Publications by authors named "Emmanuelle Tavernier"

32 Publications

Utility of 18F-FDG PET/CT in medical care of a promyelocytic sarcoma.

Curr Res Transl Med 2021 Jan 18;69(2):103272. Epub 2021 Jan 18.

Department of Nuclear Medicine, University Hospital, Saint-Etienne, France. Electronic address:

Promyelocytic sarcoma is an uncommon solid tumor made up of myeloblasts. It is characterized, like acute promyelocytic leukemia (APL), by a chromosomal translocation t(15;17) involving the retinoic acid receptor alpha (RARalpha) and the promyelocytic gene (PML). The diagnosis and monitoring of promyelocytic sarcoma is a challenge due to the rarity and severity of the disease. We describe a case with several initial sites and without APL. The patient was monitored with regular 18F-FDG PET/CT from diagnosis to complete response. The evolution of PET/CT imageries was compared to the quantification of PML-RARα fusion gene by RQ-PCR. In promyelocytic sarcoma medical care, 18F-FDG PET/CT appears to be an attractive tool for finding targets for biopsy, for the primary staging, for assessing therapeutic response and for detecting early relapse.
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http://dx.doi.org/10.1016/j.retram.2020.103272DOI Listing
January 2021

Effectiveness of a nurse-led telephone follow-up in the therapeutic management of patients receiving oral antineoplastic agents: a randomized, multicenter controlled trial (ETICCO study).

Support Care Cancer 2021 Jan 7. Epub 2021 Jan 7.

Medical Oncology Department, Lucien Neuwirth Cancer Institute, 108 bis Avenue Albert Raimond, 42270, Saint Priest en Jarez, France.

Purpose: The use of oral cancer drugs (OAD) has increased over the last two decades. The objective of this study was to measure the impact of a nurse-led telephone follow-up in the therapeutic management of patients treated with an OAD regarding toxicity, medication adherence and quality of life.

Methods: A randomized, multicenter, controlled trial was conducted. All consecutive over 18-year-old patients, treated in medical oncology, radiotherapy, or hematology departments, receiving OAD for any cancer were invited to participate to the study. A total of 183 patients treated for solid or hematological cancers with an OAD were randomly assigned to receive a nurse-led telephone follow-up or standard care for 24 weeks. Data were collected between 2015 and 2018.

Results: Nurse telephone follow-up did not improve the global score toxicity in the intervention group. However, telephone calls directed by trained nurses induced a significant decrease in number of patients with grade 3 adverse events throughout the follow-up [OR 0.45 (IC à 95%) (0.23, 0.9)](P = 0.03). There was no significant difference in quality of life and medication adherence between groups at any follow-up time point.

Conclusions: In this first French real-life study, the advice provided by qualified nurses via phone calls improved the management of grade 3 toxicities but failed to demonstrate an improvement of all grades of toxicities. More prospective studies are needed to confirm the impact of telephone calls on the toxicities related to OAD.

Trial Registration: Clinical trial registration is NCT02459483. Protection committee SUD-ESTI registration is 2015-A00527-42 on 13 April 2015. National Agency for the Safety of Medicines and Health Products registration is 150619-B on the 27 may 2015.
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http://dx.doi.org/10.1007/s00520-020-05955-3DOI Listing
January 2021

Thromboembolism prophylaxis in adult patients with acute lymphoblastic leukemia treated in the GRAALL-2005 study.

Blood 2020 07;136(3):328-338

Maladies du Sang, Centre Hospitalier Universitaire (CHU) d'Angers, Angers, France.

Patients undergoing treatment of acute lymphoblastic leukemia (ALL) are at risk for thrombosis, caused in part by the use of l-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent venous thromboembolism (VTE) and thus may increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatrics-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia- ALL were included. The incidence rate of VTE was 16%, with 69% of cases occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or who developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE. Administration of fibrinogen concentrates was associated with an increased risk of VTE, whereas transfusion of fresh frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE. Prophylactic measures were not associated with an increased risk of grade 3 to 4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1 of 34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. VTE developed despite extensive AT supplementation, which suggests the need for additional prophylactic measures. Although this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. This trial was registered at www.clinicaltrials.gov as #NCT00327678.
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http://dx.doi.org/10.1182/blood.2020004919DOI Listing
July 2020

Dysregulated pathways and differentially expressed proteins associated with adverse transfusion reactions in different types of platelet components.

J Proteomics 2020 04 20;218:103717. Epub 2020 Feb 20.

French Blood Bank (EFS) Auvergne-Rhône-Alpes, Saint-Etienne, France; GIMAP-EA3064, University of Lyon, Saint-Etienne, France. Electronic address:

Platelet components (PCs) are occasionally associated with adverse transfusion reactions (ATRs). ATRs can occur regardless of the type of PC being transfused, whether it is a single-donor apheresis PC (SDA-PC) or a pooled PC (PPCs). The purpose of this study was to investigate the proteins and dysregulated pathways in both of the main types of PCs. The proteomic profiles of platelet pellets from SDA-PCs and PPCs involved in ATRs were analysed using the label-free LC-MS/MS method. Differentially expressed proteins with fold changes >|1.5| in clinical cases versus controls were characterised using bioinformatic tools (RStudio, GeneCodis3, and Ingenuity Pathways Analysis (IPA). The proteins were confirmed by western blotting. The common primary proteins found to be dysregulated in both types of PCs were the mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20), multimerin-1 (MMRN1), and calumenin (CALU), which are associated with the important enrichment of platelet activation, platelet degranulation, and mitochondrial activity. Furthermore, this analysis revealed the involvement of commonly dysregulated canonical pathways, particularly mitochondrial dysfunction, platelet activation, and acute phase response. This proteomic analysis provided an interesting contribution to our understanding of the meticulous physiopathology of PCs associated with ATR. A larger investigation would assist in delineating the most relevant proteins to target within preventive transfusion safety strategies. BIOLOGICAL SIGNIFICANCE: Within platelet transfusion strategies, the two primary types of PCs predominantly processed in Europe, include (i) single donor apheresis PCs (SDA-PCs) from one donor and (ii) pooled PCs (PPCs). The current study used PCs from five buffy coats derived from five whole blood donations that were identical in ABO, RH1 and KEL1 groups. Both PC types were shown to be associated with the onset of an ATR in the transfused patient. Several common platelet proteins were found to be dysregulated in bags associated with ATR occurrences regardless of the type of PCs transfused and of their process. The dysregulated proteins included mitochondrial carnitine/acylcarnitine carrier protein (SLC25A20), which is involved in a fatty acid oxidation disorder; calumenin (CALU); and multimerin-1 (MMRN1), which is chiefly involved in platelet activation and degranulation. Dysregulated platelet protein pathways for ATRs that occurred with SDA-PCs and PPCs could support the dysregulated functions found in association with those three proteins. Those common platelet proteins may become candidates to define biomarkers associated with the onset of an ATR from PC transfusions, including monitoring during the quality steps of PC manufacturing, provided that the results are confirmed in larger cohorts. This study enriches our knowledge of platelet proteomics in PCs under pathological conditions.
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http://dx.doi.org/10.1016/j.jprot.2020.103717DOI Listing
April 2020

