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1.
Eur J Haematol ; 2024 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-39129130

RESUMO

INTRODUCTION: Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. MATERIALS AND METHODS: We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. RESULTS: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). CONCLUSION: VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.

3.
Angew Chem Int Ed Engl ; 63(6): e202312392, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38055209

RESUMO

For the first time, we report calculations of the free energies of activation of cracking and isomerization reactions of alkenes that combine several different electronic structure methods with molecular dynamics simulations. We demonstrate that the use of a high level of theory (here Random Phase Approximation-RPA) is necessary to bridge the gap between experimental and computed values. These transformations, catalyzed by zeolites and proceeding via cationic intermediates and transition states, are building blocks of many chemical transformations for valorization of long chain paraffins originating, e.g., from plastic waste, vegetable oils, Fischer-Tropsch waxes or crude oils. Compared with the free energy barriers computed at the PBE+D2 production level of theory via constrained ab initio molecular dynamics, the barriers computed at the RPA level by the application of Machine Learning thermodynamic Perturbation Theory (MLPT) show a significant decrease for isomerization reaction and an increase of a similar magnitude for cracking, yielding an unprecedented agreement with the results obtained by experiments and kinetic modeling.

4.
Langmuir ; 39(45): 15962-15973, 2023 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-37929920

RESUMO

The efficient separation and adsorption of critical gases are, more than ever, a major focus point in important energy processes, such as CH4 enrichment of biogas or natural gas, CO2 separation and capture, and H2 purification and storage. Thanks to its physicochemical properties, cation-exchanged chabazite is a potent zeolite for such applications. Previous computational screening investigations have mostly examined chabazites exchanged with monovalent cations. Therefore, in this contribution, periodic density functional theory (DFT) calculations in combination with dispersion corrections have been used for a systematic screening of divalent cation exchanged chabazite zeolites. The work focuses on cheap and readily available divalent cations, Ca(II), Mg(II), and Zn(II), Fe(II), Sn(II), and Cu(II) and investigates the effect of the cation nature and location within the framework on the adsorption selectivity of chabazite for specific gas separations, namely, CO2/CH4, N2/CH4, and N2/H2. All the cationic adsorption sites were explored to describe the diversity of sites in a typical experimental chabazite with a Si/Al ratio close to 2 or 3. The results revealed that Mg-CHA is the most promising cation for the selective adsorption of CO2. These predictions were further supported by ab initio molecular dynamics simulations performed at 300 K, which demonstrated that the presence of CH4 has a negligible impact on the adsorption of CO2 on Mg-CHA. Ca(II) was found to be the most favorable cation for the selective adsorption of H2 and CO2. Finally, none of the investigated cations were suitable for the preferential capture of N2 and H2 in the purification of CH4 rich mixtures. These findings provide valuable insights into the factors influencing the adsorption behavior of N2, H2, CH4, and CO2 and highlight the crucial role played by theoretical calculations and simulations for the optimal design of efficient adsorbents.

5.
Genes Chromosomes Cancer ; 59(1): 30-39, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31340059

RESUMO

INTRODUCTION: In BCR-ABL1-negative myeloproliferative neoplasms, myelofibrosis (MF) is either primary (PMF) or secondary (SMF) to polycythemia vera or essential thrombocythemia. MF is characterized by an increased risk of transformation to acute myeloid leukemia (AML) and a shortened life expectancy. METHODS: Because natural histories of PMF and SMF are different, we studied by targeted next generation sequencing the differences in the molecular landscape of 86 PMF and 59 SMF and compared their prognosis impact. RESULTS: PMF had more ASXL1 (47.7%) and SRSF2 (14%) gene mutations than SMF (respectively 27.1% and 3.4%, P = .04). Poorer survival was associated with RNA splicing mutations (especially SRSF2) and TP53 in PMF (P = .0003), and with ASXL1 and TP53 mutations in SMF (P < .0001). These mutations of poor prognosis were associated with biological features of scoring systems (DIPSS and MYSEC-PM score). Mutations in TP53/SRSF2 in PMF or TP53/ASXL1 in SMF were more frequent as the risk of these scores increased. This allowed for a better stratification of MF patients, especially within the DIPSS intermediate-1 risk group (DIPSS) or the MYSEC-PM high risk group. AML transformation occurred faster in SMF than in PMF and patients who transformed to AML were more SRSF2-mutated and less CALR-mutated at MF sampling. CONCLUSIONS: PMF and SMF have different but not specific molecular profiles and different prognosis depending on the molecular profile. This may be due to differences in disease history. Combining mutations and existing scores should improve prognosis assessment.

