Touzeau C.,Service d'hematologie clinique
Leukemia | Year: 2017
The therapeutic landscape of multiple myeloma (MM) has evolved spectacularly over the past decade with the discovery and validation of proteasome inhibitors and immunomodulatory agents as highly active agents, both in front-line therapy as well as in the relapse and maintenance settings. Although previous attempts to apply available monoclonal antibodies (Mabs) to the treatment of patients with MM has until recently been disappointing, novel targets specifically explored in the context of MM have recently lead to the first approvals of Mabs for the treatment of patients with MM. We have performed a literature search to identify preclinical targeting of MM, including in vitro and in vivo models using monoclonal antibodies, as well as clinical trials of monoclonal antibodies in patients with MM. Sources used were peer-reviewed publications, congress abstracts and on-line clinical trials data (such as clinicaltrials.gov). Several targets have been evaluated in preclinical models and a growing number of agents are being evaluated in clinical trials, as single agents or in combination and under various antibody formats. Two agents, targeting for the first time CD38 and SLAMF7, respectively, have recently been approved for the treatment of patients with MM. The recent approval of these two antibodies is expected to have a strong impact on treatment modalities and outcome in patients with MM, including both transplant eligible and elderly patients.Leukemia advance online publication, 10 March 2017; doi:10.1038/leu.2017.60. © 2017 Macmillan Publishers Limited, part of Springer Nature.
Dohner H.,University of Ulm |
Estey E.H.,Seattle Cancer Center Alliance |
Amadori S.,University of Rome Tor Vergata |
Appelbaum F.R.,Fred Hutchinson Cancer Research Center |
And 14 more authors.
Blood | Year: 2010
In 2003, an international working group last reported on recommendations for diagnosis, response assessment, and treatment outcomes in acute myeloid leukemia (AML). Since that time, considerable progress has been made in elucidating the molecular pathogenesis of the disease that has resulted in the identification of new diagnostic and prognostic markers. Furthermore, therapies are now being developed that target diseaseassociated molecular defects. Recent developments prompted an international expert panel to provide updated evidenceand expert opinion-based recommendations for the diagnosis and management of AML, that contain both minimal requirements for general practice as well as standards for clinical trials. A new standardized reporting system for correlation of cytogenetic and molecular genetic data with clinical data is proposed. © 2010 by The American Society of Hematology.
Preudhomme C.,Lille University Hospital Center |
Guilhot J.,French Institute of Health and Medical Research |
Nicolini F.E.,Hematologie Clinique Hopital Edouard Herriot |
Guerci-Bresler A.,Nancy University Hospital Center |
And 19 more authors.
New England Journal of Medicine | Year: 2010
Background: Imatinib (400 mg daily) is considered the best initial therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in the chronic phase. However, only a minority of patients treated with imatinib have a complete molecular remission. Methods: We randomly assigned 636 patients with untreated chronic-phase CML to receive imatinib alone at a dose of 400 mg daily, imatinib (400 mg daily) plus cytarabine (20 mg per square meter of body-surface area per day on days 15 through 28 of each 28-day cycle) or pegylated interferon (peginterferon) alfa-2a (90 μg weekly), or imatinib alone at a dose of 600 mg daily. Molecular and cytogenetic responses, time to treatment failure, overall and event-free survival, and adverse events were assessed. An analysis of molecular response at 12 months was planned. A superior molecular response was defined as a decrease in the ratio of transcripts of the tyrosine kinase gene BCR-ABL to transcripts of ABL of 0.01% or less, corresponding to a reduction of 4 log10 units or more from the baseline level, as assessed by means of a real-time quantitative polymerase-chain-reaction assay. Results: At 12 months, the rates of cytogenetic response were similar among the four groups. The rate of a superior molecular response was significantly higher among patients receiving imatinib and peginterferon alfa-2a (30%) than among patients receiving 400 mg of imatinib alone (14%) (P = 0.001). The rate was significantly higher among patients treated for more than 12 months than among those treated for 12 months or less. Gastrointestinal events were more frequent among patients receiving cytarabine, whereas rash and depression were more frequent among patients receiving peginterferon alfa-2a. Conclusions: As compared with other treatments, the addition of peginterferon alfa-2a to imatinib therapy resulted in significantly higher rates of molecular response in patients with chronic-phase CML. (Funded by the French Ministry of Health and others; ClinicalTrials.gov number, NCT00219739.). Copyright © 2010 Massachusetts Medical Society.
Ivanoff S.,Service dHematologie Clinique |
Gruson B.,Service dHematologie Clinique |
Chantepie S.P.,Caen University Hospital Center |
Lemasle E.,Center Henri Becquerel |
And 7 more authors.
