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ABSTRACT: The use of tyrosine kinase inhibitors (TKIs) targeted against the BCR-ABL1 oncoprotein has proven remarkably successful in chronic myeloid leukemia (CML) and long-term survival has become a reality. Despite this outstanding progress, detection of minimal residual disease precludes therapy termination in most TKI-receiving patients. CML has thus turned into a chronic illness, raising concerns about long-term safety, medication adherence, and health care costs. Although treatment cessation may be feasible in few selected patients achieving deep molecular responses, a definitive cure remains elusive owing to the discovery that TKIs spare quiescent leukemic stem cells (LSC). Understanding mechanisms underlying LSC behavior in TKI-treated patients may provide important clues to develop an array of strategies that ensure the complete destruction of LSC reservoirs and thereby offer CML patients a definitive cure.
Current Hematologic Malignancy Reports 03/2012; 7(2):103-8.
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ABSTRACT: There is now substantial evidence that imatinib may affect immune responses, especially those mediated by T lymphocytes. Fas (CD95/Apo-1), a cell death receptor, is a key regulator of the immune system. We have explored the consequences of treatment on the Fas system in chronic myeloid leukemia patients treated with imatinib. In comparison with healthy controls, we found not only a mild blood lymphopenia but also impairment of phytohemagglutinin activation in CD4Fas and CD8Fas lymphocytes of imatinib-treated patients. Moreover, these lymphocyte populations were more sensitive to FasL-induced cell death in relation to an increase in Fas expression at the cell surface. Taken together, these results reveal the role of Fas receptor in the lymphopenia observed in patients treated with imatinib, with potential deleterious consequences on antileukemic responses against this immunogenic hematological malignancy.
Journal of immunotherapy (Hagerstown, Md.: 1997) 02/2012; 35(2):154-8. · 3.20 Impact Factor
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British Journal of Haematology 01/2012; 157(3):407-10. · 4.94 Impact Factor
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CancerSpectrum Knowledge Environment 08/2011; 103(17):1347-8. · 14.07 Impact Factor
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Fabien Le Bras,
Marie Sebert,
Charikleia Kelaidi,
Thierry Lamy,
François Dreyfus,
Jacques Delaunay,
Anne Banos,
Michel Blanc,
Norbert Vey,
Aline Schmidt,
Sorin Visanica,
Virginie Eclache,
Pascal Turlure,
Odile Beyne-Rauzy,
Agnès Guerci,
Alain Delmer,
Stéphane de Botton, Delphine Rea,
Pierre Fenaux,
Lionel Adès
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ABSTRACT: We treated 95 RBC transfusion dependent lower risk MDS with del 5q with Lenalidomide (10mg/day, 3 weeks/4 weeks). Median age was 70.4, median interval from diagnosis 29 months. IPSS was low in 31% and intermediate-1 in 69% patients. Del 5q was isolated, with 1 additional and >1 additional abnormality in 79%, 14%, and 6% patients, respectively. 62 (65%) patients achieved transfusion independence (TI). The only significant factor predicting TI was baseline platelet count >150 G/L and platelet decrease by at least 50% during the first weeks of treatment (p=0.001). Grade III-IV neutropenia and thrombocytopenia were seen in 74% and 37.9% of the cases, respectively, and 3 deaths were attributed to cytopenias. Eight (8%) patients developed deep venous thrombosis (DVT). Platelet decrease by less than 50% predicted a higher risk of DVT. Only 6 patients (6.3%) patients progressed to AML, but median follow-up time was short (18 months). We confirm the high rate of TI with Lenalidomide in lower risk MDS with del 5q. Very close patient monitoring for cytopenias and DVT is mandatory, especially during the first weeks of treatment.
Leukemia research 06/2011; 35(11):1444-8. · 2.36 Impact Factor
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Claude Preudhomme,
Joëlle Guilhot,
Franck Emmanuel Nicolini,
Agnès Guerci-Bresler,
Françoise Rigal-Huguet,
Frederic Maloisel,
Valérie Coiteux,
Martine Gardembas,
Christian Berthou,
Anne Vekhoff, [......],
Alain Delmer,
Philippe Rousselot,
Laurence Legros,
Marc Berger,
Selim Corm,
Gabriel Etienne,
Catherine Roche-Lestienne,
Virginie Eclache,
François-Xavier Mahon,
François Guilhot
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ABSTRACT: 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.
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 log(10) units or more from the baseline level, as assessed by means of a real-time quantitative polymerase-chain-reaction assay.
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.
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.).
New England Journal of Medicine 12/2010; 363(26):2511-21. · 53.30 Impact Factor
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ABSTRACT: Dasatinib (Sprycel) is a new-targeted therapy used since 2005 in the treatment of chronic myelogenous leukemia and de novo Philadelphia positive acute lymphoblastic leukaemia patients, intolerant or resistant to imatinib. Despite its high efficacy in such patients in terms of hematologic, cytogenetic and molecular responses, the onset of frequent and sometimes serious side effects particularly in advanced phase patients, especially myelosuppressions and pleural effusions, may impair optimal administration of the drug. Recently, dasatinib dose optimisation in chronic-phase has reduced the incidence of such adverse events without modification of the efficacy, however, their optimal overall management can efficiently reduce their severity and minimize their impact on disease response. Hereby, we attempted to propose a series of guidelines that might be of help in daily practice, in order to control properly these side effects.
