Publications by authors named "Pierre Bories"

30 Publications

  • Page 1 of 1

Activation of Vitamin D Receptor Pathway Enhances Differentiating Capacity in Acute Myeloid Leukemia with Isocitrate Dehydrogenase Mutations.

Cancers (Basel) 2021 Oct 19;13(20). Epub 2021 Oct 19.

Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, Centre National de Recherche Scientifique, CEDEX 1, 31037 Toulouse, France.

Relapses and resistance to therapeutic agents are major barriers in the treatment of acute myeloid leukemia (AML) patients. These unfavorable outcomes emphasize the need for new strategies targeting drug-resistant cells. As IDH mutations are present in the preleukemic stem cells and systematically conserved at relapse, targeting IDH mutant cells could be essential to achieve a long-term remission in the IDH mutant AML subgroup. Here, using a panel of human AML cell lines and primary AML patient specimens harboring IDH mutations, we showed that the production of an oncometabolite (R)-2-HG by IDH mutant enzymes induces vitamin D receptor-related transcriptional changes, priming these AML cells to differentiate with pharmacological doses of ATRA and/or VD. This activation occurs in a CEBPα-dependent manner. Accordingly, our findings illuminate potent and cooperative effects of IDH mutations and the vitamin D receptor pathway on differentiation in AML, revealing a novel therapeutic approach easily transferable/immediately applicable to this subgroup of AML patients.
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http://dx.doi.org/10.3390/cancers13205243DOI Listing
October 2021

The CADM1 tumor suppressor gene is a major candidate gene in MDS with deletion of the long arm of chromosome 11.

Blood Adv 2021 Oct 12. Epub 2021 Oct 12.

Belgian Cancer Registry, Brussels, Belgium.

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic stem-cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and in a substantial proportion of cases to acute myeloid leukemia. The deletion of the long arm of chromosome 11, del(11q), is a rare but recurrent clonal event in MDS. Here, we detail the largest series of 113 cases of MDS and myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) harboring a del(11q) analyzed at clinical, cytological, cytogenetic and molecular levels. Female predominance, a survival prognosis similar to other MDS, a low monocyte count and dysmegakaryopoiesis were the specific clinical and cytological features of del(11q) MDS. In most cases, del(11q) was isolated, primary and interstitial encompassing the 11q22-23 region containing ATM, KMT2A and CBL genes. The common deleted region at 11q23.2 is centered on an intergenic region between CADM1 (also known as TSLC1, Tumour Suppressor in Lung Cancer 1) and NXPE2. CADM1 was expressed in all myeloid cells analyzed in contrast to NXPE2. At the functional level, the deletion of Cadm1 in murine Lineage-Sca1+Kit+ cells modifies the lymphoid to myeloid ratio in bone marrow although not altering their multi-lineage hematopoietic reconstitution potential after syngenic transplantation. Together with the frequent simultaneous deletions of KMT2A, ATM and CBL and mutations of ASXL1, SF3B1 and CBL, we show that CADM1 may be important in the physiopathology of the del(11q) MDS, extending its role as tumor-suppressor gene from solid tumors to hematopoietic malignancies.
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http://dx.doi.org/10.1182/bloodadvances.2021005311DOI Listing
October 2021

A deep dive into fat: Investigating blubber lipidomic fingerprint of killer whales and humpback whales in northern Norway.

Ecol Evol 2021 Jun 1;11(11):6716-6729. Epub 2021 May 1.

Akvaplan-niva AS Fram Centre Tromsø Norway.

In cetaceans, blubber is the primary and largest lipid body reservoir. Our current understanding about lipid stores and uses in cetaceans is still limited, and most studies only focused on a single narrow snapshot of the lipidome. We documented an extended lipidomic fingerprint in two cetacean species present in northern Norway during wintertime. We were able to detect 817 molecular lipid species in blubber of killer whales () and humpback whales (). The profiles were largely dominated by triradylglycerols in both species and, to a lesser extent, by other constituents including glycerophosphocholines, phosphosphingolipids, glycerophosphoethanolamines, and diradylglycerols. Through a unique combination of traditional statistical approaches, together with a novel bioinformatic tool (LION/web), we showed contrasting fingerprint composition between species. The higher content of triradylglycerols in humpback whales is necessary to fuel their upcoming half a year fasting and energy-demanding migration between feeding and breeding grounds. In adipocytes, we assume that the intense feeding rate of humpback whales prior to migration translates into an important accumulation of triacylglycerol content in lipid droplets. Upstream, the endoplasmic reticulum is operating at full capacity to supply acute lipid storage, consistent with the reported enrichment of glycerophosphocholines in humpback whales, major components of the endoplasmic reticulum. There was also an enrichment of membrane components, which translates into higher sphingolipid content in the lipidome of killer whales, potentially as a structural adaptation for their higher hydrodynamic performance. Finally, the presence of both lipid-enriched and lipid-depleted individuals within the killer whale population in Norway suggests dietary specialization, consistent with significant differences in δN and δC isotopic ratios in skin between the two groups, with higher values and a wider niche for the lipid-enriched individuals. Results suggest the lipid-depleted killer whales were herring specialists, while the lipid-enriched individuals might feed on both herrings and seals.
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http://dx.doi.org/10.1002/ece3.7523DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207449PMC
June 2021

Physician practice variation in head and neck cancer therapy: Results of a national survey.

Oral Oncol 2021 06 14;117:105293. Epub 2021 Apr 14.

Service d'otorhinolaryngologie et chirurgie cervico-faciale, Institut Universitaire du Cancer de Toulouse-Oncopole, Institut Claudius Regaud, 1avenue Hubert Curien, 31100 Toulouse, France. Electronic address:

Objectives: Choice between surgical or medical treatments in head and neck cancer depends of many patient-related and disease-related factors. We investigated how patients' socioeconomic status and practitioners' specialty could affect medical decision-making.