6.
Am J Hematol ; 95(11): 1314-1323, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32720700

RESUMO

FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia (F/P+ MN-eo) is a rare disease: robust epidemiological data are lacking and reported issues are scarce, of low sample-size and limited follow-up. Imatinib mesylate (IM) is highly efficient but no predictive factor of relapse after discontinuation has yet been identified. One hundred and fifty-one patients with F/P+ MN-eo (143 males; mean age at diagnosis 49 years; mean annual incidence: 0.18 case per million population) were included in this retrospective nationwide study involving all French laboratories who perform the search of F/P fusion gene (study period: 2003-2019). The main organs involved included the spleen (44%), skin (32%), lungs (30%), heart (19%) and central nervous system (9%). Serum vitamin B12 and tryptase levels were elevated in 74/79 (94%) and 45/57 (79%) patients, respectively, and none of the 31 patients initially treated with corticosteroids achieved complete hematologic remission. All 148 (98%) IM-treated patients achieved complete hematologic and molecular (when tested, n = 84) responses. Forty-six patients eventually discontinued IM, among whom 20 (57%) relapsed. In multivariate analysis, time to IM initiation (continuous HR: 1,01 [0.99-1,03]; P = .05) and duration of IM treatment (continuous HR: 0,97 [0,95-0,99]; P = .004) were independent factors of relapse after discontinuation of IM. After a mean follow-up of 80 (56) months, the 1, 5- and 10-year overall survival rates in IM-treated patients were 99%, 95% and 84% respectively. In F/P+ MN-eo, prompt initiation of IM and longer treatment durations may prevent relapses after discontinuation of IM.


Assuntos
Corticosteroides/administração & dosagem , Eosinofilia , Neoplasias Hematológicas , Transtornos Mieloproliferativos , Proteínas de Fusão Oncogênica , Receptor alfa de Fator de Crescimento Derivado de Plaquetas , Fatores de Poliadenilação e Clivagem de mRNA , Adulto , Intervalo Livre de Doença , Eosinofilia/sangue , Eosinofilia/tratamento farmacológico , Eosinofilia/genética , Eosinofilia/mortalidade , Feminino , França/epidemiologia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/mortalidade , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/mortalidade , Proteínas de Fusão Oncogênica/sangue , Proteínas de Fusão Oncogênica/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/sangue , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Estudos Retrospectivos , Taxa de Sobrevida , Triptases/sangue , Vitamina B 12/sangue , Fatores de Poliadenilação e Clivagem de mRNA/sangue , Fatores de Poliadenilação e Clivagem de mRNA/genética
7.
Angew Chem Int Ed Engl ; 59(43): 18938-18942, 2020 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-32568440

RESUMO

Zeolite-catalyzed alkene cracking is key to optimize the size of hydrocarbons. The nature and stability of intermediates and transition states (TS) are, however, still debated. We combine transition path sampling and blue moon ensemble density functional theory simulations to unravel the behavior of C7 alkenes in CHA zeolite. Free energy profiles are determined, linking π-complexes, alkoxides and carbenium ions, for B1 (secondary to tertiary) and B2 (tertiary to secondary) ß-scissions. B1 is found to be easier than B2 . The TS for B1 occurs at the breaking of the C-C bond, while for B2 it is the proton transfer from propenium to the zeolite. We highlight the dynamic behaviors of the various intermediates along both pathways, which reduce activation energies with respect to those previously evaluated by static approaches. We finally revisit the ranking of isomerization and cracking rate constants, which are crucial for future kinetic studies.

