Le consentement éclairé est au cœur de la démarche de soin moderne. Il est obligatoire sous forme écrite pour toute inclusion dans un essai clinique, après information du patient. Cependant peu de données sont disponibles sur les critères de décision qui mènent les patients à participer à un essai clinique. Afin d'explorer le processus de consentement, nous avons réalisé une étude qualitative descriptive rétrospective auprès de patients inclus dans un essai clinique en oncohématologie. Un questionnaire a été adressé aux patients ayant accepté d'être inclus dans un essai clinique. Étaient inclus les patients majeurs ayant été inclus dans un essai clinique entre 3 mois et 2 ans avant le début de notre étude. Étaient exclus les incapables majeurs et les patients dont l'espérance de vie était estimée inférieure à 3 mois. Des entretiens semi-directifs étaient proposés dans un second temps aux patients ayant renvoyé le questionnaire. Soixante-deux patients répondaient aux critères d'inclusion, 31 ont retourné le questionnaire (15 hommes et 16 femmes, âge moyen 54 ans), dont 10 ont participé à un entretien. Les patients étaient atteints de lymphomes, de leucémies aiguës ou de leucémies chroniques. Le modèle de relation médecin/patient allégué par les patients était paternaliste pour 23 %, autonomiste pour 19 % et le modèle de décision partagée pour 52 %. Tous les patients sauf un estimaient avoir bénéficié de consultations suffisamment longues pour appréhender l'essai clinique (temps nécessaire estimé en moyenne à 42 minutes). Deux tiers des patients étaient accompagnés à la consultation, dont 76 % par leur conjoint, 12 % par leurs parents, et 12 % par un ami. La première source d'information citée était la consultation avec le spécialiste qui propose l'essai (94 % de patients), suivie par le médecin traitant (39 %), internet (26 %) et les proches exerçant une profession de santé (16 %). La fiche d'information remise était jugée adaptée pour 97 % des patients et complète pour 85 % des patients. Seuls 14 % des patients estimaient avoir assez peu compris l'essai. Les avis recueillis en vue de la décision de consentement étaient en premier lieu celui du spécialiste (45 %), puis de la famille (37 %) et du médecin traitant (26 %). Le délai de réflexion était de 1 à 15 jours. Les motivations alléguées étaient la confiance dans le médecin (74 %), l'altruisme – faire progresser la connaissance pour en faire bénéficier les patients des années à venir (58 %), recevoir un traitement nouveau (32 %), être mieux soigné (29 %), montrer au médecin qu'on lui fait confiance (3 %). Le rôle du spécialiste proposant l'essai est central : il est souvent à la fois celui qui a établi le diagnostic, celui qui va mettre en œuvre le traitement, celui qui informe, et celui dont l'avis compte le plus. Le médecin traitant joue également un rôle important, bénéficiant d'une relation tissée de plus longue date. Le conjoint tient enfin un rôle central, notamment dans la réception de l'information lorsqu'il assiste à la consultation. La notion d'équivalence (« equipoise » en anglais) des deux bras de l'essai (le plus souvent traitement de référence contre traitement de référence + nouvelle molécule) est difficile à appréhender par les patients qui acceptent l'inclusion. La plupart sont influencés par trois mythes irrationnels : l'aura de la recherche, la reconnaissance envers le médecin qui a diagnostiqué leur pathologie, l'urgence ressentie du traitement. La recherche de bénéfice personnel apparaît dans les entretiens comme le principal déterminant de la décision, dans un mécanisme de double pari : celui de ne pas avoir d'effet secondaire lié à la nouvelle molécule et celui que cette molécule conférera un bénéfice de survie. Ainsi les patients sont-ils « déçus » lorsqu'ils sont randomisés dans le bras placebo. Sans doute une meilleure information du grand public pourrait-elle améliorer la compréhension de la randomisation et de l'équivalence a priori des deux bras d'un essai clinique. Le processus de consentement éclairé en recherche clinique est imparfait, notamment car il suit souvent de peu l'annonce diagnostique d'une maladie grave qui déstabilise le patient. Le spécialiste joue un rôle majeur dans l'information du patient et sa décision d'être inclus dans l'essai clinique. Ce dernier s'appuie également sur son médecin traitant et sur son conjoint pour établir sa décision.

