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Baron et al report excellent responses to temozolomide in 21 patients (19 relapsed/refractory) with primary vitreoretinal lymphoma. Treatment is well tolerated, even in elderly patients.

TO THE EDITOR : Patients with chronic lymphocytic leukemia (CLL) exhibit a variety of skin lesions including mostly non-specific cutaneous manifestations (such as cutaneous infections or exaggerated reactions to insect bite) and secondary cutaneous malignancies, as patients are at high risk of developing basal cell carcinoma, squamous cell carcinoma, melanoma, and Merkel cell carcinoma. Specific cutaneous infiltration by neoplastic B lymphocytes with clinically identifiable skin lesions, also called leukemia cutis (LC), is more uncommon and has seldom been reported in chronic lymphocytic leukemia. [...]

We report the case of a man with a primary diagnosis of Waldenstrom macroglobulinemia. He secondarily presented a diffuse large B cell lymphoma (DLBCL) located in the nasal fossae, which relapsed later in the eye. The diagnosis of these two malignancies is based on a multidisciplinary biological approach using new sensitive and specific techniques. These techniques revealed that the two diseases harbor different B cell clones, indicating a distinct origin. This observation highlights the importance of targeted biological techniques for the diagnosis of these two rare hemopathies. It also shows that it is possible to prove the independent nature of the two tumor clones, thus allowing optimized therapeutic management.

