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Limited knowledge exists on the effectiveness of preventive preparedness plans for the care of outpatient cancer patients during epidemics or pandemics. To ensure adequate, timely and continuous clinical care for this highly vulnerable population, we propose the establishment of preventive standard safety protocols providing effective early phase identification of outbreaks at outpatient cancer facilities and communicating adapted standards of care. The prospective cohort study Protect-CoV conducted at the LMU Klinikum from mid-March to June 2020 investigated the effectiveness of a rapid, proactive and methodical response to protect patients and interrupt SARS-CoV-2 transmission chains during the first pandemic wave. The implemented measures reduced the risk of infection of individual cancer patients and ensured safe adjunctive infusion therapy in an outpatient setting during the early COVID-19 pandemic. In addition to the immediate implementation of standard hygiene procedures, our results underscore the importance of routine PCR testing for the identification of asymptomatic or pre-symptomatic COVID-19 cases and immediate tracing of positive cases and their contacts. While more prospective controlled studies are needed to confirm these results, our study illustrates the importance of including preventative testing and tracing measures in the standard risk reduction procedures at all out patient cancer centers.

The German study groups, the German Low-Grade Lymphoma Study Group (GLSG) and Ostdeutsche Studiengruppe Hamatologie und Onkologie (OSHO), initiated in 2007 a double randomized trial to investigate efficacy and safety of rituximab maintenance versus observation in remission after randomly assigned induction treatment in the first-line follicular lymphoma. Previously untreated patients with stage II-IV follicular lymphoma in need of therapy were randomized to receive 6 cycles of R-CHOP, R-MCP, or R-FCM. Responding patients were subsequently randomized to 2 years rituximab maintenance or observation, stratified by type of immunochemotherapy, quality of remission, and Follicular Lymphoma International Prognostic Index (FLIPI). Recruitment was stopped in 2011 after the PRIMA results had been published. Median age of the 206 recruited patients was 66 years (range, 24-86), and (FLIPI) was low in 13%, intermediate in 28%, and high in 60%. High and comparable overall response rates were observed after R-CHOP (88%), R-MCP (89%), and R-FCM (91%). Rituximab maintenance substantially prolonged progression-free survival (PFS) in comparison to observation in remission (hazard ratio 0.39, P = 0.0064). In the rituximab maintenance group, the 3-year PFS was 89% compared with 69% in the observation group. No differences in overall survival were observed for maintenance vs. observation (hazard ratio 1.04, 95% confidence interval 0.32-3.43, P = 0.95). In this randomized trial, 2 years of rituximab maintenance was associated with significantly prolonged PFS in comparison to observation after response to first-line immunochemotherapy in follicular lymphoma. Our data represent an independent confirmation of the PRIMA trial results. (Clinical Trial EudraCT Number: 2005-005473-29, 2006-09-26).

Summary Background Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome. Methods This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II–IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II–IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222. Findings Of 497 patients (median age 55 years [IQR 49–60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6·1 years (95% CI 5·4–6·4), time to treatment failure was significantly longer in the cytarabine group (median 9·1 years [95% CI 6·3–not reached], 5 year rate 65% [95% CI 57–71]) than in the control group (3·9 years [3·2–4·4], 40% [33–46]; hazard ratio 0·56; p=0·038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3·4%]) in both groups. Interpretation Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma. Funding European Commission, Lymphoma Research Foundation, and Roche.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

Purpose The GALLIUM study ( ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101; G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P; CHOP); CVP; or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety. Patients and Methods A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter ≥ 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m2 on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression. Results Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68; 95% CI, 0.54 to 0.87; P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63; 95% CI, 0.46 to 0.88; CHOP: HR, 0.72; 95% CI, 0.48 to 1.10; CVP: HR, 0.79; 95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles. Conclusion Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation.