8.
Biol Blood Marrow Transplant ; 25(9): 1803-1809, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31128325

RESUMO

Haploidentical stem cell transplantation (haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is an alternative treatment for acute myeloid leukemia (AML) patients who lack HLA-matched donors. Relapse after haplo-SCT remains a major concern, especially after nonmyeloablative conditioning regimens. Promising results were reported for TBF-based conditioning regimens (thiotepa, busulfan, and fludarabine) in patients transplanted from different categories of donors and for various disease types but not specifically in PT-Cy haplo-SCT for AML. Here we evaluate the outcome of 100 AML patients who received haplo-SCT with PT-Cy after TBF conditioning regimens (reduced-intensity conditioning, n = 77; myeloablative conditioning, n = 23) in 2 transplant programs. Cumulative incidences of grades III to IV acute and moderate or severe chronic graft-versus-host disease (GVHD) were 7% and 14%, respectively. NRM at 2 years was 28%, significantly influenced by disease status at haplo-SCT (first complete response [CR1] versus advanced AML: 16% versus 38%, P = .016) but not by conditioning intensity or age. The cumulative incidences of relapse at 2 years were 17% and 24% in CR1 and advanced AML, respectively (not significant). Progression-free survival, overall survival, and GVHD and relapse-free survival at 2 years were 67%, 71%, and 49% in CR1 patients, respectively, whereas comparative values in patients with advanced disease were 37%, 41%, and 32%. Our study suggests that TBF conditioning for PT-Cy haplo-SCT is safe and effective for AML patients in CR1. In patients with more advanced disease, the relatively low incidence of relapse seems counterbalanced by a high nonrelapse mortality, underlining the need for alternative strategies to decrease relapse risk, without increasing the intensity of conditioning regimen.


Assuntos
Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro , Leucemia Mieloide Aguda , Transplante de Células-Tronco , Linfócitos T , Tiotepa/administração & dosagem , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Idoso , Aloenxertos , Doença Crônica , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Vidarabina/administração & dosagem
9.
Biol Blood Marrow Transplant ; 24(7): 1449-1454, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29448057

RESUMO

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Transplante Homólogo/métodos , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Irmãos , Doadores de Tecidos , Doadores não Relacionados
10.
Haematologica ; 103(3): 438-446, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29217781

RESUMO

We have previously described the safety and efficacy of pegylated interferon-α2a therapy in a cohort of 62 patients with myeloproliferative neoplasm-associated myelofibrosis followed in centers affiliated to the French Intergroup of Myeloproliferative neoplasms. In this study, we report their long-term outcomes and correlations with mutational patterns of driver and non-driver mutations analyzed by targeted next generation sequencing. The median age at diagnosis was 66 years old, the median follow-up since starting pegylated interferon was 58 months. At the time of analysis, 30 (48.4%) patients were alive including 16 still being treated with pegylated interferon. The median survival of patients with intermediate and high-risk prognostic Lille and dynamic International Prognostic Scoring System scores treated with pegylated interferon was increased in comparison to that of historical cohorts. In addition, overall survival was significantly correlated with the duration of pegylated interferon therapy (70 versus 30 months after 2 years of treatment, P<10-12). JAK2V617F allele burden was decreased by more than 50% in 58.8% of patients and two patients even achieved complete molecular response. Next-generation sequencing analyses performed in 49 patients showed that 28 (57.1%) of them carried non-driver mutations. The presence of at least one additional mutation was associated with a reduction of both overall and leukemia-free survival. These findings in a large series of patients with myelofibrosis suggest that pegylated interferon therapy may provide a survival benefit for patients with intermediate- or high-risk Lille and dynamic International Prognostic Scoring System scores. It also reduced the JAK2V617F allele burden in most patients. These results further support the use of pegylated interferon in selected patients with myelofibrosis.


Assuntos
Interferon-alfa/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/mortalidade , Mielofibrose Primária/genética , Mielofibrose Primária/mortalidade , Prognóstico , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Análise de Sobrevida
11.
Am J Hematol ; 93(3): 330-338, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29148089

RESUMO

Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P = .0001), TET2 (P = .011) and SRSF2 (P = .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT…) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase.