Adult T-cell acute lymphoblastic leukemias with IL7R pathway mutations are slow-responders who do not benefit from allogeneic stem-cell transplantation.

Leukemia 2020 07 28;34(7):1730-1740. Epub 2020 Jan 28.

Université de Paris, Institut Necker-Enfants Malades, Institut National de Recherche Médicale U1151, Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris, France.

The prognostic value of IL7-receptor pathway (IL7Rp) mutations in T-cell acute lymphoblastic leukemia (T-ALL) remains unclear. We performed a comprehensive study of 200 adult patients with T-ALL included in the GRAALL2003/2005 protocols to address the clinical significance of IL7Rp mutations. Next-generation sequencing of the IL7Rp (IL7R/JAK1/JAK3/STAT5B) revealed that IL7Rp mutations were frequent in adult T-ALL (28%) particularly in immature/early T-cell progenitor (ETP)-ALL. They were associated with mutations of NOTCH-pathway, PHF6, and PRC2 components but not with K/NRAS. IL7Rp mutated (IL7Rp) T-ALL were slow-responders, with a high rate of M2/M3 day-8 marrow compared with IL7Rp non-mutated (IL7Rp) T-ALL (p = 0.002) and minimal residual disease positivity at 6-weeks (MRD1) (p = 0.008) but no difference in MRD2 positivity at 12-weeks. Despite this, no adverse prognosis was evidenced when censored for allogeneic hematopoietic stem cell transplantation (HSCT). In time-dependent analysis, HSCT did not benefit IL7Rp patients whereas it was of marked benefit to IL7Rp cases. IL7Rp-mutations identify a subgroup of slow-responder T-ALLs which benefit from post-induction chemotherapy regimens but not from HSCT. Our data suggest that prior knowledge of the mutation status of IL7Rp may influence HSCT decision and help to guide therapy reduction.
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http://dx.doi.org/10.1038/s41375-019-0685-4DOI Listing
July 2020

Human herpesvirus 6 infection after autologous stem cell transplantation: A multicenter prospective study in adult patients.

J Infect 2019 07 7;79(1):36-42. Epub 2019 May 7.

Hematology Department, Institut de Cancérologie Lucien Neuwirth, 108, bis avenue Albert Raymond, 42270 Saint-Priest-en-Jarez, France.

Objectives: to prospectively evaluate the incidence and the clinical relevance on hematopoietic reconstitution of HHV-6 infection in autologous hematopoietic stem cell transplantation (ASCT) recipients.

Methods: HHV-6 DNA load was measured in whole blood specimens once during the 7 days before stem cell re-infusion and once a week after transplantation until hematopoietic recovery. Active HHV-6 infection was defined by 2 consecutive positive DNA loads.

Results: from July 2012 to February 2015, 196 adult patients undergoing ASCT were enrolled. Twenty-two (11.2%) patients developed active HHV-6 infection with a cumulative incidence of 19% at 40 days after transplantation. The onset of active HHV-6 infection occurred with a median of 13 days after stem cell re-infusion. HHV-6 infection was associated with an increased frequency of non-infectious complications (OR = 5.05; 95%CI 1.78-14.32; P < 0.001). Moreover, the severity of these non-infectious complications was higher in recipients exhibiting HHV-6 infection (OR = 4.62; 95%CI 1.32-16.2; p < 0.01). Delayed neutrophils 10 (IQR: 8-14) vs 8 (IQR: 6-11) days and platelets recoveries 15 (IQR: 11.8-18.5) vs 8 (IQR: 4-14) days were observed in patients with active HHV-6 infection compared to non-infected ones.

Conclusions: in this study, 11.2% ASCT recipients presented active HHV-6 infection associated with significantly delayed hematologic reconstitution.
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http://dx.doi.org/10.1016/j.jinf.2019.05.001DOI Listing
July 2019

A complex mutational profile and a distinct clonal evolution during NPM1 myeloid sarcoma.

Leuk Lymphoma 2019 09 1;60(9):2328-2330. Epub 2019 Feb 1.

Laboratory of Hematology - Molecular Biology, University Hospital of Saint-Etienne , Saint-Etienne , France.

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http://dx.doi.org/10.1080/10428194.2019.1571199DOI Listing
September 2019

Differential protein expression of blood platelet components associated with adverse transfusion reactions.

J Proteomics 2019 03 24;194:25-36. Epub 2018 Dec 24.