Background: The clinical course of follicular lymphoma (FL) is characterized by a slow progression over years with continuous relapses despite good response to initial treatment. The median overall survival is 10 to more than 15 years. Standard therapy for patients requiring treatment consists of an anti-CD 20 antibody combined with chemotherapy followed by antibody maintenance. With this combination a 1-year-PFS of 93% was seen in the GLSG-2000 trial (Hiddemann et al, Blood 2005). Because of the substantial side effects of chemotherapy such as infections, secondary malignancies and impairment of the stem cell reserve novel "chemotherapy-free" treatment approaches could substantially improve the treatment tolerability in FL. The BTK-inhibitor ibrutinib has demonstrated promising activity in patients with iNHL, CLL and MCL. Anticipating the recent reports on a superior activity of obinutuzumab as compared to rituximab in the GALLIUM trial (Marcus et al., NEJM 2017), the GLSG initiated a phase II study combining ibrutinib and obinutuzumab to explore the efficacy and safety of this "chemotherapy-free" alternative. Methods: ALTERNATIVE is a prospective multicenter single-arm phase 2 study of the combination of ibrutinib and obinutuzumab in 98 patients with previously untreated FL and a high tumor burden (defined by modified GELF criteria) in need of treatment. Induction comprises 6 cycles of obinutuzumab at a dose of 1000 mg by intravenous infusion on days 1, 8, 15 of cycle 1 and on day 1 of cycles 2-6 to be given every 21 days. Ibrutinib is administered orally at a dose of 560 mg once daily throughout all 6 cycles. In patients with at least partial response (defined by Cheson Response Criteria 2007) after the end of induction, maintenance with obinutuzumab (1000mg every 8 weeks) plus ibrutinib (560mg daily) is given for an additional 24 months. In patients remaining MRD positive at 30 months ibrutinib is continued for another 12 months in an extended maintenance setting without obinutuzumab. The primary efficacy endpoint is the rate of investigator-assessed PFS one year after registration. Response rates at end of induction, after one year and after end of maintenance, duration of response, percentage of progression during induction and maintenance, time to treatment failure, overall survival, duration of molecular remission in MRD negative patients and safety are key secondary endpoints. Results: 98 patients with advanced stage FL were included, The median age was 59 years (29-81), 60% were male and 40% had a high risk FLIPI, 90% stage III/IV disease and 10% were stage II with a high tumor burden. Response to in induction was 90% (87/97) with 85% (82/97) PR and 5% (5/97) CR. 5 patients (5%) progressed during induction. Of the 82 patients with PR after end of induction, 8 patients achieved a CR during the first 6 months of maintenance treatment. 95 patients were evaluable for the primary endpoint of 1-year-PFS and 76 patients (80%) remained alive and free of progression at this timepoint. 18 patients progressed in the first year, two of whom died due to progressive disease. One additional death was caused by a non-lymphoma related event. An MRD-marker was found in 65 patients. MRD at the end of induction was evaluable for 63 patients. 44 patients (70%) were MRD negative after induction treatment. Of the 42 patients with follow-up MRD peripheral blood or bone marrow samples, 35 (83%) were MRD negative one year after registration. Therapy was generally well tolerated. Most common adverse events were diarrhea in 30% of patients, rash in 25% and fatigue and nasopharyngitis (common cold) in 23% and 20%, respectively. Concerning hematotoxicity grade 3-4 neutropenia and thrombopenia were seen in 8% and 4% of patients, respectively. Severe (>=grade 3) infectious complications were rare (6% pneumonia/bronchitis, 2% sepsis, 7% other infections). Conclusions: The chemotherapy - free combination of ibrutinib and obinutuzumab showed high anti-lymyphoma activity with high overall response rates and a high proportion of MRD negativity at one year. While the combination of ibrutinib and obinutuzumab was associated with a low toxicity profile, the combination was inferior to the published results of conventional immunochemotherapies in terms of the primary efficacy endpoint (1-year-PFS). Further evaluations might demonstrate whether subgroups exist which particularly benefit clinically from this low toxicity regime. Figure Figure. Disclosures Schmidt: Celgene: Honoraria; Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Buske:Bayer: Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Viardot:Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Keller:BMS: Consultancy; Roche: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; MSD: Consultancy; Celgene: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Hänel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Liersch:Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Dürig:Celgene: Honoraria; Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria. Hoster:Roche Pharma AG: Other: Travel support, Research Funding; F. Hoffman-La Roche: Other: Travel support, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Hiddemann:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding.

