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Peripheral T cell lymphomas are rare malignancies with aggressive course, with several different subtype described in the 2016 WHO classification. Their distribution across the world is heterogenous, with marked difference between Western and Asian country. Their clinical presentation often comprise extra-nodal involvement, B symptoms and immune system disorder which can lead to wrong diagnosis orientation. Make a right diagnosis need a experienced pathologist in close collaboration with clinical datas. Peripheral T cell lymphomas are in general associated with poor prognosis when treated with anthracyclines-based regimen, and several studies and trials focused on the use of intensified regimen or novel targeted agents, whose proper indication still remain to be clarified.

Peripheral T cell lymphomas are rare malignancies with aggressive course, with several different subtype described in the 2016 WHO classification. Their distribution across the world is heterogenous, with marked difference between Western and Asian country. Their clinical presentation often comprise extra-nodal involvement, B symptoms and immune system disorder which can lead to wrong diagnosis orientation. Make a right diagnosis need a experienced pathologist in close collaboration with clinical datas. Peripheral T cell lymphomas are in general associated with poor prognosis when treated with anthracyclines-based regimen, and several studies and trials focused on the use of intensified regimen or novel targeted agents, whose proper indication still remain to be clarified.

Background Health policies require improving the efficiency of healthcare by supporting the development of biosimilar drugs. French policies request that appropriate information should be given to patients who receive a biosimilar. According to an international study, only 6% of the general population is aware of what is a biosimilar. This data suggests that appropriate information about biosimilar is complicated and time-consuming. Few data are published on patients’ opinions concerning cost and biosimilar drugs. Purpose We aimed to establish a consensus on the important information that should be given to patients during an initial consultation, and to define to what extent we can discuss cost and biosimilar choice. Material and methods This study was conducted in the department of haematology, a panel of 72 ‘experts’ consisting of 50 patients and 22 healthcare professionals (HCP). The DELPHI method allowed the collection of the experts’ opinions in a prospective way. We defined 12 items to be assessed in two rounds: one, choosing information useful to know; and two, prioritising essential information. In the third round, after correct explanations about biosimilars, experts were given a choice: accept or reject the biosimilar drug with detailed arguments. Results First, experts assessed: ‘cost of treatment’, ‘biosimilar/generic drug’ useful to know up to 45% (patients: 63%, HCP: 38%) and 43% (patients: 57%, HCP: 38%), respectively. The following items: ‘side effects (SE)’ and ‘food/drug prohibited’ were selected as useful to know by 100% of the experts. Then, ‘correct conduct in case of SE’, ‘SE’ and ‘intake modalities’ were considered essential by the experts. Unexpectedly, ‘cost’ was mentioned by only 7% of the patients. At the third round, 55% of the patients accepted the biosimilar, 40% did not decide and trusted in their HCP’s decision and one patient rejected a biosimilar even when not convinced by HCP. Among HCP, 93% accepted a biosimilar and only one HCP refused it. The main argument for choosing a biosimilar drug was ‘economic reason’. Conclusion These results suggest that patients and HCP are aware of the increasing cost of the drugs and the economic impact on society. Most patients trust their HCP in the choice of the most efficient therapy. Further investigations are needed to confirm these results, with a larger cohort of patients. References and/or acknowledgements No conflict of interest.

Despite substantial improvements in the management and treatment of mantle cell lymphoma (MCL), the disease is still considered incurable. While high-dose cytarabine followed by autologous stem cell transplantation (ASCT) is considered as the gold standard in younger patients, the Rituximab, Cyclophosphomide, Doxorubicin, Oncovin, Prednisone (R-CHOP) regimen followed by rituximab maintenance is the recommended treatment for the elderly. Our better understanding of the pathogenesis of the disease through the identification of different altered signaling pathways has contributed to the development of new-targeted therapies offering a new era in the management of MCL. Early results achieved with these therapies are promising. However, new questions are arising regarding how and when to use these agents. This paper reviews these different approaches in patients with MCL.

La neutropenie febrile (NF) est une complication frequente des chimiotherapies anticancereuses. Les protocoles de prise en charge de la NF sont clairement definis en oncologie, mais il n’a pas ete demontre qu’ils etaient applicables et adaptes aux urgences. Quarante-sept services d’urgence francais ont participe a cette etude observationnelle multicentrique prospective pendant une periode de six mois. Ont ete inclus tous les patients adultes se presentant aux urgences avec une NF postchimiotherapie. La severite de l’infection a ete definie selon les criteres de Bone pour le sepsis severe et le choc septique (SS/CS) et le risque de complications selon les criteres de MASCC (Multinational Association of Supportive Care in Cancer) pour les patients ne presentant pas de signes infectieux de gravite. L’objectif principal etait de determiner si ces recommandations etaient suivies aux urgences, en comparant la pratique a la prise en charge recommandee. Cette prise en charge adaptee variait selon les grades de severite: pour les patients avec des signes de SS/CS: 1) une antibiotherapie intraveineuse (IV) adaptee debutee dans les 90 minutes (au moins une β-lactamine a large spectre); 2) un remplissage vasculaire (500 cc); 3) un dosage de lactatemie; 4) au moins une hemoculture; et 5) l’hospitalisation. Pour les patients sans SS/CS: 1) non-initiation d’un traitement par facteur de croissance granulocytaire (G-CSF); 2) une antibiotherapie IV adaptee (β-lactamine a large spectre) et une hospitalisation pour les patients a « haut risque » selon les criteres de MASCC; 3) une antibiotherapie orale adaptee (quinolone ou amoxicilline/acide clavulanique ou cephalosporine) et 4) une prise en charge ambulatoire pour les patients a « faible risque ». Cent quatre-vingt-dix-huit patients ont ete inclus; 89 patients presentaient un SS/CS, dont 19 ont recu une antibiotherapie adaptee dans les 90 minutes et 42 un remplissage vasculaire. Des hemocultures ont ete prelevees pour 87 patients, et une lactatemie a ete dosee chez 29. Au total, seuls six (7 %) patients avec un SS/CS ont ete pris en charge selon les recommandations. Parmi les 108 patients sans SS/CS, 38 (35 %) etaient a « haut risque » et 70 (65 %) a « faible risque ». Dans le groupe a « haut risque », une antibiotherapie adaptee a ete prescrite pour 31 patients, un traitement par G-CSF initie pour quatre et une hospitalisation decidee pour 35. Dans le groupe a « faible risque », quatre patients ont recu une antibiotherapie orale adaptee (une antibiotherapie IVayant ete prescrite chez 59), un traitement par G-CSF a ete initie chez 12 patients et six ont ete traites en ambulatoire. Au total, une prise en charge adaptee aux recommandations a ete proposee a 26/38 (68 %) patients a « haut risque » et 1/70 patients a « faible risque ». Les facteurs associes a une prise en charge adaptee aux recommandations etaient l’absence de SS/CS (p = 0,0009) et le « haut risque » selon les criteres de MASCC (p < 0,0001). Dans cet echantillon de patients se presentant aux urgences avec une NF, la prise en charge a ete le plus souvent inadaptee, et les signes de gravite ont ete sousevalues pour les patients les plus severes.