Materials And Methods: We conducted a cross-sectional online, nationwide survey, send to surgeons, oncologists and radiotherapists specialized in head and neck oncology. We collected data on medical decision-making for seven clinical scientific scenarios involving head and neck carcinoma and physicians' demographic data. Patients' gender and socioeconomic position were distributed across scientific scenarios using a Latin square design. The scientific scenarios were grouped into several categories according to the prognostic and functional impact of the therapeutic choice.

Results: We obtained 206 assessable answers. Surgeons seemed to propose surgery in 49% of cases, whereas oncologists and radiotherapists opted for it in 34% of cases only. This was particularly relevant when the oncological result of surgery and the medical approach were equivalent, and when the surgery appeared to be superior in terms of curative potential but was burdened by a large functional impact. Patient's socioeconomic position also influence therapeutic decision. Among surgeons, the "single male manager" had significantly more chance of being offered surgery than the "married male blue-collar worker". Among oncologists and radiotherapists, the "single male blue-collar worker" had the lowest probability of being proposed surgery. Regarding gender, surgeons tended to offer surgical management more to women regardless of their clinical profile.

Conclusions: Patients' sex, marital status, socioeconomic status, practitioners' specialty affect therapeutic management decisions in head and neck oncology.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105293DOI Listing
June 2021

Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

J Exp Med 2021 05;218(5)

Institut de Recherche en Cancérologie de Montpellier, Institut National de la Santé et de la Recherché Médicale, Université de Montpellier, Institut Régional du Cancer Montpellier, Montpellier, France.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.
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http://dx.doi.org/10.1084/jem.20200924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7995203PMC
May 2021

Baseline SUVmax is related to tumor cell proliferation and patient outcome in follicular lymphoma.

Haematologica 2020 12 17;Online ahead of print. Epub 2020 Dec 17.

Centre de Recherches en Cancérologie de Toulouse (CRCT), UMR1037 INSERM, Université Toulouse III: Paul-Sabatier, ERL5294 CNRS, Université de Toulouse, Toulouse, France; Laboratoire d'Excellence TOUCAN, Toulouse, France; Programme Hospitalo-Universitaire en Cancérologie CAPTOR, Toulouse, France; CALYM Carnot Institute, Pierre-Bénite, France; Département de pathologie, Institut Universitaire du Cancer de Toulouse, Toulouse.

Follicular lymphoma (FL) is the most common indolent lymphoma. Despite the clear benefit of CD20-based therapy, a subset of FL patients still progress to aggressive lymphoma. Thus, identifying early biomarkers that incorporate PET metrics could be helpful to identify patients with a high risk of treatment failure with Rituximab. We retrospectively included a total of 132 untreated FL patients separated into training and validation cohorts. Optimal threshold of baseline SUVmax was first determined in the training cohort (n=48) to predict progression-free survival (PFS). The PET results were investigated along with the tumor and immune microenvironment, which were determined by immunochemistry and transcriptome studies involving gene set enrichment analyses and immune cell deconvolution, together with the tumor mutation profile. We report that baseline SUVmax >14.5 was associated with poorer PFS than baseline SUVmax ≤14.5 (HR=0.28; p=0.00046). Neither immune T-cell infiltration nor immune checkpoint expression were associated with baseline PET metrics. By contrast, FL samples with Ki-67 staining ≥10% showed enrichment of cell cycle/DNA genes (p=0.013) and significantly higher SUVmax values (p=0.007). Despite similar oncogenic pathway alterations in both SUVmax groups of FL samples, 4 out of 5 cases harboring the infrequent FOXO1 transcription factor mutation were seen in FL patients with SUVmax >14.5. Thus, high baseline SUVmax reflects FL tumor proliferation and, together with Ki-67 proliferative index, can be used to identify patients at risk of early relapse with R-chemotherapy.
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http://dx.doi.org/10.3324/haematol.2020.263194DOI Listing
December 2020

Predictive factors of early progression after CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma.

Blood Adv 2020 11;4(22):5607-5615

Department of Hemato-Oncology, Saint-Louis Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as an option for relapsed/refractory aggressive B-cell lymphomas that have failed 2 lines of therapy. Failures usually occur early after infusion. The purpose of our study was to identify factors that may predict failure, particularly early progression (EP), within the first month after infusion. Characteristics of 116 patients were analyzed at the time of decision (TD) to use commercial CAR (axicabtagene ciloleucel, n = 49; tisagenlecleucel n = 67) and at the time of treatment (TT), together with total metabolic tumor volume (TMTV) at TT. With a median follow-up of 8.2 months, 55 patients failed treatment; 27 (49%) were early progressors. The estimated 12-month progression-free survival (PFS) and overall survival (OS) were 47.2% (95% confidence interval [CI], 38.0-58.6) and 67.0% (95% CI, 57-79), respectively. Univariate analyses for PFS and OS identified Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2, stage III/IV disease, extranodal (EN) sites ≥2, elevated lactate dehydrogenase (LDH), increased C-reactive protein (CRP), high International Prognostic Index at TD and at TT, as well as increased CRP, bulky mass, and high TMTV at TT, as risk factors. Multivariate analyses for PFS, EP, and OS identified elevated LDH and EN sites ≥2 at TD and the same predictors at TT (ie, increased CRP, EN sites ≥2, and TMTV >80 mL). In summary, risk factors identified for early progression at TD and at TT were EN involvement (≥2 sites) and lymphoma burden (LDH, TMTV).
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http://dx.doi.org/10.1182/bloodadvances.2020003001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686887PMC
November 2020

Impact of TP53 mutations in acute myeloid leukemia patients treated with azacitidine.

PLoS One 2020 1;15(10):e0238795. Epub 2020 Oct 1.

Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

Hypomethylating agents are a classical frontline low-intensity therapy for older patients with acute myeloid leukemia. Recently, TP53 gene mutations have been described as a potential predictive biomarker of better outcome in patients treated with a ten-day decitabine regimen., However, functional characteristics of TP53 mutant are heterogeneous, as reflected in multiple functional TP53 classifications and their impact in patients treated with azacitidine is less clear. We analyzed the therapeutic course and outcome of 279 patients treated with azacitidine between 2007 and 2016, prospectively enrolled in our regional healthcare network. By screening 224 of them, we detected TP53 mutations in 55 patients (24.6%), including 53 patients (96.4%) harboring high-risk cytogenetics. The identification of any TP53 mutation was associated with worse overall survival but not with response to azacitidine in the whole cohort and in the subgroup of patients with adverse karyotype. Stratification of patients according to three recent validated functional classifications did not allow the identification of TP53 mutated patients who could benefit from azacitidine. Systematic TP53 mutant classification will deserve further exploration in the setting of patients treated with conventional therapy and in the emerging field of therapies targeting TP53 pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238795PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529302PMC
November 2020

Dactinomycin in acute myeloid leukemia with NPM1 mutations.

Eur J Haematol 2020 Sep 25;105(3):302-307. Epub 2020 May 25.

Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

Objectives: Complete responses have been observed in NPM1-mutated AML patients with dactinomycin, a nucleolar stress-inducing drug. Here, we report a single-center experience of compassionate use of dactinomycin in untreated or relapsed/ refractory NPM1-mutated AML.

Methods: From September 2015 to February 2019, 26 adult patients with NPM1-mutated AML received dactinomycin in different situations: front-line treatment in 4 unfit patients (16%); morphologic (n = 16, 62%), molecular relapses (n = 4, 16%), refractory disease (n = 1, 13%), or postremission therapy in second complete response (n = 1, 13%).

Results: Median age was 62.5 years. Median number of dactinomycin cycle was 1 (1-8), and 7 patients (27%) received more than 3 cycles. Three out of 17 patients (18%) in morphologic relapse or refractory to chemotherapy achieved complete remission after the first cycle of dactinomycin. None of the 4 patients unfit for intensive chemotherapy responded to dactinomycin as front-line therapy. Grade 3-4 adverse events were thrombocytopenia (n = 11, 42%), neutropenia (n = 11, 42%), GI toxicity (n = 6, 23%), mucositis (n = 5, 19%), lung infection (n = 5, 19%), and skin rash (n = 2, 7.6%).

Conclusions: Dactinomycin is an inexpensive and easily available drug that may induce significant responses in few AML patients with NPM1 mutations with an acceptable safety profile.
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http://dx.doi.org/10.1111/ejh.13438DOI Listing
September 2020

CD34CD38CD123 Leukemic Stem Cell Frequency Predicts Outcome in Older Acute Myeloid Leukemia Patients Treated by Intensive Chemotherapy but Not Hypomethylating Agents.

Cancers (Basel) 2020 May 6;12(5). Epub 2020 May 6.

Université Toulouse III Paul Sabatier, 31330 Toulouse, France.

The prognostic impact of immunophenotypic CD34CD38CD123 leukemic stem cell (iLSC) frequency at diagnosis has been demonstrated in younger patients treated by intensive chemotherapy, however, this is less clear in older patients. Furthermore, the impact of iLSC in patients treated by hypomethylating agents is unknown. In this single-center study, we prospectively assessed the CD34CD38CD123 iLSC frequency at diagnosis in acute myeloid leukemia (AML) patients aged 60 years or older. In a cohort of 444 patients, the median percentage of iLSC at diagnosis was 4.3%. Significant differences were found between treatment groups with a lower median in the intensive chemotherapy group (0.6%) compared to hypomethylating agents (8.0%) or supportive care (11.1%) ( <0.0001). In the intensive chemotherapy group, the median overall survival was 34.5 months in patients with iLSC ≤0.10% and 14.6 months in patients with >0.10% ( = 0.031). In the multivariate analyses of this group, iLSC frequency was significantly and independently associated with the incidence of relapse, event-free, relapse-free, and overall survival. However, iLSC frequency had no prognostic impact on patients treated by hypomethylating agents. Thus, the iLSC frequency at diagnosis is an independent prognostic factor in older acute myeloid patients treated by intensive chemotherapy but not hypomethylating agents.
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http://dx.doi.org/10.3390/cancers12051174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281486PMC
May 2020

Are social inequalities in acute myeloid leukemia survival explained by differences in treatment utilization? Results from a French longitudinal observational study among older patients.

BMC Cancer 2019 Sep 5;19(1):883. Epub 2019 Sep 5.

LEASP, UMR 1027, Equipe labellisée Ligue Nationale Contre le Cancer, Faculté de médecine de Purpan, Inserm-Université Toulouse III Paul Sabatier, 37 allées Jules Guesde, 31000, Toulouse, France.

Background: Evidences support social inequalities in cancer survival. Studies on hematological malignancies, and more specifically Acute Myeloid Leukemia (AML), are sparser. Our study assessed: 1/ the influence of patients' socioeconomic position on survival, 2/ the role of treatment in this relationship, and 3/ the influence of patients' socioeconomic position on treatment utilization.

Methods: This prospective multicenter study includes all patients aged 60 and older, newly diagnosed with AML, excluding promyelocytic subtypes, between 1st January 2009 to 31st December 2014 in the South-West of France. Data came from medical files. Patients' socioeconomic position was measured by an ecological deprivation index, the European Deprivation Index. We studied first, patients' socioeconomic position influence on overall survival (n = 592), second, on the use of intensive chemotherapy (n = 592), and third, on the use of low intensive treatment versus best supportive care among patients judged unfit for intensive chemotherapy (n = 405).

Results: We found an influence of patients' socioeconomic position on survival (highest versus lowest position HR: 1.39 [1.05;1.87] that was downsized to become no more significant after adjustment for AML ontogeny (HR: 1.31[0.97;1.76] and cytogenetic prognosis HR: 1.30[0.97;1.75]). The treatment was strongly associated with survival. A lower proportion of intensive chemotherapy was observed among patients with lowest socioeconomic position (OR: 0.41[0.19;0.90]) which did not persist after adjustment for AML ontogeny (OR: 0.59[0.25;1.40]). No such influence of patients' socioeconomic position was found on the treatment allocation among patients judged unfit for intensive chemotherapy.

