Publications by authors named "Eric Jourdan"

70 Publications

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

Leukemia 2021 Jan 22. Epub 2021 Jan 22.

Hematology Department, INSERM U1052, CRCL, Centre Leon Berard, Lyon, France.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
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http://dx.doi.org/10.1038/s41375-020-01117-wDOI Listing
January 2021

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study.

Leukemia 2020 Sep 18. Epub 2020 Sep 18.

Hematology Biology, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopôle, Université Toulouse III Paul Sabatier, Toulouse, France.

We previously reported the benefit of lomustine addition to conventional chemotherapy in older acute myeloid leukemias with nonadverse chromosomal aberrations in the LAM-SA 2007 randomized clinical trial (NCT00590837). A molecular analysis of 52 genes performed in 330 patients included in this trial, 163 patients being treated with lomustine in combination with idarubicin and cytarabine and 167 without lomustine, identified 1088 mutations with an average of 3.3 mutations per patient. NPM1, FLT3, and DNMT3A were the most frequently mutated genes. A putative therapeutic target was identified in 178 patients (54%). Among five molecular classifications analyzed, the ELN2017 risk classification has the stronger association with the clinical evolution. Patients not treated with lomustine have an expected survival prognosis in agreement with this classification regarding the overall and event-free survivals. In strong contrast, lomustine erased the ELN2017 classification prognosis. The benefit of lomustine in nonadverse chromosomal aberrations was restricted to patients with RUNX1, ASXL1, TP53, and FLT3-ITD/NPM1 mutations in contrast to the intermediate and favorable ELN2017 patients. This post-hoc analysis identified a subgroup of fit elderly AML patients with intermediate cytogenetics and molecular markers who may benefit from lomustine addition to intensive chemotherapy.
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http://dx.doi.org/10.1038/s41375-020-01031-1DOI Listing
September 2020

Fedratinib in patients with myelofibrosis previously treated with ruxolitinib: An updated analysis of the JAKARTA2 study using stringent criteria for ruxolitinib failure.

Am J Hematol 2020 06 17;95(6):594-603. Epub 2020 Apr 17.

University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28-day cycles. The JAKARTA2 outcomes were initially reported using a last-observation-carried forward (LOCF) analysis in a "Per Protocol" population. This updated analysis of JAKARTA2 employs intention-to-treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; ≥35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (≥50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3-4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.
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http://dx.doi.org/10.1002/ajh.25777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317815PMC
June 2020

Association of Occupational Pesticide Exposure With Immunochemotherapy Response and Survival Among Patients With Diffuse Large B-Cell Lymphoma.

JAMA Netw Open 2019 04 5;2(4):e192093. Epub 2019 Apr 5.

Department of Biostatistics, Clinical Epidemiology, Public Health, and Innovation in Methodology, Nîmes University Hospital, University of Montpellier, Montpellier, France.

Importance: Professional use of pesticides is a risk factor for non-Hodgkin lymphoma. The main biological mechanisms of pesticides and chemotherapy are genotoxicity and reactive oxygen species generation. Cellular adaptation among patients exposed to low doses of genotoxic and oxidative compounds might hinder chemotherapy efficiency in patients with lymphoma.

Objective: To examine the association of occupational exposure to pesticides with immunochemotherapy response and survival among patients treated for diffuse large B-cell lymphoma.

Design, Setting, And Participants: This retrospective cohort study assessed patients treated from July 1, 2010, to May 31, 2015, for diffuse large B-cell lymphoma, with a 2-year follow-up. The study took place at 6 university and nonuniversity hospitals in Languedoc-Roussillon, France. A total of 404 patients with newly diagnosed diffuse large B-cell lymphoma treated with anthracycline-based immunochemotherapy were included before the study began. Occupational history was reconstructed for 244 patients and analyzed with the PESTIPOP French job-exposure matrix to determine likelihood of occupational exposure to pesticides. Analysis of the data was performed from July 15, 2017, to July 15, 2018.

Main Outcomes And Measures: Treatment failure (ie, partial response, stable disease, disease progression, or interruption for toxic effects) rate, 2-year event-free survival, and overall survival between exposed and nonexposed patients after adjustment for confounding factors.