GIMAP-EA3064, University of Lyon, Saint-Etienne, France; French Blood Bank (EFS) Auvergne-Rhône-Alpes, Saint-Etienne, France. Electronic address:

Platelets found within platelet components (PCs) intended for transfusion release inflammatory molecules. Despite the implementation of leukoreduction, some of these PCs are occasionally associated with adverse transfusion reactions (ATRs). The aim of this study was to decipher the platelet proteome in two types of PCs, buffy-coat-derived pooled PCs (PPCs) and single-donor apheresis PCs (SDA-PCs), associated with ATRs. A label-free LC-MS/MS method was used for the proteomic analysis of washed platelet pellets from 3 PPCs and 3 SDA-PCs associated with ATRs, compared to matched controls. Bioinformatics tools allowed us to characterise the differentially expressed (DE) proteins between cases (ATR-PCs) and controls (no.ATR-PCs). From the PPCs and SDA-PCs, 473 and 146 proteins were DE, respectively. The functional interpretation of these proteins revealed enrichment in platelet activation and degranulation as the most important biological process. The most dysregulated pathways were integrin signaling for PPCs and acute phase response signaling for SDA-PCs. Interestingly, inflammatory disorders were found to be enriched in both PC types. Profound proteome changes were found in the platelets of PCs that led to clinical ATRs in patients. This study presents the first exploration of the platelet proteomic signature associated with ATRs and could provide clues to improving transfusion medicine. BIOLOGICAL SIGNIFICANCE: Adverse transfusion reactions (ATRs) can still occur after transfusion of platelet components (PC). This is the first report on the proteomic analysis of PCs associated with ATR. In this study, the contents of PC bags implicated in ATRs were examined. The aims of this study were to characterise molecules that could be central to the inflammation of ATRs and to highlight dysregulated mechanisms to explain the onset of ATRs. Two types of PCs were used: 3 PPCs (each from 5 donors) and 3 SDA-PCs (each from one donor). We have shown that the two types of PCs, from bags undergoing different processing (i.e., sampling, preparation), involve two types of dysregulated - pathophysiological mechanisms associated with the onset of ATRs. The most dysregulated signaling pathways were cytoskeleton and integrin regulation for PPCs, acute phase response signaling and remodelling of adherens junctions for SDA-PCs. Inflammation, platelet activation and degranulation processes were present in both PC types but were more important for PPCs. This proteomics analysis provides a better understanding of the pathophysiological mechanisms involved in ATRs and may lead to novel steps to ensure safe PC transfusion.
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http://dx.doi.org/10.1016/j.jprot.2018.12.019DOI Listing
March 2019

Fulminant hepatitis due to very severe sinusoidal obstruction syndrome (SOS/VOD) after autologous peripheral stem cell transplantation: a case report.

BMC Res Notes 2018 Jul 3;11(1):436. Epub 2018 Jul 3.

Department of Clinical Hematology, Institut de Cancérologie Lucien Neuwirth, 108 Bis Avenue Albert Raimond, 42270, Saint Priest en Jarez, France.

Background: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (SOS/VOD), is a potentially fatal complication of allogeneic or autologous hematopoietic stem cell transplantation. A plethora of transplant and patient-related risk factors predispose to SOS/VOD and should be taken into account for prognosis assessment as well as for adequate therapeutic intervention.

Case Presentation: We describe the case of a mantle cell lymphoma patient who developed a fulminant hepatitis following oxaliplatin-containing intensive chemotherapy and autologous transplantation. This clinical manifestation was secondary to a very severe SOS/VOD. The patient did not exhibit the usual risk factors and presented a non-classical form with major cytolysis, thus puzzling SOS/VOD diagnosis in this context.

Conclusion: SOS has been previously reported after oxaliplatin-based chemotherapy regimens for colorectal cancers, in particular in patients with colorectal liver metastases. We therefore suspected a potential relationship with oxaliplatin-based regimen as a driver of SOS/VOD in a non-susceptible lymphoma patient. With regards to this case, clinicians and especially intensivists should be aware of this atypical presentation.
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http://dx.doi.org/10.1186/s13104-018-3533-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029059PMC
July 2018

Potential Role of OCT4 in Leukemogenesis.

Stem Cells Dev 2017 11 16;26(22):1637-1647. Epub 2017 Oct 16.

1 Laboratoire d'Hématologie, Centre Hospitalier Universitaire de Saint-Etienne , Saint-Etienne, France .

Embryonic stem cells typically show properties of long-term self-renewal and lack of differentiation. When appropriately stimulated, they are able to differentiate into all cell lineages, and lose their self-renewal characteristics. These properties are controlled by a series of genes encoding several transcription factors, including OCT4, the product of POU5F1 gene. OCT4 is expressed in germ cell tumors but also aberrantly in cancers developing in differentiated tissues. In a previous study, we observed a high expression of OCT4 in acute myeloid cell lines and primary cells, regardless of the acute myeloid leukemia (AML) subtype. In this study, we investigated the putative oncogenic role of OCT4 in proliferation and differentiation arrest. OCT4 expression was assessed in a panel of myeloid cell lines, together with clonogenic and proliferation properties, before and after differentiation in the presence of retinoic acid (RA). Same experiments were performed under short hairpin RNA (shRNA)-mediated OCT4 inhibition. In the presence of RA, we observed a decrease of OCT4 expression, associated with a loss of clonogenic and proliferation capacities, cell cycle arrest, and upregulation of p21, in HL60, NB4, KASUMI, and Me-1 cell lines. This effect was absent in the KG1a cell line, which did not differentiate. Downregulation of OCT4 by shRNA resulted in the same pattern of differentiation and loss of proliferation. Although KG1a did not differentiate, a decrease in proliferation was observed. Our findings suggest that OCT4 is implicated in the differentiation arrest at least in some types of AML, and that it also plays a role in cell proliferation through different oncogenic mechanisms. OCT4 might be a potential new target for antileukemic treatments.
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http://dx.doi.org/10.1089/scd.2017.0134DOI Listing
November 2017

Antithrombotic therapy and platelet transfusions in hematologic malignancy patients presenting chemotherapy-induced thrombocytopenia: a French survey.

Transfusion 2017 07 25;57(7):1717-1723. Epub 2017 Apr 25.

Centre d'Investigation Clinique-CIC 1408.

Background: Patients with hematologic malignancies are at high risk for both thrombosis and bleeding. During the prolonged periods of thrombocytopenia experienced by patients who are receiving intensive chemotherapy, clinicians often hesitate to prescribe any protection against thrombosis. In case of anticoagulant prescription, it is the prescribers' responsibility to weigh risks and benefits for each patient. Current guidelines exist but do not take into account types of thrombosis, patients' comorbidities, or previous bleeding events.

Study Design And Methods: We proposed to gain insight into hematologists' beliefs about antithrombotic prescription in hematologic malignancy patients, to design future clinical trials. Therefore, we conducted a survey in France to evaluate the practices among a panel of hematologists.

