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The European Society for Medical Oncology (ESMO) consensus conference onmalignant lymphoma was held on 20 June 2015 in Lugano, Switzerland, and included a multidisciplinary panel of 25 leading experts. The aim of the conference was to develop recommendations on critical subjects difficult to consider in detail in the ESMO Clinical Practice Guidelines. The following areas were identified: (1) the elderly patient, (2) prognostic factors suitable for clinical use and (3) the 'ultra-high-risk' group. Before the conference, the expert panel was divided into three working groups; each group focused on one of these areas in order to address clinically relevant questions relating to that topic. All relevant scientific literature, as identified by the experts, was reviewed in advance. During the consensus conference, each working group developed recommendations to address each of the questions devised by their group. These recommendations were then presented to the entire multidisciplinary panel and a consensus was reached. This manuscript presents recommendations regarding the management of the following 'ultra-high-risk' situations: (1) early central nervous system relapse of diffuse large B-cell lymphoma, (2) primary refractory Hodgkin lymphoma and (3) plasmablastic lymphoma. Results, including a summary of evidence supporting each recommendation, are detailed in this manuscript. All expert panel members approved this final article.

7507 Background: This randomized phase III trial assessed whether intensification of rituximab (R) during the first 4 cycles of R-CHOP can improve outcome of diffuse large B-cell lymphoma (DLBCL) patients compared with standard R-CHOP. Patients in complete remission (CR) after induction treatment were randomized between rituximab maintenance and observation. Intensification of rituximab was not more effective than standard R-CHOP, showing same CR-rates and progression free survival after induction (ASCO 2016 # 7504). Here, we report the results of the second randomization for rituximab maintenance therapy. Methods: Patients in CR after R-CHOP were randomized between 24 months of rituximab maintenance 375 mg/m2 intravenous every 8 weeks (n = 199 ) or observation (n = 199). CT scans were performed at 6, 12, 18 and 24 months in both arms. The primary endpoint was disease free survival (DFS) from maintenance randomization. Secondary endpoints were overall survival (OS) and adverse events (AEs). ( www.trialregister.nl NTR1014). Results: Median age was 65 years (range 31-80), 48% were 66 years or older and 49% were male. The majority of patients (54%) had a high-intermediate or high aa-IPI score. After a median follow-up of 79.9 months (maximum 125.7 months), the 5-year DFS rate was 79% for rituximab maintenance versus 74% for observation. This difference was not statistically significant, with a hazard ratio of 0.83 (95% confidence interval 0.57-1.19, p= 0.31, adjusted for age and aa-IPI). The secondary endpoint OS was also not significantly different (85% versus 83% at 5 years). No clinical subgroup benefited from rituximab maintenance. Toxicity was mild. Among patients who received rituximab maintenance CTCAE grade 3 and 4 AEs were reported in 17% and 6% of patients, respectively. Infection was the most frequent AE, a grade 3 infection occurred in 6% of patients. Neutropenia was seen in 1% (grade 3) and 3% (grade 4) of patients. Conclusions: Rituximab maintenance therapy provides no additional benefit for DLBCL patients in first CR after R-CHOP. Clinical trial information: www.trialregister.nl NTR1014.

Background: Not all patients have benefited equally from the advances in non-Hodgkin lymphoma (NHL) survival. This study investigates several individual-level markers of socioeconomic position (SEP) in relation to NHL survival, and explores whether any social differences could be attributed to comorbidity, disease and prognostic factors, or the treatment given. Methods: This registry-based cohort study links clinical data on prognostic factors and treatment from the national Danish lymphoma database to individual socioeconomic information in Statistics Denmark including 6234 patients diagnosed with NHL in 2000–2008. Results: All-cause mortality was 40% higher in NHL patients with short vs higher education diagnosed in the period 2000–2004 (hazard ratio (HR)=1.40 (1.27–1.54)), and 63% higher in the period 2005–2008 (HR=1.63 (1.40–1.90)). Further, mortality was increased in unemployed and disability pensioners, those with low income, and singles. Clinical prognostic factors attenuated, but did not eliminate the association between education and mortality. Radiotherapy was less frequently given to those with a short education (odds ratio (OR)= 0.84 (0.77–0.92)), low income (OR=0.80 (0.70–0.91)), and less frequent to singles (OR=0.79 (0.64–0.96)). Patients living alone were less likely to receive all treatment modalities. Conclusion: Patients with low SEP have an elevated mortality rate after a NHL diagnosis, and more advanced disease at the time of diagnosis explained a part of this disparity. Thus, socioeconomic disparities in NHL survival might be reduced by improving early detection among patients of low SEP.