Bulletin du cancer 11/2008; 95(9):805-11. · 0.67 Impact Factor
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The Lancet 09/2008; 372(9640):713-4. · 38.28 Impact Factor
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Jean-Pierre Marolleau,
Valérie Vanneaux, Delphine Rea,
Brigitte Ternaux,
Veronique Delasse,
Valérie Hubert,
Elisabeth Chantre,
Richard Traineau,
Marie Robin,
Marc Benbunan,
Gerard Socié,
Jérôme Larghero
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ABSTRACT: In allogeneic bone marrow transplantation (BMT), a higher nucleated and CD34+ cell dose has been reported to improve various outcomes. Other cell types, such as lymphocyte subsets, also influenced BMT results. While nucleated red blood cells (NRBCs) represent a subset of bone marrow (BM) cell subpopulation, the question of their quantification in BM grafts and the impact of BM processing on their recovery has not been addressed.
In a prospective study on 77 BM products, NRBCs were enumerated by flow cytometry and the recovery analyzed after manipulation. Because NRBCs could compromise white blood cell count, the impact of NRBC count on CD34+ cell percentage and total nucleated cell (TNC) dose were also determined.
The mean percentage of NRBCs in BM grafts was 21.6 percent (range, 7.8%-40.9%). Mean NRBC recoveries after BM concentration or RBC depletion were 98.4 and 28.7 percent, respectively, close to those obtained for TNC cells (88.6 and 31.3%, respectively). When corrected with NRBC count, the mean percentages of corrected CD34+ cell and TNC dose were significantly modified when compared with uncorrected values, whatever the type of BM manipulation.
Our data show that NRBC quantification might be of importance to improve quality control of BM products and to evaluate the influence of NRBCs cell dose on outcomes after BMT.
Transfusion 03/2007; 47(2):266-71. · 3.22 Impact Factor
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Philippe Rousselot,
Francoise Huguet, Delphine Rea,
Laurence Legros,
Jean Michel Cayuela,
Odile Maarek,
Odile Blanchet,
Gerald Marit,
Eliane Gluckman,
Josy Reiffers,
Martine Gardembas,
François-Xavier Mahon
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ABSTRACT: In the present study, we address the issue of the discontinuation of imatinib mesylate (Gleevec) in chronic myelogenous leukemia with undetectable residual disease for more than 2 years. Twelve patients were included. The median duration of real-time quantitative-polymerase chain reaction (RTQ-PCR) negativity and imatinib therapy were, respectively, 32 months (range, 24-46 months) and 45 months (range, 32-56 months) before imatinib interruption. Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response in most patients. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). We hypothesize that relapses observed within 6 months reflect the kinetics of undetectable dividing chronic myelogenous leukemia (CML) cells. Those cells may be eradicated or controlled in long-term nonrelapsing patients, as described in our study.
Blood 02/2007; 109(1):58-60. · 9.90 Impact Factor
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Nicolas Boissel, Delphine Rea,
Vannary Tieng,
Nicolas Dulphy,
Manuel Brun,
Jean-Michel Cayuela,
Philippe Rousselot,
Ryad Tamouza,
Philippe Le Bouteiller,
François-Xavier Mahon,
Alexander Steinle,
Dominique Charron,
Hervé Dombret,
Antoine Toubert
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ABSTRACT: MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. In chronic myeloid leukemia, a malignancy caused by the BCR/ABL fusion oncoprotein, we showed cell surface expression of MICA on leukemic, but not healthy, donor hemopoietic CD34+ cells. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8+ T cells, which were restored by imatinib mesylate (IM) therapy. In the BCR/ABL+ cell line K562, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels, but decreased MICA protein production and release. Sucrose density gradient fractionation of K562 cytoplasmic extracts treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, consistent with decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mammalian target of rapamycin were shown to control MICA expression. These data provide evidence for direct control of MICA expression by an oncogene in human malignancy and indicate that posttranscriptional mechanisms may participate in the regulation of MICA expression.