The objective of this registry study was to analyse the outcome of patients who underwent allogeneic or autologous haematopoietic stem cell transplantation (HSCT) for hepatosplenic T-cell lymphoma (HSTL), a rare and extremely aggressive peripheral T-cell lymphoma subtype. Patients were eligible if they had histologically verified HSTL and underwent HSCT between 2003 and 2011. Seventy-six patients were identified in the European Society for Bone and Marrow Transplantation database. Additional baseline and follow-up information could be obtained from the referring centres for 36 patients. Eleven of these were excluded following histopathology review, leaving 25 patients in the final study cohort (alloHSCT 18, autoHSCT 7). With a median follow-up of 36 months, 2 patients relapsed after alloHSCT, resulting in a 3-year progression-free survival of 48%. After autoHSCT, 5 patients relapsed and subsequently died. This study indicates that graft-versus-lymphoma activity conferred by alloHSCT can result in long-term survival for a substantial proportion of patients with HSTL.

Introduction There are insufficient data regarding the efficacy and safety of vaccination in patients with auto-immune disease (AID) and/or drug-related immune deficiency (DRID). The objective of this study was to obtain professional agreement on vaccine practices in these patients. Methods A Delphi survey was carried out with physicians recognised for their expertise in vaccinology and/or the caring for adult patients with AID and/or DRID. For each proposed vaccination practice, the experts’ opinion and level of agreement were evaluated. Results The proposals relating to patients with AID specified: the absence of risk of AID relapse following vaccination; the possibility of administering live virus vaccines (LVV) to patients not receiving immunosuppressants; the pertinence of determining protective antibody titre before vaccination; the absence of need for specific monitoring following the vaccination. The proposals relating to patients with DRID specified that a 3–6 month delay is needed between the end of these treatments and the vaccination with LVV. There is no contraindication to administering LVV in patients receiving systemic corticosteroids prescribed for less than two weeks, regardless of their dose, or at a daily dose not exceeding 10 mg of prednisone, if this involves prolonged treatment. Out of 14 proposals, the level of agreement between the experts was “very good” for eleven, and “good” for the remaining three. Conclusion Proposals for vaccine practices in patients with AID and/or DRID should aid with decision-making in daily medical practice and provide better vaccine coverage for these patients.

En France pres de la moitie des greffes allogeniques est desormais realisee a partir de donneurs non apparentes. C’est grâce a cette source supplementaire de greffons que le nombre de patients pouvant beneficier de ce traitement potentiellement curatif pour de nombreuses hemopathies a double depuis 1990 (donnees SFGM-TC 2007). On sait maintenant comment selectionner au mieux le donneur qui conviendra pour un patient precis, on sait quelle est l’efficacite et la toxicite des greffes a partir de ces donneurs. Bref, on peut choisir le meilleur donneur parmi des options diversifiees grâce a la solidarite internationale et aux efforts de celles et ceux qui ont cree les fichiers de donneurs volontaires.

Les cancers de l'enfant et de l'adolescent sont des maladies rares. Malgre les progres therapeutiques accomplis (plus de deux cas sur trois gueris), le cancer demeure la premiere cause de deces par maladie chez l'enfant de plus de 1 an. L'acces a des nouveaux medicaments plus efficaces et / ou mieux toleres est donc une priorite de Sante Publique. Notre table ronde s'est ainsi fixe comme objectif de faire un etat des lieux et de proposer des recommandations visant a faciliter un acces coordonne, rationnel et plus rapide aux nouvelles therapies. La participation active de cancerologues pediatres, de parents, d'industriels du medicament et des autorites reglementaires s'est averee necessaire et tres constructive. Tres peu de nouveaux agents anticancereux ont ete developpes par les firmes pharmaceutiques chez l'enfant au cours des 10 dernieres annees. La table ronde a identifie une evolution actuelle du contexte qui semble favorable : mobilisation des parents et associations de parents ; initiatives europeennes pour inciter les industriels a evaluer les medicaments chez l'enfant ; initiatives reglementaires pour guider les developpements ; et existence de reseaux de recherche clinique structures en cancerologie pediatrique, y compris pour le developpement therapeutique precoce. La table ronde fait les recommandations suivantes pour ameliorer l'acces aux nouveaux traitements pour les enfants et adolescents souffrant d'une pathologie maligne : 1. Conduire l'evaluation preclinique pediatrique de tout agent anticancereux entrant en developpement chez l'adulte (recherche et validation des cibles therapeutiques ; evaluation pharmacologique sur modeles experimentaux pertinents) afin d'aider au choix des molecules a etudier chez l'enfant. 2. Initier le developpement clinique pediatrique avant le premier depot de dossier pour autorisation de mise sur le marche chez l'adulte, lorsque des donnees suffisantes de securite d'emploi et de tolerance sont disponibles, a savoir apres les essais de phase I chez l'adulte, et au mieux pendant les essais de phase II. 3. Optimiser l'evaluation clinique pediatrique en definissant tot des plans de developpement et en reduisant au mieux la duree des etudes (elargissement des reseaux de recherche therapeutique precoce pour assurer les recrutements ; nouvelles methodologies d'evaluation ; meilleure extrapolation des donnees pharmacologiques disponibles de l'adulte vers l'enfant pour les recherches de dose). 4. Ameliorer l'information et la participation des parents et des patients a la recherche clinique sur les nouvelles therapies. Le pre-requis au succes de cette demarche est apparu tres vite, a tous les participants de la table ronde, comme etant une concertation et un travail en partenariat entre academiques, associations de parents, industriels du medicament et autorites reglementaires. C'est au prix de cette concertation mutipartenariale que les progres therapeutiques et de nouveaux espoirs de guerison pourront voir le jour.