Results: We found that more than 92% of the respondents prescribed therapeutic anticoagulation in case of pulmonary embolism or deep venous thrombosis. In the case of therapeutic anticoagulation, only 64% of the physicians reconsidered treatment under a platelet threshold of 50 × 10 /L. None of the respondents decided to renounce treatment, nor to discontinue it because of thrombocytopenia, except in distal venous thrombosis or superficial vein thrombosis. One-fifth of clinicians proposed the insertion of a vena cava filter.

Conclusion: As observed in the United States and Canada, we noticed discrepancies between recommendations and current practices in France. This highlights the urgent need to conduct studies to evaluate both efficacy and safety of antithrombotics in patients with hematologic cancer and thrombocytopenia.
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http://dx.doi.org/10.1111/trf.14120DOI Listing
July 2017

Diagnostic Utility of Flow Cytometry in Myelodysplastic Syndromes.

Front Oncol 2016 27;6:161. Epub 2016 Jun 27.

CNRS UMR5239, Université de Lyon, Saint-Etienne, France; Laboratoire d'Hématologie, CHU de Saint-Etienne, Saint-Etienne, France.

Myelodysplastic syndromes (MDSs) are clonal disorders of hematopoiesis that exhibit heterogeneous clinical presentation and morphological findings, which complicates diagnosis, especially in early stages. Recently, refined definitions and standards in the diagnosis and treatment of MDS were proposed, but numerous questions remain. Multiparameter flow cytometry (MFC) is a helpful tool for the diagnostic workup of patients with suspected MDS, and various scores using MFC data have been developed. However, none of these methods have achieved the sensitivity that is required for a reassuring diagnosis in the absence of morphological abnormalities. One reason may be that each score evaluates one or two lineages without offering a broad view of the dysplastic process. The combination of two scores (e.g., Ogata and Red Score) improved the sensitivity from 50-60 to 88%, but the positive (PPV) and negative predictive values (NPV) must be improved. There are prominent differences between study groups when these scores are tested. Further research is needed to maximize the sensitivity of flow cytometric analysis in MDS. This review focuses on the application of flow cytometry for MDS diagnosis and discusses the advantages and limitations of different approaches.
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http://dx.doi.org/10.3389/fonc.2016.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4921489PMC
July 2016

Epidemiology of invasive fungal infections during induction therapy in adults with acute lymphoblastic leukemia: a GRAALL-2005 study.

Leuk Lymphoma 2017 03 11;58(3):586-593. Epub 2016 Jul 11.

a Department of Hematology and UMR 5525 CNRS-UJF , University Hospital , Grenoble , France.

Little data have been published concerning invasive fungal infections during treatment of acute lymphoblastic leukemia (ALL). Patients included between May 2006 and October 2012 in the multicenter phase III trial for newly diagnosed ALL (GRAALL-2005) were retrospectively reviewed for the occurrence of IFI using the EORTC modified criteria. These patients did not routinely receive antifungal prophylaxis. Among 969 patients included (median age 47 years), 65 (6.7%) developed IFI during induction chemotherapy: 26 (3.3%) invasive aspergillosis (IA), 33 (3.4%) invasive candidiasis (IC) and six other IFI. For IA, the median time between induction therapy and IA diagnosis was 20 days. Diagnosis was probable in 22 cases and proven in four. Aspergillus antigen in serum was tested in all cases and positive in 24. Overall 12-week mortality after diagnosis of IA was 5/26 and attributable mortality related to the infection was 4/26 (15.4%). For IC, the median time between induction therapy and diagnosis was 19 days. Diagnosis was proven in 29 episodes. Candida albicans was the major pathogen in yeast infections (16/27). Overall 12-week mortality after diagnosis of IC was 8/33 (24.2%) and attributable mortality related to the infection was 7/33. The median delay between induction chemotherapy initiation and attributable death related to IC was 15 days. These findings may help to optimize the future management of ALL patients, and as in AML advocate systematic monitoring and the development of prophylactic or preemptive antifungal treatments.
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http://dx.doi.org/10.1080/10428194.2016.1204652DOI Listing
March 2017

Worsening of respiratory status during neutropenia recovery in noncritically ill hematological patients: results of a prospective multicenter study.

Respiration 2015 31;90(3):229-34. Epub 2015 Jul 31.

Department of Hematology, Lucien Neuwirth Oncology Institute, Saint-Priest-en-Jarrez,France.

Background: Neutropenia recovery (NR) has been associated with worsening preexisting lung injury in up to 50% of critically ill cancer patients. However, only limited relevant data exist in the general population of hematological patients.

Objectives: To assess the incidence of acute respiratory deterioration during NR in patients with hematological malignancies.

Methods: Adult patients with neutropenia expected to last more than 7 days were included. Worsening of respiratory status (WRS) was defined as a decrease in oxygen saturation of ≥5%, the need for oxygen therapy for ≥24 h, an increase in oxygen flow of ≥50% in patients previously treated with oxygen, or the need for mechanical ventilation. NR was defined as the 3 days preceding or following a neutrophil count of >0.5 × 109/l.

Results: A total of 16 of 50 patients included in this pilot study experienced WRS during NR (32%), and 13 patients had WRS during neutropenia (26%). The incidence density of WRS was 0.53 (±0.79) episodes per 10 days during NR and 0.20 (±0.39) episodes per 10 days during neutropenia (p = 0.004). Sepsis, stem cell transplantation, preexisting pneumonia, or the use of granulocyte colony-stimulating factor were not associated with WRS during NR.

Conclusion: Up to one third of noncritically ill hematological patients with expected neutropenia of more than 7 days experience WRS during NR. Clinical consequences and risk factors for WRS during NR remain to be evaluated.
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http://dx.doi.org/10.1159/000433556DOI Listing
July 2016

Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.

Blood 2015 Jun 15;125(24):3711-9. Epub 2015 Apr 15.

Division of Hematology, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, University Paris Diderot, Paris, France;

In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678.
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http://dx.doi.org/10.1182/blood-2015-02-627935DOI Listing
June 2015

Core-binding factor acute myeloid leukemia in first relapse: a retrospective study from the French AML Intergroup.