Assuntos
Genes Neoplásicos , Leucemia Mieloide Aguda/genética , Transtornos Mieloproliferativos/patologia , Lesões Pré-Cancerosas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , DNA de Neoplasias/genética , Proteínas de Ligação a DNA/genética , Dioxigenases , Feminino , Genes p53 , Transplante de Células-Tronco Hematopoéticas , Humanos , Cariotipagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Transtornos Mieloproliferativos/genética , Cuidados Paliativos , Lesões Pré-Cancerosas/genética , Prognóstico , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas/genética , Análise de Sequência de DNA , Fatores de Processamento de Serina-Arginina/genética , Análise de Sobrevida
12.
Biol Blood Marrow Transplant ; 20(10): 1560-5, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24933658

RESUMO

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is recommended for patients with high-risk acute myeloid leukemia (AML). In many situations, a matched related (MRD) or matched unrelated donor (MUD) is lacking, in which case unrelated cord blood units (UCB) provide an alternative. We analyzed the outcome of consecutive high-risk AML patients prepared with reduced-intensity conditioning (RIC) regimens and allografted with UCB (n = 32) and compared their outcome with high-risk AML patients who underwent transplantation with MRD/MUD (n = 49) in the same period of time. Grade III to IV acute graft-versus-host disease (GVHD) occurred slightly more frequently in the UCB group (25%) than in the MRD/MUD group (8%) (P = .069). Conversely, we found a lower incidence of extensive chronic GVHD in the UCB group (6%) than in the MRD/MUD group (20%, P = .085). Nonrelapse mortality at 4 years was 16% and 22% in the UCB and MRD/MUD groups, respectively (P = .529). The cumulative incidence of relapse at 4 years was significantly higher in the UCB group (60%) than in the MRD/MUD group (27%, P = .006). Leukemia-free survival (LFS) and overall survival (OS) at 4 years were 25% and 34%, respectively, in the UCB group and 50% and 56%, respectively, in the MRD/MUD group (LFS, P = .029; OS, P = .072). Multivariate analyses adjusted by cytogenetics and disease status at the time of Allo-HSCT revealed that use of UCB remained an independent predictive factor of shorter LFS (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.6; P = .018), and was associated with a trend for shorter OS (hazard ratio, 1.7; 95% confidence interval, .9 to 3.2; P = .093). Whereas UCB provides an alternative for patients with high-risk AML lacking an MRD/MUD, the high incidence of relapse after RIC-based UCB Allo-HSCT is a concern. Attempts to improve leukemic control with UCB Allo-HSCT are warranted, as well as the evaluation of other alternative donors in this context.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Doença Crônica , Análise Citogenética , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos , Análise de Sobrevida , Transplante Homólogo , Doadores não Relacionados
13.
Biol Blood Marrow Transplant ; 20(3): 370-4, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24315846

RESUMO

Nonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation-specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease.


Assuntos
Soro Antilinfocitário/uso terapêutico , Antineoplásicos/uso terapêutico , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Bussulfano/uso terapêutico , Doença Crônica , Feminino , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Vidarabina/análogos & derivados , Vidarabina/uso terapêutico
14.
Haematologica ; 99(1): 37-45, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23996481

RESUMO

Myelofibrosis is a myeloproliferative neoplasm that occurs de novo (primary myelofibrosis) or results from the progression of polycythemia vera or essential thrombocytemia (hereafter designated as secondary myelofibrosis or post-polycythemia vera/ essential thrombocythemia myelofibrosis). To progress in the understanding of myelofibrosis and to find molecular prognostic markers we studied 104 samples of primary and secondary myelofibrosis at chronic (n=68) and acute phases (n=12) from 80 patients, by using array-comparative genomic hybridization and sequencing of 23 genes (ASXL1, BMI1, CBL, DNMT3A, EZH2, IDH1/2, JAK2, K/NRAS, LNK, MPL, NF1, PPP1R16B, PTPN11, RCOR1, SF3B1, SOCS2, SRSF2, SUZ12, TET2, TP53, TRPS1). We found copy number aberrations in 54% of samples, often involving genes with a known or potential role in leukemogenesis. We show that cases carrying a del(20q), del(17) or del(12p) evolve in acute myeloid leukemia (P=0.03). We found that 88% of the cases were mutated, mainly in signaling pathway (JAK2 69%, NF1 6%) and epigenetic genes (ASXL1 26%, TET2 14%, EZH2 8%). Overall survival was poor in patients with more than one mutation (P=0.001) and in patients with JAK2/ASXL1 mutations (P=0.02). Our study highlights the heterogeneity of myelofibrosis, and points to several interesting copy number aberrations and genes with diagnostic and prognostic impact.