Childhood and adolescent cancers are rare diseases. Despite the progress in treatment (more than two-thirds of all cases are cured), cancer remains the leading cause of death by disease in children older than 1 year. Access to new drugs that are more efficacious or better tolerated is therefore an important public health priority. The objective of our round table was thus to take inventory of the situation and to propose recommendations aimed at facilitating coordinated, rational and more rapid access to new treatments. The active participation of paediatric oncologists, parents, pharmaceutical companies and regulatory authorities proved not only necessary but very constructive. Pharmaceutical companies have developed very few new anticancer agents for children during the past 10 years. The round table identified current trends that appear propitious: the mobilisation of parents and patients’ associations; European initiatives to encourage companies to assess drugs in children; regulatory initiatives to guide drug development; and the existence of structured clinical research networks in paediatric oncology, including for the development of early treatment. The round table recommends the following measures to improve access to new treatments for children and adolescents with cancer: 1. Conduct preclinical paediatric evaluation of all anticancer agents that begin the development process for adults (research and validation of treatment targets; pharmacological evaluation in relevant experimental models) to help choose the agents to study in children. 2. Initiate paediatric clinical development before the first application for authorisation for adults is filed, when sufficient safety and tolerability data are available, that is, after the phase I trials in adults and optimally during the phase II trials. 3. Optimise paediatric clinical evaluation by defining development plans early and by reducing the duration of studies (enlargement of the early treatment research network to ensure adequate recruitment; new evaluation methods; better extrapolation of pharmacological data from adults to children for dose-finding). 4. Improve information to and participation of parents and patients in clinical research for new treatments. The prerequisite for the success of this project became rapidly clear to all the round-table participants: cooperation and partnership between specialists and other scientists from academia, parent associations, pharmaceutical companies and regulatory authorities. Only with such cooperation can progress in treatment occur and new hopes for recovery be fulfilled.

Published data on transplantation in Waldenstrom's macroglobulinemia (WM) are still limited. We present a retrospective multicentric study of 27 WM patients who underwent 19 autologous (median age, 54 years) and 10 allogeneic (median age, 46 years) transplantations. Median time between diagnosis and transplantation was 36 months; 66% of patients had received three or more treatment lines and 72 % had chemosensitive disease. High-dose therapy (HDT) and autologous transplantation induced a 95% response rate (RR), including 10 major responses. With a median follow-up of 18 months, 12 patients are alive at 10 to 81 months and eight are free of disease progression at 10 to 34 months. The toxic mortality rate (TRM) was 6%. Allogeneic transplantation was preceded by HDT in nine patients and by a nonmyeloablative regimen in one patient. The RR was 80%, including seven major responses. With a median follow-up of 20.5 months, six patients are alive and free of progression at 3 to 76 months. Four patients died, all from toxicity, resulting in a TRM of 40%. HDT followed by autologous transplantation is feasible in WM, even in heavily pretreated patients, with some prolonged responses but a high relapse rate. Conversely, allogeneic transplantation is more toxic, but likely induces a graft-versus-WM effect and may, for some patients, result in long-term disease control.

Thousands of autologous and at less extent allogeneic hematopoietic stem cells (HSC) bags are cryopreserved in France. The majority of autologous HSC grafts are used within a year after collection. However, many bags are still unused and cryopreserved for many years. In France and on a European scale, the ever-growing number of cryopreserved bags represents a real economic health concern. Indeed, the cost of storage is about 100€ per bag and per year. In addition, quality and therapeutic value of these long-term cryopreserved grafts needs to be evaluated. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from its member centers across France. These workshops took place in September 2013 in Lille. In this article, we addressed the issue of the destruction of long-term cryopreserved grafts be them autologous or allogeneic and provide recommendations regarding their destruction.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of common issues related to the donor: pre-transplant pregnancy and monoclonal gammopathy.

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here we report our results and recommendations regarding the management of pre-transplant donor's cytomegalovirus, Epstein-Barr virus, Toxoplasma gondii, or syphilis IgM positive serology test.

PURPOSE To compare the results achieved with myeloablative therapy followed by either allogeneic bone marrow transplantation (alloBMT) or autologous bone marrow transplantation (ABMT) for patients with Hodgkin's disease (HD). PATIENTS AND METHODS Of more than 1,200 patients with HD reported to the European Bone Marrow Transplantation (EBMT) registry, 49 underwent alloBMT. Of these, 45 with sufficient data were matched to 45 patients who underwent ABMT. The matching criteria were sex, age at time of transplantation, stage of disease at diagnosis, bone marrow involvement at diagnosis and at transplantation, year of transplantation, disease status at time of transplantation, time from diagnosis to transplantation, and conditioning regimen with or without total-body irradiation (TBI). RESULTS The 4-year actuarial probabilities of survival, progression-free survival (PFS), relapse, and non-relapse mortality were 25%, 15%, 61%, and 48% and 37%, 24%, 61%, and 27% after alloBMT and ABMT, respectively. The toxic death rate at 4 years was significantly higher for alloBMT patients (P = .04). For patients with sensitive disease at the time of transplantation, the 4-year actuarial probability of survival was 30% after alloBMT and 64% after ABMT (P = .007). This difference is mainly due to a higher transplant-related mortality rate after alloBMT (65% v 12%, P = .005). Acute graft-versus-host disease (aGVHD) > or = grade II was associated with a significantly lower risk of relapse, but also with a lower overall survival (OS) rate. CONCLUSION Based on this study, alloBMT from a human leukocyte antigen (HLA)-identical sibling donor does not appear to offer any advantage when compared with ABMT. A graft-versus-Hodgkin effect is associated with > or = grade II aGVHD, but its positive effect on relapse is largely offset by its toxicity. In most circumstances, alloBMT cannot be recommended for patients with HD.