BACKGROUNDTreatment with escalated BEACOPP achieved a superior time to treatment failure over ABVD in patients with disseminated Hodgkin lymphoma. However, recent clinical trials have failed to confirm BEACOPP overall survival (OS) superiority over ABVD. In addition, the gain in low-risk patients is still a matter of debate.PATIENTS AND METHODSWe randomly compared ABVD (8 cycles) with BEACOPP (escalated 4 cycles ≥ baseline 4 cycles) in low-risk patients with an International Prognostic Score (IPS) of 0-2. The primary end point was event-free survival (EFS). This parallel group, open-label phase 3 trial was registered under #RECF0219 at French National Cancer Institute.RESULTSOne hundred and fifty patients were randomized in this trial (ABVD 80, BEACOPP 70): 28 years was the median age, 50% were male and IPS was 0-1 for 64%. Complete remission rate was 85% for ABVD and 90% for BEACOPP. Progression or relapses were more frequent in the ABVD patients than in the BEACOPP patients (17 versus 5 patients). With a median follow-up period of 5.5 years, seven patients died: six in the ABVD arm and one in the BEACOPP arm (HL 3 and 0, 2nd cancer 2 and 1, accident 1 and 0). The EFS at 5 years was estimated at 62% for ABVD versus 77%, for BEACOPP [hazards ratio (HR) = 0.6, P = 0.07]. The progression-free survival (PFS) at 5 years was 75% versus 93% (HR = 0.3, P = 0.007). The OS at 5 years was 92% versus 99% (HR = 0.18, P = 0.06).CONCLUSIONFewer progressions/relapses were observed with BEACOPP, demonstrating the high efficacy of the more intensive regimen, even in low-risk patients. However, additional considerations, balancing treatment-related toxicity and late morbidity due to salvage may help with decision-making with regard to treatment with ABVD or BEACOPP.

Abstract Abstract 3921 Introduction: Hairy cell leukemia (HCL) is a rare hematologic disorder, and the place of emerging treatments, such as BRAF inhibitors, remains to be defined. We conducted a large, multi-center, retrospective survey in France to determine the frequency of malignancy in HCL patients (pts) and their families, and to analyze the long-term effects of the established purine nucleotide analogs (PNA) cladribine (C) and pentostatin (P). Methods: Physician members of the Société Française d'Hématologie were surveyed on their management of HCL pts over the past 30 years. Clinicians completed a form that collected data concerning personal and familial medical history of pts, with particular focus on hematologic malignancies, solid tumors, clinical and biological presentation at HCL diagnosis, therapeutic options, response to treatment, time to relapse, secondary malignancies and cause of death. Results: The survey included 36 French clinical centers and 487 HCL cases (mean patient age 59y; range 29–90y). In the centers surveyed, HCL diagnosis was established after examination of peripheral blood and/or bone marrow and by immunophenotyping. Solid tumors and hematologic malignancies were present before HCL diagnosis in 45 cases (9.2%). A further 38 pts (7.8%) with pre-existing cancers were diagnosed with HCL after a median time of 89mo (range 1–529mo). At diagnosis, three HCL pts presented with follicular lymphoma, monoclonal gammopathy of undetermined significance, or large cell B cell lymphoma. Four pts developed HCL within a median time of 33mo (range 30–38mo) after diagnosis of B-cell lymphoproliferative disorders. In 93 pts (19.1%), at least one family member developed neoplasia: solid tumors=75 pts (15.4%); acute or chronic hematologic malignancies=18 pts (3.7%) with one familial HCL case. Twenty-three pts (4.7%) received no treatment for a median follow-up of 32mo (1–293). Three hundred and forty-five pts (70.8%) received just one first-line treatment (C=68.1%, P=23.8%, interferon [IFN]=3.8%, other=4.3%), and 119 pts (16.6%) received two-to-seven lines of therapy. After first-line treatment, complete responses were observed in 365 pts (74.9%; P=85.1%, C=85.0%, IFN=61.1%). Median duration of response was 41 months (1–270; C=40.5mo [1–188; 234 pts], P=43.0mo [1–209; 80 pts], IFN=74mo [24–270; 13 pts], other=21mo [2–186; 15 pts]). After second line treatment, the median duration of response decreased to 33mo (1–261; 80 pts) (C=27mo [1–159; 39 pts], P=38.5mo [0–206; 24 pts]) and also tended to differ according to first-line regimen (Table). After third-line treatment, the median duration of response decreased again to 24mo (2–224; 24 pts) (C=46mo [2–92], P=20mo [2–166], other=22mo [2–224]). After 60 months follow-up (range 1–384mo), overall survival at 5 years was 95%. Twenty-nine pts (6%) had died (11 deaths were HCL-related), and a further 53 pts (10.9%) developed second malignancies (39 solid tumors and 14 hematologic malignancies). Second malignancies occurred 6 months after HCL diagnosis in 50 pts. Conclusions: This study highlights the high frequency of cancers in HCL pts and their family members, suggesting a role for genetic factors in the development of the disease. The survey also confirms the high efficacy of PNA, and we therefore need to be cautious in adopting innovative new therapies treatment such as BRAF inhibitors or immunotoxins into first-line care. Disclosures: No relevant conflicts of interest to declare.