Blood 2014 Aug 8;124(8):1312-9. Epub 2014 Jul 8.

Department of Hematology, EA-3518, Paris 7 University, Hôpital Saint-Louis, Paris, France;

Although core-binding factor-acute myeloid leukemia (CBF-AML) (t[8;21] or inv[16]/t[16;16]) represents a favorable cytogenetic AML subgroup, 30% to 40% of these patients relapse after standard intensive chemotherapy. The encouraging results of gemtuzumab ozogamicin (GO) in newly diagnosed AML, and particularly in CBF-AML, incited us to retrospectively investigate the impact of GO-based salvage in these patients. We retrospectively analyzed the outcome of 145 patients with CBF-AML (59 t[8;21], 86 inv[16]/t[16;16]) in first relapse. As salvage, 48 patients received GO-based chemotherapy and 97 patients received conventional chemotherapy. Median age was 43 years (range, 16-76). Median first complete remission duration was 12.1 months (range, 2.1-93.6). Overall, second complete remission (CR2) rate was 88%. With a median follow-up from relapse of 3.5 years, the estimated 5-year disease-free survival (DFS) was 50% and 5-year overall survival (OS) was 51%. Older age and shorter first complete remission duration was associated with a shorter OS. Patients treated with GO had similar CR2 rate but significantly higher 5-year DFS (68% vs 42%; P = .05) and OS (65% vs 44%; P = .02). In multivariate analysis, GO salvage was still associated with a significant benefit in DFS and OS. In the 78 patients who received allogeneic hematopoietic stem cell transplantation in CR2, GO before transplant significantly improved posttransplant DFS and OS without excess of treatment-related mortality.
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http://dx.doi.org/10.1182/blood-2014-01-549212DOI Listing
August 2014

[CXCR4: a new therapeutic target of the leukaemic cell? Role of the SDF-1/CXCR4 axis in acute myeloid leukaemia].

Bull Cancer 2014 Jun;101(6):593-604

Institut de cancérologie Lucien-Neuwirth, Service d'hématologie, 108 bis, avenue Albert-Raimond, 42270 Saint-Priest-en-Jarez, France, Université Jean-Monnet, UMR 5239, Laboratoire de biologie moléculaire de la cellule, 42000 Saint-Etienne, France.

CXCR4, receptor of the chemokine SDF-1 (stromal cell-derived factor 1) plays a major role in the normal hematopoiesis but also in the biology of the leukaemic cell. This receptor is expressed on the surface of blasts and is a key molecule in "the anchoring" of the leukaemic stem cell (LSC) within the bone marrow niche. The interactions of the LSC with the bone marrow microenvironment promote survival signals and drug resistance. Recent flow cytometry analyses reported that CXCR4 expression levels have a major prognostic impact in acute myeloid leukaemia (AML). CXCR4 expression is associated with poor prognosis and can be useful to stratify patients, according to their phenotype, in order to establish risk-adapted strategies. Newly diagnosed AML are now routinely stratified according to molecular markers which guide prognosis and treatment. Many leukaemia are composed of multiples subclones with differential susceptibility to treatment and specific targeted therapies are missing. Despite therapeutic improvements for the treatment of AML, long term survival remains poor. Targeting CXCR4 is a novel promising approach of therapy. CXCR4 antagonists are used in combination with chemotherapy in preclinical and clinical studies. This review summarises our current knowledge regarding the key role of CXCR4 in AML and discusses how targeting this pathway could provide an interesting approach to eradicate the LSC.
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http://dx.doi.org/10.1684/bdc.2014.1925DOI Listing
June 2014

Heat Shock Protein 90 is overexpressed in high-risk myelodysplastic syndromes and associated with higher expression and activation of Focal Adhesion Kinase.

Oncotarget 2012 Oct;3(10):1158-68

Laboratoire d'Hématologie, University Hospital of Saint-Etienne, University Hospital of Saint-Etienne, 42055 Saint-Etienne Cedex 2,

Myelodysplastic syndromes are characterized by a high risk of evolution into acute myeloid leukaemia which can involve activation of signalling pathways. As the chaperone heat shock protein 90 (HSP90) has a key role in signal transduction, we investigated its role in the pathogenesis and evolution of myelodysplastic syndromes. Expressions of HSP90 and signalling proteins clients (phosphorylated-AKT (pAKT), Focal Adhesion Kinase (FAK) and phosphorylated-FAK (pFAK)), were assessed in bone marrow mononuclear and CD34-positive (CD34+) cells from 177 patients with myelodysplasia. Effects of HSP90 inhibition were also evaluated in 39 samples. The levels of all proteins studied were significantly higher in patients with high grade disease, than those with low grade myelodysplastic syndrome or chronic myelomonocytic leukaemia. High levels of HSP90, FAK, pFAK and pAKT were associated with shorter survival and increased risk of progression into acute leukaemia. A down regulation of pFAK and pAKT and increased apoptosis was observed in mononuclear and CD34+ cells after 12 hours of incubation with 17-AAG. In conclusion, our data suggest the implication of HSP90 and FAK and AKT activation in the pathogenesis of myelodysplastic syndromes with excess of blasts and evolution to leukaemia. Moreover this signalling network could be a therapeutic target through HSP90 inhibition.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3717957PMC
http://dx.doi.org/10.18632/oncotarget.557DOI Listing
October 2012

HSP90 inhibition results in apoptosis of Philadelphia acute lymphoblastic leukaemia cells: an attractive prospect of new targeted agents.

J Cancer Res Clin Oncol 2012 Oct 17;138(10):1753-8. Epub 2012 Jun 17.

Département d'Hématologie, Institut de Cancérologie Lucien Neuwirth, 108 bis avenue Albert Raimond, 42270 Saint Priest en Jarez, France.

Purpose: HSP90 targeting is a promising therapeutic approach in cancer. 17-AAG is an HSP90 inhibitor with completed Phase I trials in patients with advanced cancer and recently published Phase II trials. The aim of this work was to study the expression of HSP 90 and apoptotic proteins, the effects in culture of 17-AAG on cell survival and apoptosis and to compare Philadelphia-positive (Ph+) ALL to common B cell ALL, in ALL cell lines and in patients' cells collected at ALL diagnosis.