Introduction La rosacee est une dermatose faciale frequente, aux diagnostics differentiels varies. Nous rapportons ici trois hemopathies lymphoides B avec atteinte cutanee secondaire atypique evoquant une rosacee. Observations Cas 1 : un homme de 76 ans presentait un rhinophyma depuis un an. Devant l’aspect atypique micropapuleux violace sans antecedent de rosacee, pouvant suggerer un angiosarcome, une biopsie etait realisee, montrant une localisation d’un lymphome de la zone marginale (LZM). La TDM montrait des adenopathies lomboaortiques et la biopsie medullaire un envahissement. Un traitement par 6 cures de R-CVP etait realise, permettant une regression de l’atteinte cutanee nasale et une stabilite des adenopathies profondes. Cas 2 : une femme de 75 ans, suivie depuis un an en hematologie pour un LZM avec hyperlymphocytose moderee et splenomegalie, en abstention therapeutique, etait adressee en dermatologie pour une dermatose du visage consideree comme une rosacee. On observait de multiples papules rosees millimetriques, sans pustule ni couperose. La biopsie confirmait la localisation cutanee du LZM. Apres 2 lignes de traitement inefficaces, un traitement par fludarabine et cyclophosphamide permettait une remission clinique cutanee. Trois ans plus tard, une transformation en lymphome B diffus a grandes cellules de localisation ORL conduisait a son deces. Cas 3 : une femme de 75 ans, suivie pour une hyperlymphocytose consideree comme une leucemie lymphoide chronique (LLC) en abstention therapeutique depuis 5 ans, etait adressee en dermatologie apres l’exerese d’un nodule cutane dont l’histologie etait en faveur d’un LZM. On notait un erytheme des paupieres inferieures non infiltre, des micropapules rosees du visage et du cuir chevelu et une adenopathie cervicale. L’histologie cutanee et ganglionnaire concluait a un lymphome lymphoplasmocytaire et un traitement par rituximab etait debute. Discussion Les LZM cutanes primitifs se presentent classiquement comme des nodules ou des tumeurs isolees ou multiples du tronc et des membres. L’atteinte cutanee de nos trois patients est donc differente, particuliere et stereotypee. Il ne s’agit pas non plus de l’atteinte cutanee classique de la LLC a type d’infiltration des lobules des oreilles et du nez. Cette presentation clinique rare et trompeuse a ete rapportee dans des lymphoproliferations B a petites cellules, lymphomes folliculaires et LZM essentiellement cutanes primitifs, comme dans 10 des 12 cas de la serie de Barzilai et al. en 2012. Les autres observations publiees isolees sont egalement cutanees primitives sous reserve de l’exhaustivite du bilan, pas toujours precisee. Conclusion L’atteinte cutanee primitive ou secondaire des hemopathies lymphoides B peut mimer une rosacee et etre revelatrice. Cette presentation trompeuse doit etre connue du dermatologue.

Resume L'allogreffe de cellules souches hematopoietiques reste un excellent moyen de guerir de nombreuses hemopathies malignes. L'effet curateur est, au moins en partie, medie par les cellules immunocompetentes du donneur capables d'un effet « greffon contre maladie ». Cependant, la toxicite de cette technique limite son utilisation a des patients selectionnes. L'objectif des greffes a conditionnement non myeloablatif est de s'affranchir de la toxicite des conditionnements preparatoires, et de conserver l'effet « antitumoral » du systeme immunitaire du donneur. Plusieurs etudes temoignent de la justesse du concept. Cette strategie therapeutique nouvelle, multi-etapes, est complexe et doit faire l'objet d'evaluation protocolaires, avant d'etre appliquee a un plus grand nombre de patients.

In the absence of systemic chemotherapy after the diagnosis of primary granulocytic sarcoma (PGS), all patients will subsequently develop acute myelogenous leukemia (AML). The authors describe a case of PGS of the head of the pancreas found at laparotomy in a 32-year-old man. The patient received early after surgery, two courses of high-dose chemotherapy and, with a follow-up of 2 years, never developed AML. This rare observation illustrates the necessity of further early systemic chemotherapy after surgical excision of PGS.

Resume Nous rapportons trois cas d'infection fusariale survenue chez des patients neutropeniques porteurs d'une hemopathie. Le premier patient presente une fusariose cutanee extensive. Le deuxieme presente une fusariose pulmonaire participant a un tableau de defaillance multiviscerale apres allogreffe de moelle osseuse. Le troisieme patient, porteur d'une leucemie aigue myeloblastique refractaire, developpe une fusariose cutanee et decedera d'une defaillance respiratoire. Le traitement de l'infection fusariale est decevant et repose sur l'amphotericine B, souvent associee aux facteurs de croissance medullaire. Le role d'associations chimiotherapiques antifungiques et celui de nouveaux agents reste a determiner. C'est la sortie d'aplasie qui permet le controle de l'infection.

Allogeneic stem cell transplantation is able to cure many hematologic malignancies, through, at least partially, a graft versus disease effect of the donor's immune system transfer. However, the toxicity of this technique limits its use to selected patients. The aim of non-myeloablative stem cell transplantation is to reduce the toxicity of the conditioning regimen while allowing the engrafement of donor's stem cells and the immunological antitumoral activity of the donor's immune system. Several reports have already demonstrated the validity of this concept. This new multi-step therapeutic strategy is complex, raises many questions and deserves further studies to be fully applicable to a greater number of patients.

