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Bouabdallah K.,Service des Maladies du Sang | Ribrag V.,Institute Of Cancerologie Gustave Roussy | Terriou L.,Service dHematologie | Soria J.-C.,Institute Of Cancerologie Gustave Roussy | Delarue R.,Service dHematologie
Current Opinion in Oncology | Year: 2013

Purpose of Review: Temsirolimus (Torisel) is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). The recommended dosage in this indication (175mg once weekly for 3 weeks and then 75 S mg once weekly as maintenance) is higher than that for renal cell carcinoma; thus, the safety profile is quite different in the two indications. The aim of this review is to examine safety data for temsirolimus in MCL and provide guidance on the incidence and management of adverse events. Medline and EMBASE searches using the search terms 'temsirolimus' and 'mantle cell lymphoma' Findings: Four main published phase II-III clinical studies of temsirolimus in MCL were identified. Many adverse events are class-effect toxicities of mTOR inhibitors but, for others, often an accurate relationship with temsirolimus is difficult to assess with certainty. Haematological adverse events are the most frequently reported, but these are generally successfully managed by dose reductions or treatment delay. Gastrointestinal toxicity, especially diarrhoea, is a frequent and common adverse effect, but the incidence of grade 3-4 events is low. Other nonhaematological toxicities include stomatological/dermatological and endocrinological adverse events. Incidence of these adverse events can be reduced by careful management and/or prevention. Grade 3 or higher pneumonitis, a known mTOR inhibitorassociated toxicity, was rarely reported in this indication, but the incidence was higher when temsirolimus was administered in combination with rituximab. Other adverse events include fatigue/asthenia, infection, hypersensitivity and extravasation. Sexual disorders, foetal malformations and psychiatric disorders are rarely reported. SUMMARY: Most temsirolimus-associated adverse events in patients with relapsed/refractory MCL are manageable, often without impacting administration of temsirolimus. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Delarue R.,Service dHematologie | Haioun C.,Service dHematologie | Ribrag V.,Institute Gustave Roussy | Brice P.,Service dHematologie | And 8 more authors.
Blood | Year: 2013

Treatment of mantle cell lymphoma (MCL) in younger patients remains a challenge. We report results of a phase 2 trial using cytarabine and rituximab as induction regimen before autologous stem cell transplantation. Patients younger than 66 years with stage 3 or 4 MCL were included. Treatment consisted of 3 courses of CHOP21 with rituximab at the third one and 3 of R-DHAP. Responding patients were eligible for autologous stem cell transplantation with TAM6 or BEAM. Sixty patients were included. Median age was 57 years. Characteristics of patients were: BM involvement 85%, leukemic disease 48%, gastrointestinal involvement 52%, Performance Status > 16%, lactate dehydrogenase > 1N 38%, Mantle Cell Lymphoma International Prognostic Index (low 55%, intermediate 38%, high 13%). The overall response rate was 93% after (R)-CHOP and 95% after R-DHAP. Although uncommon after (R)-CHOP (12%), 57% of patients were in complete response after R-DHAP. With median follow-up of 67 months, median event-free survival is 83 months, and median overall survival is not reached. Five-year overall survival is 75%. Comparison with a previous study without rituximab shows improvement of outcome (median event-free survival, 51 vs 83 months). No toxic death or unexpected toxicities were observed. This study confirms that induction with rituximab and cytarabine-based regimens is safe and effective in MCL patients. This regimen is currently compared with R-CHOP21 induction in a multicentric European protocol. © 2013 by The American Society of Hematology.

Desrames A.,French National Center for Scientific Research | Cassar O.,French National Center for Scientific Research | Gout O.,Rothschild | Hermine O.,Service dHematologie | And 3 more authors.
Journal of virology | Year: 2014