Background: Extranodal natural killer (NK)/T-cell lymphoma, nasal type, and aggressive NK-cell leukemia are highly aggressive diseases with a poor outcome.Patients and methods: We report a multicentric French retrospective study of 15 patients with relapsed, refractory, or disseminated disease, treated with L-asparaginase-containing regimens in seven French centers. Thirteen patients were in relapse and/or refractory and 10 patients were at stage IV.Results: All but two of the patients had an objective response to L-asparaginase-based treatment. Seven patients reached complete remission and only two relapsed.Conclusion: These data, although retrospective, confirm the excellent activity of L-asparaginase-containing regimens in refractory extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia. Therefore, L-asparaginase-based regimen should be considered as a salvage treatment, especially for patients with disseminated disease. First-line L-asparaginase combination therapy for extranodal NK/T-cell lymphoma and aggressive NK-cell leukemia should be tested in prospective trials.

We report 28 patients (pts) who experienced late onset severe neutropenia (NCI/CTC grade III/IV) after rituximab. Rituximab had been given for the treatment of DLCL(N=15), follicular lymphoma (N=9), mantle cell lymphoma (N=2), CLL (N=2). Rituximab was administered as a front line treatment (N=11), for recurrent disease (N=17), before ASCT (N=1) or after ASCT (N=5). Rituximab was given as a single agent (N=14), with CHOP (N=9) or with other regimen (N=5). Rituximab was given at a dose of 375mg/m2 at weekly intervals over a period of 4 weeks when used as a single agent, or as a single dose of 375mg/m2 with chemotherapy. Characteriscs of neutropenia are summarized in Table. At the time of the neutropenia, all the pts were in CR or VGPR. In 3 pts, the neutropenia had relapsed. All 3 pts were still in CR, and had not been retreated with rituximab. 3 patients were retreated with rituximab for a recurrence of their NHL after the outbreak of neutropenia and 1 pt experienced a further episode of neutropenia after the reintroduction of rituximab. Tests for anti PMN antibodies were performed in 6 pts. In 4 pts, antibodies bound to the surface of neutrophils were detected by the direct neutrophil immunofluorescence test. No antibody could be detected in the serum. A direct toxic effect of rituximab can be ruled out as granulocytes and uncommitted hematopoietic precursor stem cells do not express CD 20. We propose the following hypothesis. The rituximab-induced depletion of the normal B-lymphocyte population was followed by the acquisition of a new immune repertoire under non physiological condition which could promote the transient production of autoantibodies. Some of these antibodies might target either neutrophils or hematopoietic precursors. Some of these antibodies might also be directed against other cells since other delayed-onset cytopenia have been reported after the administration of rituximab, pure red aplasia in particular. An other possible mechanism can be proposed. Rituximab administration could lead to the production of antibodies directed against the complex formed when rituximab is bound to the FcγRIIIb receptor on the PMN. This hypothesis does not account for the delay between the administration of rituximab and the onset of the neutropenia. Characteristics of neutropenic episodes.