Results: A total of 244 patients (mean [SD] age, 61.3 [15.2] years; 153 [62.7%] male) had complete occupational data. Of these patients, 67 (27.4%) had occupational exposure to pesticides, with 38 exposed through agricultural occupations. Occupational exposure was not associated with clinical and biological characteristics at diagnosis. Occupationally exposed patients had a significantly higher treatment failure rate (22.4% vs 11.3%; P = .03; adjusted odds ratio [AOR] for confounding factors, 3.0; 95% CI, 1.3-6.9); this difference was higher among patients with exposing agricultural occupations compared with other patients (29.0% vs 11.7%; AOR, 5.1; 95% CI, 2.0-12.8). Two-year event-free survival was 70% in the occupationally exposed group vs 82% in the unexposed group (adjusted hazard ratio [AHR] for confounding factors, 2.2; 95% CI, 1.3-3.9). Among patients with exposing agricultural occupations compared with other patients, the difference was more pronounced (2-year event-free survival, 56% vs 83%; AHR, 3.5; 95% CI, 1.9-6.5). Similarly, 2-year overall survival was lower in the group of patients with exposing agricultural occupations compared with other patients (81% vs 92%; AHR, 3.9; 95% CI, 1.5-10.0).

Conclusions And Relevance: This retrospective study showed that agricultural occupational exposure to pesticides was associated with treatment failure, event-free survival, and overall survival among patients with diffuse large B-cell lymphoma.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.2093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481431PMC
April 2019

Pomalidomide, cyclophosphamide, and dexamethasone for relapsed multiple myeloma.

Blood 2018 12 3;132(24):2555-2563. Epub 2018 Oct 3.

Centre Hospitalier Universitaire, Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France.

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.
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http://dx.doi.org/10.1182/blood-2018-07-863829DOI Listing
December 2018

Improved Survival by Adding Lomustine to Conventional Chemotherapy for Elderly Patients With AML Without Unfavorable Cytogenetics: Results of the LAM-SA 2007 FILO Trial.

J Clin Oncol 2018 Nov 27;36(32):3203-3210. Epub 2018 Sep 27.

Arnaud Pigneux and Pierre-Yves Dumas, Bordeaux University Hospital, Bordeaux University, INSERM 1035; Louis-Rachid Salmi, Ariane Mineur, and Julien Asselineau, Bordeaux University Hospital, Bordeaux; Marie C. Béné, and Jacques Delaunay, Nantes University Hospital, Nantes; Caroline Bonmati, Nancy University Hospital, Nancy; Romain Guièze, Clermont-Ferrand University Hospital, Clermont Ferrand; Isabelle Luquet, Eric Delabesse, and Christian Récher, Toulouse University Hospital, Toulouse; Pascale Cornillet-Lefebvre, Reims University Hospital, Reims; Jean-Christophe Ianotto, Brest University Hospital, Brest; Mario Ojeda-Uribe, Mulhouse Regional Hospital, Mulhouse; Mathilde Hunault and Norbert Ifrah, Angers University Hospital and INSERM U 892/CNRS 6299, Angers; Anne Banos, Cote Basque General Hospital, Bayonne; Luc Matthieu Fornecker, Strasbourg University Hospital, Strasbourg; Marc Bernard, Rennes University Hospital, Rennes; Eric Jourdan, Nîmes University Hospital, Nîmes; Norbert Vey, Institut Paoli Calmettes, Marseilles; Hacene Zerazhi, Avignon General Hospital, Avignon; Yosr Hishri, Montpellier University Hospital, Montpellier; Roselyne Delepine, Tours University Hospital, Tours; and Jean-Yves Cahn, Grenoble University Hospital, Grenoble, France.

Purpose: Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin.

Patients And Methods: Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety.

Results: From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( = .01). The proportional hazards assumption was rejected for OS ( = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( = .04), and fewer patients required a second treatment after ICL.

Conclusion: Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.
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http://dx.doi.org/10.1200/JCO.2018.78.7366DOI Listing
November 2018

Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia.

Blood 2018 07 24;132(2):187-196. Epub 2018 Apr 24.

INSERM Lille, University of Lille, Lille, France.