The timing of transplantation in chronic myeloid leukaemia is still debated and previous treatment with interferon (IFN) alpha has been reported to be deleterious. We have analysed the outcome of 438 allogeneic transplants performed between 1984 and 1995 and reported to the Société Française de Greffe de Moelle (SFGM) registry. One hundred and two patients (group I) received IFN for more than 6 weeks (median = 9 months) before transplant. Their outcome was compared with 336 other patients (group II) not pretreated with IFN. There were no significant differences between the groups for engraftment and chronic graft-versus-host disease (GVHD) incidence. However, other significant differences included the incidence of acute GVHDor = 2 at 3 months which was higher in group I (65 +/- 10%) than in group II (38 +/- 5%; P = 0.01). Moreover, disease-free survival (DFS) and overall survival (OS) at 5 years were significantly shorter for group I than for group II (33 +/- 10% vs. 41 +/- 6%; P = 0.005)(95% CI) and (41 +/- 10% vs. 55 +/- 6%; P = 0.002)(95% CI) respectively. After adjustment for patient and transplant covariables in a multivariate analysis, prior IFN was not found to adversely affect transplant outcome.

In a randomized study that compared human leucocyte antigen-identical allogeneic granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) versus bone marrow (BM) transplantation, the expression of activation markers, CD23, CD25 and CD45RO by B cells, was compared in blood before and after G-CSF mobilization and in PBSC versus BM grafts. The fractions of CD23+ and CD25+ B cells were higher in PBSC than in BM grafts. Moreover, we observed a G-CSF-induced increase in B-cell fractions in blood as well as in PBSC grafts when compared with BM grafts. Such an enhanced B-cell activation could contribute to the accelerated kinetics of immuno-haematological reconstitution, the occurrence of acute haemolysis in the ABO minor incompatibility setting, as well as the increased incidence of chronic graft-versus-host disease observed after PBSC transplantation.

Cryptococcus is an opportunistic infection that affects immunodepressed patients and is a classical complication of AIDS-stage HIV infection. The aim of this study was to investigate Cryptococcus neoformans infections in patients with hematological malignancies.Six cases have been described of cryptococcosis detected in Nantes, France over the past 10 years in patients with hematological malignancies.This infection has been found particularly in the context of lymphoproliferative disorders (chronic lymphocytic leukemia, Waldenström macroglobulinemia, Hodgkin's disease, and non-Hodgkin's lymphoma), and also following cytotoxic therapy. In four cases, the patients were treated with fludarabine, which rapidly caused long-duration marked lymphocytopenia, notably in CD4 cells. Cell-mediated immunity plays a major role in systemic defense against C. neoformans. It therefore seems that fludarabine favors the spread of cryptococcal infections.In the context of lymphoproliferative syndromes treated with cytotoxic drugs, in particular fludarabine, it appears important to take into account the possible presence of cryptococcal infection in the presence of respiratory, neurological or cutaneous disorders, so that a correct diagnosis can be made and the appropriate treatment administered.

Autologous stem cell transplantation (ASCT) in the front line treatment of non-Hodgkin's lymphoma (NHL) remains controversial. Anaplastic large-cell lymphoma (ALCL) is known to have its own clinical and biological features. The outcome of ALCL patients treated with high-dose chemotherapy and ASCT as part of their first-line therapy was analysed in 202 intermediate or high-grade NHL patients in a prospective randomized trial. First-line chemotherapy comprised two alternating anthracycline-containing regimens. Responding patients were autografted after a BEAM (BCNU, cytarabine, etoposide and melphalan) regimen. Patients with bulky or residual masses were irradiated. Fifteen patients with ALCL were identified by morphological and immunological features (CD30 was expressed in 14 out of 15 patients, three patients expressed B-cell markers, five patients expressed T-cell markers and seven patients did not express cell markers). Anaplastic lymphoma kinase (ALK) expression was confirmed in seven cases. The median age was 39 years with a predominant male sex ratio (2.75). Thirteen patients were stage/= III and six presented with two or more adverse prognostic factors. According to the international age-adjusted prognostic index, the expected complete remission (CR), event-free survival (EFS) and overall survival (OS) rates were 69%, 71% and 69%. Two deaths were observed (one due to interstitial pneumonitis, one due to pulmonary carcinoma). All patients entered CR, no relapse occurred and EFS and survival reached 87% with a follow-up of more than 5 years. These results differ significantly from those observed in the other 176 lymphoma patients: event-free survival was only 53 +/- 5% and OS reached 60 +/- 4% with a median follow-up of 56 months (P = 0.006). Intensified chemotherapy with autologous stem cell support appeared effective in the treatment of ALCL, offering patients the real chance of a cure.

B-lymphoproliferative post-transplant disorder (BLPD) is a severe complication of organ and bone marrow transplantation. The reduction of immuno-suppressive therapy or surgery for localized disease may cure some BLPDs. Other therapeutic approaches such as chemotherapy and antiviral drugs are toxic and of limited efficacy. Adoptive immunotherapy with donor T-cell infusions has yielded promising results but is, at the present time, easily applicable only in bone marrow-transplanted patients. Anti-B-cell Murine monoclonal antibodies (MoAbs) have proven effective but are no longer available for human use. We report the activity of a humanized anti CD 20 Mo Ab (Rituximab-MABTHERA Roche) in 32 episodes of BLPD treated in 14 French centers.Between November 1997 and September 1998, 32 patients were diagnosed with BLPD. Twenty-six patients had undergone solid organ transplants (liver 8, kidney 8, heart 4, lung 3, heart lung 1, kidney-pancreas 1, liver-kidney 1) and six patients had received bone marrow transplantations. The median age of the patients was 34 years (3-67 years) and the median delay between graft and tumor 5 months (1-156 months). In organ recipients, tumors were classified as polymorphic and monomorphic in 10 and 15 cases, respectively; 4 of 6 bone marrow transplant recipients were treated without pathology documentation because of a rise in EBV load, fever and lymph node enlargement. Tumors were associated with EBV in 22 of 26 tested cases. Rituximab was used as first-line therapy in 30 patients (after reduction of immunosuppressive treatment in 27 patients) and as salvage therapy in 2 patients (after failure of chemotherapy). The median time from diagnosis of BLPD to treatment with Rituximab was 14 days (1-110 days). Two patients received eight infusions, twenty-six patients four infusions, one patient three infusions and three patients two infusions of 375 mg/m2.The tolerance of rituximab was good. The overall response rate was 69%, with 20 complete responses and 2 partial responses. In solid organ transplant the response rate was 65% (15 CR and 2 PR) while it was 83% in bone marrow-transplanted patients (5 CR). With a median follow-up of 8 months (1-16 months) 24 patients are still alive. The one-year projected survival is 73%. Of the 22 patients who achieved response, 15 patients (11 solid organ transplant and 4 bone marrow transplant) are alive with no evidence of disease, 4 patients relapsed a median of 7 months (3-10 months) after treatment and 3 died while in CR of concurrent diseases. Of the 10 patients who did not respond to Rituximab 5 are alive with no evidence of disease after salvage therapy.The use of rituximab appears to be a safe and relatively efficient therapy in BLPDs. The results need to be confirmed in a prospective multicentric trial.