This study presents the first large clinical analysis of 105 unselected mantle cell lymphoma (MCL) patients diagnosed from 1992 to 2000 in a well-defined Danish population. The annual incidences were 0.7/100000 for men and 0.2/100000 for women, with no significant change during the study period. Of 97 evaluable cases, 43% achieved a complete response (CR) after initial therapy. The median disease-free (DFS) and overall survival (OS) rates were 15 and 30 months, respectively. In multivariate analysis, splenomegaly (P=0.002), anaemia (P=0.0001) and age (P=0.002), but not the international prognostic index (IPI) and the Ann Arbor staging system, had an independent impact on survival. Moreover, in a sub-analysis of 45 younger MCL patients (

Chronic myeloproliferative disorders (MPDs) are characterized by a high incidence of thrombohaemorrhagic complications, possibly caused by platelet dysfunction. In an attempt to define platelet functional abnormalities, we assessed the expression of activation-dependent membrane proteins in unstimulated and agonist [ADP and thrombin receptor-activating peptide (TRAP)]-stimulated platelets using quantitative whole blood flow cytometry in samples from 50 MPD patients and 30 controls. The receptor densities of activation markers and glycoproteins (GPs) were quantified using standardized fluorescent beads. Compared with controls, the mean percentage of P-selectin-positive (15.3% vs. 7.2%; P < 0.001) and thrombospondin (TSP)-positive (6.6% vs. 3.7%; P = 0.003) platelets was increased in unstimulated platelets from patients. Patients having experienced a thrombotic event had a higher mean percentage of TSP-positive non-stimulated platelets than patients without a history of thrombosis (9.0% vs. 4.6%; P = 0.02) and a higher GPIV molecules of equivalent fluorochrome (MEF) value (33113 vs. 24471 MEF; P = 0.02). Mean MEF values of monoclonal antibodies (mAbs) against GPIb (34055 vs. 38945 MEF; P < 0.001) and GPIIb/IIIa (1416 vs. 1648 MEF; P < 0. 001) were significantly reduced among patients, whereas surface expression of GPIV was increased in patients (28273 vs. 16258 MEF; P < 0.001). In TRAP (10 micromol/l) stimulated whole blood, the MEF of P-selectin (9611 vs. 13293 MEF; P = 0.004) and CD63 (2385 vs. 5177 MEF; P < 0.001) and the ratio of PAC-1/GPIIb/IIIa MEF (0.98 vs. 2. 00; P < 0.001) was reduced in patients, indicating either a reduced granule GP content or an intrinsic cellular defect in receptor-mediated granule secretion and activation of the GPIIb/IIIa complex. Expressed as the relative change of MEF compared with unstimulated platelets, TRAP induced decrease of GPIb (7.8% vs. 45%; P < 0.001) and increase of GPIIb/IIIa (49.1% vs. 95.7%; P < 0.001) and GPIV expression (17.8% vs. 55.2%; P < 0.001) was attenuated in patients.