Introduction While systemic post-transplant lymphoproliferations (PTLDs) have a good prognosis, with a median survival of more than 6 years, PTLD of the central nervous system (CNS-PTLD) have a very poor prognosis with a CR rate of 38% and overall survival (OS) of 43% at 3 years. The main prognostic criterion being the response to the first line (Evens AM et al. Am J Transpl 2013), we hypothesized that the majority of treatment failures were due to the absence or underuse of the major drug in CNS NHL treatment, namely methotrexate (Mtx), due to the high rate of renal failure in transplanted patients. Patients and methods Since April 2017, CNS-PTLD treated at Pitie-Salpetriere Hospital, Paris, France, have been systematically treated with a combination of methotrexate on day 1, Cytarabine on days 2 and 3, every 15 days for 6 cures. Cytarabine is given at 2g/m 2/d when the creatinine clearance (cc) is > 50ml/min, 1g/m 2/d below. The dose of Mtx of the first treatment is 100 mg/m 2 in case of dialysis or cc 65 years, 3000mg/m 2 in other cases. The dose of Mtx during the following treatments depends on the dosage of Mtx at 24h: below 1 microM the following dose is increased, above 5 microM it is reduced otherwise it remains the same. The results are compared to those of CNS-PTLDs treated in the same unit before April 2017 Results Of the 182 PTLDs treated since 1990 at Pitie-Salpetriere hospital, 49 are CNS-PTLD, including 16 processed with the new algorithm. The median age is 58 years, 9 patients have kidney or kidney-pancreas transplants, 2 heart, 1 lung and 3 liver, all are EBV positive diffuse large B cell CNS-PTLDs. The diagnosis is made in median 88 months after the transplantation. The cc at the diagnosis is in median of 50 ml / min. Of these 16 patients, only 2 had a cc> 60 ml/min, and only two were able to receive 3000 mg/m 2 of Mtx. The other patients received between 100 and 1000 mg/m 2 at the first treatment, 6 had an increased dose during the next cycles following the algorithm. No worsening of renal function or overdose of Mtx have been rated. Of the 16 patients 14 achieved complete remission (93%), 1 a PR, 1 died of progression after the first cycle, 1 relapsed within 3 months and 1 after 1 year of CR. Median overall survival (OS) is not achieved (448 days +). In comparison, of the 33 CNS-PTLDs treated before April 2017, 10 obtained a CR (30%), 6 a PR and the median OS is 211 days, for the 9 CNS-PTLDs treated without Mtx, only one obtained a CR, 1 a PR and their OS is only 180 days (p=0.016) cf figure Conclusion Contrary to general belief, methotrexate can be used regardless of the renal function by adapting its dose to the cc then to the dosages at H24. This new simple algorithm increased the CR rate from 30% to more than 90% and improve OS. In case of confirmation on further series, this new attitude should revolutionize the management of CNS-PTLDs ... but also other CNS-NHLs in case of renal failure Figure 1 Figure 1. Disclosures Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Introduction.The BCL-2 inhibitor venetoclax has demonstrated high efficiency in relapsed/refractory (R/R) CLL patients with an overall response rate (ORR) of 79%, regardless of the TP53gene status. Venetoclax has then been EMEA-approved for CLL patients with TP53disruption who are unsuitable for or have failed a BCR inhibitor (BCRi) and those without TP53 inactivation who have failed both immunochemotherapy and a BCRi. Whether this agent provides a well-balanced safety/efficacy profile and a prolonged survival in real-world practice remains to be investigated. Methods. An early access program (ATU) of venetoclax was available in France between July 22thand December 4th, 2016 for R/R CLL patients as per EMEA label. We retrospectively analyzed the outcome of patients included in this program who had received at least one day of venetoclax. Data quality was ensured using on-site data verification and computerized discrepancy errors. Results. Data concerning both clinical features andoutcome were available for 72 of the 93 patients for whom venetoclax was requested in this program. Among them, only 63 patients received at least one day of venetoclax for progressive CLL or Richter syndrome (RS) and were included in the present analysis. Median age was 69 years (range, 25-89) and sex ratioM/F was 47/16. A total of 56 patients received venetoclax for CLL and 7 for RS. Patients had previously received a median of 4 prior therapeutic lines (range, 0-7) including FCR in 43 (68%) of them, BTK inhibitor (BTKi) in 46 (73%) and PI3Kδ inhibitor (PI3Kδi) in 21 (33%); 5 had prior autologous stem cell transplantation (SCT) and 4 allogeneic SCT. At time of treatment with venetoclax, 32 (76%) patients carried TP53disruption (data available for 42 patients) and 19 (61%) had complex karyotype (CK) defined as ≥ 3 abnormalities (data available for 31 patients). IGHV mutational status was available for 26 patients. Treatment was administered as per label recommandations with a 5-week ramp up phase until the target dosage of 400 mg per day. Median follow-up was 17 months. Median time on therapy was 11.9 months (range, 0.1-24.6). Among adverse events of interest, tumor lysis syndrome (TLS) was observed in 19% of case, most of them being biological TLS and 3% were clinical TLS, and 15 (24%) patients developed infections requiring hospitalization. Autoimmune cytopenia was seen in 9.5% of patients. Four (7%) patients developed RS while on venetoclax for progressive CLL. To date, a total of 30% of patients remains on therapy. Three patients proceeded to allo-SCT after venetoclax therapy. Among the 7 patients who received venetoclax for RS, 2 had an objective response that lasted 7 and 14 months. However, median overall survival (OS) was only 1.1 months (95% CI, 0.7-1.5). Regarding the CLL cohort, ORR was 73%. It did not significantly differ according to the TP53status (90% with TP53disruption vs 69%, P= 0.189). Conversely, CK was associated with a lower ORR (92% vs 56%, P= 0.024). No impact of the type of prior BCRi (BTKi vs PI3Kδ inhibitor) was noted. 2-year progression-free survival (PFS) was 62% without significant impact of the TP53status (59% in case of TP53disruption vs 68% if wt-TP53,P= 0.587). Patients with CK had 2-year PFS of 44% compared to 78% for those without CK (P= 0.182). 2-year overall survival (OS) was 65% for the whole cohort and significantly better for responding patients than for non responders (76% vs 31%, P< 0.001). TP53disruption was associated with 2-year OS of 65% vs 90% (P= 0.176). Patients with CK had 53% of 2-year OS vs 62% for the remaining cohort (P= 0.236). There was no difference for the type of prior therapies (BTKi, PI3Kδ inhibitor or prior SCT) or IGHV mutational status. Patients who stopped venetoclax therapy had a very poor outcome with a median OS of 5 months. Conclusions.Our real-life study shows response rates and survival data that are in line with those observed in pioneer venetoclax clinical trials. CK should be evaluated as a predictive factor for response to venetoclax. Disclosures Herbaux: Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead Sciences, Inc.: Consultancy, Honoraria. Laribi:Roche: Other: Grant; Teva: Other: Grant; Hospira: Other: Grant; Sandoz: Other: Grant; Gilead: Other: Personal fees; Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Amgen: Other: Personal fees. Feugier:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guieze:abbvie: Honoraria; janssen: Honoraria; gilead: Honoraria.

