Olivier Hequet

Subclinical Late Cardiomyopathy After Doxorubicin Therapy for Lymphoma in Adults

PURPOSE To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkins lymphoma or Hodgkins lymphoma. PATIENTS AND METHODS We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. RESULTS Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m(2)), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P <.01), older age (P <.01), higher cumulative dose of doxorubicin or association with another anthracycline (P =.04), radiotherapy (P =.04), and being overweight (P =.04). CONCLUSION Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.

Outcome in relation to treatment modalities in 48 patients with localized gastric MALT lymphoma: A retrospective study of patients treated during 1976-2001

The aim of this study was to retrospectively analyze survival and tumor response data in patients with localized gastric MALT lymphoma treated by different treatment modalities other than anti- Helicobacter pylori treatment (diagnosis made before 1993, or after failure of antibiotics+anti-acid), including surgery, chemotherapy or combined treatment. Here we studied a series of 48 patients with stage IE or IIE disease treated during the past 11 years. These patients received different treatments: chemotherapy was proposed to 19 (40%) patients; gastric surgery to 21 (43%) patients, consisting of partial gastrectomy of 7 patients and total gastrectomy in 14 patients; combined treatment to 8 (17%) patients, consisting of surgery+chemotherapy in 7 patients and surgery+chemotherapy+radiotherapy in 1 patient. At diagnosis, 85% of the patients had good PS and no B symptoms. Complete response after treatment was reached in 45 (94%) patients (chemotherapy: 84% of the patients; surgery alone: 95%; combined treatment: 100%). Progression was observed in 16 (33%) patients. No statistical difference in the survival was found among the different therapeutic modalities: 5-year overall survival year FFP survival was 81% for chemotherapy, 86% for surgery alone and 95% for combined treatment. Prognostic factors for survival were age, performance status and hemoglobin level at diagnosis. Considering the natural bias of a retrospective analysis, surgery or chemotherapy was associated with a similar outcome in patients with MALT lymphoma after antibiotics failure.

The superoxide dismutase content in erythrocytes predicts short-term toxicity of high-dose cyclophosphamide

Patients receiving high‐dose cyclophosphamide as a conditioning regimen for peripheral stem cell collection are subjected over a short period of time to significant exposure to reactive oxygen species (ROS). All these patients undergo profound leucopenia. Various other short‐term toxicities are observed in a fraction of the patients, including febrile aplasia requiring hospitalization, thrombocytopenia and mucositis. Although stem cell collection is feasible in the majority of patients stimulated with haematopoietic growth factors, in some instances, graft collection cannot be performed because of insufficient concentrations of stem cells in peripheral blood. There is currently no predictive assay to determine which patients treated with high‐dose cyclophosphamide have a high risk of febrile aplasia or will successfully undergo cytaphereses for stem cell collection. In order to identify such predictive factors, we analysed the level of expression before treatment of various ROS detoxification mechanisms in the peripheral blood of 37 patients receiving high‐dose cyclophosphamide for lymphoproliferative diseases. Various parameters involved in the metabolism of ROS were measured in plasma and/or erythrocytes, including superoxide dismutase, glutathione, glutathione peroxidase, glutathione reductase and malondialdehyde. High levels of erythrocyte superoxide dismutase before cyclophosphamide therapy were correlated with an increased risk of hospitalization for febrile aplasia (65% vs. 29%, P = 0·013). High superoxide dismutase and low erythrocyte glutathione reductase were associated with lower CD34 yields. These data suggest that components of the ROS detoxification system modulate the degree of short‐term toxicity of cyclophosphamide and could be used as predictive markers in individual patients.

Photochemotherapy Induces the Apoptosis of Monocytes Without Impairing Their Function

Background. Extracorporeal photopheresis (ECP) is a powerful therapy currently used to treat various hematological disorders as in graft versus host disease. Clinical data clearly demonstrate its efficacy and immunomodulation toward the pathogenic T cells. However, ECP mechanism of action is still poorly understood. Monocytes represent up to 30% of the total amount of treated cells and are known to play an important role in adaptive immunity. However, data from previous reports analyzing the effect of psoralen and UV-A irradiation (PUVA) on their functions are heterogeneous. In this study, we focused on the effect of PUVA on human monocytes functions in adaptive immunity. Design and Methods. Purified human monocytes were treated in vitro by PUVA. We measured their kinetic of apoptosis after the treatment. We also determine whether their phenotype and functionalities were modified. Finally, we assessed the functionalities of PUVA-treated monocytes-derived dendritic cells (DC). Results. PUVA treatment sentenced purified monocytes to die in 6 days and immediately altered their migratory capacities without impairing their ability of endocytosis. It also up-regulated co-stimulatory molecules and production of inflammatory cytokines on activation and consequently stimulated allogeneic or autologous T cells as efficiently as untreated monocytes. Moreover, PUVA-treated monocytes retained their ability to differentiate into fully functional DC that maturated and stimulated T cells as well as normal DC. Conclusions. Our data demonstrate that monocytes undergo apoptosis and loose a part of their migratory capacity after ECP and the surviving cell functionalities are not impaired, suggesting that monocytes have a minor effect on ECP-mediated immunomodulation.