This study presents the first large clinical analysis of 105 unselected mantle cell lymphoma (MCL) patients diagnosed from 1992 to 2000 in a well-defined Danish population. The annual incidences were 0.7/100000 for men and 0.2/100000 for women, with no significant change during the study period. Of 97 evaluable cases, 43% achieved a complete response (CR) after initial therapy. The median disease-free (DFS) and overall survival (OS) rates were 15 and 30 months, respectively. In multivariate analysis, splenomegaly (P=0.002), anaemia (P=0.0001) and age (P=0.002), but not the international prognostic index (IPI) and the Ann Arbor staging system, had an independent impact on survival. Moreover, in a sub-analysis of 45 younger MCL patients (65 years), a trend towards an OS plateau of 58% was observed in cases without splenomegaly and anaemia (n=29). Thus, in contrast to previously suggested prognostic factors, these variables may prove useful for clinical decisions in a significant subset of MCL patients.

Platelet-leukocyte adhesion may occur as a consequence of platelet activation and possibly plays a key role in the deposition of activated platelets and fibrin in the thrombotic plug. The aim of the present study was to assess by whole blood flow cytometry the presence of circulating platelet-leukocyte aggregates (PLA) and the platelet-leukocyte response to platelet agonist stimulation (ADP and TRAP) in 50 patients with chronic myeloproliferative disorders (MPD) and 30 controls. PLA were identified as platelet-granulocyte/monocyte aggregates (PGMA), platelet-monocyte aggregates (PMA) and defined as the percentage of leukocytes coexpressing the platelet-specific marker glycoprotein Ib. Compared to controls the mean percentage of PGMA and PMA was increased in unstimulated whole blood from patients with MPD (7.98 vs. 1.76%; p0.001 and 12.34 vs. 3.2%; p0.001, respectively). The percentage of PGMA was correlated to the platelet count (r=0.46; p0.001), percentage of P-selectin (r=0.69; p0.001) and thrombospondin (r=0.58; p0.001) positive platelets and platelet expression of GPIV (r=0.33; p=0.02). The mean percentage of PGMA and PMA was significantly increased in ADP-stimulated whole blood of patients (57.14 vs. 47.92%; p=0.009 and 54.91 vs. 45.89%; p0.001, respectively). Compared to patients without a history of thrombosis, patients having experienced microvascular disturbances or a thrombotic event had a higher mean percentage of PGMA and PMA in non-stimulated whole blood (10.07 vs. 6.34%; p=0.025 and 14.81 vs. 10.48%; p=0.021, respectively) and a higher percentage of PGMA in ADP stimulated whole blood (64.32 vs. 51.50%; p0.01). These data document an increased frequency of PLA in non-stimulated whole blood in MPD associated with a previous history of thrombosis or microvascular disturbances.

Udgivelsesdato: 2000-Oct The INK4a/ARF locus at chromosome 9p21 encodes two structurally and functionally distinct molecules with tumor-suppressive properties. p16INK4a controls cell cycle progression by inhibiting phosphorylation of the retinoblastoma protein (Rb), while ARF prevents MDM2-mediated degradation of p53. By using a panel of PCR-based methods, we have examined the status of the p16INK4a, ARF and p53 genes in 123 cases of non-Hodgkin's lymphoma (NHL) at diagnosis. Alterations of one or more of these genes were detected in seven of 36 (19%) cases with low- to intermediate-grade histology, and in 35 of 87 (40%) cases with aggressive histology. For the aggressive lymphomas, the Kaplan-Meier estimate of overall survival for cases with disruption of either p16INK4a or the ARF-p53 pathway was not different from cases with retention of both pathways (5 year survival 45% vs 35%; P= 0.85), suggesting that selective inactivation of one of the pathways does not significantly influence overall survival. By contrast, the 5-year survival was only 7% for cases with concurrent disruption of p16INK4a and the ARF-p53 pathway vs 38% for cases with retention of one or both pathways (P = 0.005). Similar results were obtained when the analysis was confined to diffuse large B cell lymphomas (P= 0.019). On stepwise multivariate regression analysis including factors from the international prognostic index, concurrent disruption of p16INK4a and the ARF-p53 pathway was an independent negative prognostic factor in NHL with aggressive histology (P = 0.006). Our results suggest that the compound status of the p16INK4a and ARF-p53 pathways is a major determinant of outcome in NHL.