Methods: We analysed 2 ALL cell lines and 63 leukaemic samples from patients treated in our institution (44 common B cell ALL and 19 Ph+ ALL). We performed flow cytometry analysis of bone marrow aspiration and cell lines with a combination of anti-HSP90, Bax, Bcl-2 and Bcl-xl antibodies. Apoptosis after cell culture (in presence or not of 17-AAG) was assessed using Annexin V and activated caspase-3 staining.

Results: Ph+ ALL cells appeared to be more sensitive to 17-AAG cytotoxicity with a 100 % mortality rate after exposure to 10 μM for 24 h (vs. 62 % for B-common ALL). A high percentage of HSP90-positive cells (in Ph+ ALL samples) was associated with high sensitivity to 17-AAG. 17-AAG induced apoptosis in a dose-dependent manner and was associated with down-regulation of Bcl-2 and Bcl-Xl expression and up-regulation of Bax expression.

Conclusion: Considering that Bcr-Abl constitutes HSP 90 substrates, HSP 90 inhibition could be of particular interest for Ph+ ALL disease, even in patients harbouring resistance to tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1007/s00432-012-1247-6DOI Listing
October 2012

Focal adhesion protein abnormalities in myelodysplastic mesenchymal stromal cells.

Exp Cell Res 2011 Nov 16;317(18):2616-29. Epub 2011 Aug 16.

Laboratoire Hématologie, CHU de Saint-Etienne, 42055 Saint-Etienne, France.

Direct cell-cell contact between haematopoietic progenitor cells (HPCs) and their cellular microenvironment is essential to maintain 'stemness'. In cancer biology, focal adhesion (FA) proteins are involved in survival signal transduction in a wide variety of human tumours. To define the role of FA proteins in the haematopoietic microenvironment of myelodysplastic syndromes (MDS), CD73-positive mesenchymal stromal cells (MSCs) were immunostained for paxillin, pFAK [Y(397)], and HSP90α/β and p130CAS, and analysed for reactivity, intensity and cellular localisation. Immunofluorescence microscopy allowed us to identify qualitative and quantitative differences, and subcellular localisation analysis revealed that in pathological MSCs, paxillin, pFAK [Y(397)], and HSP90α/β formed nuclear molecular complexes. Increased expression of paxillin, pFAK [Y(397)], and HSP90α/β and enhanced nuclear co-localisation of these proteins correlated with a consistent proliferative advantage in MSCs from patients with refractory anaemia with excess blasts (RAEB) and negatively impacted clonogenicity of HPCs. These results suggest that signalling via FA proteins could be implicated in HPC-MSC interactions. Further, because FAK is an HSP90α/β client protein, these results suggest the utility of HSP90α/β inhibition as a target for adjuvant therapy for myelodysplasia.
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http://dx.doi.org/10.1016/j.yexcr.2011.08.007DOI Listing
November 2011

Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study.

Blood 2011 Nov 11;118(19):5099-107. Epub 2011 Aug 11.

Université Paris Descartes, Hôpital Necker-Enfants-Malades, Assistance Publique-Hopitaux de Paris, Laboratoire d'hématologie and Centre National de la Recherche Scientifique Unité Mixte de Recherche, France.

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B(low)) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B(low) in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B(low) and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.
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http://dx.doi.org/10.1182/blood-2011-02-334219DOI Listing
November 2011

Long-term oncological outcome after post-chemotherapy retroperitoneal lymph node dissection in men with metastatic nonseminomatous germ cell tumour.

BJU Int 2010 Sep 19;106(6):779-85. Epub 2010 Jan 19.

Department of Medical Oncology, Centre Léon Bérard, Lyon, France.

Objective: To determine whether conformity to standard recommendations of retroperitoneal lymph node dissection (RPLND) after chemotherapy for testicular and primary retroperitoneal nonseminomatous germ cell tumours (NSGCT) and completeness of surgical excision have an effect on oncological outcome.

Patients And Methods: This was a retrospective study of patients with testicular and primary retroperitoneal NSGCT, with initial involvement of RPLNs, treated between June 1992 and December 2002 in one institution. We reviewed the clinical, surgical and histological charts of 151 such patients who had a RPLND after first-line platinum-based chemotherapy. The recommendations used to define conformity to RPLND standards were: the indication based on initial and residual lymph node size, shrinkage, extension of dissection and completeness of resection.

Results: RPLND conformed to standard recommendations in 70 of the 151 (46%) patients. Conformity was complete for the surgeon who operated on 48 patients and was 26% of the others. Fifteen patients (10%) relapsed in the retroperitoneum, 14 of whom had initial lymph nodes of > or =5 cm. Two patients (3%) relapsed in the group of 70 patients with conformed and complete RPLND, vs 13 (16%) in the 81 with conformed but incomplete resection or with non-conformed and complete or incomplete RPLND. After a median (range) follow-up of 77 (1.3-186.5) months 132 patients were alive with no evidence of disease, 18 died and one was alive with progressive disease. The limitations of this study were the relatively few patients and that it was retrospective.

Conclusion: There was conformity of RLNPD to the recommendations, and completeness of resection, in half of the patients operated; this might have an effect on oncological outcome. Our data suggest that patients should be treated in tertiary centres.
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http://dx.doi.org/10.1111/j.1464-410X.2009.09175.xDOI Listing
September 2010

Acute myeloid leukemia with translocation (8;21) or inversion (16) in elderly patients treated with conventional chemotherapy: a collaborative study of the French CBF-AML intergroup.

J Clin Oncol 2009 Oct 31;27(28):4747-53. Epub 2009 Aug 31.

Institut Paoli-Calmettes, 13009 Marseille, France.

Purpose: Acute myeloid leukemia (AML) with translocation (t) (8;21) or inversion (inv) (16) is associated with a favorable prognosis when treated with intensive chemotherapy. In elderly patients, these AML types are rare, and intensive treatments are much less tolerated. We conducted a retrospective study to evaluate the characteristics and outcome of AML with t(8;21) or inv(16) in the elderly.