Conclusions: Finally, these results suggest an indirect influence of patients' socioeconomic position on survival through AML initial presentation.
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http://dx.doi.org/10.1186/s12885-019-6093-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6729078PMC
September 2019

Outcome of patients aged 60-75 years with newly diagnosed secondary acute myeloid leukemia: A single-institution experience.

Cancer Med 2019 07 7;8(8):3846-3854. Epub 2019 Jun 7.

Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

A recent phase 3 trial showed that outcome of older patients with secondary acute myeloid leukemia (AML) may be improved by a liposomal encapsulation of cytarabine and daunorubicin (CPX-351). This phase 3 study represents a unique example of prospective data in this rare subgroup providing basis for comparison with real life data. Here, we retrospectively assessed characteristics and outcome of patients aged 60-75 years with secondary or therapy-related AML in real life. Out of 218 patients that fulfilled CPX-351 study criteria, 181 patients (83.0%) received antileukemic treatment either intensive chemotherapy (n = 121) or hypomethylating agents (HMA, n = 60). As compared with patients treated by chemotherapy, HMA-treated patients were older, had lower WBC, more often AML with antecedent myelodysplastic syndrome and adverse cytogenetic risk. In chemotherapy-treated patients, the complete response rate was 69%, median overall survival (OS) was 11 months whereas 3-year and 5-year OS was 21% and 17%, respectively. In HMA-treated patients, the complete response rate was 15%, median OS was 11 months whereas 3-year and 5-year OS was 15% and 2%, respectively. In conclusion, although outcome of older patients with high-risk AML is very poor, a significant proportion of patients treated by standard intensive chemotherapy but not HMA are long-term survivors.
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http://dx.doi.org/10.1002/cam4.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639188PMC
July 2019

Outcome of AML patients with IDH2 mutations in real world before the era of IDH2 inhibitors.

Leuk Res 2019 06 27;81:82-87. Epub 2019 Apr 27.

Université Toulouse III Paul Sabatier, Toulouse, France; Cancer Research Center of Toulouse, UMR1037-INSERM, ERL5294 CNRS, Toulouse, France; Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France. Electronic address:

Describing the prognosis of sub-groups of acute myeloid leukemia (AML) patients treated in real world with current therapies is becoming increasingly relevant to estimate the benefit that new targeted drugs will bring in the field. This is particularly the case when novel drugs are registered on the basis of non-randomized studies. IDH2 inhibitors have recently emerged as promising drugs in patients with IDH2 or IDH2 mutations. Enasidenib, a first-in-class IDH2 inhibitor, has been approved following promising results of a phase 1-2 clinical trial in relapsed or refractory AML patients with IDH2 mutations. In this study, we described the characteristics, treatments and outcome of 75 IDH2 mutated patients both at diagnosis and relapse or refractory disease. Among the 33 relapsed/refractory AML patients with either IDH2 or IDH2, 28 (84.8%) patients received salvage therapy and 14 achieved a complete response (50%). Median duration of response was 15.2 months. Median, 1-y, 3-y and 5-y OS were 15.1 months (IQR, 4.6-37.7), 53.1% (95% CI, 33.2-69.5), 29.2% (95% CI, 12.6-48.1) and 24.4% (95% CI, 9.3-43.1), respectively. In responding patients, median OS was 37.7 months and 1-y, 3-y and 5-y OS was 85.7%, 57.1% and 47.6%, respectively. In non-responding patients, median OS was 5.0 months (IQR, 4.5-8.6) and 1-y and 3-y OS was 17.9% and 0%, respectively. Thus, a substantial number of R/R AML patients with IDH2 mutations can be salvaged by current treatments and benefit from prolonged survival. It is expected that novel targeted agents such as enasidenib will further improve efficacy and safety in the next future.
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http://dx.doi.org/10.1016/j.leukres.2019.04.010DOI Listing
June 2019

Physician uncertainty aversion impacts medical decision making for older patients with acute myeloid leukemia: results of a national survey.

Haematologica 2018 12 13;103(12):2040-2048. Epub 2018 Jul 13.

INRA, UR 1303 ALISS, Ivry-sur-Seine, France.

Elderly patients with acute myeloid leukemia can be treated with intensive chemotherapy, low-intensity therapy such as low-dose aracytine or hypomethylating agents, or best supportive care. The choice between these treatments is a function of many patient-related and disease-related factors. We investigated how physicians' behavioral characteristics affect medical decision-making between intensive and non-intensive therapy in this setting. A nationwide cross-sectional online survey of hematologists collected data on medical decision-making for 6 clinical vignettes involving older acute myeloid leukemia patients that were representative of routine practice. Questionnaires elicited physicians' demographic and occupational characteristics along with their individual behavioral characteristics according to a decision theory framework. From the pattern of responses to the vignettes, a K-means clustering algorithm was used to distinguish those who were likely to prescribe more intensive therapy and those who were likely to prescribe less intensive or no therapy. Multivariate analyses were used to identify physician's characteristics predictive of medical decision-making. We obtained 230 assessable answers, which represented an adjusted response rate of 45.4%. A multivariate model (n=210) revealed that physicians averse to uncertainty recommend significantly more intensive chemotherapy: Odds Ratio (OR) [95% Confidence Interval (CI)]: 1.15 [1.01;1.30]; =0.039. Male physicians who do not conform to the expected utility model (assumed as economically irrational) recommend more intensive chemotherapy [OR (95% CI) = 3.45 (1.34; 8.85); =0.01]. Patient volume per physician also correlated with therapy intensity [OR (95% CI)=0.98 (0.96; 0.99); =0.032]. The physicians' medical decision-making was not affected by their age, years of experience, or hospital facility. The significant association between medical decision and individual behavioral characteristics of the physician identifies a novel non-biological factor that may affect acute myeloid leukemia patients' outcomes and explain variations in clinical practice. It should also encourage the use of validated predictive models and the description of novel bio-markers to best select patients for intensive chemotherapy or low-intensity therapy.
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http://dx.doi.org/10.3324/haematol.2018.192468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269286PMC
December 2018

Azacitidine or intensive chemotherapy for older patients with secondary or therapy-related acute myeloid leukemia.

