Michele Ghielmini

Aim: Clinical trials have led to a remarkable improvement of treatment outcome for patients with Hodgkin's lymphoma (HL) over the last 3 decades. Prognosis of patients enrolled in clinical trials may even be superior than the one of patients treated in the community. Since the mid 90ies, many patients with HL treated in our Institution have been prospectively included in the German Hodgkin Lymphoma Group (GHSG) trials. However, many other patients with HL have not been included in these trials for various reasons. Methods: We performed a retrospective population-based analysis using the electronic lymphoma database of our Institution and included all patients with HL from January 1996 to December 2012. Primary endpoint was OS which was defined according to the NCI criteria and estimated by the method of Kaplan–Meier. The Cox proportional hazards model was used for the estimation of hazard ratio and its confidence interval in a multivariate analysis. Results: 172 patients were identified. Clinical characteristics at diagnosis were: median age 38 years, 54% male, 13% stage I, 56% stage II, 15% stage III, 16% stage IV, 40% B symptoms, 10% GHSG early stage, 40% GHSG early unfavorable stage and 50% had GHSG advanced stage. With a median follow-up of 5.6 years, the 5-year overall survival of the whole studied population was 79%. The rate of enrollment in the GHSG trials in our Institution was 24%; participation of patients younger than 40 years in randomized trials was significantly higher compared with those older than 40 years. Patients entered in clinical trials had a significantly better outcome irrespectively of age (p = 0.0047). The inclusion in a clinical study maintained its prognostic value at a multivariate analysis in a Cox model controlling for age and for the GHSG risk group. Conclusions: This analysis suggests that patients enrolled in clinical trials may have a better outcome than patients with similar clinical characteristics at diagnosis. We plan to conduct a national survey in collaboration with the Swiss Cancer registries; the proposed research project may allow a better understanding of the different parameters behind this observation and their impact on treatment modalities and prognosis. Disclosure: All authors have declared no conflicts of interest.

Cancer patients receiving chemotherapy are at increased risk of venous thromboembolism (VTE). The presence of cancer and anticoagulant use are risk factors for bleeding, yet data on bleeding risk are limited in these patients. This analysis evaluated the risk of major bleeding in cancer patients receiving chemotherapy using a US claims database. This retrospective cohort study used the MarketScan^® databases, a nationwide database containing data from about 100 payers and covering > 30 million patients annually. Adult cancer patients receiving chemotherapy within 6 months of cancer diagnosis between January 2004 and December 2010 were included. Cancers of interest were: lung, colon/rectum, pancreas, bladder, stomach, and ovary. The index date was the first date of chemotherapy. Patients were followed until the earliest of: 1) first diagnosis of major bleeding; 2) termination of enrolment in the health plan; 3) end of study. The primary outcome was the first occurrence of major bleeding, based on selected ICD-9-CM/CPT codes, following chemotherapy initiation. Of 74,575 patients identified, exclusion of those with prior history of bleeding at baseline (∼5%) resulted in 70,822 patients included in the analysis. Mean age was 62 years, 37% were ≥ 65 years, and 52% were male. Average time of follow up and chemotherapy were 14.3 and 8.6 months, respectively; 6% had a history of VTE within 6 months prior to the index date. Major bleeding occurred in 5.8% of patients and the incidence rate for all cancers combined was 4.9 per 100 person-year (PY) and 10.5, 9.3, 6.2, 4.3, 3.6, and 3.3/100 PY for pancreatic, stomach, lung, bladder, colon/rectum, and ovarian cancer, respectively. Approximately 14% of patients (N = 10,456) developed VTE after chemotherapy initiation (> half in the first 3 months of chemotherapy treatment). Of these, 7.8% experienced major bleeding with incidence rates ranging from 5.9-17.7/100 PY after VTE. Major bleeding incidence in cancer patients receiving chemotherapy varies by cancer type with the highest rates in patients with upper gastrointestinal cancer. Compared to the overall cohort, major bleeding risk was higher in cancer patients who developed VTE.