Mutations in receptor tyrosine kinase/RAS signaling pathway genes are frequent in core-binding factor (CBF) acute myeloid leukemias (AMLs), but their prognostic relevance is debated. A subset of CBF AML patients harbors several signaling gene mutations. Genotyping of colonies and of relapse samples indicates that these arise in independent clones, thus defining a process of clonal interference (or parallel evolution). Clonal interference is pervasive in cancers, but the mechanisms underlying this process remain unclear, and its prognostic impact remains unknown. We analyzed a cohort of 445 adult and pediatric patients with CBF AML treated with intensive chemotherapy and with deep sequencing of 6 signaling genes (, , , , , ). A total of 152 (34%), 167 (38%), and 126 (28%) patients harbored no, a single, and multiple signaling clones (clonal interference), respectively. Clonal interference of signaling mutations was associated with older age ( = .004) and inv(16) subtype ( = .025) but not with white blood cell count or mutations in chromatin or cohesin genes. The median allele frequency of signaling mutations was 31% in patients with a single clone or clonal interference ( = .14). The repertoire of , , and / variants differed between groups. Clonal interference did not affect complete remission rate or minimal residual disease after 1-2 courses, but it did convey inferior event-free survival ( < 10), whereas the presence of a single signaling clone did not ( = .44). This inferior outcome was independent of clinical parameters and of the presence of specific signaling clones. Our results suggest that specific clonal architectures can herald distinct prognoses in AML.
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http://dx.doi.org/10.1182/blood-2018-03-837781DOI Listing
July 2018

Interim PET Response-adapted Strategy in Untreated Advanced Stage Hodgkin Lymphoma: Results of GOELAMS LH 2007 Phase 2 Multicentric Trial.

Clin Lymphoma Myeloma Leuk 2018 03 31;18(3):191-198. Epub 2018 Jan 31.

Hematology Department, Grenoble University Hospital, Grenoble, France.

Background: Patients with advanced stage Hodgkin lymphoma still present unsatisfactory outcomes.

Patients And Methods: The Groupe d'étude des Leucémies Aigues et des Maladies du Sang (GOELAMS) group conducted a prospective multicentric trial (NCT00920153) for advanced stage Hodgkin lymphoma to evaluate a positron emission tomography (PET)-adapted strategy. Patients received an intensive regimen (VABEM [vindesine, doxorubicin, carmustine, etoposide, and methylprednisolone]) in front-line and interim FDG-PET evaluation after 2 courses (PET-2). Patients with negative PET-2 findings received 1 additional course. Patients with positive PET-2 findings underwent early salvage therapy followed by high-dose therapy/autologous stem cell transplantation.

Results: Fifty-one patients were included. The final complete remission rate was 88%. With a median follow up of 5.3 years, 5-year event-free survival and overall survival rates were 75.3% and 85.3%, respectively, for the whole cohort. Patients who were PET-2-negative had 5-year event-free survival and overall survival rates of, respectively, 77.8% and 88.2% versus 85.1% and 91.7% for patients who were PET-2-positive.

Conclusion: A PET-guided strategy with early salvage therapy and high-dose therapy/autologous stem cell transplantation for patients with interim PET-2-positive findings is safe and feasible and provide similar outcome as patients with a negative PET-2.
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http://dx.doi.org/10.1016/j.clml.2018.01.003DOI Listing
March 2018

SNP-array lesions in core binding factor acute myeloid leukemia.

Oncotarget 2018 Jan 8;9(5):6478-6489. Epub 2018 Jan 8.

CHU Lille, Laboratory of Hematology, Biology and Pathology Center, Lille, France.

Acute myeloid leukemia (AML) with t(8;21) and inv(16), together referred as core binding factor (CBF)-AML, are recognized as unique entities. Both rearrangements share a common pathophysiology, the disruption of the CBF, and a relatively good prognosis. Experiments have demonstrated that CBF rearrangements were insufficient to induce leukemia, implying the existence of cooperating events. To explore these aberrations, we performed single nucleotide polymorphism (SNP)-array in a well-annotated cohort of 198 patients with CBF-AML. Excluding breakpoint-associated lesions, the most frequent events included loss of a sex chromosome (53%), deletions at 9q21 (12%) and 7q36 (9%) in patients with t(8;21) compared with trisomy 22 (13%), trisomy 8 (10%) and 7q36 deletions (12%) in patients with inv(16). SNP-array revealed novel recurrent genetic alterations likely to be involved in CBF-AML leukemogenesis. mutations (20% of t(8;21)-AML) were shown to be a target of copy-neutral losses of heterozygosity (CN-LOH) at chromosome 19p. focal deletions were identified in 5% of inv(16)-AML while sequence analysis revealed that 2% carried truncating mutations. Finally, disruption was found in both subtypes (4.5% of the whole cohort) and possibly highlighted a new lesion associated with aberrant tyrosine kinase signaling in this particular subtype of leukemia.
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http://dx.doi.org/10.18632/oncotarget.24031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814226PMC
January 2018

Erratum: Efficacy and safety of ClairYg®, a ready-to-use intravenous immunoglobulin, in adult patients with primary immune thrombocytopenia.