American Journal of Hematology | Year: 2013
Despite progress in the understanding of leukemia pathophysiology, the treatment of acute myeloid leukemia (AML) remains challenging. In patients with refractory or relapsed (R/R) AML, the prognosis is still poor and this group is targeted for new drug development. We reviewed the outcome of 47 patients, with R/R AML after at least one course of intensive chemotherapy, treated with 5-azacytidine in three different French institutions. The overall response rate was 38% including complete remission in 21%, partial remission in 11%, and hematological improvement in 6% of cases. Median time to relapse was 6 (range, 1-39) months. Median overall survival was 9 months (not reached by responders vs. 4.5 months for nonresponders patients, P = 0.0001). Univariate analysis identified the absence of peripheral blood blasts and <20% bone marrow blasts as prognostic factors for both overall response and survival, but not age, ECOG/PS, type of AML, cytogenetic, status of the disease, number of previous lines of therapy, previous hematological stem cell transplantation, or white blood cells count. Bone marrow blasts percentage <20% was the only independent prognostic factor identified by multivariate analysis for overall response (P = 0.0013) and survival (P = 0.0324). Six patients in remission could proceed to an allogenic hematological stem cell transplantation. The drug-related grade 3/4 adverse events were hematopoietic toxicities (38%) and infection (32%). In conclusion, this study suggests that a salvage therapy with 5-azacytidine is an interesting option for patients with R/R AML after intensive chemotherapy. Prospective randomized studies are needed to demonstrate a superiority of this approach over others strategies. © 2013 Wiley Periodicals, Inc.
Gohring G.,Hannover Medical School |
Giagounidis A.,Johannes Hospital |
Busche G.,Hannover Medical School |
Hofmann W.,Hannover Medical School |
And 4 more authors.
Haematologica | Year: 2011
In patients with low and intermediate risk myelodysplastic syndrome and deletion 5q (del(5q)) treated with lenalidomide, monitoring of cytogenetic response is mandatory, since patients without cytogenetic response have a significantly increased risk of progression. Therefore, we have reviewed cytogenetic data of 302 patients. Patients were analyzed by karyotyping and fluorescence in situ hybridization. In 85 patients, del(5q) was only detected by karyotyping. In 8 patients undergoing karyotypic evolution, the del(5q) and additional chromosomal aberrations were only detected by karyotyping. In 3 patients, del(5q) was only detected by fluorescence in situ hybridization, but not by karyotyping due to a low number of metaphases. Karyotyping was significantly more sensitive than fluorescence in situ hybridization in detecting the del(5q) clone. In conclusion, to optimize therapy control of myelodysplastic syndrome patients with del(5q) treated with lenalidomide and to identify cytogenetic non-response or progression as early as possible, fluorescence in situ hybridization alone is inadequate for evaluation. Karyotyping must be performed to optimally evaluate response. © 2011 Ferrata Storti Foundation.
Lainey E.,French Institute of Health and Medical Research |
Sebert M.,Service dHematologie Clinique |
Thepot S.,Service dHematologie Clinique |
Scoazec M.,French Institute of Health and Medical Research |
And 7 more authors.
Cell Cycle | Year: 2012
Erlotinib was originally developed as an epidermal growth factor receptor (EGFR)-specific inhibitor for the treatment of solid malignancies, yet also exerts significant EGFR-independent antileukemic effects in vitro and in vivo. The molecular mechanisms underlying the clinical antileukemic activity of erlotinib as a standalone agent have not yet been precisely elucidated. Conversely, in preclinical settings, erlotinib has been shown to inhibit the constitutive activation of SRC kinases and mTOR, as well as to synergize with the DNA methyltransferase inhibitor azacytidine (a reference therapeutic for a subset of leukemia patients) by promoting its intracellular accumulation. Here, we show that both erlotinib and gefitinib (another EGFR inhibitor) inhibit transmembrane transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein (P-gp), multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP), also in acute myeloid leukemia (AML) cells that do not overexpress these pumps. Thus, inhibition of drug efflux by erlotinib and gefitinib selectively exacerbated (in a synergistic or additive fashion) the cytotoxic response of KG-1 cells to chemotherapeutic agents that are normally extruded by ABC transporters (e.g., doxorubicin and etoposide). Erlotinib limited drug export via ABC transporters by multiple mechanisms, including the downregulation of surface-exposed pumps and the modulation of their ATPase activity. The effects of erlotinib on drug efflux and its chemosensitization profile persisted in patient-derived CD34+ cells, suggesting that erlotinib might be particularly efficient in antagonizing leukemic (stem cell) subpopulations, irrespective of whether they exhibit or not increased drug efflux via ABC transporters. © 2012 Landes Bioscience.
Ades L.,Service dhematologie clinique |
Santini V.,University of Florence
Bailliere's Best Practice and Research in Clinical Haematology | Year: 2013
Until recently, the treatment of higher risk myelodysplastic syndrome was based on  Intensive chemotherapy using anthracycline-AraC combinations, leading to a lower complete remission rates and a shorter CR duration compared with de novo AML , low dose chemotherapy with limited CR rate mainly restricted to patients with normal karyotype. Azacitidine was the first drug to significantly improve survival in higher risk MDS, although it is not curative. Thus, the survival improvement obtained with azacitidine must be the starting point for combination studies, and for utilization of this drug in other situations (before allo SCT, or after chemotherapy or allo SCT as maintenance treatment). © 2013 Elsevier Ltd. All rights reserved.
