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Hôpital-Camfrout, France

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. Source

Bories C.,Service des Maladies du Sang | Jagannath S.,Mt Sinai Medical Center
Clinical Lymphoma, Myeloma and Leukemia | Year: 2014

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent the earlier phases of plasma cell dyscrasias. Their definition is based on absence of end-organ damage with presence of a malignant clone that grows in the bone marrow. They share, as a common feature, the risk of progression to a symptomatic disease. MGUS progression risk is approximately 1% per year, and SMM has a risk of progression of 10% for the first 5 years which tapers off over time. The main purpose of identification of these earlier phases of the plasma cell dyscrasia was to identify patients who do not warrant treatment with chemotherapy, in whom the risk of treatment outweighs the benefit. Over the years, the definitions have not been modified to incorporate developments in imaging (magnetic resonance or positron emission and computed tomography), or genomics to identify patients at highest risk of progression within 2 years, where wait and watch might not be an appropriate option. In the absence of such definition, patients who have only a 50% chance of progression within 2 years are being offered therapy, which might also not be an optimal approach. In this review, we provide an overview of the definition, current prognostic factors, and risk stratifications in asymptomatic gammopathies, and discuss clinical trial outcomes in high-risk SMM. © 2014 Elsevier Inc. Source

Cortes J.,University of Houston | Lipton J.H.,Princess Margaret Hospital | Rea D.,Service des Maladies du Sang | Digumarti R.,Nizams Institute of Medical Sciences | And 7 more authors.
Blood | Year: 2012

Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n - 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219. © 2012 by The American Society of Hematology. Source

Itzykson R.,University of Paris 13 | Kosmider O.,Service dhematologie biologique | Cluzeau T.,Nice University Hospital Center | Mansat-De Mas V.,Toulouse University Hospital Center | And 10 more authors.
Leukemia | Year: 2011

The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P0.03, P0.047 and P0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P0.007). Mutated TET2 (P0.04) and favorable cytogenetic risk (intermediate risk: P0.04, poor risk: P0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype. © 2011 Macmillan Publishers Limited All rights reserved. Source

Sulahian A.,University Paris Diderot | Porcher R.,University Paris Diderot | Bergeron A.,University Paris Diderot | Touratier S.,Pharmacie | And 4 more authors.
Journal of Clinical Microbiology | Year: 2014

This study was undertaken to examine the performance of the Fungitell-glucan (BG) assay, to compare it with that of the galactomannan (GM) test for the diagnosis of invasive aspergillosis (IA) in patients with hematological malignancies, and to examine the rates of false-positive BG and GM test results due to β-lactam antibiotics among sera of patients with Gram-positive or Gram-negative bacteremia and selected sera with false-positive results from the GM test. Serum samples from 105 patients with proven (n=14) or probable (n=91) IA, 97 hematology patients at risk for invasive fungal infections, 50 healthy blood donors, and 60 patients with bacteremia were used to study the sensitivities and specificities of the assays. The GM test was more specific than the BG assay (97% versus 82%, respectively; P<0.0001) and the BG assay was more sensitive than the GM test (81% versus 49%, respectively; P<0.0001) for IA diagnosis. The study of 49 separate batches of β-lactam antibiotics showed high and very similar rates of false-positive results for the GM and BG assays (29 and 33%, respectively; P=0.82) but with an almost complete lack of concordance between the 2 assays. For patients with bacteremia, the rate of false-positive results was much higher with the BG test than with the GM test (37% versus 2%, respectively; P<0.0001), with no significant difference between Gram-positive and Gram-negative bacteremia. In conclusion, the BG test may be useful for the diagnosis of IA because of its high sensitivity in comparison with the GM test, but the overall benefit of this assay remains limited because of its inadequate specificity and its cost. Copyright © 2014, American Society for Microbiology. All Rights Reserved. Source

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