Assuntos
Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/genética , Deleção Cromossômica , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Progressão da Doença , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/mortalidade , Prognóstico , Análise de Sequência de DNA
15.
Eur J Haematol ; 92(2): 127-36, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24118452

RESUMO

OBJECTIVES: To identify switch modalities used when initiating second- or third-line anagrelide for essential thrombocythemia (ET), assess whether anagrelide is initiated consistently with Summary of Product Characteristics (SPC) recommendations, and determine whether different observed switch regimens have any relationship with maintenance, platelet response, or tolerability. METHODS: This observational study was conducted across 43 centers in France. High-risk patients (>60 yr of age and/or history of thrombosis and/or platelet count >1000 × 10(9) /L) with ET starting second- or third-line anagrelide therapy were identified and monitored for 6 months. RESULTS: A total of 177 patients were enrolled. The SPC-recommended starting dose (1 mg/d) was used in 52.6% of patients; 0.5 mg/d was used in 41.1%. 77.1% of patients underwent an anagrelide dose increase during the study. At 6-month follow-up, 84.7% of patients (n = 144/170) were still receiving anagrelide; 70.6% (n = 120/170) achieved a platelet response. A higher proportion of patients who discontinued previous cytoreductive therapy (CRT) after initiating anagrelide achieved a platelet response (n = 34/39, 87.2%) vs. patients who discontinued their previous CRT before anagrelide initiation (n = 77/115, 67.0%). Platelet response rates were higher in patients whose anagrelide initiation was consistent (n = 100/133, 75.2%) vs. inconsistent (n = 20/37, 54.1%) with the SPC. The incidence of adverse drug reactions was lower in patients whose anagrelide treatment was consistent (n = 52/133, 39.1%) vs. inconsistent (n = 25/37, 67.6%) with the SPC. CONCLUSIONS: To our knowledge, the FOX study provides the first comprehensive real-world data on the modalities used when switching from previous CRT to anagrelide. Highest platelet responses were observed when previous CRT was discontinued after anagrelide initiation or when anagrelide was initiated consistently with the SPC. Safety data corresponded with the SPC.


Assuntos
Inibidores da Agregação Plaquetária/uso terapêutico , Quinazolinas/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Medicamentos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/efeitos adversos , Contagem de Plaquetas , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Retratamento , Trombocitemia Essencial/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
ChemSusChem ; : e202400134, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-39031793

RESUMO

Aliphatic polyesters and polythioesters are very interesting alternatives for current fossil-based and degradation-resistant plastics, due to their high (bio)degradability and (chemical) recyclability potential. Two important examples include polylactide (PLD), currently leading the synthetic bioplastics market, and its sulfur analog polythiolactide (PTLD). Both polymers can be made by ring-opening polymerization (ROP) of their corresponding (thio)dilactones, lactide (LD) and thiolactide (TLD) respectively. In this work, the benefits of esters and thioesters were combined in one material by the successful catalytic synthesis and ROP of monothiolactide (MTL), an unprecedented monomer containing half a LD and half a TLD structural unit. MTL can be obtained by a simple direct condensation of biobased lactic acid and thiolactic acid aided by Brønsted acid catalysis. The novel, but simple monomer showed to be easily polymerized with triethylamine to materials containing alternating lactic and thiolactic ester units with a very high molar mass. The lower stability of MTL (vs. TLD) resulted in improved ROP thermodynamics, while also fast and controllable polymerization kinetics were observed. The new polymers feature a good chemical recycling and hydrolytic degradation potential with important improvements compared to PTLD and PLD. Finally, a successful co-polymerization with commercial LD was shown, paving the way towards industrialization.

17.
Leuk Res ; 141: 107500, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38636413

RESUMO

Mutations in spliceosome genes (SRSF2, SF3B1, U2AF1, ZRSR2) correlate with inferior outcomes in patients treated with intensive chemotherapy for Acute Myeloid Leukemia. However, their prognostic impact in patients treated with less intensive protocols is not well known. This study aimed to evaluate the impact of Spliceosome mutations in patients treated with Venetoclax and Azacitidine for newly diagnosed AML. 117 patients treated in 3 different hospitals were included in the analysis. 34 harbored a mutation in at least one of the spliceosome genes (splice-mut cohort). K/NRAS mutations were more frequent in the splice-mut cohort (47% vs 19%, p=0.0022). Response rates did not differ between splice-mut and splice-wt cohorts. With a median follow-up of 15 months, splice mutations were associated with a lower 18-month LFS (p=0.0045). When analyzing splice mutations separately, we found SRSF2 mutations to be associated with poorer outcomes (p=0.034 and p=0.037 for OS and LFS respectively). This negative prognostic impact remained true in our multivariate analysis. We believe this finding should warrant further studies aimed at overcoming this negative impact.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Mutação , Fatores de Processamento de Serina-Arginina , Humanos , Fatores de Processamento de Serina-Arginina/genética , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Prognóstico , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Azacitidina/uso terapêutico , Azacitidina/administração & dosagem , Adulto Jovem , Spliceossomos/genética , Sulfonamidas
18.
Br J Haematol ; 162(6): 783-91, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23848933