Patients And Methods: Patients with t(8;21) or inv(16) AML who were age 60 years or older and who received at least one course of induction chemotherapy were included. Postremission therapy consisted of low-dose maintenance chemotherapy (n = 72) or intensive consolidation (n = 56).

Results: A total of 147 patients were analyzed. The median age was 67 years. Sixty patients had t(8;21), and 87 patients had inv(16). A total of 129 patients achieved complete response (CR) after one or two induction courses (ie, 88% CR rate), and 15 patients (10%) died early (ie, during the 8 weeks after induction). During a median follow-up of 48 months, the 5-year probabilities of overall survival (OS) and leukemia-free survival (LFS) were 31% and 27%, respectively. Multivariate analysis showed a negative impact of high WBC, impaired performance status, and deletion (9q) on OS and LFS. Administration of intensive consolidation was associated with better LFS only in patients with t(8;21). In addition, the need for critical care during induction independently predicted lower LFS.

Conclusion: Because of a high CR rate, induction chemotherapy should be considered systematically for elderly patients who have AML with t(8;21) or inv(16). The high risk of relapse suggests that alternative strategies of postremission therapy are warranted.
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http://dx.doi.org/10.1200/JCO.2008.21.0674DOI Listing
October 2009

NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study.

Blood 2009 Apr 23;113(17):3918-24. Epub 2008 Dec 23.

Université Paris 5 Descartes and Assistance Publique Hôpitaux de Paris (AP-HP) and Hematology Department, Hôpital Necker-Enfants-Malades, Paris, France.

Many somatic genetic abnormalities have been identified in T-cell acute lymphoblastic leukemia (T-ALL) but each individual abnormality accounts for a small proportion of cases; therapeutic stratification consequently still relies on classical clinical markers. NOTCH1 and/or FBXW7 mutations both lead to activation of the NOTCH1 pathway and are among the most frequent mutations in T-ALL. We screened 141 adult diagnostic T-ALL samples from patients treated on either the Lymphoblastic Acute Leukemia in Adults (LALA)-94 (n = 87) or the GRAALL-2003 (n = 54) trials. In 88 cases (62%) there were demonstrated NOTCH1 mutations (42% heterodimerization [HD], 10% HD+proline glutamate serine threonine [PEST], 6% PEST, 2% juxtamembrane mutations, 2% transactivation domain [TAD]) and 34 cases (24%) had FBXW7 mutations (21 cases had both NOTCH1 and FBXW7 mutations); 40 cases (28%) were wild type for both. There was no significant correlation between NOTCH1 and/or FBXW7 mutations and clinico-biologic features. Median event-free survival (EFS) and overall survival (OS) were 36 versus 17 months (P = .01) and not reached versus 32 months (P = .004) in patients with NOTCH1 and/or FBXW7 mutations versus other patients, respectively. Multivariate analysis showed that the presence of NOTCH1/FBXW7 mutations was an independent good prognostic factor for EFS and OS (P = .02 and P = .01, respectively). These data demonstrate that NOTCH1 pathway activation by either NOTCH1 or FBXW7 mutation identifies a large group of patients with a favorable outcome that could justify individual therapeutic stratification for T-ALL.
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http://dx.doi.org/10.1182/blood-2008-10-184069DOI Listing
April 2009

Significance of heat-shock protein (HSP) 90 expression in acute myeloid leukemia cells.

Cell Stress Chaperones 2008 Sep 3;13(3):357-64. Epub 2008 Apr 3.

Laboratoire d'Hématologie, Hôpital Nord, CHU de Saint-Etienne, Saint-Etienne Cedex 02, France.

The 90-kDa heat shock protein (HSP90) is implicated in the conformational maturation and stabilization of a variety of client proteins with receptor and signal transduction functions. The objective of this study was to assess its expression in primary acute myeloid leukemia (AML) cells and to evaluate its biological and clinical significance. The in vitro effects of 17-AAG, a selective inhibitor of HSP90, was also evaluated. Cells from 65 patients with newly diagnosed AML were studied. The expression of HSP90 correlated with that of CD34, p170, and bcl-2 proteins but not with white cell counts, FAB or WHO subtype, or cytogenetics. HSP90 levels were also higher in samples exhibiting an autonomous growth in liquid culture or forming spontaneous colonies. A concomitant constitutive activation of the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase/AKT pathways was observed in a majority of samples and was significantly correlated with HSP90 expression. All patients received induction chemotherapy. The percentages of HSP90-, CD34-, bcl-2-, and p170-positive cells were higher in patients who did not attain complete remission. Survival was also shorter in patients with high levels of HSP90. In vitro exposure of leukemic cells to 17-allylamino-demethoxy geldanamycin (17-AAG) resulted in inhibition of growth in liquid and clonogeneic cultures and in apoptosis, at concentrations which in most cases were not toxic for normal CD34-positive or progenitor cells. The concentration inhibiting 50% growth at 72 h in liquid culture correlated with HSP90 expression. Our study suggests that HSP90 is overexpressed in poor-prognosis AML cells and plays a role in cell survival and resistance to chemotherapy. Targeted therapy with 17-AAG represents a promising antileukemic strategy in adult AML.
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http://dx.doi.org/10.1007/s12192-008-0035-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2673940PMC
September 2008

Secondary or concomitant neoplasms among adults diagnosed with acute lymphoblastic leukemia and treated according to the LALA-87 and LALA-94 trials.

Cancer 2007 Dec;110(12):2747-55

Hôpital Nord, Saint-Etienne, France.

Background: Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). Although treatment intensity and outcome were not comparable, with improvements in survival it is important to evaluate the rate and the type of second neoplasms in adults with ALL.

Methods: The data from the GET-LALA group were analyzed. A cohort of 1494 patients, aged 15 to 60 years and enrolled in 2 successive multicenter protocols between 1987 and 2002, was observed to determine the incidence of second neoplasms and associated risk factors. The median follow-up from diagnosis was 6 years.