Monoclonal antibodies (mAb) are one of the successes of modern cancer medicine, with rituximab the first to enter widespread clinical application following the demonstration of significant activity as a single agent, and superior results when combined with chemotherapy for a variety of CD20+ lymphoma types. In parallel to extensive clinical studies, we continue to uncover novel aspects of biology of the lymphoid cell surface. The molecules to which mAb have been targeted were identified several decades ago and few new ones have emerged recently, but there is now increasing interest in effector mechanisms, selective delivery of radionuclides or toxins, and bispecific molecules to target T- or NK- cells. Once thought of as a comparatively inert component of the cell membrane, CD20 is in fact a dynamic molecule. It can undergo rapid redistribution, and different mAb cause different effects: those like Rituximab (“type I”) elicit redistribution into lipid-rich rafts, mediate complement fixation and antibody-directed cell-mediated cytotoxicity (ADCC). In contrast, those like the first anti-B-cell mAb characterised, B1 (“type II”) do not cause redistribution into rafts but mediate homotypic cell adhesion and programmed cell death. These differences have important therapeutic results, and we have found that in lymphomas expressing the CD32 antigen (Fcgamma-R2b), type ImAb mediate rapid internalization of CD20 with lysosomal consumption, while type II do not. This has potential consequences for the therapeutic effect, as does the avidity with which mAb with different sugar groups bind to various Fc receptors. As well as radioconjugates, we are also returning to previously discarded approaches such as immunotxins, which have benefitted from advances in linker chemistry to improve their therapeutic ratio. Problems of toxin liberation and systemic toxicity have been largely overcome, and a new generation of conjugates is finding application in lymphoma therapy. Finally, the capacity to generate bispecific constructs that allow targeting of T-cells to the malignant cell surface holds the promise of harnessing cellular as well as humoral immunity. The initial promise of antibody therapy for lymphoma is already being fulfilled, and the next generation of compounds holds exciting challenges and great potential.

8065 Background: The F158V variant of the Fc gamma 3A receptor (FCGR3A) correlates with clinical response to rituximab. In SAKK 35/98 (NCT00003280), patients (pts) received rituximab induction therapy followed by observation or MT. Pts with a 158V/V genotype showed improved event-free survival. Further analyses of FCGR3A genotype and response to rituximab induction therapy and MT in this trial were conducted. Methods: 306 pts with indolent NHL [follicular (FL) or mantle cell] were treated with rituximab induction (375 mg/m² qw x4). Pts with stable disease, or partial or complete response at 12 weeks (N=212) were randomized to observation or MT. MT consisted of single injections of rituximab (375 mg/m²) every 2 months for 4 additional doses. FCGR3A genotype in FL pts from whom complete data were available (N=151) was analyzed for response at 12 and 52 weeks. Association of genotype with clinical endpoints was determined using the exact Cochran Armitage trend test. Results: Pts with 1 or 2 copies of the V allele (F/V, N=74 or V/V, N=26) demonstrated a 57% overall response rate (ORR) at 12 weeks compared to 39% in F/F pts (N=51; p=0.0412). The genotype effect on response was long-lasting; in the observation arm, V/V pts had a marginally higher ORR (58%) than V/F pts (54%), but much higher than F/F carriers (33%; p=0.20), and showed a greater clinical benefit (CR+PR+SD; 75% vs 54% vs 33%; p=0.028) when assessed at 52 weeks. In the maintenance arm, 89% of V/V pts achieved an ORR vs 68% of V/F pts, and 35% of F/F pts (p=0.0066). A similar pattern was identified for clinical benefit (89% vs 71% vs 41%; p=0.0114). Comparison between arms suggests that V/V pts benefit most from MT over observation (ORR 89% vs 58%), while F/F pts received the least benefit (ORR 35% vs 33%). Conclusions: These exploratory analyses expand upon previous findings that FCGR3A genotype correlates with response to induction treatment with rituximab in FL. Pts with 158V/V and 158F/V genotypes responded better to rituximab induction and MT than did pts with the 158 F/F genotype, suggesting that F/F pts may not benefit from rituximab MT. Studies are planned to validate the utility of FCGR3A genotyping in additional pts with FL.