Nguyen S.,French Institute of Health and Medical Research |
Nguyen S.,University Pierre and Marie Curie |
Beziat V.,French Institute of Health and Medical Research |
Beziat V.,University Pierre and Marie Curie |
And 3 more authors.
Journal of Innate Immunity | Year: 2011
Natural killer (NK) cells play a crucial role in the innate immune system and are responsible for the initial responses in the surveillance against malignant cells and virally infected cells. NK cells express their own repertoire of receptors, including activating and inhibitory receptors, which bind to major histocompatibility complex class I or class-I-related molecules. Binding of NK cell inhibitory receptors to their major histocompatibility complex class I ligands protects the target cells from NK cell-mediated cytotoxicity. NK cell alloreactivity has been put to use in allogeneic hematopoietic stem cell transplantation to reduce the rate of relapse and of graft-versus-host disease. A variety of findings have been observed in clinical studies, showing either beneficial or deleterious effects on clinical outcome. This article reviews the results of major clinical trials in relation to the model used to define NK cell alloreactivity. Copyright © 2011 S. Karger AG, Basel.
Ghrenassia E.,DHU i2B |
Martis N.,Service Route |
Boyer J.,Service Route |
Burel-Vandenbos F.,University of Nice Sophia Antipolis |
And 2 more authors.
Journal of Autoimmunity | Year: 2015
The Diffuse Infiltrative Lymphocytosis Syndrome (DILS) is a rare multisystemic syndrome described in HIV-infected patients. It is characterised by CD8+ T-cell lymphocytosis associated with a CD8+ T-cell infiltration of multiple organs. DILS is usually seen in uncontrolled or untreated HIV infection but can also manifest itself independently of CD4+ T-cell counts. The syndrome may present as a Sjögren-like disease that generally associates sicca signs with bilateral parotiditis, lymphadenopathy, and extraglandular organ involvement. The latter may affect the lungs, nervous system, liver, kidneys, and digestive tract. Anomalies of the respiratory system are often identified as lymphocytic interstitial pneumonia. Facial nerve palsy, aseptic meningitis or polyneuropathy are among the more frequent neurological features. Hepatic lymphocytic infiltration, lymphocytic interstitial nephropathy and digestive tract lymphocytic infiltration account for more rarely noted complications. Sicca syndrome, organomegaly and/or organ dysfunction associated with polyclonal CD8+ T-cell organ-infiltration are greatly suggestive of DILS in people living with HIV. Labial salivary gland biopsy is therefore helpful when the focus score is equal or greater than 1 (or Chisholm Score≥3). Primary Sjögren syndrome, chronic HCV or HTLV1 infection, graft versus host disease, IgG4-related disease, and immune reconstitution inflammatory syndrome are among the differential diagnoses that need to be considered. Treatment consists in highly active anti-retroviral therapy (HAART), which is usually effective in resolving clinical signs and symptoms. Steroids, however, may also be occasionally required when organ infiltration does not respond to HAART. This review should provide an insight into this rare entity complicating the course of HIV infection. © 2015 Elsevier Ltd.
Legros L.,Service dhematologie clinique
Annals of hematology | Year: 2012
Myelodysplastic syndromes (MDS) are associated with increased bone marrow vascularity and increased levels of various angiogenic factors including Vascular Endothelial Growth Factor (VEGF) which is implicated in the proliferation and survival of leukemic cells. Before the approval of hypomethylating agents in this indication, the GFM conducted a multicenter phase II trial testing the efficacy and tolerance of bevacizumab, a humanized monoclonal antibody against VEGF, in MDS with excess of marrow blasts and its impact on bone marrow angiogenesis. Twenty-one patients were enrolled (16 males and five females) with a median age of 70 years and 19 were evaluable for haematological response after treatment (5 mg/kg IV every 2 weeks for 12 weeks). WHO diagnosis at baseline was RAEB-1 (38%) and RAEB-2 (62%). Treatment was well tolerated and was associated with significant decrease of VEGF plasma level [median (low quartile-high quartile)] from 65.5 pg/ml [LQ (low-quartile)-HQ (high quartile), 35.3-87.3 to 30.4 pg/ml (LQ-HQ, 22.5-34.0 pg/ml)] (p < 0.01) and reduction of bone marrow angiogenesis from a median of 20 vessels/mm(3) (LQ-HQ, 16.5-33 vessels/mm(3)) to 15.5 vessels/mm(3) (LQ-HQ, 10-23.2 vessels/mm(3)) (p = 0.03). On the other hand, only one patient had a significant haematological response with achievement of RBC transfusion independence. Thus, although bevacizumab had a significant impact on VEGF levels and angiogenesis in our patients, very few responses were seen when this drug was used as single agent. Given its good tolerability profile, however, combination of bevacizumab with other drugs, especially hypomethylating agents, could be considered in MDS.