Oncotarget 2017 Oct 7;8(45):79126-79136. Epub 2017 Mar 7.

Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.

The treatment of older patients with acute myeloid leukemia that is secondary to previous myelodysplastic syndrome, myeloproliferative neoplasm, or prior cytotoxic exposure remains unsatisfactory. We compared 92 and 107 patients treated, respectively, with intensive chemotherapy or azacitidine within two centres. Diagnoses were 37.5% post-myelodysplastic syndrome, 17.4% post-myeloproliferative neoplasia, and 45.1% therapy-related acute myeloid leukemia. Patients treated by chemotherapy had less adverse cytogenetics, higher white blood-cell counts, and were younger: the latter two being independent factors entered into the multivariate analyses. Median overall-survival times with chemotherapy and azacitidine were 9.6 (IQR: 3.6-22.8) and 10.8 months (IQR: 4.8-26.4), respectively ( = 0.899). Adjusted time-dependent analyses showed that, before 1.6 years post-treatment, there were no differences in survival times between chemotherapy and azacitidine treatments whereas, after this time-point, patients that received chemotherapy had a lower risk of death compared to those that received azacitidine (adjusted HR 0.61, 95%CI: 0.38-0.99 at 1.6 years). There were no interactions between treatment arms and secondary acute myeloid leukemia subtypes in all multivariate analyses, indicating that the treatments had similar effects in all three subtypes. Although a comparison between chemotherapy and azacitidine remains challenging, azacitidine represents a valuable alternative to chemotherapy in older patients that have secondary acute myeloid leukemia because it provides similar midterm outcomes with less toxicity.
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http://dx.doi.org/10.18632/oncotarget.15988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668025PMC
October 2017

A Phase II Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia.

Clin Lymphoma Myeloma Leuk 2016 Mar 21;16(3):139-45. Epub 2015 Dec 21.

Hospital Saint-Louis, University Institute of Hematology, University Paris Diderot, Paris, France.

Background: Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and the treatment options are limited for those patients with relapse or a failure to respond after initial therapy. We conducted a dose-escalation/expansion phase II, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting.

Patients And Methods: The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for the evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (≤ 8 weekly doses). The responding patients were eligible for maintenance therapy (biweekly administration for ≤ 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m(2). The primary endpoint was the objective response rate (ORR). The secondary endpoints included the duration of response (DOR) and safety.

Results: A total of 36 patients were treated: 19 during dose escalation and 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m(2) (grade 3 peripheral motor neuropathy); therefore, 70 mg/m(2) was selected for the dose-expansion phase. Five patients discontinued therapy because of adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of the 17 evaluable patients treated at the selected dose, 4 had a disease response (estimated ORR using the Bayesian method: 25.5% (80% confidence interval, 14.2%-39.6%). The DOR was 1.9 months (range, 1-5.6 months). Because of these results, the study was prematurely discontinued.

Conclusion: Coltuximab ravtansine was well tolerated but was associated with a low clinical response rate in patients with relapsed or refractory ALL.
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http://dx.doi.org/10.1016/j.clml.2015.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5557033PMC
March 2016

Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience.

Am J Hematol 2015 Nov 8;90(11):986-91. Epub 2015 Oct 8.

Maladies Du Sang/INSERM U892 PRES LUNAM, Angers, CHU, France.

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4).
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http://dx.doi.org/10.1002/ajh.24130DOI Listing
November 2015

A Phase 2 study of L-asparaginase encapsulated in erythrocytes in elderly patients with Philadelphia chromosome negative acute lymphoblastic leukemia: The GRASPALL/GRAALL-SA2-2008 study.

Am J Hematol 2015 Sep;90(9):811-8

Haematology Department of Saint-Louis AP-HP Paris, France.

Purpose: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia.

Findings: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively.

Conclusions: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782).
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http://dx.doi.org/10.1002/ajh.24093DOI Listing
September 2015

Contribution of Revised International Prognostic Scoring System Cytogenetics to Predict Outcome After Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes: A Study From the French Society of Bone Marrow Transplantation and Cellular Therapy.

Transplantation 2015 Aug;99(8):1672-80

1 CHRU Lille, Pôle Spécialités Médicales et Gérontologie, Service des Maladies du Sang, Secteur Allogreffe de Cellules Souches Hématopoïétiques, F59037, Lille, France. 2 Université de Lille, UFR Médecine F59000, Lille, France. 3 Hematology Department, Caen University Hospital, Amiens, France. 4 Department of Biostatistics, Lille University Hospital, Lille, France. 5 Hematology Department and Hematopoietic Stem Cell Transplantation Unit, Saint-Louis Hospital, Paris, France. 6 Hematology Department, Lyon-Sud Hospital, Lyon, France. 7 Hematology Department, Nantes, France. 8 Hematology Department CH-Liège, Liège, Belgium. 9 Hematology Department, Pitié-Salpêtrière Hospital, Paris, France. 10 Hematology Department, Strasbourg University Hospital, Strasbourg, France. 11 Hematopoietic Stem Cell Transplantation Unit, Paoli Calmettes Institute, Marseille, France. 12 Hematology Department, Loire Oncology Institute (ICL), Saint Priest en Jarez, France. 13 Hematology Department, Nantes University Hospital, Nantes, France. 14 Hematology Department, Saint-Antoine Hospital, Paris, France. 15 Hematology Department, Toulouse University Hospital, Toulouse, France. 16 Hematology Department, Grenoble University Hospital, Grenoble, France. 17 Hematology Department, Bordeaux University Hospital, Bordeaux, France.