Introduction La neutropenie febrile (NF) est une complication frequente des chimiotherapies anticancereuses. Les protocoles de prise en charge de la NF sont clairement definis en oncologie, mais il n’a pas ete demontre qu’ils etaient applicables et adaptes aux urgences.

The place of allogeneic bone marrow transplantation (BMT) in the treatment of aggressive non-Hodgkin's lymphoma (NHL) remains controversial. We conducted a retrospective study of French experience in allografting NHL between 1984 and 1994. To improve the homogeneity of the study population, cases of low-grade, Burkitt and lymphoblastic NHL were excluded. 73 patients were included in the analysis. Median age at transplantation was 35 years (range 9-61 years); 64 patients were in stage IV and 45 had bone marrow involvement at diagnosis. At the time of transplantation, 46 patients had sensitive disease (25 in complete remission; CR). The overall survival (OS) and progression-free survival (PFS) rates were 41% and 40% respectively at 5 years (median follow-up of survivors 90 months). The probability of disease progression was 30% at 5 years, and only one relapse occurred after 15 months. 32 patients died of transplantation-related complications. In multivariate analysis, pretransplant complete remission was the main factor associated with longer survival (OS at 60 months of 76% among the 25 patients in CR at transplant and of 23% among the 48 patients not in CR at transplant). Neither acute nor chronic graft-versus-host disease (GvHD) influenced the relapse rate. In conclusion, in this high-risk population the overall results of allogeneic BMT were encouraging, despite a high transplant-related mortality rate. We believe this procedure should be studied further in prospective controlled trials.

We designed a randomized trial of IC with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients agedor = 65 years with high risk MDS. Patients were randomized to receive Mitoxantrone 12 mg/m2/d d2-5 + AraC 1 g/m2/12 h d1-5, with (Q+) or without (Q-) quinine (30 mg/kg/day). 131 patients were included. PGP expression analysis was successfully made in 91 patients and 42 patients (46%) had positive PGP expression. In PGP positive cases, 13 of the 25 (52%) patients who received quinine achieved CR, as compared to 3 of the 17 (18%) patients treated with chemotherapy alone (p = 0.02). In PGP negative cases, the CR rate was 35% and 49%, respectively in patients who received quinine or chemotherapy alone (difference not significant). In the 42 PGP positive patients, median Kaplan-Meier (KM) survival was 13 months in patients allocated to the quinine group, and 8 months in patients treated with chemotherapy alone (p = 0.01). In PGP negative patients, median KM survival was 14 months in patients allocated to the quinine group, and 14 months in patients treated with chemotherapy alone. Side effects of quinine mainly included vertigo and tinnitus that generally disappeared with dose reduction. Mucositis was significantly more frequently observed in the quinine group. No life threatening cardiac toxicity was observed. In conclusion, results of this randomized study show that quinine increases the CR rate and survival in PGP positive MDS cases treated with IC. The fact that quinine had no effect on the response rate and survival of PGP negative MDS suggests a specific effect on PGP mediated drug resistance rather than, for instance, a simple effect on the metabolism of Mitoxantrone and/or AraC.

To determine the prognostic factors and outcome of first-line induction failure Hodgkin's disease patients who were treated with a salvage regimen of high-dose chemotherapy and autologous stem-cell transplantation, and to compare them with matched, conventionally treated patients.We retrospectively analyzed data relating to 86 Hodgkin's disease patients who underwent autologous stem-cell transplantation after failure of the first chemotherapy regimen, either because they did not enter a complete remission and experienced progression of disease less than 3 months after the end of their first-line treatment or because they showed evidence of disease progression during first-line therapy. Graft patients were matched with 258 conventionally treated patients (three controls per case) for age, sex, clinical stage, B symptoms, and time at risk; patient data were obtained from international databases.Among the 86 graft patients, the median age at diagnosis was 29 years (range, 14 to 57 years). Thirty-nine percent of patients had stage II disease, 23% had stage III disease, and 38% had stage IV disease. Seventy percent of the patients received chemotherapy and 30% received combined modality therapy; 60% of the patients received a seven- or eight-drug regimen. After this first-line treatment, 91% had disease progression and 9% had a brief partial response. Eighty patients received a second-line treatment; pretransplantation status was as follows: 24% of patients had a complete remission, 38% had a partial remission (PR), 14% had stable disease, and disease progression occurred in 24%. With a median follow-up of 22 months (range, 4 to 105 months) from diagnosis, the 5-year event-free survival and overall survival rates from transplantation were 25% and 35% (95% confidence intervals, 15 to 36 and 23 to 49), respectively. In multivariate analysis, the pretransplantation disease status after salvage therapy was the only significant prognostic factor for survival (PR: relative risk = 2.8, P = .017; progressive disease: relative risk (RR) = 5.26, P.001). From diagnosis, the 6-year overall survival rates of the graft patients and 258 matched conventionally treated patients were 38% and 29%, respectively (P = .058).Autologous stem-cell transplantation represents the best therapeutic option currently available for patients with primary induction failure and is associated with acceptable toxicity. Response to second-line treatment before high-dose chemotherapy is the only prognostic factor that can be correlated with survival.

The outcome of neutropenic patients with Pseudallescheria boydii infection is poor.We report the first case of Pseudallescheria boydii hip arthritis in a patient treated for acute lymphoblastic leukemia. In vitro susceptibility testing showed that the strain was resistant to amphotericin B, fluorocytosine and nystatin, but susceptible to itraconazole. The patient received oral itraconazole (600 mg/day) and clinical symptoms initially resolved. Two months later, after a course of chemotherapy and high-dose steroids while receiving oral itraconazole treatment, the patient developed fever, skin lesions and disseminated lung infiltrates due to Pseudallescheria boydii and finally died.This case illustrates the severity of fungal infections due to Pseudallescheria boydii despite a presumably well-conducted antifungal therapy.