G-CSF-induced aneuploidy does not affect CD34+ cells and does not require cell division.

To the editor: Lymphocytes from granulocyte colony-stimulating factor (G-CSF)–mobilized donors display epigenetic and genetic alterations similar to those observed in leukemia patients.[1][1] To further evaluate the scope and duration of G-CSF–induced genetic alterations, 24 healthy donors were

Mesenchymal stem cell and immunosuppressive drug interactions.

The authors declare no conflict of interest. The authors thank Eddie Takahashi for the English translation. Address correspondence to: Prof. Georges Mourad, M.D., Department of Nephrology and Transplantation, University of Montpellier, Hôpital Lapeyronie 191, Avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 05, France. E-mail: g-mourad@chu-montpellier.fr Received 5 November 2008. Revision requested 30 January 2009. Accepted 5 March 2009. Copyright

Higher percentage of CD34 + CD38- cells detected by multiparameter flow cytometry from leukapheresis products predicts unsustained complete remission in acute myeloid leukemia.

Abstract Relapse in acute myeloid leukemia (AML) after chemotherapy reflects the persistence of resistant leukemia stem cells (LSCs). These cells have been described in the CD34 + CD38− cell fraction. Leukapheresis products were harvested in 123 patients in morphological complete remission and analyzed by multiparameter flow cytometry. The CD34 + CD38− cell population showed a prognostic impact on survival. Median event-free survival (EFS) was 8.2 months (3-year EFS: 29%) for those with a higher percentage of CD34 + CD38− versus 91.9 months (3-year EFS: 62%) for those with a lower percentage for the entire cohort. These differences were confirmed in patients undergoing autologous stem cell transplant, with median EFS of 7.3 months versus 91.1 months (3-year EFS: 31% vs. 70%). Higher proportions of CD34 + CD38− cells were associated with adverse cytogenetics and with earlier relapses. Higher percentages of CD34 + CD38− cells in apheresis products reflect inadequate in vivo purging and reliably distinguish samples enriched in LSCs from those involving mainly normal cells.

Extracorporeal photopheresis for GVHD prophylaxis after reduced intensity conditioning allogeneic hematopoietic stem cell transplantation: a prospective multicenter phase 2 study

Abstract We performed a prospective multicenter phase 2 study to evaluate the safety and efficacy of prophylactic Extracorporeal Photopheresis (ECP) in adult patients with hematological malignancies early after RIC allo-HSCT on day 21 twice per week during the first two weeks and then once per week for the next four weeks for a total of eight ECP courses. A total of 20 patients were included; 10 were males, median age was 60 years. All patients engrafted, 17 (85%) received the total eight ECP courses. There were no adverse effects related to ECP. Seven patients developed acute graft-versus-host disease (GVHD), with 15% grade ≥ II cumulative incidence at day 100. The cumulative incidence of chronic GVHD at 2 years was 22%. The 2 years probability of overall survival (OS) and progression-free survival (PFS) were 84 and 74%, respectively. This study shows encouraging results with low acute and chronic GVHD incidence and no interference with graft-versus-leukemia (GVL) effect.

Impact of rituximab on stem cell mobilization following ACVBP regimen in poor-risk patients with diffuse large B-cell lymphoma: results from a large cohort of patients.

BACKGROUND: The ACVBP regimen is an efficient induction regimen for poor‐risk patients with diffuse large B‐cell lymphoma (DLBCL) before consolidative autologous stem cell transplantation. Adjunction of the monoclonal anti‐CD20 antibody rituximab (R‐ACVBP) was recently found to be superior to ACVBP alone. This study assessed the impact of rituximab on stem cell mobilization in two similar consecutive groups of patients treated with ACVBP in two prospective, controlled trials.

Management of psychiatric complications in unrelated donor before unrelated peripheral hematopoietic stem cell collections

Allogeneic hematopoietic stem cell transplantation can efficiently treat patients with severe hematological diseases. A human leukocyte antigen-compatible donor is required for performing transplantation. The occurrence of unexpected acute severe diseases in a donor can compromise the feasibility of allogeneic hematopoietic stem cell transplantation. However, when a severe health problem occurs in a donor while the recipient has already received a conditioning regimen, hematologists have to find the best solutions for the recipient, while the team in charge of the donor has to find the best medical solutions for the donor. We describe here the occurrence of psychiatric acute complications in an unrelated donor while the myeloablative conditioning regimen had already been given to the recipient. We report the successive decisions that were made in an emergency based upon the expertise of physicians specialized in hematology, apheresis, cell therapy, and psychiatry to preserve the donor’s health and recipient’s life.