In an attempt to characterise the clinical features, incidence and outcome of essential thrombocythaemia (ET) we report our experience in a large unselected series of patients from a well defined region. All new cases of ET in the County of Copenhagen were registered during the period 1977-98. We identified 96 cases of ET, yielding an age- and sex-adjusted annual incidence rate of 0.59/100.000 and a point-prevalence at last follow up of 11/100.000. The overall incidence rate was 0.31 and 1.00 per 100.000 population during the consecutive periods 1977-89 and 1990-98, respectively, corresponding to a 3.2-fold increase. Median age at diagnosis was 67 yr (females 68 yr, males 66 yr, range 18-87 yr), and the female to male (F/M) ratio was 2.6:1. At diagnosis, 52% of the patients displayed no ET-related symptoms and were discovered fortuitously by a routine platelet count. Forty-eight percent presented with thrombohaemorrhagic phenomena, of which microvascular disturbances of the central nervous system (CNS), extremities and skin were most frequently observed (23%). Compared to patients diagnosed after 1989, patients diagnosed before 1990 had a significantly higher mean platelet count, white blood cell (WBC) count, lactate dehydrogenase (LDH) value and alkaline phosphatase value. With a median follow up of 70 months, 5-yr survival was 76%, significantly lower than the expected survival of an age- and sex-matched control group (p = 0.0052). Thirty-seven patients experienced a total of 55 thrombohaemorrhagic events during follow-up, corresponding to an incidence of thrombosis and microvascular disturbances or haemorrhage of 8.1% per pt-yr and 2.5% per pt-yr, respectively. The number of patients experiencing thrombosis or microvascular disturbances was significantly higher among the 29 patients who never received acetylsalicylic acid (ASA) compared to the 67 patients who received ASA during follow up (45% vs. 21%; p = 0.017). This study provides population-based data suggesting the benefit of treatment with low-dose ASA in a non-selected population of patients with ET.

Chronic myeloproliferative disorders (MPDs) are characterized by a high incidence of thrombohaemorrhagic complications, possibly caused by platelet dysfunction. In an attempt to define platelet functional abnormalities, we assessed the expression of activation-dependent membrane proteins in unstimulated and agonist [ADP and thrombin receptor-activating peptide (TRAP)]-stimulated platelets using quantitative whole blood flow cytometry in samples from 50 MPD patients and 30 controls. The receptor densities of activation markers and glycoproteins (GPs) were quantified using standardized fluorescent beads. Compared with controls, the mean percentage of P-selectin-positive (15.3% vs. 7.2%; P0.001) and thrombospondin (TSP)-positive (6.6% vs. 3.7%; P = 0.003) platelets was increased in unstimulated platelets from patients. Patients having experienced a thrombotic event had a higher mean percentage of TSP-positive non-stimulated platelets than patients without a history of thrombosis (9.0% vs. 4.6%; P = 0.02) and a higher GPIV molecules of equivalent fluorochrome (MEF) value (33113 vs. 24471 MEF; P = 0.02). Mean MEF values of monoclonal antibodies (mAbs) against GPIb (34055 vs. 38945 MEF; P0.001) and GPIIb/IIIa (1416 vs. 1648 MEF; P0. 001) were significantly reduced among patients, whereas surface expression of GPIV was increased in patients (28273 vs. 16258 MEF; P0.001). In TRAP (10 micromol/l) stimulated whole blood, the MEF of P-selectin (9611 vs. 13293 MEF; P = 0.004) and CD63 (2385 vs. 5177 MEF; P0.001) and the ratio of PAC-1/GPIIb/IIIa MEF (0.98 vs. 2. 00; P0.001) was reduced in patients, indicating either a reduced granule GP content or an intrinsic cellular defect in receptor-mediated granule secretion and activation of the GPIIb/IIIa complex. Expressed as the relative change of MEF compared with unstimulated platelets, TRAP induced decrease of GPIb (7.8% vs. 45%; P0.001) and increase of GPIIb/IIIa (49.1% vs. 95.7%; P0.001) and GPIV expression (17.8% vs. 55.2%; P0.001) was attenuated in patients.