Background: The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation is critically determined by cytogenetic abnormalities, as previously defined by International Prognostic Scoring System (IPSS) cytogenetics. It has been shown that a new cytogenetic classification, included in the IPSS-R (cytogenetic-IPSS-R [C-IPSS-R]), can better predict the outcome of untreated MDS patients.

Methods: In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 MDS patients transplanted from HLA-identical siblings or HLA allele-matched unrelated donors.

Results: According to the C-IPSS-R, 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk, and 10 (3%) in the very poor risk group. In multivariate analysis, after a median follow-up of 4 years, the poor and very poor-risk categories correlated with shorter overall survival (OS) (4-year OS, 32%; hazard ratio [HR], 1.59; P = 0.009 and OS, 10%; HR, 3.18; P = 0.002, respectively) and higher cumulative incidence of relapse (CIR) (CIR, 52%; HR, 1.82; P = 0.004 and CIR, 60%; HR, 2.44; P = 0.060, respectively).

Conclusions: Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group, the very poor C-IPSS-R category, with dismal outcome after allogeneic stem cell transplantation (10% 4-year OS, 60% 4-year CIR). Posttransplantation maintenance therapy should be investigated in prospective trials for patients with high-risk C-IPSS-R karyotypes.
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http://dx.doi.org/10.1097/TP.0000000000000649DOI Listing
August 2015

Intensive chemotherapy, azacitidine, or supportive care in older acute myeloid leukemia patients: an analysis from a regional healthcare network.

Am J Hematol 2014 Dec 20;89(12):E244-52. Epub 2014 Oct 20.

Département d'Hématologie-Médecine Interne, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France; Service d'Hématologie, Hôpitaux Universitaires de Strasbourg, F-67098, Strasbourg, France.

We assessed in a French regional healthcare network the distribution of treatments, prognostic factors, and outcome of 334 newly diagnosed acute myeloid leukemia patients aged 60 years or older over a 4-year period of time (2007-2010). Patients were selected in daily practice for intensive chemotherapy (n = 115), azacitidine (n = 95), or best supportive care (n = 124). In these three groups, median overall survival was 18.9, 11.3, and 1.8 months, respectively. In the azacitidine group, multivariate analysis showed that overall survival was negatively impacted by higher age (P = 0.010 for one unit increase), unfavorable cytogenetics (P = 0.001), lymphocyte count <0.5 G/L (P = 0.015), and higher lactate dehydrogenase level (P = 0.005 for one unit increase). We compared the survival of patients treated by azacitidine versus intensive chemotherapy and best supportive care using time-dependent analysis and propensity score matching. Patients treated by intensive chemotherapy had a better overall survival compared with those treated by azacitidine from 6 months after diagnosis, whereas patients treated by azacitidine had a better overall survival compared with those treated by best supportive care from 1 day after diagnosis. This study of "real life" practice shows that there is a room for low intensive therapies such as azacitidine in selected elderly acute myeloid leukemia patients.
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http://dx.doi.org/10.1002/ajh.23848DOI Listing
December 2014

Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

Biol Blood Marrow Transplant 2014 Sep 14;20(9):1349-55. Epub 2014 May 14.

Departement d'Hématologie, Centre Hospitalier Régionale Universitaire, Lille, France. Electronic address:

Cytoreduction before allogeneic stem cell transplantation (allo-SCT) for patients with myelodysplastic syndromes remains a debatable issue. After excluding patients who had received preconditioning induction chemotherapy, we analyzed 128 consecutive patients with myelodysplastic syndrome who received reduced-intensity or nonmyeloablative conditioning (RIC/NMA) allo-SCT. Among them, 40 received azacitidine (AZA) before transplant (AZA group) and 88 were transplanted up front (best supportive care [BSC] group). At diagnosis, 55 patients had intermediate 2 or high-risk scores per the International Prognostic Scoring System and 33 had a high cytogenetic risk score. Progression to a more advanced disease before allo-SCT was recorded in 22 patients. Source of stem cells were blood (n = 112) or marrow (n = 16) from sibling (n = 78) or HLA-matched unrelated (n = 50) donors. With a median follow-up of 60 months, 3-year overall survival, relapse-free survival, cumulative incidence of relapse, and nonrelapse mortality were, respectively, 53% versus 53% (P = .69), 37% versus 42% (P = .78), 35% versus 36% (P = .99), and 20% versus 23% (P = .74), for the AZA group and BSC group, respectively. Multivariate analysis confirmed the absence of statistical differences in outcome between the AZA and BSC groups, after adjusting for potential confounders using the propensity score approach. The absence of cytoreduction before RIC/NMA allo-SCT did not seem to alter the outcome. However, our results emphasize the need to perform prospective protocols to delineate the role of debulking strategy and to identify subsets of patients who may benefit from this approach.
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http://dx.doi.org/10.1016/j.bbmt.2014.05.010DOI Listing
September 2014

Transonic, thermodilution, or ionic dialysance to manage vascular access: which method is best?

Hemodial Int 2014 Jan 9;18(1):127-35. Epub 2013 Sep 9.

Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Toulouse, France.