We designed a randomized trial of IC with or without quinine, an agent capable of reverting the multidrug resistance (mdr) phenotype, in patients aged < 65 years with high risk MDS. Patients were randomized to receive Mitoxantrone 12mg/m2/d d2–5 + AraC 1g/m2/12h d1–5, with (Q+) or without (Q) quinine (30mg/kg/day). 131 patients were included. PGP expression analysis was successfully made in 91 patients and 42 patients (46%) had positive PGP expression. In PGP positive cases, 13 of the 25 (52%) patients who received quinine achieved CR, as compared to 3 of the 17 (18%) patients treated with chemotherapy alone (p=0.02). In PGP negative cases, the CR rate was 35% and 49%, respectively in patients who received quinine or chemotherapy alone (difference not significant). In the 42 PGP positive patients, median Kaplan-Meier (KM) survival was 13 months in patients allocated to the quinine group, and 8 months in patients treated with chemotherapy alone (p=0.01). In PGP negative patients, median KM survival was 14 months in patients allocated to the quinine group, and 14 months in patients treated with chemotherapy alone. Side effects of quinine mainly included vertigo and tinnitus that generally disappeared with dose reduction. Mucositis was significantly more frequently observed in the quinine group. No life threatening cardiac toxicity was observed. In conclusion, results of this randomized study show that quinine increases the CR rate and survival in PGP positive MDS cases treated with IC. The fact that quinine had no effect on the response rate and survival of PGP negative MDS suggests a specific effect on PGP mediated drug resistance rather than, for instance, a simple effect on the metabolism of Mitoxantrone and/or AraC.

HLA-DP incompatibility is not considered as an exclusion criterion for bone marrow donors, because such incompatibility was not shown to affect significantly the risk for acute graft-versus-host disease (GVHD). In line with this clinical observation, it was proposed that in the context of bone marrow transplantation, HLA-DP determinants did not function as transplantation antigens in the same way as HLA-A, -B or -DR. In contrast to the above conclusion, we recently demonstrated the presence of HLA-DPB1*0501 specific T cell clones in a skin biopsy of a patient who developed aGVHD after receiving a bone marrow transplant (BMT) in which the only mismatched allele in the GVHD direction was HLA-DPB1*0501. At that time, this case was unique and occurred in a relatively uncommon graft setting where the patient received purified CD34+ BM cells from an unrelated donor. In the present study, we analyzed the immunological events associated with an aGVHD which occurred in the context of a 'regular' allogeneic BMT involving a single HLA-DPB1*1001 mismatch between donor and recipient in the GVHD direction. To this end, we analyzed several amplified T cell subsets present within a T cell line derived from a skin biopsy performed at the onset of GVHD. Our results demonstrated that T cell populations belonging to the TCRBV2, TCRB6.7, TCRBV14 and TCRBV17 subsets were specific for the HLA-DPB1*1001 mismatched allele. These data strengthen and generalize our first conclusion that a single HLA-DP mismatch between donor and recipient can activate a strong T cell response in vivo and consequently challenge the notion that HLA-DP incompatibility should not be taken into account in the choice of BM donors. Moreover, they also underline the idea that HLA-DP antigens may represent an interesting immune target for future therapeutic approaches.

Three intensive consolidation strategies are currently proposed to younger adults with acute myeloid leukemia (AML) in first complete remission (CR): allogeneic or autologous bone marrow transplantation (BMT) and intensive consolidation chemotherapy (ICC). Patients aged 15 to 50 years with de novo AML received an induction treatment with 7 days of cytarabine and either idarubicin or rubidazone. After achievement of a CR, patients up to the age of 40 and having an HLA-identical sibling were assigned to undergo an allogeneic BMT. All the other patients received a first course of ICC with high-dose cytarabine and the same anthracycline as for induction. They were then randomly assigned to either receive a second course of ICC with amsacrine and etoposide or a combination of busulfan and cyclosphosphamide followed by an unpurged autologous BMT. Of 517 eligible patients, 367 had a CR, but only 219 (59.5%) actually received the planned intensive postremission treatment (73 allogeneic BMT, 75 autologous BMT, and 71 ICC). With a median follow-up of 62 months, the 4-year disease-free survival (DFS) of the 367 patients in CR was 39.5%. The 4-year overall survival (OS) of the 517 eligible patients was 40.5%. In multivariate analysis, DFS and OS were influenced only by the initial white blood cell count and by the French-American-British classification. The type of postremission therapy had no significant impact on the outcome. There was no difference in the 4-year DFS and OS between 88 patients for whom an allogeneic BMT was scheduled (respectively, 44% and 53%) and 134 patients of the same age category and without an HLA-identical sibling (respectively, 38% and 53%). Similarly, there was no difference in the outcome between autologous BMT and ICC. The 4-year DFS was 44% for the 86 patients randomly assigned to autologous BMT and 40% for the 78 patients assigned to ICC (P = .41). The 4-year OS was similar in the two groups (50% v 54.5%, P = .72). The median duration of hospitalization and thrombocytopenia were longer after autologous BMT (39 v 32 days, P = .006, and 109.5 v 18.5 days, P = .0001, respectively). After a first course of ICC, a second course of chemotherapy is less myelotoxic than an unpurged autologous BMT but yields comparable DFS and OS rates.