Summary. We studied 86 bone marrow biopsies (BMB) from 58 patients presenting with primary splenic marginal zone lymphoma (PSMZL). In 42 patients, a splenectomy was performed which enabled a histopathological diagnosis. In these patients, 44 biopsies were carried out before, and 25 after, splenectomy. In 16 recently observed patients, 17 BMB led to PSMZL diagnosis, and these patients were treated without splenectomy. Seven different patterns of infiltrates were recognized: intravascular, interstitial, nodular, massive, plasmacytic mimicking myeloma and transformation into large B‐cell lymphoma (DLBCL). The association of an intravascular infiltrate and nodules with a germinal centre and/or a marginal zone favoured a diagnosis of MZL. Immunohistochemistry demonstrated the expression of B cell‐associated antigens and, in 40% of the patients, a monotypic lymphoplasmacytic cell component. These patients often presented a serum M component and autoimmune disorders. In the past, such cases have been diagnosed as lymphoplasmacytic lymphoma. BM involvement was present in all patients. Successive biopsies showed progression and, after chemotherapy, a slight decrease in infiltrates. Transformation into DLBCL occurred in 11 of 34 patients. The patterns described are not specific for PSMZL and occur also in primary nodal MZL and, more rarely, in MALT‐type lymphoma.

In chronic myelogenous leukemia (CML), autologous stem cell transplantation could be a promising new approach for patients with no cytogenetic response after interferon α (IFN-α) therapy. We report data on 28 CML patients autotransplanted in chronic phase with peripheral blood progenitor cells mobilized with G-CSF (5 μg/kg/day x 5 days) given subcutaneously while continuing IFN-α therapy. At mobilization, 23 patients (82%) were in complete hematological remission (CHR), 16 (57%) achieved a minor cytogenetic response (mcr). We obtained, after stimulation, a median of 37.4 × 10 9 /l (6.9–108) white blood cells, 7.2 × 10 8 /kg (2.2–16.6) mononuclear cells, 39 × 10 4 /kg (4.8–403.5) CFU-GM and 4.2 × 10 6 /kg (0–58.6) CD34 + cells. Six patients received GM-CSF after transplantation. All patients engrafted, with no significant influence stemming from the Sokal index score and pretransplantation IFN-α therapy duration. The first cytogenetic evaluation after transplantation showed 11 (39%) major cytogenetic response (Mcr), and nine (32%) mcr with no significant correlation between these responses, the Sokal index score, and pretransplantation IFN-α therapy duration, although there was a significant impact from GM-CSF administration ( P = 0.01). After transplantation, 26 patients received IFN-α alone or associated with hydroxyurea. The median follow-up was 12 months after transplantation and 57 months after diagnosis. At the time of follow-up, nine patients were in CHR, six remained stable in chronic phase, three presented an mcr and one remained in Mcr. At the last follow-up, 22 patients were alive. We conclude that the results of this strategy are encouraging in poor IFN-α responders but that other prospective studies that try to maintain the cytogenetic responses obtained immediately after transplantation are needed.

