 5 year cumulative incidence of relapse (CIR) was 5.5%, 0% and 8.2%. (p=0.001). In higher risk APL (n=214), 5-year EFS was 85.5% vs 92.1% (p=0.38) in the chemotherapy and chemotherapy+ arsenic groups, respectively and 5-year CIR of 4.6% and 3.5% (p= 0.99) in the chemotherapy and chemotherapy+ arsenic groups. Due to prolonged myelosuppression in the chemotherapy+ arsenic arm, an amendment excluded AraC during consolidation cycles in the chemotherapy+ arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation where we found myelosuppression to be significant. (ClinicalTrials.gov Identifier: NCT00378365).

11.
Cancer ; 124(14): 2956-2963, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29723417

RESUMO

BACKGROUND: The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. METHODS: Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. RESULTS: Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. CONCLUSIONS: This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.

13.
Mol Oncol ; 12(6): 814-829, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29575763

RESUMO

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.

14.
Leukemia ; 32(6): 1380-1392, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29572506

RESUMO

In myelodysplastic syndromes (MDS), health-related quality of life (HRQoL) represents a relevant patient-reported outcome, which is essential in individualized therapy planning. Prospective data on HRQoL in lower-risk MDS remain rare. We assessed HRQOL by EQ-5D questionnaire at initial diagnosis in 1690 consecutive IPSS-Low/Int-1 MDS patients from the European LeukemiaNet Registry. Impairments were compared with age- and sex-matched EuroQol Group norms. A significant proportion of MDS patients reported moderate/severe problems in the dimensions pain/discomfort (49.5%), mobility (41.0%), anxiety/depression (37.9%), and usual activities (36.1%). Limitations in mobility, self-care, usual activities, pain/discomfort, and EQ-VAS were significantly more frequent in the old, in females, and in those with high co-morbidity burden, low haemoglobin levels, or red blood cells transfusion need (p < 0.001). In comparison to age- and sex-matched peers, the proportion of problems in usual activities and anxiety/depression was significantly higher in MDS patients (p < 0.001). MDS-related restrictions in the dimension mobility were most prominent in males, and in older people (p < 0.001); in anxiety/depression in females and in younger people (p < 0.001); and in EQ-VAS in women and in persons older than 75 years (p < 0.05). Patients newly diagnosed with IPSS lower-risk MDS experience a pronounced reduction in HRQoL and a clustering of restrictions in distinct dimensions of HRQoL as compared with reference populations.

15.
Leuk Res ; 67: 21-26, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29407183

RESUMO

Conventional karyotype is one of the most relevant prognostic factors in MDS. However, about 50% of patients with MDS have a normal karyotype. Usually, 20-25 normal metaphases (nMP) are considered to be optimal to exclude small abnormal clones which might be associated with poor prognosis. This study evaluated the impact of examining a suboptimal number of metaphases in patients recruited to the EUMDS Registry with low and intermediate-1 risk according to IPSS. Only 179/1049 (17%) of patients with a normal karyotype had a suboptimal number of nMP, defined as less than 20 metaphases analyzed. The outcome (overall survival and progression-free survival) of patients with suboptimal nMP was not inferior to those with higher numbers of analyzed MP both in univariate and multivariate analyses. For patients with an abnormal karyotype, 224/649 (35%) had a suboptimal number of MP assessed, but this did not impact on outcome. For patients with a normal karyotype and suboptimal numbers of analyzable metaphases standard evaluation might be acceptable for general practice, but we recommend additional FISH-analyses or molecular techniques, especially in candidates for intensive interventions.

16.
Leuk Res ; 60: 94-102, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28772207

RESUMO

Although it has been well-demonstrated that bone marrow mesenchymal stromal cells (MSCs) from CML patients do not belong to the Ph1-positive clone, there is growing evidence that they could play a role in the leukemogenesis process or the protection of leukemic stem cells from the effects of tyrosine kinase inhibitors (TKIs). The aim of the present study was to identify genes differentially expressed in MSCs isolated from CML patients at diagnosis (CML-MSCs) as compared to MSCs from healthy controls. Using a custom gene-profiling assay, we identified six genes over-expressed in CML-MSCs (BMP1, FOXO3, MET, MITF, NANOG, PDPN), with the two highest levels being documented for PDPN (PODOPLANIN) and NANOG. To determine whether this aberrant signature persisted in patients in deep molecular response induced by TKIs, we analyzed MSCs derived from such patients (MR-MSCs). This analysis showed that, despite the deep molecular responses, BMP1, MET, MITF, NANOG, and PDPN mRNA were upregulated in MR-MSCs. Moreover, BMP1, MITF, and NANOG mRNA expressions in MR-MSCs were found to be intermediate between control MSCs and CML-MSCs. These results suggest that CML-MSCs exhibit an abnormal gene expression pattern which might have been established during the leukemogenic process and persist in patients in deep molecular response.