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the number of granulocytes in peripheral blood and myeloid cells in the bone marrow were studied in seven patients with chronic lymphocytic leukemia (CLL). The neutrophil count in the peripheral blood rose by a median of 193% (range 142-980%), p = 0.02, and the increase persisted for more than 2 weeks after discontinuation of the treatment. The percentage of myeloid cells in bone marrow increased by 166% (range--57-1800%). In neutropenic CLL patients with recurrent infections GM-CSF treatment may constitute a new treatment modality.

Treatment with antibodies in patients with lymphoproliferative diseases was, until recently, limited to phase I studies due to limited response or subsequent development of anti-globulin response. The introduction of the hybridoma technique during the 1970s facilitated large scale production of antibodies, including the development of the Campath rat-antibodies. The epitope was launched against CD52, a glycoprotein present in large amounts on the surface of lymphocytes, and the primary use was in-vitro depletion of bone marrow from allogeneic bone marrow transplantation donors. The development of the human Campath-1H antibody was successful in 1988, leading to minimized anti-globulin response when used in vivo, and large multi-center studies were initiated. In this study we present an overview of the preclinical and clinical experiences with Campath-1H, including data from patients treated with the antibody in our clinic.

Survival from cancer in childhood and adolescence was studied in a population-based series of 8312 cases in children aged 0-19 years notified to the Danish Cancer Registry during 1943-87. During the first period (1943-72), 5-year survival rates from all malignant neoplasms increased from 23% (1943-52) to 33% (1963-72). The greatest improvement was seen during the period 1973-87 when 5-year survival rates reached 64% (1983-87). Between 1973-77 and 1983-87, 5-year survival rates increased from 32% to 62% for leukaemia, from 40% to 70% for acute lymphoblastic leukaemia, from 35% to 54% for non-Hodgkin's lymphoma, from 50% to 66% for central nervous system neoplasms and from 25% to 49% for bone tumours. An improvement in 5-year survival rates from Wilms' tumour was seen between 1960 (19%) and 1980 (81%). Up to 1972, the 5-year survival rate from germ-cell neoplasms was approximately 40%; among patients diagnosed in 1983-87, 76% survived for 5-years. Annual lethality decreased by 2.5% for all malignant neoplasms in 1943-72 and by 4.4% in 1972-87. Lethality was similar for boys and girls during the period 1943-72, but was significantly lower for girls subsequently. A marked effect of age at diagnosis was seen in the early registration period, where lethality rate for the age group 0-9 years was substantially higher compared with that in the age group 10-19 years. This inequality persisted only for children less than 2 years of age at the time of diagnosis in the later period.

Introduction This study examined socio-economic inequalities in survival after non-Hodgkin lymphoma, and to what extent any disparities were explained by differences in comorbidity, disease severity at the time of diagnosis, and the treatment given. Methods Registry-based nationwide cohort study based on 5738 persons diagnosed 2000-2008 from the Danish national lymphoma database and linked for individual socioeconomic information in Statistics Denmark. Results Long-term mortality was highest in patients with a short education as compared to those higher educated. The social difference among patient ≤80 years was increasing over time (p interaction =0.01). Thus, in the period 2000–2004 the HR among the short educated compared with the higher educated was 1.47 (95% CI 1.34 to 1.61) and increased to HR=1.70 (95% CI 1.37 to 2.11) in 2005–2008. However, no educational differences were seen among the oldest patients of 81 years and above. The educational gradient was attenuated by including comorbidity in the models, and further slightly attenuated by including lymphoma-specific prognostic factors (stadium, elevated lactatdehydrogenase, extranodal involvement). However, the educational gradient was still significant, as was the interaction with calendar period (p interaction =0.03). No socio-economic differences were found with respect to treatment with chemotherapy, radiation, or immunotherapy. Conclusion Differences in survival among NHL patients with different socio-economic position are partly caused by differences in comorbidity and the severity of disease at the time of diagnosis, while no differences in treatment were found. The increasing social gradient over time may be partly explained by a more pronounced decrease in lifestyle-associated comorbidity among higher social groups in recent years.

