We aimed to study the prognostic impact of the mutational landscape in primary and secondary myelofibrosis. The study included 479 patients with myelofibrosis recruited from 24 French Intergroup of ...Myeloproliferative Neoplasms (FIM) centers. The molecular landscape was studied by high-throughput sequencing of 77 genes. A Bayesian network allowed the identification of genomic groups whose prognostic impact was studied in a multistate model considering transitions from the 3 conditions: myelofibrosis, acute leukemia, and death. Results were validated using an independent, previously published cohort (n = 276). Four genomic groups were identified: patients with TP53 mutation; patients with ≥1 mutation in EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS, or KRAS (high-risk group); patients with ASXL1-only mutation (ie, no associated mutation in TP53 or high-risk genes); and other patients. A multistate model found that both TP53 and high-risk groups were associated with leukemic transformation (hazard ratios HRs 95% confidence interval, 8.68 3.32-22.73 and 3.24 1.58-6.64, respectively) and death from myelofibrosis (HRs, 3.03 1.66-5.56 and 1.77 1.18-2.67, respectively). ASXL1-only mutations had no prognostic value that was confirmed in the validation cohort. However, ASXL1 mutations conferred a worse prognosis when associated with a mutation in TP53 or high-risk genes. This study provides a new definition of adverse mutations in myelofibrosis with the addition of TP53, CBL, NRAS, KRAS, and U2AF1 to previously described genes. Furthermore, our results argue that ASXL1 mutations alone cannot be considered detrimental.
•Mutations of TP53 and high-risk genes (EZH2, CBL, U2AF1, SRSF2, IDH1, IDH2, NRAS or KRAS) are adverse prognostic factors in myelofibrosis.•ASXL1 isolated mutations (ie, without TP53 or high-risk mutations) have no prognostic impact in myelofibrosis.
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Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) can occur as a de novo (Primary MF, PMF), or as secondary MF (SMF) resulting from transformation of Polycythemia Vera or Essential ...Thrombocythemia. In all cases, altered hematopoiesis results in abnormal blood counts (either hyperproliferation or cytopenias), splenomegaly and general symptoms related to inflammation, all of which are the intended targets of treatments.
Unfortunately, few therapeutic options exist and, besides allogeneic stem cell transplantation (ASCT), none is curative. We previously reported that pegylated-interferon-a2a (Peg-Ifn-α2a ) treatment in MF was able to induce significant clinical and hematological responses (1). We now present the long-term follow-up of this prospective cohort and correlations with driver and non-driver mutations.
Sixty-two MF patients (pts) treated with Peg-Ifn-α2a were included between 2006 and 2011 in a prospective observational study in 17 centers of the FIM group. Clinical and biological parameters and treatments were collected at Peg-Ifn-α2a initiation, every 3 months during two years and every 6 months thereafter. All 62 pts were genotyped for the 3 major MPN mutations (JAK2V617F, CALR, MPL), and 49 were also screened by next generation sequencing (NGS) for mutations in the whole coding sequence of 25 genes frequently mutated in chronic myeloid disorders.
The median age at Peg-Ifn-α2a initiation was 64 and 70.5 years-old, in PMF (n=29) and SMF (n=33) pts, respectively. The median follow-up was 58 months (range: 9-107) after Peg-Ifn-α2a initiation and 69.6 months (range: 10-178) from MF diagnosis. Median Peg-Ifn-α2a treatment duration was 39 months (range: 6-107). At the time of analysis, 30 patients (48.4%) were still alive. The median overall survival (OS) was 7.4 years from MF diagnosis. The Lille and the DIPSS scores clearly differentiated pts in terms of OS, but median OS observed in this cohort was clearly longer than that reported in the reference cohorts used for the establishment of these prognostic scores, especially in higher risk categories: according to the Lille score (8.9 vs. 7.75 yrs for low, 5.42 vs. 2.17 yrs for intermediate and 4.46 vs. 1.08 yrs for high risks) and to the DIPSS score (6.9 vs. 4 yrs for intermediate-2 and 4.58 vs. 1.5 yrs for high-risk pts).