RESUMO

Myeloproliferative neoplasm-related myelofibrosis is associated with cytopenic or proliferative phases, splenomegaly and constitutional symptoms. Few effective treatments are available and small series suggested that interferon could be an option for myelofibrosis therapy. We performed a retrospective study of pegylated-interferon α-2a (Peg-IFNα-2a) therapy in myelofibrosis. Sixty-two patients treated with Peg-IFNα-2a at 17 French and Belgian centres were included. Responses were determined based on the criteria established by the International Working Group for Myelofibrosis Research and Treatment. Mean follow-up was 26 months. Sixteen of 25 anaemic patients (64%) (eight concomitantly receiving recombinant erythropoietin) achieved a complete response and transfusion-independence was obtained in 5/13 patients (38·5%). Constitutional symptoms resolved in 82% of patients. All five leucopenic patients normalized their leucocyte counts, whereas a normal platelet count was obtained in 5/8 thrombocytopenic patients. Splenomegaly was reduced in 46·5% of patients, and complete resolution of thrombocytosis and leucocytosis were observed in 82·8% and 68·8% of patients, respectively. Side effects (mostly haematological) were mainly of grade 1-2. The only factor independently associated with treatment failure was a spleen enlargement of more than 6 cm below the costal margin. In conclusion, Peg-IFNα-2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.


Assuntos
Interferon-alfa/efeitos adversos , Interferon-alfa/uso terapêutico , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/uso terapêutico , Mielofibrose Primária/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Mielofibrose Primária/patologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
19.
Genes Chromosomes Cancer ; 51(8): 743-55, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22489043

RESUMO

Since the discovery of the JAK2V617F tyrosine kinase-activating mutation several genes have been found mutated in nonchronic myeloid leukemia (CML) myeloproliferative neoplasms (MPNs), which mainly comprise three subtypes of "classic" MPNs; polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We searched for mutations in ASXL1, CBL, DNMT3A, IDH1, IDH2, JAK2, MPL, NF1, SF3B1, SUZ12, and TET2 genes in 149 non-CML MPNs, including 127 "classic" MPNs cases. JAK2 was mutated in 100% PV, 66% ET and 68% MF. We found a high incidence of ASXL1 mutation in MF patients (20%) and a low incidence in PV (7%) and ET (4%) patients. Mutations in the other genes were rare (CBL, DNMT3A, IDH2, MPL, SF3B1, SUZ12, NF1) or absent (IDH1).


Assuntos
Proteínas de Ligação a DNA/genética , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteínas de Transporte/genética , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Análise Mutacional de DNA , Dioxigenases , Feminino , Humanos , Isocitrato Desidrogenase/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias , Neurofibromina 1/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Complexo Repressor Polycomb 2 , Proteínas Proto-Oncogênicas c-cbl/genética , Fatores de Processamento de RNA , Receptores de Trombopoetina/genética , Ribonucleoproteína Nuclear Pequena U2/genética , Fatores de Transcrição
20.
EJHaem ; 4(3): 779-791, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37601853

RESUMO

Primary myelofibrosis (PMF) and polycythaemia vera (PV) are rare BCR-ABL1-negative myeloproliferative neoplasms, associated with an increased risk of thrombosis, haemorrhagic complications and progression to fibrosis or leukaemia or fibrosis for PV. Both diseases are characterised by biological and clinical heterogeneity, leading to great variability in their management in routine clinical practice. In this review, we present an updated overview of the diagnosis, prognosis and treatment of PMF and PV, and we discuss how our multidisciplinary expert group based across France translates this evidence-based knowledge into routine clinical practice.

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