Assuntos
Medula Óssea/patologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Células-Tronco Mesenquimais/patologia , Animais , Transformação Celular Neoplásica/genética , Perfilação da Expressão Gênica , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Camundongos , Inibidores de Proteínas Quinases , Proteínas Tirosina Quinases/antagonistas & inibidores , RNA Mensageiro/análise , Indução de Remissão , Regulação para Cima
17.
Cancer ; 123(22): 4403-4410, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28743166

RESUMO

BACKGROUND: Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation. METHODS: The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients. RESULTS: The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others. CONCLUSIONS: This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10. © 2017 American Cancer Society.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França/epidemiologia , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Resultado do Tratamento , Suspensão de Tratamento
18.
J Hematol Oncol ; 10(1): 131, 2017 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-28651604

RESUMO

BACKGROUND: Particularly since the advent of lenalidomide, lower-risk myelodysplastic syndromes (MDS) patients with del(5q) have been the focus of many studies; however, the impact of age on disease characteristics and response to lenalidomide has not been analyzed. METHODS: We assessed the effect of age on clinical characteristics and outcomes in 286 lenalidomide-treated MDS patients with del(5q) from two multicenter trials. RESULTS: A total of 33.9, 34.3, and 31.8% patients were aged <65 years, ≥65 to <75 years, and ≥75 years, respectively. Age <65 years was associated with less favorable International Prognostic Scoring System (IPSS) risk and additional cytopenias at baseline versus older age groups, significantly lower cytogenetic response rates (p = 0.022 vs. ≥65 to <75 years; p = 0.047 vs. ≥75 years), and higher rates of acute myeloid leukemia (AML) progression (Gray's test, p = 0.013). Lenalidomide was equally well tolerated across age groups, producing consistently high rates of red blood cell transfusion independence ≥26 weeks. CONCLUSIONS: Baseline disease characteristics and AML progression appear to be more severe in younger lower-risk MDS patients with del(5q), whereas older age does not seem to compromise the response to lenalidomide. TRIAL REGISTRATION: ClinicalTrials.gov NCT00065156 and NCT00179621.


Assuntos
Fatores Imunológicos/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/patologia , Talidomida/análogos & derivados , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 5/genética , Citogenética , Progressão da Doença , Transfusão de Eritrócitos , Feminino , Humanos , Lenalidomida , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Prognóstico , Fatores de Risco , Talidomida/uso terapêutico , Resultado do Tratamento
19.
Haematologica ; 102(8): 1368-1377, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28522576

RESUMO

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).


Assuntos
Mesilato de Imatinib/uso terapêutico , Células Matadoras Naturais/citologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Contagem de Células , Intervalo Livre de Doença , Humanos , Interferon gama/análise , Células Matadoras Naturais/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Células Matadoras Naturais/análise , Recidiva
20.
J Clin Oncol ; 35(14): 1591-1597, 2017 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-28350519

RESUMO

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 5 , Leucemia Mieloide Aguda/etiologia , Síndromes Mielodisplásicas/terapia , Idoso , Idoso de 80 Anos ou mais , Anemia/etiologia , Anemia/terapia , Soro Antilinfocitário/uso terapêutico , Antineoplásicos/uso terapêutico , Arsênico/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Ciclosporina/uso terapêutico , Citarabina/uso terapêutico , Decitabina , Progressão da Doença , Inibidores Enzimáticos/uso terapêutico , Transfusão de Eritrócitos , Feminino , Hematínicos/uso terapêutico , Humanos , Hidroxiureia/uso terapêutico , Fatores Imunológicos/uso terapêutico , Lenalidomida , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/genética , Recidiva , Retratamento , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Talidomida/análogos & derivados , Talidomida/uso terapêutico , Falha de Tratamento , Tretinoína/uso terapêutico , Ácido Valproico/uso terapêutico
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