The type of driver mutation statistically impacted survival: CALR -mutated pts had 13.5 yrs of median OS compared to 7 yrs for JAK2 -mutated pts (p<0.0001). Forty-five pts (72.6%) discontinued Peg-Ifn-α2a: 25 (55.6%) due to resistance and 20 (44.4%) due to intolerance. Patients developing intolerance to Peg-Ifn-α2a had longer median OS and leukemia-free survival (LFS) than those with resistance (p=10-5 and p=0.048, respectively). The median survival after Peg-Ifn-α2a cessation was 17 months (3-62m), but differed according to the subsequent treatment received: 22 months for those who received ruxolitinib compared to 14 months for those who received another drug (p=0.12) and 10 months for pts who underwent ASCT (p=0.003).
Sequential quantification of JAK2V617F allele burden was available in 27 pts, showing a decrease of mutant allele burden of more than 50% in 10/27 pts (37%). Four pts (15%) achieved a reduction over 90% including 3 complete molecular responses. Of the 49 pts analyzed with targeted NGS, 28 (57.1%) carried at least one additional mutation. Patients who harbored at least one non-driver mutation had shorter OS (6.1 vs. not reached, p=0.06) and LFS (not reached both, p=0.026) than those with only driver mutations. The presence of “high molecular risk” mutations previously associated with poorer prognosis (in ASXL1, EZH2, SRSF2, IDH1/2) was not associated with a poorer OS or LFS than other mutations in this series of pts treated with interferon.
In conclusion, this large cohort of MF pts treated with Peg-Ifn-α2a demonstrates that a long-term use of this treatment is safe, and is associated with improved OS compared to historical series as well as significant decrease in driver mutation allele burden. The presence of additional mutations remains associated with poorer prognosis. The role of interferon therapy should be discussed in pts with MF, optimal target population possibly being high-risk pts without ASCT project and with a proliferative disease.
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Ianotto:Novartis: Other: Grant. Laribi:MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Cony-Makhoul:BMS: Speakers Bureau. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Background: Therapeutic guidelines in essential thrombocytemia (ET) are based on established criteria, ie. age more than 60 years, history of thrombosis, platelets more than 1000-1500 ×109/L and to ...lesser degree cardio-vascular risk factors. Hydroxyurea and anagrelide are the most commonly used cytoreductive therapy for high risk ET. Despite a proven activity in Ph negative myeloproliferative disorders, generalized use and efficacy of Interferon-alpha (IFN-α) have been hampered by frequent side effects. Nonetheless it is a non leukemogenic therapeutic option for younger patients (pts) and during pregnancy. Two phase II trials using Pegylated (Peg) forms of IFN-α in pts with polycythemia vera (PV) or high risk ET have provided interesting results: i) an improved toxicity profile generally associated with a rapid hematolologic response, ii) a molecular response described in a subset of JAK2V617F positive PV or ET pts treated with PegIFN-α.
Aim: To estimate the rationale of PegIFN-α therapy selection in high risk ET patients, efficacy and tolerance.
Methods:Cases of high risk ET patients, who started PegIFN-α therapy between 2006 and 2011, were reported by centres of the French Intergroup of Myeloproliferative disorders and included in an observational study. We collected information regarding history of MPN, treatment, hematologic response at different timepoints, toxicities related to PegIFN-α, thrombo-hemorrhagic events and hematologic progression. The current analysis was performed on 103 consecutive pts.
Results: Median follow-up from ET diagnosis was 9 years (3-27). 74% of pts were female, median age was 37 years (range 16-67). Previous vascular event was observed in 36% of cases and JAK2V617F mutation was detected in 52% of pts. .
Median time from diagnosis to PegIFN-α was 40 months (1-255). PegIFN-α was administered after hydroxyurea and anagrelide in second or third line (56% and 27% respectively). No prior therapy has been used for 16% of pts. Reasons for starting PegIFN-α were lack of hematologic response (21%), toxicity to prior therapies (17%), pregnancy (15%), or medical decision for younger pts (47%). Pts received either PegIFNα-2a (n=91) or PegIFNα-2b (n=12), based on physician decision.
According to the 2009 European LeukemiaNet criteria and with a median exposure to PegIFN-α of 29 months (1-92), 81% of pts achieved a complete hematologic response (CHR). Cumulative incidence of CHR were 58 % (95% CI: 49-68), 73% (95% CI: 65-81) and 80% (95% CI: 71-87) at 6, 12 and 24 months respectively.