e18565 Background: The study is a multicenter phase II single arm efficacy and safety study of PXD 101 (belinostat, B) monotherapy in patients (pts) with relapsed/refractory peripheral T-cell lymph...

Patients with B cell chronic lymphocytic leukemia (B-CLL) have decreased capacity to mount relevant antibody responses upon immunization, and development of hypogammaglobulinemia is part of the natural history of the disease. We investigated the influence of histamine type-2 (H2) receptor blockade by ranitidine on the in vivo antibody production in B-CLL patients following vaccination. Anti-polysaccharide antibodies in B-CLL patients, vaccinated with a tetanus-toxoid conjugated vaccine against Haemophilus influenzae type-B (Hib), reached long-term protective levels in more than 90% of B-CLL patients randomized to ranitidine treatment, as compared to 43% of the untreated patients (P = 0.024). No difference in the response to vaccination against influenza virus types A and B protein could be detected between the two groups. Plasma histamine levels were 2-fold to 20-fold higher in 23 out of 31 B-CLL patients, compared to normal controls, and these levels showed a significant positive correlation to disease duration. These findings indicate the possibility of improving in vivo antibody production against a highly relevant pathogen in B-CLL patients by histamine type-2 receptor blockade, and the combined finding of an immune-stimulatory effect of ranitidine and increased plasma histamine levels, strongly suggests the involvement of histamine in the pathogenesis of B-CLL immunodeficiency.

In 1991 we reported the results from a prospective randomised phase 3 trial comparing 7 days continuous infusion of cytosine arabinoside (ara-C) combined with either daunorubicin (DNR) or aclarubicin (ACR) as direct i.v. injection for 3 days as induction chemotherapy (CT) for patients with de novo acute myeloid leukemia (AML) followed by early intensive consolidation CT with two alternating cycles of high-dose ara-C and two cycles of amsacrine plus etoposide, and finally 3 days of daunomycin plus 7 days of ara-C as administered for induction of remission. A total of 174 patients with de novo AML in the age group 17-65 years were included. The patients have now been followed till death or for at least 7 years, and an evaluation of the long-term survival and the risk of developing secondary neoplasms has been made. The overall survival rate 5-years after diagnosis was 23%, and after 10 years 19%. No difference was found between the two treatment regimens in overall survival or disease-free survival (DFS). For the subgroup of 99 patients who achieved complete remission after one or two induction courses, 5- and 10-year survival rates were 35% and 31% respectively, with the highest survival rates in the age group 17-39 years (57% at 5 years) as compared with 27% in patients aged 40-60 years (P= 0.007). Seven secondary neoplasms were diagnosed simultaneously with or after the diagnosis of AML indicating a standardized incidence ratio (SIR) of 3.41, (95% CI: 1.60-7.26). In three cases the secondary neoplasms were diagnosed simultaneously with the AML diagnosis and were for that reason completely unrelated to the chemotherapy administered for AML, as the psammomatous meningeoma diagnosed after only 8 months. The remaining three neoplasms which developed subsequently did not significantly exceed the expected number, with a SIR = 1.46 (0.47-4.57). Thus, no increased risk of solid tumors causally related to the intensive chemotherapy for de novo AML was observed. However, a generally increased risk of solid tumors in patients diagnosed simultaneously with the AML diagnosis seems likely. Over 20% of the patients were alive and in complete remission 5 years after the AML diagnosis, and they have a high probability of surviving the next 5-year period.