Am J Blood Res 2017 15;7(3):29. Epub 2017 Jun 15.

Department of Internal Medicine, University Hospital Henri MondorFrance.

[This corrects the article on p. 1 in vol. 7, PMID: 28203488.].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498821PMC
June 2017

Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study.

Lancet Haematol 2017 Jul 8;4(7):e317-e324. Epub 2017 Jun 8.

Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Scottsdale, AZ, USA.

Background: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis.

Methods: This single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (≥5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a ≥35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171.

Findings: Between May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination.

Interpretation: This phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed.

Funding: Sanofi.
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http://dx.doi.org/10.1016/S2352-3026(17)30088-1DOI Listing
July 2017

Relapsed chronic lymphocytic leukemia retreated with rituximab: interim results of the PERLE study.

Leuk Lymphoma 2017 06 9;58(6):1366-1375. Epub 2017 Feb 9.

q Hématologie, CHU Robert Debré , Reims , France.

This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.
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http://dx.doi.org/10.1080/10428194.2016.1243673DOI Listing
June 2017

Efficacy and safety of ClairYg, a ready-to-use intravenous immunoglobulin, in adult patients with primary immune thrombocytopenia.

Am J Blood Res 2017 15;7(1):1-9. Epub 2017 Jan 15.

Department of Internal Medicine, University Hospital Henri Mondor France.

Purpose: The present study was designed to assess the efficacy and safety of IGNG that is a new liquid, saccharose and maltose-free highly purified ready-to-use 5% intravenous immunoglobulin (IVIg), in primary immune thrombocytopenic patients with severe thrombocytopenia.

Methods: Nineteen adults with a platelet count ≤ 25 × 10/L received a single dose of IGNG (1 g/kg) on Day 1, with a second identical dose on Day 3 if needed. Patients were followed for 30 days. Primary endpoint was the response rate, defined as the proportion of patients with a platelet count ≥ 50 × 10/L within 96 hours after the first IGNG dose.

Results: All but one of the 17 evaluable patients for efficacy responded with an overall response rate of 94.1% (95% CI 71.3%-99.9%). Response was observed after only one infusion (1 g/kg boby weight) in 11 patients (59%) and the others required a second dose. Mean time to response was 2.2 days. Maximum platelet count was reached within 1 week after the first dose and lasted for approximately 2 weeks. Patients requiring a second dose had lower platelet counts at baseline than patients requiring a single dose. In the 19 evaluable patients for safety, IGNG demonstrated good safety, good hepatic and renal tolerance, and did not induce hemolysis. This trial was registered at the French Medical Agency (AFSSAPS) as #DI n°060735.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306448PMC
January 2017

Addition of Androgens Improves Survival in Elderly Patients With Acute Myeloid Leukemia: A GOELAMS Study.

J Clin Oncol 2017 Feb 24;35(4):387-393. Epub 2016 Oct 24.

Arnaud Pigneux and Mathieu Sauvezie, Centre Hospitalier Universitaire (CHU) Bordeaux, Université Bordeaux, Institut National de la Santé et de la Recherche Médicale (INSERM) 1035, Bordeaux; Marie C. Béné and Jean-Luc Harousseau, Hôpital Hôtel Dieu, Nantes; Philippe Guardiola, Mathilde Hunault, and Norbert Ifrah, CHU Angers, UMR INSERM U892/CNRS 6299; Jean-Francois Hamel, Université Nantes Angers Le Mans, CHU Angers, Angers; Christian Recher, CHU de Toulouse, Université de Toulouse III, Toulouse; Olivier Tournilhac, CHU Clermont Ferrand, Clermont Ferrand; Francis Witz, CHU Nancy, Nancy; Christian Berthou, Hôpital Augustin Morvan, Brest; Martine Escoffre-Barbe, Hôpital Pontchaillou, Rennes; Denis Guyotat, Institut de Cancérologie de la Loire, Saint Etienne; Nathalie Fegueux, Hôpital Lapeyronie, Montpellier; Chantal Himberlin, CHU Reims, Reims; Martine Delain, Hôpital Bretonneau, Tours; Bruno Lioure, CHU Hautepierre, Strasbourg; Eric Jourdan, Hôpital Caremeau, Nîmes; Frederic Bauduer, Centre Hospitalier Cote Basque, Bayonne; Francois Dreyfus, Hôpital Cochin, Paris; and Jean-Yves Cahn and Jean-Jacques Sotto, Hôpital Michallon, Grenoble, France.

Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m on days 1 to 5, cytarabine 100 mg/m on days 1 to 7, and lomustine 200 mg/m on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m on day 1, cytarabine 100 mg/m on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 10/L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.
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http://dx.doi.org/10.1200/JCO.2016.67.6213DOI Listing
February 2017

Assessment of a new biological complex efficacy on dysseborrhea, inflammation, and Propionibacterium acnes proliferation.

Clin Cosmet Investig Dermatol 2016 31;9:233-9. Epub 2016 Aug 31.

Direction Scientifique Bioderma (NAOS), Lyon, France.

Introduction: Acne vulgaris is a common chronic inflammatory disease of the pilosebaceous unit triggered by Propionibacterium acnes. A bakuchiol, Ginkgo biloba extract, and mannitol (BGM) complex has been developed to provide patients with acne with a specific dermocosmetic to be used adjunctively with conventional treatments.

Objective: The aim of these studies was to assess the antibacterial, anti-inflammatory, and antioxidative potential of BGM complex and its individual compounds as well as its impact on sebum composition.

Methods: The antibacterial, anti-inflammatory, and antioxidative potential of BGM complex and its compounds was assessed through in vitro, ex vivo, and clinical studies. The clinical benefit of BGM complex formulated in a cream was assessed in subjects prone to acne through sebum composition analysis and photometric assessments.

Results: Results from the studies showed that the BGM complex has significant antibacterial, anti-inflammatory, and antioxidative properties. At similar concentrations, bakuchiol has up to twice the antioxidative potential than vitamin E. In subjects, BGM complex regulated the sebum composition in acne patients by increasing the level of sapienic and linolenic acid and reducing the level of oleic acid. The reduced number of porphyrins on the skin surface showed that it is also effective against P. acnes.

Conclusion: BGM complex provides a complete adjunctive care in patients with acne by targeting etiopathogenic factors of acne: dysseborrhea, inflammation, and P. acnes proliferation.
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http://dx.doi.org/10.2147/CCID.S110655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5012630PMC
September 2016

Dasatinib and low-intensity chemotherapy in elderly patients with Philadelphia chromosome-positive ALL.

Blood 2016 08 27;128(6):774-82. Epub 2016 Apr 27.

Institute of Cancer & Genetics, Cardiff University School of Medicine, Cardiff, United Kingdom.

Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy.
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http://dx.doi.org/10.1182/blood-2016-02-700153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5085255PMC
August 2016

Comprehensive mutational profiling of core binding factor acute myeloid leukemia.

Blood 2016 05 15;127(20):2451-9. Epub 2016 Mar 15.

Biology and Pathology Center, Laboratory of Hematology, Centre Hospitalier Universitaire (CHU) Lille, Lille, France; Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, Lille, France;

Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been recognized as unique entities within AML and are usually reported together as core binding factor AML (CBF-AML). However, there is considerable clinical and biological heterogeneity within this group of diseases, and relapse incidence reaches up to 40%. Moreover, translocations involving CBFs are not sufficient to induce AML on its own and the full spectrum of mutations coexisting with CBF translocations has not been elucidated. To address these issues, we performed extensive mutational analysis by high-throughput sequencing in 215 patients with CBF-AML enrolled in the Phase 3 Trial of Systematic Versus Response-adapted Timed-Sequential Induction in Patients With Core Binding Factor Acute Myeloid Leukemia and Treating Patients with Childhood Acute Myeloid Leukemia with Interleukin-2 trials (age, 1-60 years). Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.
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http://dx.doi.org/10.1182/blood-2015-12-688705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457131PMC
May 2016

Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents.

Nat Commun 2016 Feb 24;7:10767. Epub 2016 Feb 24.

INSERM U1170, Gustave Roussy, 114, rue Edouard Vaillant, 94805 Villejuif, France.

The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.
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http://dx.doi.org/10.1038/ncomms10767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770084PMC
February 2016

Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial.

Haematologica 2016 Mar 3;101(3):328-35. Epub 2015 Dec 3.

Laboratoire d'hématologie, Centre de Biologie-Pathologie, CHRU de Lille; Equipe 3 INSERM U837, JPARC Lille, France.

In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558).
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http://dx.doi.org/10.3324/haematol.2015.131946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815724PMC
March 2016

Safety and Efficacy of Fedratinib in Patients With Primary or Secondary Myelofibrosis: A Randomized Clinical Trial.

JAMA Oncol 2015 Aug;1(5):643-51

Department of Medicine, Mayo Clinic, Rochester, Minnesota.