By analysing the response according to JAK2 status, cumulative incidence of CHR was better for the JAK2V617F positive subgroup (p=0.0183, overall). At 36 months estimated CHR rates were 89% (95% CI: 79-95) and 70% (95% CI: 57-82) for JAK2VF positive vs negative subgroup respectively. Median exposure to PegIFN-α was 29 months in both groups.
At last follow-up, with a median of 42 months since PegIFN-α initiation, 53% of the pts were still treated with PegIFN-α. Among them, 76% have maintained a CHR. Reasons for discontinuation of PegIFN-α (47% of pts) were consecutive to PegIFN-α toxicity (59%), -mainly chronic moderate non hematologic toxicity-, or hematologic responses were considered insufficient in16%. In addition, PegIFN-α has been stopped in a subset of pts who achieved a durable stable CHR.
In Conclusion, This study provides results of PegIFN-α therapy in a cohort of high risk ET pts not included in clinical trials. In this selected population of young pts, a durable efficacy of therapy was observed in half of patients. Characteristics of hematologic response according to molecular status will be presented. These results support the PegIFN-α as an alternative therapy to hydroxyurea and anagrelide in high risk ET, and warrant its investigation in further prospective randomized studies.
Roy:Merck: Peg-Interferon provided for academic clinical trial in CML Other. Off Label Use: Peg-Interferon in essential thrombocythemia. Gyan:Roche: Research Funding. Nicolini:BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Kiladjian:Roche: Peg-Interferon provided for academic clinical trial in PV Other.
La ville entrelacs Bernard, Élisa Violette; Böhmert, Lydia; Coelho Ferreira, Maria da Conceição ...
08/2021
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Façonnées par l’histoire, les villes sont en constante évolution, comme les sociétés qui les habitent, les transforment et qui sont en retour transformées par elles : des quartiers disparaissent, des ...populations se déplacent, des constructions voient le jour. Par la force des choses, les réseaux qu’abritent ces espaces urbains se modifient aussi ; des liens se resserrent, d’autres se distendent. Dans ce paysage en mouvement, l’artiste doit trouver sa place. Comment l’écrivain ou le peintre réussit-il à rendre compte de ces changements ? De quelle façon l’environnement de l’artiste influence-t-il son œuvre, et de quelle façon l’artiste influence-t-il à son tour son environnement ? À travers l’étude d’œuvres picturales et littéraires – de Louis Aragon, Graham Swift, Alfred Döblin, etc. –, cet ouvrage alimente la réflexion sur la ville et ses représentations. Dans une approche pluridisciplinaire (analyse littéraire, histoire, esthétique) balayant différents lieux (Europe, Asie, Amériques) et différentes époques, les auteurs cherchent à démêler les écheveaux de ces entrelacs topographiques, historiques, narratifs et humains, qui ne sont, bien souvent, que le reflet de notre quête d’identité.
Acute myeloid leukemias (AML) represent a vast and complex group of diseases where numerous molecular lesions have been and keep being described. From the immunophenotypic point of view, probably ...because of the variety of cells in the myeloid lineage, a rather large variety also exists. The detection of minimal residual disease (MRD) in such conditions therefore meets the challenge of tracking the proper anomaly and correctly separate leukemic cells from their normal counterparts. In an oligocentric project initiated in France in late 2006, ten cytometry platforms and six molecular biology laboratories collaborated to detect MRD concomitantly in flow and with molecular techniques. The flow cytometry part of this work is reported here.