Purpose Mantle-cell lymphoma (MCL) is a distinct B-cell lymphoma associated with poor outcome. In 2008, the MCL International Prognostic Index (MIPI) was developed as the first prognostic stratification tool specifically directed to patients with MCL. External validation was planned to be performed on the cohort of the two recently completed randomized trials of the European MCL Network. Patients and Methods Data of 958 patients with MCL (median age, 65 years; range, 32 to 87 years) treated upfront in the trials MCL Younger or MCL Elderly were pooled to assess the prognostic value of MIPI with respect to overall survival (OS) and time to treatment failure (TTF). Results Five-year OS rates in MIPI low, intermediate, and high-risk groups were 83%, 63%, and 34%, respectively. The hazard ratios for OS of intermediate versus low and high versus intermediate risk patients were 2.1 (95% CI, 1.5 to 2.9) and 2.6 (2.0 to 3.3), respectively. MIPI was similarly prognostic for TTF. All four clinical baseline characteristics constituting the MIPI, age, performance status, lactate dehydrogenase level, and WBC count, were confirmed as independent prognostic factors for OS and TTF. The validity of MIPI was independent of trial cohort and treatment strategy. Conclusion MIPI was prospectively validated in a large MCL patient cohort homogenously treated according to recognized standards. As reflected in current guidelines, MIPI represents a generally applicable prognostic tool to be used in research as well as in clinical routine, and it can help to develop risk-adapted treatment strategies to further improve clinical outcome in MCL.

Purpose Mantle-cell lymphoma (MCL) is a rather aggressive B-cell malignancy whose considerable variability of individual outcome is associated with clinical characteristics (Mantle Cell Lymphoma International Prognostic Index [MIPI]). The Ki-67 index is a strong independent prognostic factor; however, the biologic MIPI (MIPI-b) distinguishes only two groups, which does not appropriately depict the clinical heterogeneity. By using the cohort from the European MCL Younger and MCL Elderly trials, we aimed to evaluate the additional prognostic impact of cytology and growth pattern and to improve risk stratification with the Ki-67 index and MIPI. Patients and Methods Diagnostic tumor biopsies were reviewed by the European Mantle Cell Lymphoma Pathology Panel to determine Ki-67 index by using published guidelines, cytology, and growth pattern. We evaluated prognostic effects for overall survival (OS) by Cox regression. For the cohort used for MIPI-b development (German Low-Grade Lymphoma Study Group [GLSG] 1996 and GLSG2000), we checked whether the equally weighted combination of Ki-67 index (dichotomized at the validated 30% cutoff) and MIPI risk groups was adequate and compared the prognostic power of this modified combination to MIPI and MIPI-b for the MCL Younger/MCL Elderly cohort. Results The Ki-67 index was assessed in 508 of 832 patients (median age, 62 years). Blastoid cytology was associated with inferior OS independently of MIPI but not independently of the Ki-67 index. Growth pattern was not independently prognostic. The modified combination of the Ki-67 index and MIPI separated four groups with 5-year OS: 85%, 72%, 43%, and 17% (P < .001) and was more discriminative than MIPI and MIPI-b. Conclusion Using the Ki-67 index is superior to using cytology and growth pattern as prognostic factors in MCL. The modified combination of the Ki-67 index and MIPI showed a refined risk stratification, reflecting their strong complementary prognostic effects while integrating the most relevant prognostic factors available in clinical routine.

Radioimmunotherapy in relapsed/refractory mantle cell lymphoma patients: final results of a European MCL Network Phase II Trial

BACKGROUNDThe long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission.METHODSWe randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression.RESULTSOf the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P = 0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P = 0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P = 0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P = 0.005).CONCLUSIONSR-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.)

Follicular lymphoma (FL), the most common indolent lymphoma, typically presents in advanced-stage disease. Currently available therapy does not generally result in a curative outcome, but survival in FL has improved since the introduction of anti-CD20 monoclonal antibody immunotherapy. The goals of treatment include prolongation of survival and effective palliation of symptoms while limiting the duration of therapy to minimize adverse effects and reduce costs. Multiple rounds of treatment over many years characterize the clinical course for most patients with FL. Rituximab in combination with chemotherapy has been shown to improve overall survival in patients with FL compared with chemotherapy alone. Rituximab maintenance further improves disease control in patients with FL after a successful induction therapy in both first-line treatment and relapse. Consolidation with radioimmunotherapy is an innovative treatment approach to increase rates of complete remission and duration of remission. Here we summarize the data from actual trials and the resulting treatment indications.