Results: By February 2005 secondary or concomitant neoplasms were documented in 23 patients, including 9 acute myeloid leukemias (AML) or myelodysplasias (MDS), 4 non-Hodgkin lymphomas (NHL), 5 skin tumors, and 5 other solid tumors (1 lung cancer, 1 tongue carcinoma, 1 thymoma, 1 condrosarcoma, 1 histiocytosis). Neoplasms developed 0.5 to 13.8 years (median, 4.5 years) after the diagnosis of ALL. There were 22 patients in first remission and 1 was in second remission. The overall cumulative risk of secondary neoplasms was 2.1% at 5 years, 4.9% at 10 years, and 9.4% at 15 years. The cumulative risk of developing a second hematologic malignancy was 1.8% at 5 years, 2.2% at 10 years, 3.3% at 18 years; that of developing a solid tumor was 0.2% at 5 years, 2.8% at 10 years, 6.2% at 15 years. The development of secondary neoplasm was not associated with the use of any specific cytotoxic agent. However, the risk of skin tumor increased with radiation dose and transplantation (P = .01). Overall survival (OS) after the diagnosis of a second malignant neoplasm was 55% at 10 years. However, the median OS in patients developing AML/MDS was 5.7 months.

Conclusions: The data document that adult ALL survivors are at an increased risk of later malignancy. The risk of secondary or concomitant neoplasm appeared higher than that of childhood ALL previously reported in the literature. Considering the low survival rate of this large unselected adult ALL cohort (32% at 10 years) as compared with that observed in childhood ALL, the risk of second malignancy remains underestimated. Larger series with long-term follow-up are necessary, as well as methods of screening and identification of patients at increased risk.
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http://dx.doi.org/10.1002/cncr.23097DOI Listing
December 2007

Autologous hematopoietic stem cell transplantation for adults with acute myeloid leukemia in complete remission: the Edouard Herriot Hospital experience.

Hematology 2006 Jun;11(3):157-64

Service d'Hématologie, Hôpital Edouard Herriot, Lyon, France.

We retrospectively assess the long-term outcome and determined prognostic factors correlated with outcomes in adults with acute myeloid leukemia (AML) undergoing autologous hematopoietic stem cell transplantation (HSCT) in our institution over a 19-year period. A total of 78 adults who received autologous HSCT for AML in first complete remission (CR) and of 21 adults in further CR were included in the study. Bone marrow (n = 14) or peripheral blood stem cells (PBSC) (n = 85) transplantation was performed at a median of 2.9 months from CR. Hematologic recovery was significantly reduced in the PBSC group. Five-year cumulative incidences of relapse were 56 and 49%, respectively. Corresponding 5-year probabilities of event-free survival (EFS) were 33 and 35%, while those of overall survival (OS) were 38 and 49%, respectively. In multivariate analyses, cytogenetics was the main prognostic factor for outcome. Treatment-related mortality (TRM) was of 15% at 5 years, but higher in females as compared to males (p = 0.04). We confirmed that long-term EFS can be achieved after autologous HSCT in adult patients with AML. Results in adults who experience a relapse after conventional chemotherapy support the use of autologous HSCT as salvage therapy if such patients achieve a subsequent CR.
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http://dx.doi.org/10.1080/10245330600702794DOI Listing
June 2006

Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial.

Ann Hematol 2005 Jun 22;84(6):376-82. Epub 2005 Mar 22.

Service d'Hématologie, Hôpital Edouard Herriot, 69437, Lyon cedex 03, France.

Following a dose-escalation study performed to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection combined with chemotherapy, a phase II trial (EMA 2000 regimen) was performed in patients with refractory or relapsed acute myelogenous leukemia (AML) between October 2000 and December 2003. Sixty-two patients entered the study and received mitoxantrone 45 mg/m(2) on day 1 in combination with cytarabine and etoposide. Overall, 39 patients (63%) achieved complete remission (CR). Four patients died during remission induction, and 19 patients had resistant disease. Median time to granulocyte and platelet recovery was 34 and 39 days, respectively. The predominant non-hematologic toxicity was infection, with 53% severe infections. Thirty-three of the 39 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 17 patients, allogeneic stem cell transplantation (SCT) in 7 patients, and autologous SCT in 9 patients. The median overall survival of the entire cohort was 8.1 months, with 18% at 2.5 years. EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of high-risk AML. CR proportion was significantly higher in patients with a first CR duration > or =6 months when compared with those from a control trial using standard-dose mitoxantrone (90 vs 70%, p=0.03).
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http://dx.doi.org/10.1007/s00277-005-1037-1DOI Listing
June 2005

Philadelphia chromosome-positive acute lymphoblastic leukemia in the elderly: prognostic factors and treatment outcome.

Hematology 2004 Oct-Dec;9(5-6):369-76

Service d'Hématologie, Hôpital Edouard Herriot, Lyon, France.

Data on all patients diagnosed with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) aged 55 or older, seen in our institution over a 17-year period, were studied to determine the incidence and range of clinical and biological subtypes, and the outcome of different therapeutic approaches. Twenty-five Ph+ ALL cases (median age: 64 years) were diagnosed between 1986 and 2003 (28% of all B-lineage elderly ALL seen during this period). Karyotypic analysis was performed successfully in 22 cases, while 3 were only diagnosed by molecular biology analysis. All patients had B-cell lineage ALL. Co-expression of myeloid markers was observed in 20% of tested cases. One patient died before chemotherapy could be given. All other patients received "curative" treatment according to different protocols used during the period of study. Overall the complete remission (CR) rate was 76% (95% confidence interval, CI: 55-91%). Fifteen patients achieved CR after one course of chemotherapy and 4 patients after salvage therapy. Median disease-free survival (DFS) of the entire cohort was 5.6 months (95% CI: 4.5-8.4 months) and median overall survival was 10.1 months (95% CI: 7.9-13 months). In multivariate analysis, age>or=70 years was of poor prognostic value for achieving CR (p=0.05) and hyperleukocytosis at diagnosis was of poor prognostic value for overall survival (p=0.001). Overall survival duration was not significantly influenced by achieving CR. Ph+ ALL patients did not show a significant difference in terms of outcome as compared with Philadelphia-negative ALL patients. The very poor overall outcome in elderly patients with Ph+ ALL may be significantly improved by the introduction of imatinib mesylate into current treatment regimens.
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http://dx.doi.org/10.1080/10245330400001983DOI Listing
April 2005