Importance: Myelofibrosis (MF) is a BCR-ABL-negative myeloproliferative neoplasm characterized by anemia, splenomegaly, debilitating constitutional symptoms, and shortened survival. Fedratinib, a JAK2-selective inhibitor, previously demonstrated clinically beneficial activity in patients with MF in early-phase trials.

Objective: To evaluate the efficacy and safety of fedratinib therapy in patients with primary or secondary (post-polycythemia vera or post-essential thrombocythemia) MF.

Design, Setting, And Participants: Double-blind, randomized, placebo-controlled phase 3 study in 94 sites in 24 countries in which 289 adult patients (≥18 years of age) with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF were randomly assigned between December 2011 and September 2012 to once-daily oral fedratinib, at a dose of 400 mg or 500 mg, or placebo, for at least 6 consecutive 4-week cycles.

Main Outcomes And Measures: The primary end point was spleen response (≥35% reduction in spleen volume from baseline as determined by magnetic resonance imaging or computed tomography) at week 24 and confirmed 4 weeks later. The main secondary end point was symptom response (≥50% reduction in total symptom score, assessed using the modified Myelofibrosis Symptom Assessment Form).

Results: The primary end point was achieved by 35 of 96 (36% [95% CI, 27%-46%]) and 39 of 97 (40% [95% CI, 30%-50%]) patients in the fedratinib 400-mg and 500-mg groups, vs 1 of 96 (1% [95% CI, 0%-3%]) in the placebo group (P < .001). Symptom response rates at week 24 were 33 of 91 (36% [95% CI, 26%-46%]), 31 of 91 (34% [95% CI, 24%-44%]), and 6 of 85 (7% [95% CI, 2%-13%]) in the fedratinib 400-mg, 500-mg, and placebo groups, respectively (P < .001). Common adverse events with fedratinib treatment were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Encephalopathy was reported in 4 women who received fedratinib 500 mg/d. A diagnosis of Wernicke encephalopathy was supported by magnetic resonance imaging in 3 cases and suspected clinically in 1 case.

Conclusions And Relevance: Fedratinib therapy significantly reduced splenomegaly and symptom burden in patients with MF. These benefits were accompanied by toxic effects in some patients, the most important being encephalopathy of unknown mechanism. Clinical development of fedratinib was subsequently discontinued.

Trial Registration: clinicaltrials.gov identifier: NCT01437787.
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http://dx.doi.org/10.1001/jamaoncol.2015.1590DOI Listing
August 2015

A dermocosmetic containing bakuchiol, Ginkgo biloba extract and mannitol improves the efficacy of adapalene in patients with acne vulgaris: result from a controlled randomized trial.

Clin Cosmet Investig Dermatol 2015 10;8:187-91. Epub 2015 Apr 10.

Laboratoire Bioderma, Lyon, France.

Background: Acne vulgaris is an inflammatory disorder of the pilosebaceous unit.

Aim: To confirm that BGM (bakuchiol, Ginkgo biloba extract, and mannitol) complex increases the established clinical efficacy of adapalene 0.1% gel in patients with acne.

Methods: A clinical trial was conducted in acne patients. A total of 111 subjects received adapalene 0.1% gel and BGM complex or vehicle cream for 2 months. Assessments comprised Investigator Global Assessment (IGA), global efficacy, seborrhea intensity, inflammatory and non-inflammatory lesions, and subject perception, as well as overall safety and local tolerance and quality of life.

Results: At the end of the trial, inflammatory and non-inflammatory lesions, IGA, global efficacy, and seborrhea intensity had significantly improved in both treatment groups. Differences were statistically significant (P<0.05) in favor of BGM complex for inflammatory lesions as well as IGA and seborrhea intensity. Global efficacy assessments and subject perception confirmed the superiority of BGM complex-including treatment over the comparative combination. Quality of life had improved more with the active combination than with the vehicle combination. In the active group, four subjects had to interrupt temporarily BGM complex and 12 adapalene compared to seven subjects interrupting the vehicle and eleven adapalene in the vehicle group. One subject withdrew from the trial due to an allergy to adapalene. The majority of all events were mild.

Conclusion: BGM complex improves the treatment outcome of adapalene 0.1% gel in patients with acne vulgaris. Overall, safety and local tolerance of BGM complex were good.
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http://dx.doi.org/10.2147/CCID.S81691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401329PMC
April 2015

Unlike ASXL1 and ASXL2 mutations, ASXL3 mutations are rare events in acute myeloid leukemia with t(8;21).