Introduction: Advanced follicular lymphoma (FL) is a clinically and molecularly heterogeneous disease. About 20% of patients have early progression of disease (POD) and short overall survival (OS). We have previously shown that integration of lymphoma-specific gene mutations and clinical factors improves pretreatment risk stratification (Pastore, 2015) and prediction of early POD (i.e., within 24 months, POD24; Jurinovic, 2016). Recently, we have shown that high-dose therapy (HDT) followed by autologous stem-cell transplantation (ASCT) is an effective treatment option for eligible patients with high-risk disease as defined by POD24 (Jurinovic, 2018). Here, we aimed to explore whether HDT/ASCT is an effective frontline therapy for patients identified to be high-risk by clinical (i.e., FLIPI) or clinicogenetic risk models (i.e., m7-FLIPI, POD24-PI). Methods: We performed targeted DNA deep-sequencing of >150 genes in available diagnostic FL biopsies from 165 patients ≤60 years with advanced FL from the GLSG2000 trial who uniformly received R-CHOP as frontline treatment. Of these, 87 patients (53%) were randomized to receive consolidative HDT/ASCT, 78 (47%) were randomized to interferon maintenance. We performed intention-to-treat (ITT) survival and regression analyses to explore whether known clinical and clinicogenetic risk factors can be overcome by ASCT. Results: The HDT/ASCT and no-HDT/ASCT cohorts were balanced regarding age (48 vs 50 years), sex (49% vs 64% male patients), high-risk FL International Prognostic Index (FLIPI; 25% vs 29%), Eastern Cooperative Oncology Group Performance Score >1 (6% vs 5%) and mutation status of EZH2 (23% vs 18%) and TP53 (3% vs 3%). The incidence of POD24 was not significantly lower in the HDT/ASCT cohort (8% vs 14%, p=0.32). After a median follow-up of 7.5 years, 5-year failure-free survival (FFS) rates in the HDT/ASCT and no-HDT/ASCT cohorts were 77% and 69% (HR 0.7, p=0.16), 5-year OS rates were 95% and 90% (HR 0.6, p=0.21), respectively. The high-risk cohorts identified by FLIPI, m7-FLIPI, and POD24-PI comprised 27% (n=45), 18% (n=29) and 22% (n=37) of patients, respectively (Fig. A). The m7-FLIPI reclassified 10% (n=16) of patients from high-risk FLIPI to low-risk m7-FLIPI. The POD24-PI reclassified 5% (n=9) of patients from high-risk FLIPI to low-risk POD24-PI; one patient was reclassified from low-risk FLIPI to high-risk POD24-PI. Patients identified to be high-risk by all three indices had shorter FFS (FLIPI: HR 2.8, p=0.0002; m7-FLIPI: HR 3.0, p=0.0003; POD24-PI: HR 2.5, p=0.0013), but OS was not different (FLIPI: HR 1.4, p=0.47; m7-FLIPI: HR 1.5, p=0.45; POD24-PI: HR 1.5, p=0.47). The risk to develop POD24 was increased in high-risk patients (FLIPI: OR 4.4, p=0.007; m7-FLIPI: OR 4.8, p=0.005; POD24-PI: OR 4.3, p=0.008). Consolidative HDT/ASCT did not prolong FFS in high-risk patients as defined by FLIPI (HR 1.2, p=0.67), m7-FLIPI (HR 1.2, p=0.70; Fig. B) and POD24-PI (HR 1.3, p=0.63; Fig. B). Similarly, OS was not significantly improved in all three high-risk cohorts (FLIPI: HR 0.2, p=0.13; m7-FLIPI: HR n/a, p>0.99; and POD24-PI: HR 0.3, p=0.22). In low-risk patients, HDT/ASCT was associated with a non-significant trend towards prolonged FFS (FLIPI: HR 0.5, p=0.061; m7-FLIPI: HR 0.6, p=0.16; POD24-PI: HR 0.5, p=0.068; Fig. B), but again OS was not significantly different (FLIPI: HR 0.8, p=0.69; m7-FLIPI: HR 0.8, p=0.66; and POD24-PI: HR 0.7, p=0.52). Conclusions: Our ITT-analysis confirms that consolidative HDT/ASCT should not be offered to unselected cohorts of patients with previously untreated, advanced FL after R-CHOP. Also, our current clinicogenetic risk models are not optimized to select high-risk patients who may benefit from frontline HDT/ASCT. The fraction of patients identified to be high-risk by FLIPI, m7-FLIPI and POD24-PI is low when applied to younger, medically fit patients. Moreover, the fraction of patients being reclassified by integrating gene mutation data is low in this patient cohort. Therefore, we are developing specific stratification algorithms for younger, medically fit patients who are eligible for dose-intensified approaches. Figure. Figure. Disclosures Klapper: F.Hoffman-La Roche: Honoraria, Research Funding; HTG Molecular Diagnostics, Inc.: Research Funding; Regeneron: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Hess:CTI: Research Funding; Celgene: Consultancy, Honoraria, Other: travel expenses, 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; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Unterhalt:F. Hoffman-La Roche: Other: Travel support. Dreyling:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Hoster:F. Hoffman-La Roche: Other: Travel support, Research Funding; Roche Pharma AG: Other: Travel support, Research Funding. Hiddemann:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La 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; Bayer: Consultancy, Research Funding. Weigert:Roche: Research Funding; Novartis: Research Funding.