Graft-versus-host disease (GVHD) is a major complication after bone marrow transplantation, which may be refractory to immunosuppressive drugs. As preliminary case reports suggested that extracorporeal photochemotherapy (ECP) using a Therakos device might be beneficial, we conducted a pilot study to assess the efficacy and safety of a new ECP method that does not require administration of 8-methoxypsoralen (8-MOP) to the patient.ECP was performed three times a week for 3 weeks and then tapered according to the patient's course. Soluble 8-MOP was added ex vivo to an enriched mononuclear cell suspension obtained by a cell separator. This cellular suspension was then ultraviolet A irradiated and reinfused into the patient. Evaluation was performed using specific objective tests depending on clinical conditions.The two patients in the study with acute GVHD and severe liver dysfunction resistant to steroid pulse showed no improvement with ECP treatment. The five patients with chronic GVHD (c-GVHD) had the following clinical features: three patients had myositis and two patients had severe cutaneous c-GVHD, including one patient with sclerodermoid lesions, one with bronchiolitis obliterans, one with bronchitis, and one with liver involvement. Immunosuppressive drugs were either prohibited or ineffective. The number of procedures for each patient ranged from 13 to 30. Cytapheresis required the use of a double-lumen catheter (4/5) or an arteriovenous fistula (1/5). No side effects were related to 8-MOP or ultraviolet A irradiation. Four of five patients improved after ECP; one patient with bronchiolitis obliterans, a fibrotic condition, remained stable.ECP treatment may be helpful for the treatment of severe c-GVHD and the avoidance of increased immunosuppression.

Low-dose chemotherapy in myelodysplastic syndromes (MDS) gives overall limited results in high-risk MDS [1–3]. Intensive chemotherapy in MDS and secondary leukemias (i.e., acute myeloid leukemia, AML, following de novo or therapy-related MDS) gives lower complete remission (CR) rates and shorter CR duration than in de novo AML [4–11]. This may be due in part to a higher incidence of mdr gene expression in MDS than in de novo AML as mdr gene expression is associated in our experience, with very low CR rates with intensive chemotherapy [12]. These recent results suggested that the use of agents capable of reverting mdr gene expression could improve the CR rate in MDS and secondary leukemias.

The International Prognostic Index (IPI) is widely used to predict outcome of patients with aggressive lymphomas. Our goal was to assess the prognostic value of this index for low-grade lymphoma.One hundred eighty-two patients with disseminated (stage III or IV) low-grade lymphoma were enrolled in a prospective multicenter trial. According to the initial features, treatment either was started immediately or was deferred until indicated by disease progression. Patients received the same polychemotherapy regimen, given monthly for six cycles. They were assigned to one of four risk groups according to the number of presenting risk factors: low-risk (0 or 1), low-intermediate-risk (2), high-intermediate-risk (3), high-risk groups (4).Survival curves (Kaplan-Meier method) demonstrated a high significant difference for the four groups (log-rank: P0.0001). Median survival for the low-risk group has yet to be reached, while that for the three other groups are, respectively, 65, 34, and 12 months.In this study, the IPI has been found to be an important prognostic tool in low-grade lymphoma and may be used in the selection of appropriate therapeutic approaches for individual patients.

We have evaluated CD34+ cell positive selection from granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) in 26 patients with either multiple myeloma (MM, n = 18) or follicular non-Hodgkin's lymphoma (NHL, n = 8). 26 PBPC were collected with two leukaphereses: 16 contained sufficient numbers of CD34+ cells and were elected. The absolute number of CD34+ cells in the leukapheresis products was found to be significantly related to the duration of underlying disease and exposure to prior treatment. CD34+ cell positive selection allowed recovery of a median of 35% of CD34+ cells, the selected fraction containing a median number of 1.43 x 10(6)/kg CD34+ cells/kg (range 0.48-41.5). 10 patients were transplanted and received a median dose of 1.51 x 10(6) CD34+ cells (range 0.48-4.2). The median time to granulocyte (0.5 x 10(9)/l) and platelet (20 x 10(9)/l) engraftment was 12 and 13 d respectively (ranges 10-13 and 0-95). Lymphoma cells were found by a sensitive polymerase chain reaction technique in four out of five CD34+ cell fractions tested.

The authors report three cases of fusarial infection in neutropenic patients with hematologic malignancies. The first patient was affected by a cutaneous extensive fusariosis. The second patient developed a fusarial lung infection during a multiple organ failure following allogenic bone marrow transplantation. The third patient who presented with refractory acute myelogenous leukemia, developed fusarial skin lesions, and died from pulmonary failure. The treatment of fusarial infection is disappointing and requires amphotericin B, in association with hematopoietic growth factors. The role of new agents, or combination chemotherapy remains to be determinated. The recovery of adequate neutrophil levels is the most important factor in the resolution of fusarial infection.

To evaluate the importance of fractionating total body irradiation (TBI) in patients receiving an allogenic bone marrow transplant (BMT) for an acute myeloblastic leukemia (AML) in first complete remission (CR1).Between 1983 and 1990, 171 consecutive patients received either single dose TBI (STBI) (n = 65) or fractionated TBI (FTBI) (n = 106) after being conditioned with cyclophosphamide and before receiving a non-T-depleted Human Leucocyte Antigen (HLA)-identical marrow. Both groups were comparable except for date of BMT and diagnosis-to-BMT interval (D-BMT).After 63 months median follow-up, transplant-related mortality (TRM), probability of relapse, and 5-year disease-free survival (DFS) were 0.38 and 0.27 (p = 0.04), 0.29 and 0.26 (p = 0.22), 0.43 and 0.56 (p = 0.06), respectively, for STBI and FTBI. The supposed influence of the schedule of TBI disappeared in the multivariate analysis: TRM was enhanced by severe acute graft vs. host disease (p = 0.0002), early years of transplant (before January 1, 1987) (p = 0.0003), and longer D-BMT intervals (p = 0.038). Relapse was linked to early years of transplant (p0.00001), and the absence of chronic GVHD (p = 0.007). Longer DFSs were observed for later years of transplant (after January 1, 1987 and later) (p = 0.001), milder acute GVHD (p = 0.005), and shorter D-BMT intervals (p = 0.045). Important improvements of the results were made during the 7-year observation period: TRM, probability of relapse, and DFS were, respectively, 0.36, 0.28, and 0.46 for patients transplanted before January 1, 1987 vs. 0.21, 0.15, and 0.67 after that date.Our data strongly suggest that allogenic BMT is the best postremission treatment for AML in CR1, and the results are better when BMT shortly follows the achievement of remission. The schedule of TBI was of little importance compared with the improvements made in the management of patients undergoing BMT during the 1980s, and, therefore, reports concerning data prior to 1985 should be interpreted cautiously.