Leuk Lymphoma 2016 15;57(1):199-200. Epub 2015 May 15.

a Laboratory of Hematology and Tumor Bank, INSERM U837 Team 3, Cancer Research Institute of Lille, Centre Hospitalier Régional Universitaire of Lille, University Lille Nord de France , Lille.

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http://dx.doi.org/10.3109/10428194.2015.1037754DOI Listing
October 2016

Efficacy and tolerance assessment of a new type of dermocosmetic in infants and children with moderate atopic dermatitis.

J Cosmet Dermatol 2015 Jun 23;14(2):107-12. Epub 2015 Mar 23.

Laboratoire Bioderma, Lyon, France.

Background: Atopic dermatitis (AD) is an inflammatory and pruritic skin disorder.

Objectives: To assess the efficacy and tolerance of a new emollient (SBT complex) in subjects with moderate AD.

Methods: Subjects received twice daily for 168 days (6 months) either SBT complex or emollient base adjunctively or alternately with topical corticosteroids or calcineurin inhibitors. Evolution of AD was assessed throughout the study using usual AD assessment criteria including SCORAD and PO-SCORAD. Quality of life was assessed at Day 0 and Day 168.

Results: At Day 168, a significant decrease with SBT complex was observed for the SCORAD and the PO-SCORAD scores (P < 0.05), the primary efficacy criteria. A total of 76% of SBT complex subjects did not relapse and time-to-relapse increased compared to the emollient base subjects. Intensity, dryness, and quality of life (P < 0.05) had improved in subjects using SBT complex. The product was well tolerated with less physical and functional signs in the SBT than in the emollient base group.

Conclusion: The new emollient dermocosmetic SBT complex applied adjunctively or alternately with topical AD treatments significantly improved AD without any safety concerns. SBT complex may play an important role in the restoration of the natural skin barrier.
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http://dx.doi.org/10.1111/jocd.12145DOI Listing
June 2015

Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: a French Acute Myeloid Leukemia Intergroup trial.

Haematologica 2015 Jun 24;100(6):780-5. Epub 2015 Feb 24.

Service des Maladies du Sang, INSERM U892/CNRS 6299, CHU Angers.

Core-binding factor acute myeloid leukemia is a favorable acute myeloid leukemia subset cytogenetically defined by t(8;21) or inv(16)/t(16;16) rearrangements, disrupting RUNX1 (previously CBFA/AML1) or CBFB transcription factor functions. The receptor tyrosine kinase KIT is expressed in the vast majority of these acute myeloid leukemias and frequent activating KIT gene mutations have been associated with a higher risk of relapse. This phase II study aimed to evaluate dasatinib as maintenance therapy in patients with core-binding factor acute myeloid leukemia in first hematologic complete remission, but at higher risk of relapse due to molecular disease persistence or recurrence. A total of 26 patients aged 18-60 years old previously included in the CBF-2006 trial were eligible to receive dasatinib 140 mg daily if they had a poor initial molecular response (n=18) or a molecular recurrence (n=8). The tolerance of dasatinib as maintenance therapy was satisfactory. The 2-year disease-free survival in this high-risk population of patients was 25.7%. All but one patient with molecular recurrence presented subsequent hematologic relapse. Patients with slow initial molecular response had a similar disease-free survival when treated with dasatinib (40.2% at 2 years) or without any maintenance (50.0% at 2 years). The disappearance of KIT gene mutations at relapse suggests that clonal devolution may in part explain the absence of efficacy observed with single-agent dasatinib in these patients (n. EudraCT: 2006-006555-12).
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http://dx.doi.org/10.3324/haematol.2014.114884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450623PMC
June 2015

A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure.

Leuk Res 2014 Dec 7;38(12):1430-4. Epub 2014 Oct 7.

Hématologie Séniors, Hôpital Saint Louis, APHP, Université Paris 7, Paris, France. Electronic address:

Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.
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http://dx.doi.org/10.1016/j.leukres.2014.09.014DOI Listing
December 2014

Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: a prospective randomized comparative trial.

J Am Acad Dermatol 2015 Jan 22;72(1):189-90.e1. Epub 2014 Oct 22.

Department of Dermatology, University Hospital of Nice, Nice, France; INSERM U1065, Team 12, C3M, Nice, France. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2014.08.023DOI Listing
January 2015

Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations.

Blood 2014 Aug 27;124(9):1445-9. Epub 2014 Jun 27.