Le but de ce travail est le reperage de substances cancerogenes, mutagenes et reprotoxiques (CMR) dans les fiches de donnees de securite (FDS) de 53 entreprises adherentes, hors laboratoires d’analyses et entreprises d’usinage de metaux evalues dans le cadre du Contrat pluriannuel d’objectifs et de moyens. Materiels et methodes L’analyse de 491 FDS a ete faite pour 30 entreprises en 2014 et 23 entreprises en 2015, suite a une visite d’entreprise ou a des demandes specifiques de medecins du travail. Resultats L’analyse des FDS retrouve 34 substances CMR dans les produits utilises. Dix-neuf entreprises sur 53 utilisent au moins une substance CMR, soit 35,8 % d’entreprises exposees. Les substances les plus frequemment rencontrees dans les melanges sont : les solvants naphtas (15 fois) le styrene et le n-hexane (5 fois), le toluene, l’ethylbenzene, le formaldehyde et le trichlorethylene (3 fois), la silice cristalline, le dioxyde de titane et le nitriloacetate trisodique (2 fois). Les solvants naphtas voient leur classification dependre de leur teneur en impuretes de benzene, parfois manquante sur la FDS. Un appel au fournisseur confirme 9 fois sur 10 une teneur en benzene inferieure a 0,1 % et une absence de classification CMR. Discussion Dans cette etude, les secteurs les plus exposes sont ceux de la recherche et du developpement en chimie et pharmacie (6/19 entreprises) qui totalisent 15 des 34 substances CMR reperees. Ces secteurs sont egalement ceux qui travaillent avec des protections collectives et individuelles adaptees et une bonne connaissance du risque chimique. Six entreprises sur 19 n’utilisent qu’une seule substance CMR. Ces entreprises se repartissent entre l’hotellerie-restauration, la coiffure et l’esthetique et les cliniques de soins (2 cas chaque). Il a ete possible de substituer les produits par d’autres sans CMR dans 5 cas sur 6, en s’adressant directement au fournisseur. Sept autres entreprises utilisent au moins 2 produits CMR. On retrouve les secteurs de la plasturgie, du traitement de surface et de la mecanique automobile (2 cas chaque) et 1 entreprise fabricant des pastels. Le risque est souvent ignore. Conclusion Cette etude retrospective de 2 ans a montre que pour les 53 entreprises dont les FDS ont ete analysees, plus du tiers manipulent au moins 1 agent CMR. Quand cela etait possible, une substitution a ete proposee. Dans le cas contraire, l’analyse a permis une reflexion autour du risque, parfois meconnu. L’analyse des FDS devrait etre systematique et completer chaque fiche d’entreprise. Elle se heurte cependant trop souvent a des difficultes rencontrees sur le terrain: FDS absentes de l’entreprise ou trop anciennes, employeurs reticents.

Hydroxyurea-derived clinical and biological benefits and safety were retrospectively studied for 123 adult patients from 2 sickle cell disease referral centers during a total follow-up of 654 patient-years and total hydroxyurea exposure of 549 patient-years. Fifty-six adverse events occurred (incidence: 12%/patient-year), with leg ulcers being the most frequent. Adverse events could arise at any time and were usually reversible. No malignancy was observed. Clinical and biological benefits of our cohort were similar to those previously reported. Based on this relatively long retrospective study, the risk/benefit ratio for moderate hydroxyurea doses was satisfactory.

Serum concentrations of interleukin (IL)-1 alpha, IL-2, IL-4, IL-6 and tumour necrosis factor (TNF) were measured in 24 untreated patients with Hodgkin's disease and in 24 healthy volunteers matched for age and sex. Serum levels of IL-1 alpha were significantly higher in patients with Hodgkin's disease. The number of patients with detectable serum IL-2 or IL-6 levels was significantly higher in patients with Hodgkin's disease as compared to the control group. No difference was observed for TNF. IL-4 was undetectable in all patients. Serum cytokine levels were not significantly different in patients with and without systemic "B" symptoms (weight loss or fever and night sweats) in the different histological subtypes and clinical stages. Serum concentrations of IL-1 alpha, IL-2, IL-6 and TNF were not correlated to the erythrocyte sedimentation rate, fibrinogenaemia or thrombocyte number. These results indicate that subsets of patients with Hodgkin's disease have detectable serum IL-1 alpha, IL-2 and IL-6 levels, but that other mediators are likely to be involved in the associated clinical and biological inflammatory syndrome.

Peripheral T-cell lymphoma (PTCL) accounts for 15-20% of non-Hodgkin's lymphoma in the Western World. Clinical, histopathologic, phenotypic and genotypic data were received from 33 cases of PTCL referred to our institution. The median age order was 50 years, 78% were males, and 18% had a history of a preceding disorder of the lymphoid system. 60% had stage 4 at diagnosis and B symptoms were also present in 60%. The most frequent sites of extranodal involvement were bone marrow (54%), liver (45%) and skin (33%). Twenty-eight of 33 cases were histologically classified according to the Working Formulation (most in the diffuse mixed and large-cell subgroups) and the Kiel updated system. Phenotypic and genotypic studies of malignant cells showed a considerable heterogeneity with respect to the expression of either T-cell receptor (TCR) alpha beta and gamma delta and pan-T differentiation molecules. Of the studied cases 63% expressed TCR-alpha beta. All five patients with PTCL of the TCR-gamma delta subtype had a peculiar extra-nodal presentation. The vast majority of cases expressed an abnormal T-cell phenotype with respect to the expression of pan-T antigens, including the lack of expression of the TCR-associated CD3 molecule in 2 cases. Rearrangements of the TCR beta and/or delta-chain genes showed clonality in 21 of the 23 studied cases. Twenty-five patients were treated with a multiagent chemotherapy regimen with curative intent and the remainder received a less intensive palliative regimen. Only 9 patients achieved CR (8 of whom had received an anthracycline-containing regimen) and the 4-year survival rate was 25%.(ABSTRACT TRUNCATED AT 250 WORDS)