The Journal of Immunology 05/2006; 176(8):5108-16. · 5.79 Impact Factor
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ABSTRACT: In chronic myeloid leukemia, bcr-abl+ monocytes provide a unique opportunity to generate dendritic cells (DC) expressing a broad spectrum of leukemic antigens, and bcr-abl+ DC vaccines may allow immunological eradication of leukemic cells persisting under treatment with the tyrosine kinase inhibitor imatinib. However, the efficiency of bcr-abl+ DC vaccines will critically depend on the absence of deleterious effects of bcr-abl and of imatinib on DC functions. We show that bcr-abl+ monocytes, devoid of contamination of CD14low granulocytic precursors, differentiate into DC with typical immunophenotypical and functional features, and bcr-abl transcription decreases simultaneously. During differentiation, imatinib induces a slight increase of DC apoptosis and prevents CD1a up-regulation in a dose-dependent manner in bcr-abl+ and normal monocyte-derived DC, but at most, 25% of DC fail to acquire CD1a. When DC maturation is induced in the presence of imatinib, bcr-abl+ and normal monocyte-derived DC up-regulate major histocompatibility complex and costimulatory molecules, CC chemokine receptor 7 and CD83. However, secretion of interleukin-12p70 is decreased in a dose-dependent manner. Imatinib exposure of bcr-abl+ and normal monocyte-derived DC during differentiation and maturation is not detrimental to T cell immunostimulatory functions of DC. In sharp contrast, imatinib, when added to DC-T cell cultures, profoundly suppresses DC-mediated T cell proliferation, despite reciprocal DC-T cell activation attested by up-regulation of CD25 on T cells and of CD86 on DC. Our findings demonstrate that T cells, not normal or bcr-abl+ monocyte-derived DC, are major targets for imatinib immunomodulatory effects. It can be envisioned already that imatinib-free windows will be required to enable vaccination-induced, leukemia-specific T cell expansion.
Journal of Leukocyte Biology 05/2006; 79(4):747-56. · 4.99 Impact Factor
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Jerome Larghero, Delphine Rea,
Helene Esperou,
Nicole Biscay,
Marie-Noelle Maurer,
Marie-Noelle Lacassagne,
Brigitte Ternaux,
Richard Traineau,
Karima Yakouben,
Christine Dosquet,
Gerard Socié,
Eliane Gluckman,
Marc Benbunan,
Jean-Pierre Marolleau
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ABSTRACT: Red cell (RBC) depletion is needed to bypass ABO mismatch in allogeneic bone marrow transplantation (BMT). Technical and clinical data obtained after bone marrow (BM) processing with a continuous-flow cell separator (Cobe Spectra, Gambro BCT) are reported.
RBC depletion and recovery of nucleated cells, CD3+ cells, CD34+ cells, and colony-forming unit-granulocyte-macrophage were calculated. Bacteriologic contaminations, side effects of graft infusion, and hematopoietic recovery were analyzed.
A total of 114 BM samples were processed. The mean volume collected was 1099 mL (range, 390-2450 mL). Initial and residual mean RBCs volumes were 309.9 and 4.0 mL corresponding to a depletion of 98.6 +/- 0.78 percent. Before processing, the mean numbers of nucleated cells, granulocytes, CD3+ cells, CD34+ cells, and CFU-GM were 20.28 x 10(9), 12.79 x 10(9), 1.96 x 10(9), 356.7 x 10(6), and 195.6 x 10(5), respectively. The mean corresponding recoveries after processing were 33.66, 48.98, 82.02, 82.2, and 93.9 percent. Limited side effects were observed in 14 patients without correlation with residual RBCs volume. All but two patients engrafted.
BM processing with the Cobe Spectra cell separator provides high rates of RBC depletion without significant side effects after BMT.
Transfusion 04/2006; 46(3):398-402. · 3.22 Impact Factor
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Jerome Larghero, Delphine Rea,
Yves Brossard,
Jacqueline Van Nifterik,
Veronique Delasse,
Isabelle Robert,
Nicole Biscay,
Elisabeth Chantre,
Emmanuel Raffoux,
Gerard Socié,
Eliane Gluckman,
Marc Benbunan,
Jean-Pierre Marolleau
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ABSTRACT: Cord blood (CB) represents an alternate source of stem cells in transplantation. Nucleated red blood cells (NRBCs) are a physiological subset of CB population. Although it is important to have an accurate estimate of CD34(+) cell number, NRBCs could compromise white blood cell count and interfere with CD34(+) cell quantification.
A total of 826 CB units were analyzed for total nucleated cells (TNCs), NRBCs, and CD34(+) cells by flow cytometry. NRBCs were also counted conventionally by manual microscopy. Percentages of CD34(+) cells corrected by NRBC count (CD34+c) were determined as follows: %CD34+c = CD34(+)/CD45(+) (x10(6))/(TNCs (x10(8)) - NRBCs (x10(8))).
The mean percentages of CD34+ cells and NRBCs were 0.27 percent (range, 0.01%-1.25%) and 7.64 percent (range, 0.13%-84%), respectively. Comparison between flow cytometric and microscopic NRBC count showed a regression of y = 0.685 + 0.719x and a coefficient of determination of r(2) = 0.721. When corrected with NRBC count, the mean percentage of CD34(+) c cells was 0.295 percent (p = 0.0008 compared with CD34(+)%) and mean TNCc count was 14.8 x 10(8) (p < 10(-4) compared to TNC count).
The determination of NRBCs with a flow cytometric method might represent a new strategy for providing satisfactory quality assurance controls of CB products.
Transfusion 04/2006; 46(3):403-6. · 3.22 Impact Factor