Background: Despite high-dose therapy and ASCT some patients with aggressive HD fail to achieve long-term survival.Patients and methods: Forty-three patients with induction failure (n = 19) or very unfavorable (UF) relapse (n = 24) from HD were included in a multicentric study of tandem ASCT. They planned to receive two courses of IVA(75) with GCSF and blood stem-cell collection. ASCT1 was conditionned with CBV + mitoxantrone (30 mg/m(2)) and ASCT2 (cytarabine 6 g/m(2), melphalan 140 mg/m(2) and total body irradiation at 12 Gy or busulfan 16 (n = 4) than 12 mg/kg). After salvage therapy, response > 50% was observed in 63% of the patients (six patients were included for refractory relapse). Four patients had no ASCT for disease progression; seven patients had only ASCT1 (disease progression, n = 3) and thirty-two patients (74%) received the two ASCT.Results: Hematologic recovery was normal after ASCT1 but delayed platelet recovery was observed after ASCT2 with busulfan in the conditioning regimen. Two VOD with one fatal occured with busulfan at 16 mg/kg and one hemorragic cystis, no further grade 4 toxicity was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of these UF patients were in remission and 20% relapsed within the first year. On an intent-to-treat analysis, 22 of 43 patients are in continuous CR (including 8 patients with induction failure). For the whole population (n = 43) and for patients receiving the two ASCT (n = 32), the two-year survival from the date of progression were respectively at 65% and at 74%.Conclusion: double ASCT is feasible in very UF relapse from HD and may lead to some prolonged remission.

We report seven cases of particular cutaneous tumors selected from the register of the French Study Group on Cutaneous Lymphomas. The patients (three men, four women) were aged 37-86 years. They initially presented with cutaneous nodules or papules. Three cases presented with regional lymph nodes. Stagings were negative, except for one patient with bone marrow involvement. Histological features were relevant with pleomorphic medium T-cell lymphoma, but these cells exhibited a distinguishing phenotype. They were positive for CD4, CD56, and also CD45, CD43, and HLA-DR. All other T-cell and B-cell markers were negative. The myelomonocytic markers (CD13, CD14, CD15, CD33, CD117, myeloperoxidase, and lysozyme) were negative excepted CD68, which was clearly positive in four cases and weakly in two cases. Others natural killer cell markers (CD16, CD57, TiAl, granzyme B), TdT, and CD34 were negative. Polymerase chain reaction studies did not detect any B or T clonal rearrangement. The cytogenetic studies, performed in five cases, showed a del(5q) in two cases. All patients were treated successfully by polychemotherapy, but relapsed quickly in the skin, between 4 and 28 months. Five patients developed bone marrow involvement, with leukemia in three cases, and they died in 5-27 months. One patient died at 17 months with skin progression. The seventh patient is alive at 33 months, with cutaneous progression. The origin of these cells is unclear. Despite expression of CD4 or CD56, we failed to demonstrate a T-cell, natural killer cell origin. However, CD4 and CD56 are not specific for T or natural killer lineages. Although these two markers are also known to be expressed by monocytic cells, classic myeloid antigens were negative. These seven cases, together with other rare similar cases already reported, seem to represent a distinct entity likely developed from hematological precursor cells.

We report seven cases of particular cutaneous tumors selected from the register of the French Study Group on Cutaneous Lymphomas. The patients (three men, four women) were aged 37-86 years. They initially presented with cutaneous nodules or papules. Three cases presented with regional lymph nodes. Stagings were negative, except for one patient with bone marrow involvement. Histological features were relevant with pleomorphic medium T-cell lymphoma, but these cells exhibited a distinguishing phenotype. They were positive for CD4, CD56, and also CD45, CD43, and HLA-DR. All other T-cell and B-cell markers were negative. The myelomonocytic markers (CD13, CD14, CD15, CD33, CD117, myeloperoxidase, and lysozyme) were negative excepted CD68, which was clearly positive in four cases and weakly in two cases. Others natural killer cell markers (CD16, CD57, TiA1, granzyme B), TdT, and CD34 were negative. Polymerase chain reaction studies did not detect any B or T clonal rearrangement. The cytogenetic studies, performed in five cases, showed a del(5q) in two cases. All patients were treated successfully by polychemotherapy, but relapsed quickly in the skin, between 4 and 28 months. Five patients developed bone marrow involvement, with leukemia in three cases, and they died in 5-27 months. One patient died at 17 months with skin progression. The seventh patient is alive at 33 months, with cutaneous progression. The origin of these cells is unclear. Despite expression of CD4 or CD56, we failed to demonstrate a T-cell, natural killer cell origin. However, CD4 and CD56 are not specific for T or natural killer lineages. Although these two markers are also known to be expressed by monocytic cells, classic myeloid antigens were negative. These seven cases, together with other rare similar cases already reported, seem to represent a distinct entity likely developed from hematological precursor cells.