UNLABELLED: Although recombination is a major source of genetic variability in retroviruses, no recombinant strain had been observed for human T-lymphotropic virus type 1 (HTLV-1), the first isolated human-pathogenic retrovirus. Different genotypes exist for HTLV-1: Genotypes b and d to g are restricted to central Africa, while genotype c is only endemic in Australo-Melanesia. In contrast, the cosmopolitan genotype a is widely distributed. We applied a combination of phylogenetics and recombination analysis approaches to a set of new HTLV-1 sequences, which we collected from 19 countries throughout Africa, the continent where the virus has the largest endemic presence. This led us to demonstrate the presence of recombinants in HTLV-1. Indeed, the HTLV-1 strains currently present in North Africa have originated from a recombinant event between strains from Senegal and West Africa. This recombination is estimated to have occurred around 4,000 years ago. This recombination seems to have been generated during reverse transcription. In conclusion, we demonstrate that, albeit rare, recombination can occur in HTLV-1 and may play a role in the evolution of this retrovirus.IMPORTANCE: A number of HTLV-1 subtypes have been described in different populations, but none of the genetic differences between these subtypes have been ascribed to recombination events. Here we report an HTLV-1 recombinant virus among infected individuals in North Africa. This demonstrates that, contrary to what was thought, recombination can occur and could play a role in the evolution of HTLV-1. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Mohty B.,University of Geneva | El-Cheikh J.,Institute Paoli Calmettes | Yakoub-Agha I.,Service dHematologie | Avet-Loiseau H.,Nantes University Hospital Center | And 8 more authors.
Leukemia | Year: 2012

Treatment of multiple myeloma has evolved over the last decade, most notably with the introduction of highly effective novel agents. It is now possible to aim for deep disease responses in a greater number of patients in an attempt to prolong remission duration and survival. Initially introduced in the relapsed setting, the novel agents, namely thalidomide, bortezomib and lenalidomide, are now being increasingly incorporated into upfront treatment strategies, raising questions about the feasibility of retreatment with such agents. Also, in a disease that is characterized by multiple relapses, the sequencing of the different effective options is an important question. In the frontline setting, the first remission is likely to be the period during which patients will enjoy the best quality of life. Thus, the goal should be to achieve a first remission that is the longest possible by using the most effective treatment upfront. At relapse, the challenge is to select the optimal treatment for each patient while balancing efficacy and toxicity. The decision will depend on both disease-and patient-related factors. This review aimed to assess the available research data addressing retreatment approaches, drug sequencing and the long-term impact of upfront therapy with novel drugs. © 2012 Macmillan Publishers Limited All rights reserved.

Mahon F.-X.,University of Bordeaux 1 | Mahon F.-X.,University of Bordeaux Segalen | Mahon F.-X.,French Institute of Health and Medical Research | Rea D.,Service des Maladies du Sang | And 11 more authors.
The Lancet Oncology | Year: 2010

Background: Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. Methods: In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR-ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with, number NCT00478985. Findings: 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1-30), and 69 patients had at least 12 months follow-up (median 24 months, range 13-30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Interpretation: Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors. Funding: French Ministry of Health (Programme Hospitalier de Recherche 2006 grants), Institut National du Cancer (INCA). © 2010 Elsevier Ltd.

Moreau P.,University of Nantes | Attal M.,Service dHematologie | Facon T.,University Hospital Hurriez
Blood | Year: 2015

In the past decade, one of the major advances in the management of patients with symptomatic newly diagnosed multiple myeloma has been the introduction of novel agents, thalidomide, bortezomib, and lenalidomide, as part of frontline treatment in both transplant and nontransplant candidates. These drugs have markedly improved the rate of complete remission, and time to progression, progression-free survival, and overall survival have significantly increased. This article focuses on more recent frontline therapeutic approaches both in older patients, not eligible for high-dose therapy and autologous stem cell transplantation (ASCT), and in younger patients eligible for early ASCT. © 2015 by The American Society of Hematology.

Friedrichs B.,Asklepios Hospital St Georg | Tichelli A.,University of Basel | Bacigalupo A.,Hematologia Oncologia | Russell N.H.,University of Nottingham | And 6 more authors.
The Lancet Oncology | Year: 2010