15647 Background: Despite recent progresses in the treatment of advanced pancreatic cancer (PC), the prognosis remains poor and many patients are unsuitable for any anticancer treatment. Methods: Records of 220 patients (pts) with locally advanced (97) or metastatic (123) PC admitted to the Oncology Institute of Southern Switzerland from 1993 to 2007 were reviewed: 119 males and 101 females, mean age of 64 years (range 32–89); ECOG performance status 0: 20%, 1: 50%, 2: 20%, 3: 10%. First-line chemotherapy (CxT) was administered to 170 pts (77%): 115 received single agent Gemcitabine (GEM), 27 5-Fluorouracil (5-FU), 15 GEM/5-FU or Capecitabine (CAP), 4 GEM/Oxaliplatin, 9 were enrolled in phase I studies.Sixty-five pts were treated with second-line regimens: 20 with single agent Fluoropyrimidine, 17 GEM/5-FU or CAP, 11 GEM monotherapy, 11 XELOX or FOLFOX, and 6 enrolled in phase I studies. Best supportive care (BSC) was proposed in 85 pts after failure of first-line CxT. Twelve pts were suitable for third-line regimens: 9 were enrolled in phase I studies and 3 underwent Oxaliplatin-based CxT. Forty-six pts were managed with BSC. Results: Median overall survival (OS) for females was 7.1 months (mo) and 6.2 mo for males (p=0.83). OS was not significantly worse in pts older than 65 years as compared to younger pts (4.1 vs 3.2 mo, p=0.079). In 162 evaluable pts treated with first-line CxT, overall response rate (ORR; partial response and stable disease) was 38% for single agent GEM, 48% for 5-FU, 55% for GEM combinations; symptoms improvement was observed in 30%. Median OS was 8.6 mo for pts treated with a first-line CxT and 2.08 mo for those managed with BSC (p<0.0001). ORR for second-line monotherapy was 15% and 30% for combination regimens; pts receiving second-line CxT had a median OS of 13.3 mo. Conclusions: In our experience, pts suitable for CxT experienced a survival advantage and the extent of CxT lines might amplify this benefit. Therefore, we encourage the inclusion in clinical trials after failure of first-line CxT. No significant financial relationships to disclose.

Background: Predictive factors of rituximab efficacy and its effect on the immune system are still not defined. Patients and methods: Three hundred and six patients with follicular or mantle cell lymphoma received four weekly doses of rituximab (induction) and no further treatment (arm A) or four more doses at 2-month intervals (arm B). Results: Response rate to induction was 44%. Independent predictive factors for response were disease bulk Conclusions: We defined the characteristics predicting response and EFS to rituximab. Prolonged treatment results in longer EFS at the cost of a longer reduction in B cell and IgM levels, but without additional clinical toxicity.

6689 Background: This study was aimed to evaluate the treatment outcome of adult patients with acute myeloid leukaemia (AML) diagnosed in the Italian-speaking part of Switzerland from 1983 to 2003. Methods: Data were collected retrospectively for all adult patients diagnosed with AML in public hospitals and compared to tumour registry data to assess completeness. Univariate and multivariate analysis was performed to determine prognostic factors for progression-free survival (PFS) and overall survival (OS). Results: 132 AML patients were identified with an incidence of 2.1/100,000 per year. Complete clinicopathological data and follow-up information were available for 128 cases. Median age was 67 years. At a median follow-up time of 97 months the median OS was 6 months and the median PFS was 3 months. 35 patients were treated with supportive care only or palliative chemotherapy. The median OS for this group was 2 months. 93 patients were treated with myelosuppressive chemotherapy with curative intent. The CR-rate was 74% for patients younger than 60 years and 29% for those older than 60 years (p< 0.001) with a median OS of 16 and 6 months, respectively (p< 0.0005) and a median PFS of 8 and 2 months, respectively (p< 0.0005). Not surprisingly, survival was significantly longer (p< 0.0005) for the patients with less than 40 years (median OS, 55 months and median PFS, 54 months). 48 patients were treated in a controlled clinical trial: they were significantly younger than the others (median age 57 vs. 73 years, p<0.0005) and had a significantly better prognosis (median OS 13 vs. 4 months, p=0.0019). High dose Ara-C was given to 25 of 93 patients treated with curative intent and resulted in a OS advantage compared to standard dose (p<0.0005). Finally, patients treated after 1993 had a better OS (p= 0.026) compared to the previous cohort. A multivariate analysis performed excluding cytogenetic data (available only for 51 cases) found age (p= 0.005), PS (p= 0.001) and treatment before 1994 (p= 0.044) to be the independent prognostic factors for both OS and PFS. Conclusions: Young adults can be cured in appproximately half of the cases but the outcome for the general population of adult AML, which is mainly an elderly disease, remains disappointing. No significant financial relationships to disclose.