A total of 307 consecutive patients were tested at diagnosis with a comprehensive common panel allowing for the detection of immature markers and potential leukemia-associated immunophenotypic patterns. Follow-up samples were planned to be obtained after induction and at the end of treatment, with an optional control before the second consolidation. In fine, 274 patients had at least one point of follow up. All samples were tested in a technique of whole bone marrow lysis no wash, avoiding any cell loss. The flow cytometry panel comprised ten five-colors tubes, all containing CD45 as gating marker. A newly developed strategy was devised to analyse MRD data. The approach of the GTLLF (Arnoulet, Cytometry part B, 2011) was first applied to properly identify mature polymorphonuclears, monocytes and lymphocytes, allowing for a negative Boolean selection of immature cells in the region dubbed “bermudes” by this group. Focusing on this area, each combination of the four markers tested together with CD45 was then displayed in a total of six biparametric histograms. For each of them, on the diagnosis sample, quadrant gates were constructed so that the lower left one contained no blast cells. A Boolean operation was then designed to exclude all these six areas, thereby combining the positive blasts present in the three other parts of each quadrant. The resulting population was visualized on a CD45/side scatter biparametric histogram to check that the cells appeared as a focused cluster at a precise position. The same strategy was then applied for each patient's consecutive samples, always checking whether any cells identified with this protocol displayed the scattered pattern of cells engaged in maturation (no MRD) or constituted a focused population without maturation (positive MRD). The amount of MRD was then calculated taking into account as denominator the whole population of nucleated cells in the sample (excluding debris on a live gate). As internal control a specific feature of the Kaluza software was used to merge samples obtained for a given patient in order to display on the same worksheet the diagnosis and follow up samples using the principal component separation provided by the “radar” tool of this software. This original method proved to be easily applicable and provide a consistent help for MRD interpretation.
All patients could be assessed for MRD with only two of the ten tubes used. These contained the following combinations : CD15, CD13, CD33, CD34, CD45 and CD7, CD117, CD33, CD34, Cd45. At diagnosis, any combination of expression of CD13, CD33, CD117 and CD34 could be observed, the percentage of positive cases for each of these antigens being respectively 86%, 89%, 81% and 58%. As a whole, 93% of the follow-up samples (MRD) tested contained less than 5% of cells with an immunophenotype comparable to that of diagnosis. This figure was 77% for less than 1% and 43% for less than 0.1%. The strategy devised for files analysis was easily applicable for all patients except those with myelomonocytic leukemia. For some of them, separation of the blasts from the monocytic compartment could be problematic in regenerating bone marrow samples.
In conclusion, the flow cytometry part of this multicenter study allowed to establish that the combination of CD45 with CD13, CD33, CD117 and CD34 with the additional information provided by CD5 and CD7 represents a quasi-universal panel, now easy to implement on instruments with 8 or 10 detectors, for the detection of MRD in multiparameter in flow cytometry. Moreover, a powerful strategy of listmodes analysis was developed allowing for the direct comparison of several samples from the same patients and/or of a given sample and normal (control) bone marrow.
No relevant conflicts of interest to declare.
In response to a septic injury (pricking with a bacteria-soaked needle) larvae and adults of Drosophila produce considerable amounts of a 44-residue peptide containing 8 cysteines engaged in ...intramolecular disulfide bridges. The peptide is synthesized in the fat body, a functional homologue of the mammalian liver, and secreted into the blood of the insect. It exhibits potent antifungal activity but is inactive against bacteria. This novel inducible peptide, which we propose to name drosomycin, shows a significant homology with a family of 5-kDa cysteine-rich plant antifungal peptides recently isolated from seeds of Brassicaceae. This finding underlines that plants and insects can rely on similar molecules in their innate host defense.
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 alpha -2a (Peg-IFN alpha -2a) therapy in myelofibrosis. Sixty-two patients treated with Peg-IFN alpha -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-IFN alpha -2a induced high response rates with acceptable toxicity in a large proportion of patients with primary and secondary myelofibrosis, especially in early phases.
Given many data about the stability of antibiotics in portable pump (elastomer) are lacking, this study was designed to make a point about available data and to evaluate the stability of antibiotics ...when exposed to temperature within 35 degrees C (average temperature measured in real conditions of use).
First, to collect information about the stability of antibiotics in portable pump and to confront them with the local antibiotics protocols dedicated to the treatment of bronchial superinfection in patients with cystic fibrosis; second, to evaluate the stability of piperacillin associated with tazobactam at 35 degrees C.
While measured concentrations in tazobactam did not show significant variation during the study, piperacillin measurements showed a major reduction of concentration (up to 33%), both time and concentration related to.
Such information must be pointed out to prescribers and patients to ensure a cold accumulator is placed in the pump carrying-bag and to limit the duration of infusion to 24 h with a single pump.
This experimental program will keep on going with the stability study of both ticarcillin and cefsulodin in portable pump.
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