Background: Most allogeneic haematopoietic stem cell transplants now use peripheral blood progenitor cell transplantation (PBPCT) instead of bone-marrow transplantation (BMT). Long-term data on outcome and late effects of PBPCT compared with BMT are scarce. Here we present long-term data from a randomised study comparing PBPCT with BMT. Methods: Between February, 1995, and September, 1999, 329 patients with leukaemia received either PBPCT (n=163) or BMT (n=166) from HLA-identical sibling donors after central randomisation accounting for stratification criteria. Follow-up data were collected via questionnaires from 87% (176 of 202; 84 PBPCT, 92 BMT) patients who survived for more than 3 years (median of 9·3 years) after transplantation. Efficacy analyses included all patients who received treatment. This study is registered with, number NCT01020175. Findings: 10-year overall survival was 49·1% for patients who underwent PBPCT and 56·5% for patients who underwent BMT (HR 0·83, 95% CI 0·60-1·15; p=0·27). Leukaemia-free survival was 28·3% with BMT versus 13·0% with PBPCT (0·61, CI 0·32-1·16; p=0·12) for acute lymphoblastic leukaemia; 62·3% with BMT versus 47·1% with PBPCT for acute myeloid leukaemia (0·67, 0·39-1·16; p=0·16); and 40·2% with BMT versus 48·5% with PBPCT for chronic myeloid leukaemia (1·12, 0·73-1·74; p=0·60). More patients developed chronic graft-versus-host disease after PBPCT (n=56, 73%) than after BMT (n=46, 56%; p=0·021), with more frequent involvement of skin, liver, and oral mucosa, and more patients who underwent PBPCT needed immunosuppressive treatment 5 years after transplantation (n=20, 26%) than patients who had BMT (n=10, 12%; p=0·024). Nonetheless, there was no difference in performance status, return to work, incidence of bronchiolitis obliterans, and haematopoietic function between the two groups. 14 cases of secondary malignancies occurred (five after BMT, nine after PBPCT), resulting in a cumulative incidence of 3% and 7% after BMT and PBPCT (p=0·17), respectively. Interpretation: More than 9 years after transplantation, overall and leukaemia-free survival remain similar in patients who underwent BMT and PBPCT. Differences in the incidence of chronic graft-versus-host disease and the duration of immunosuppression exist, but do not affect survival, general health status, or late events. Funding: No external funding was received. © 2010 Elsevier Ltd.

Park S.,Service dhematologie
Expert Review of Hematology | Year: 2013

Evaluation of: Sekeres MA, Tiu RV, Komrokji R et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 120(25), 4945-4951 (2012). High-risk myelodysplastic syndrome (MDS) patients have poor prognosis, and their median age is approximately 70 years. Allogeneic stem cell transplantation and high-dose chemotherapy are restricted to a relatively small minority of MDS. A hypomethylating agent, 5-azacytidine, has revolutionized the treatment of high-risk MDS patients by prolonging their survival by approximately 2 years. However this remains insufficient, and patients relapsing or refractory to 5-azacytidine have still a very poor prognosis. It is, therefore, necessary to improve the complete response rate obtained with 5-azacytidine alone and the combination with other molecules are mandatory. In this article, we resume the results and perspectives of a Phase II trial evaluating lenalidomide and 5-azacytidine combination in patients with higher-risk MDS. © 2013 Expert Reviews Ltd.

Kaiser-Guignard J.,Service dhematologie | Canellini G.,Service Route | Lion N.,Service Route | Abonnenc M.,Service Route | And 2 more authors.
Blood Reviews | Year: 2014

Since 1990, several techniques have been developed to photochemically inactivate pathogens in platelet concentrates, potentially leading to safer transfusion therapy. The three most common methods are amotosalen/UVA (INTERCEPT Blood System), riboflavin/UVA-UVB (MIRASOL PRT), and UVC (Theraflex-UV). We review the biology of pathogen inactivation methods, present their efficacy in reducing pathogens, discuss their impact on the functional aspects of treated platelets, and review clinical studies showing the clinical efficiency of the pathogen inactivation methods and their possible toxicity. © 2014.

The training in the psychic care in cancer involves a work of reflection on the relation committed with the patient and/or his close relations. The emotional investment inherent to these relations (of support, accompaniment, and follow-up) asks to be thought so that it can be "therapeutic". Declined under various names (groups of words, clinical elaboration, analysis of practices, case study), the Balint groups' model seems to offer a convenient frame to this work of elaboration which constitutes the central element of learning to listen. © 2014 Springer-Verlag.

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