Department of Hematology and Oncology, Centre Hospitalier Universitaire de Nimes, University Montpellier-Nimes, Nimes, France.

Acute myeloid leukemia (AML) with t(8;21) (q22;q22) is considered to have favorable risk; however, nearly half of t(8;21) patients are not cured, and recent studies have highlighted remarkable genetic heterogeneity in this subset of AML. Here we identify somatic mutations in additional sex combs-like 2 (ASXL2) in 22.7% (25/110) of patients with t(8;21), but not in patients with inv(16)/t(16;16) (0/60) or RUNX1-mutated AML (0/26). ASXL2 mutations were similarly frequent in adults and children t(8;21) and were mutually exclusive with ASXL1 mutations. Although overall survival was similar between ASXL1 and ASXL2 mutant t(8;21) AML patients and their wild-type counterparts, patients with ASXL1 or ASXL2 mutations had a cumulative incidence of relapse of 54.6% and 36.0%, respectively, compared with 25% in ASXL1/2 wild-type counterparts (P = .226). These results identify a high-frequency mutation in t(8;21) AML and identify the need for future studies to investigate the clinical and biological relevance of ASXL2 mutations in this unique subset of AML.
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http://dx.doi.org/10.1182/blood-2014-04-571018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148766PMC
August 2014

Minimal residual disease monitoring in t(8;21) acute myeloid leukemia based on RUNX1-RUNX1T1 fusion quantification on genomic DNA.

Am J Hematol 2014 Jun 8;89(6):610-5. Epub 2014 Mar 8.

Laboratory of Hematology, Biology and Pathology Center, Lille, France.

Although acute myeloid leukemia (AML) with t(8;21) belongs to the favorable risk AML subset, relapse incidence may reach 30% in those patients. RUNX1-RUNX1T1 fusion transcript is a well-established marker for minimal residual disease (MRD) monitoring. In this study, we investigated the feasibility and performances of RUNX1-RUNX1T1 DNA as MRD marker in AML with t(8;21). In 17/22 patients with t(8;21)-positive AML treated in the French CBF-2006 trial, breakpoints in RUNX1 and RUNX1T1 were identified using long-range PCR followed by next-generation sequencing. RUNX1-RUNX1T1 DNA quantification was performed by real-time quantitative PCR using patient-specific primers and probe. MRD levels were evaluated in 71 follow-up samples from 16 patients, with a median of four samples [range 2-7] per patient. RUNX1 breakpoints were located in intron 5 in all cases. RUNX1T1 breakpoints were located in intron 1b in 15 cases and in intron 1a in two cases. RUNX1-RUNX1T1 MRD levels measured on DNA and RNA were strongly correlated (r = 0.8, P < 0.0001). Discordant MRD results were observed in 10/71 (14%) of the samples: in three samples from two patients who relapsed, RUNX1-RUNX1T1 was detectable only on DNA, while RUNX1-RUNX1T1 was detectable only on RNA in seven samples. MRD monitoring on genomic DNA is feasible, but with sensitivity variations depending on the patient breakpoint sequence and the qPCR assay efficiency. Although interpretation of the results is easier because it is closely related to the number of leukemic cells, this method greatly increases time, cost and complexity, which limits its interest in routine practice.
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http://dx.doi.org/10.1002/ajh.23696DOI Listing
June 2014

A multicenter phase II study of single-agent enzastaurin in previously treated multiple myeloma.

Leuk Lymphoma 2014 Sep 2;55(9):2013-7. Epub 2014 May 2.

Centre Hospitalier Regional Universitaire de Nîmes , Nîmes , France.

Enzastaurin is an oral serine/threonine kinase inhibitor of the protein kinase C (PKC) and phosphatidylinositol 3 (PI3) kinase/Akt pathways that induces apoptosis in multiple myeloma (MM) cell lines in a caspase-independent manner. A phase II study was conducted to assess response rate, time to progression (TTP), safety and biomarker association with clinical outcomes after monotherapy with the PKC inhibitor enzastaurin in previously treated patients with MM. Eligible patients (n = 14) were treated with enzastaurin 250 mg twice daily after receiving loading doses on day 1. One minimal response was observed. The median TTP was 5.11 months. There were two grade 3 adverse events, anemia and prolonged QTc interval, and no grade 4 adverse events. Single-agent enzastaurin was well tolerated but not effective in this heavily pretreated population with MM.
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http://dx.doi.org/10.3109/10428194.2013.861066DOI Listing
September 2014