Regularly monitoring blood flow through a vascular access (Qa) can predict a dysfunction and dramatically reduce the number of thromboses. The aim of our study was to compare two integrated access flow devices, thermodilution (Qa-BTM: BTM(®), Fresenius Medical Care, Bad Homburg, Germany) and ionic dialysance (Qa-ID: OCM(®), Fresenius Medical Care, Bad Homburg, Germany), with the "gold standard" saline dilution (Qa-T: Transonic(®), Systems Inc., Ithaca, NY, USA). Measurements were performed sequentially and were repeated in the first 90 minutes of a single dialysis session in 24 long-term hemodialysis patients with a vascular access. Bland-Altman, linear regression (r(2)), and intraclass correlation coefficients (ICC) assessed reproducibility, correlations, and concordance between the techniques. Average access flow for Qa-T was 1549 (± 844) mL/minute, Qa-BTM was 1530 (± 856) mL/minute (P = NS), and Qa-ID was 1619 (± 1085) mL/minute (P = NS). Respectively, ICC, (r(2)), and bias were 0.99, (0.98), and -19 mL/minute for Qa-BTM, and 0.75, (0.65), and +69 mL/minute for Qa-ID. The limits of agreement were -287 to +250 mL/minute for Qa-BTM and -1647 to +1785 mL/minute for Qa-ID. Reproducibility of thermodilution and ionic dialysance, expressed as relative differences, was not significantly different from saline dilution. Recirculation, measured by saline dilution, was 0% (0-4%), the same as the 0% measured by thermodilution, with correct placement of bloodlines and corrected for cardiopulmonary recirculation. The integrated access flow measurement devices, thermodilution and ionic dialysance, are reasonable alternatives to using saline dilution to measure Qa: Thermodilution showed better precision and correlation. They are reliable, make monitoring of vascular access easier, incur no extra costs, and use no additional consumables.
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http://dx.doi.org/10.1111/hdi.12092DOI Listing
January 2014

Prognostic impact of day 15 blast clearance in risk-adapted remission induction chemotherapy for younger patients with acute myeloid leukemia: long-term results of the multicenter prospective LAM-2001 trial by the GOELAMS study group.

Haematologica 2014 Jan 23;99(1):46-53. Epub 2013 Aug 23.

Early response to chemotherapy has a major prognostic impact in acute myeloid leukemia patients treated with a double induction strategy. Less is known about patients treated with standard-dose cytarabine and anthracycline. We designed a risk-adapted remission induction regimen in which a second course of intermediate-dose cytarabine was delivered after standard "7+3" only if patients had 5% or more bone marrow blasts 15 days after chemotherapy initiation (d15-blasts). Of 823 included patients, 795 (96.6%) were evaluable. Five hundred and forty-five patients (68.6%) had less than 5% d15-blasts. Predictive factors for high d15-blasts were white blood cell count (P<0.0001) and cytogenetic risk (P<0.0001). Patients with fewer than 5% d15-blasts had a higher complete response rate (91.7% vs. 69.2%; P<0.0001) and a lower induction death rate (1.8% vs. 6.8%; P=0.001). Five-year event-free (48.4% vs. 25%; P<0.0001), relapse-free (52.7% vs. 36.9%; P=0.0016) and overall survival (55.3% vs. 36.5%; P<0.0001) were significantly higher in patients with d15-blasts lower than 5%. Multivariate analyses identified d15-blasts and cytogenetic risk as independent prognostic factors for the three end points. Failure to achieve early blast clearance remains a poor prognostic factor even after early salvage. By contrast, early responding patients have a favorable outcome without any additional induction course. (ClinicalTrials.gov identifier NCT01015196).
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http://dx.doi.org/10.3324/haematol.2013.091819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4007924PMC
January 2014

Risk stratification for invasive aspergillosis in immunocompromised patients.

Ann N Y Acad Sci 2012 Dec;1272:23-30

Department of Oncology and Hematology, Hôpital de Hautepierre, Strasbourg, France.

Severe prolonged neutropenia, allogeneic hematopoietic stem cell or solid-organ transplantation, corticosteroids or other T cell suppressive agents, and other severe immunosuppressive factors have for many years been considered to predispose patients to invasive aspergillosis. Other conditions such as impaired innate immunity, diabetes, renal impairment, progression of the underlying malignancy, prior respiratory disease, and nosocomial or environmental exposure to fungal spores or climatic factors have recently been considered additional risk factors of invasive aspergillosis. The multiplicity of risk factors as well as the obvious synergy between them renders risk stratification difficult. An international, large-scale, multicenter, epidemiological study is necessary to develop a risk score.
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http://dx.doi.org/10.1111/j.1749-6632.2012.06829.xDOI Listing
December 2012

Impact of azacitidine before allogeneic stem-cell transplantation for myelodysplastic syndromes: a study by the Société Française de Greffe de Moelle et de Thérapie-Cellulaire and the Groupe-Francophone des Myélodysplasies.

J Clin Oncol 2012 Dec 29;30(36):4533-40. Epub 2012 Oct 29.

Centre Hospitalier Universitaire Sud, Amiens, France.

Purpose: To investigate the impact of prior-to-transplantation azacitidine (AZA) on patient outcome after allogeneic stem-cell transplantation (alloSCT) for myelodysplastic syndrome (MDS).

Patients And Methods: Of the 265 consecutive patients who underwent alloSCT for MDS between October 2005 and December 2009, 163 had received cytoreductive treatment prior to transplantation, including induction chemotherapy (ICT) alone (ICT group; n = 98), AZA alone (AZA group; n = 48), or AZA preceded or followed by ICT (AZA-ICT group; n = 17). At diagnosis, 126 patients (77%) had an excess of marrow blasts, and 95 patients (58%) had intermediate-2 or high-risk MDS according to the International Prognostic Scoring System (IPSS). Progression to more advanced disease before alloSCT was recorded in 67 patients. Donors were sibling (n = 75) or HLA-matched unrelated (10/10; n = 88). They received blood (n = 142) or marrow (n = 21) grafts following either myeloablative (n = 33) or reduced intensity (n = 130) conditioning.

Results: With a median follow-up of 38.7 months, 3-year outcomes in the AZA, ICT, and AZA-ICT groups were 55%, 48%, and 32% (P = .07) for overall survival (OS); 42%, 44%, and 29% (P = .14) for event-free survival (EFS); 40%, 37%, and 36% (P = .86) for relapse; and 19%, 20%, and 35% (P = .24) for nonrelapse mortality (NRM), respectively. Multivariate analysis confirmed the absence of statistical differences between the AZA and the ICT groups in terms of OS, EFS, relapse, and NRM.