We analyzed 33 patients with AILD T-NHL in a retrospective multicentric study. The median age was 62 yr (35-84 yr) (19 patients over 60 yr). Advanced disease (n = 31) and B-symptoms were consistently found (n = 29) and 20 patients had bone marrow involvement. The main laboratory abnormalities were: anemia (n = 13), hypereosinophilia (n = 13), lymphopenia (n = 14), hypergammaglobulinemia (n = 17), elevated lactate dehydrogenase (LDH) level (n = 24). First-line therapy was chemotherapy (ChT) alone (n = 25) or ChT after steroids (n = 8). Most patients received a CHOP-like regimen for a median number of 6 cycles and 3 patients received interferon alpha (IFN alpha) as consolidation after chemotherapy. With a median follow-up of 46 mo, 60% achieved a complete response but the outcome was poor with a relapse rate at 56%, a median survival referring to the total population was of 36 mo (2-108+ mo) and an overall survival at 5 yr of 36%. Two patients received high-dose chemotherapy (with total body irradiation) and autologous progenitor-cell transplantation for chemosensitive relapse and were free of disease at, respectively, 76 and 24 mo+. In conclusion AILD T-NHL still has a poor prognosis compared to other NHL. The role of intensive therapy and IFN alpha still remains to be evaluated.

BACKGROUND:Epstein-Barr virus (EBV)-associated lymphoproliferative disorders have recently been observed during treatment of rheumatoid arthritis and dermatomyositis with low-dose methotrexate.OBSERVATION:A patient with psoriasis developed a B-cell lymphoproliferative disorder during long-term treatment with low-dose methotrexate. The lymphoid cells expressed EBV latent membrane protein 1, and the EBV viral genome was present as demonstrated by in situ hybridization. Evaluation for EBV clonality showed that the lymph node contained clonal EBV DNA. Polymerase chain reaction studies confirmed that the B-cell lymphoproliferative disorder was mainly monoclonal, suggesting that the disorder arose from a single EBV-infected B-cell clone.CONCLUSIONS:Lymphoproliferative disorders associated with Epstein-Barr virus in which the clinicopathological presentation is similar to those occurring in patients after transplantation may be observed in patients with psoriasis treated with methotrexate. While it is impossible to rule out a fortuitous occurrence of an EBV-associated lymphoproliferative disorder and psoriasis treated with methotrexate in the same patient, EBV appears to be critical in the pathogenesis of the lymphoproliferative disorder in this patient.

Between 1985 and 1990, the French Cooperative Group on Chronic Lymphocytic Leukemia (CLL) randomized 287 stage B patients between intermittent chlorambucil plus prednisone (n=140) or CHOP (n=147), and 90 stage C patients between CHOP (n=44) or CHOP plus methotrexate (n=46). In stage B, although treatment response was improved with CHOP (p=0.007, chi-square test), no difference in survival was observed between the two randomized groups (p=0.33, score test). In stage C, no differences in treatment response and survival were shown, with median survival close to that reported with CHOP in the previous CLL-80 trial. These results associated with those from other groups raise the question whether the CHOP regimen, which has been consistently shown to improve response to therapy, is an effective treatment in advanced CLL patients.