Conclusion: With the goal of downstaging underlying disease before alloSCT, AZA alone led to outcomes similar to those for standard ICT.
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http://dx.doi.org/10.1200/JCO.2012.44.3499DOI Listing
December 2012

Vitamin E-coated polysulfone membrane improved red blood cell antioxidant status in hemodialysis patients.

J Nephrol 2013 May-Jun;26(3):556-63. Epub 2012 Sep 4.

Biochemistry Laboratory, Montpellier University Hospital, Montpellier, France.

Background: Oxidative stress has emerged as a strong pathogenic cofactor implicated in the development of long-term complications in hemodialysis (HD) patients, such as anemia, and as a major component of the malnutrition inflammation complex syndrome. This prospective multicenter study aimed at evaluating the short-term effects of the new vitamin E (vitE)-coated polysulfone (PS) membrane (VitabranE) on biocompatibility performances and anemia in HD patients.

Methods: After a 3-month washout period with a high-flux synthetic dialyzer, 43 HD patients were switched to a vitE-PS dialyzer. Sampling was performed at baseline (corresponding to the end of the washout period) and after 1, 2 and 3 months of treatment. Oxidative stress status, as well as inflammatory parameters, was investigated at the end of each study period. Hemoglobin levels and administered doses of recombinant human erythropoietin or epoetin (EPO) were available in each center.

Results: The use of vitE-coated membranes for 3 months was not associated with any change in inflammatory parameters. By contrast, vitE-PS dialyzer resulted in a progressive increase in red blood cell (RBC) vitE concentration and in RBC superoxide dismutase activity. A concomitant progressive significant decrease in advanced oxidation protein product concentration at 2 months was observed, suggesting a preventive effect on oxidative stress. Finally, a significant decrease of the erythropoietin resistance index was obtained after 3 months of treatment.

Conclusions: Use of the vitE-PS membrane during a short period improves erythrocyte antioxidant defense mechanisms and seems to lead to a reduction in EPO requirements in HD patients.
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http://dx.doi.org/10.5301/jn.5000195DOI Listing
November 2013

Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells.

PLoS One 2012 8;7(3):e32526. Epub 2012 Mar 8.

UMR 7213 CNRS, Laboratoire de Biophotonique et Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.

Polyphenols are natural compounds widely present in fruits and vegetables, which have antimutagenic and anticancer properties. The aim of the present study was to determine the anticancer effect of a polyphenol-rich Aronia melanocarpa juice (AMJ) containing 7.15 g/L of polyphenols in the acute lymphoblastic leukemia Jurkat cell line, and, if so, to clarify the underlying mechanism and to identify the active polyphenols involved. AMJ inhibited cell proliferation, which was associated with cell cycle arrest in G(2)/M phase, and caused the induction of apoptosis. These effects were associated with an upregulation of the expression of tumor suppressor p73 and active caspase 3, and a downregulation of the expression of cyclin B1 and the epigenetic integrator UHRF1. AMJ significantly increased the formation of reactive oxygen species (ROS), decreased the mitochondrial membrane potential and caused the release of cytochrome c into the cytoplasm. Treatment with intracellular ROS scavengers prevented the AMJ-induced apoptosis and upregulation of the expression of p73 and active caspase 3. The fractionation of the AMJ and the use of identified isolated compounds indicated that the anticancer activity was associated predominantly with chlorogenic acids, some cyanidin glycosides, and derivatives of quercetin. AMJ treatment also induced apoptosis of different human lymphoblastic leukemia cells (HSB-2, Molt-4 and CCRF-CEM). In addition, AMJ exerted a strong pro-apoptotic effect in human primary lymphoblastic leukemia cells but not in human normal primary T-lymphocytes. Thus, the present findings indicate that AMJ exhibits strong anticancer activity through a redox-sensitive mechanism in the p53-deficient Jurkat cells and that this effect involves several types of polyphenols. They further suggest that AMJ has chemotherapeutic properties against acute lymphoblastic leukemia by selectively targeting lymphoblast-derived tumor cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0032526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297612PMC
August 2012

Regional citrate anticoagulation in continuous venovenous haemodiafiltration using commercial solutions.

Nephrol Dial Transplant 2004 Jan;19(1):171-8

Department of Nephrology, Dialysis and Transplantation, CHU Toulouse-Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France.

Background: Treatment with trisodium citrate provides an effective means of regional anticoagulation during continuous renal replacement therapy (CRRT). We evaluated the efficacy, safety and cost of a regional citrate anticoagulation protocol using commercial solutions in 17 critically ill patients treated with continuous venovenous haemodiafiltration (CVVHDF). We performed a total of 22 sessions.

Methods: We delivered an A.C.D-A(541(R)) solution containing 112.9 mmol/l disodium citrate (3.22%) at a median rate of 260 (190-280) ml/h via the pre-filter port of a COBE PRISMA with an AN-69 dialyser, while adjusting the rate to maintain post-filtered ionized calcium (iCa(2+)) between 0.25 and 0.4 mmol/l. Plasma iCa(2+) was maintained at >1.1 mmol/l by infusion of calcium chloride at a median rate of 1.70 (1.36-2.27) mmol/h. The dialysate was easily modified according to the acid-base status of each patient. Both replacement and dialysate solutions were delivered at 1200 ml/h. Each session was scheduled for 48 h and biological parameters were assessed every 6 h.

Results: The mean dialyser survival was 39 +/- 11 h (median 41.5 h; range 13-48 h). We observed dialyser clotting in four cases (18%). There were no bleeding events or modifications of coagulation parameters. The citrate solution, replacement solution and dialysate were obtained as commercial products. Both the replacement and dialysate solutions contained calcium. The extra cost of this technique was 25 euro;/day as compared to anticoagulation with heparin.

Conclusions: We designed an efficient method of regional citrate anticoagulation for CVVHDF by using commercial solutions. The monitoring of patients was as intensive as during heparin anticoagulation for CRRT. Because of the higher cost of this method, it should be proposed only for patients with high bleeding risk.
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http://dx.doi.org/10.1093/ndt/gfg488DOI Listing
January 2004
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