Background: Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths. Difficulties to diagnose HCC at early stages remain the major obstacle to curative (surgical) therapy. Therapy in advanced stages has to be considered palliative. In this situation, a considerable amount of attention should be paid to innovative treatment strategies, e.g. including antiangiogenetic drugs. Results: We report on the successful treatment of a patient suffering from progressive HCC with a novel drug (EndoTAG®-1, formerly named LipoPac®) currently investigated in phase II studies. This drug consists of liposomally encapsulated paclitaxel. Its liposomal formulation favors the drug’s adherence to the tumor neovasculature, in effect starving the tumor. Conclusions: EndoTAG®-1 stopped tumor progression for 9 months in our patient. This, along with successes observed testing this drug against other indications, makes it a suitable candidate for future clinical trials.

Follicular lymphomas are considered incurable, but most patients survive for many years. The introduction of rituximab into the treatment of malignant lymphomas of the B-cell lineage has had a major impact on the management of these diseases. Numerous studies confirm the benefit of rituximab, in monotherapy and in combination with chemotherapy, in regard to remission rate, remission duration, and overall survival. To further improve the treatment results, rituximab has been applied as maintenance therapy after induction with rituximab alone or with immunochemotherapy including rituximab. This article reviews the trials that have incorporated rituximab maintenance in the treatment of patients with follicular lymphoma.

Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2x2.0x106/kg bw CD34+ was required for ASCT. Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma. In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P=0.0003). In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.

Purpose Mantle cell lymphomas (MCLs) represent a clinically aggressive lymphoma subtype with a poor prognosis. To explore a potential progress in outcome a historical comparison was performed using data from the Kiel Lymphoma Study Group (KLSG; 1975 to 1986) and the German Low Grade Lymphoma Study Group (GLSG; 1996 to 2004). Patients and Methods All patients with the histologically confirmed diagnosis of advanced-stage nonblastoid MCL were eligible. To minimize the potential heterogeneity of different risk profiles frequency matching was pursued. In addition, we adjusted for potential confounding variables by multiple Cox regression. Results A total of 520 patients were assessable, 150 from KLSG and 370 from GLSG studies. The median overall survival was 2.7 years for KLSG patients as compared with 4.8 years for GLSG patients (P < .0001). The 5-year survival rates were 22% in the KLSG group (95% CI, 13% to 31%) as compared with 47% for GLSG treated patients (95% CI, 38% to 55%). The hazard ratio adjusted for performance status, lactate dehydrogenase, and age was 0.44 for GLSG patients (95% CI, 0.32 to 0.59). Conclusion Median overall survival of patients with advanced nonblastoid MCL almost doubled during the past 30 years. Potential reasons for this apparent improvement in overall survival include the application of anthracycline-containing regimens and new approaches, such as antilymphoma antibodies or stem cell transplantation. Advances in general supportive care, new diagnostic tools, and general improvement of life span might have also reinforced this effect. However, our results are questioning the validity of historical comparisons which had been frequently applied in previous trials.

Introduction: Immunochemotherapy has become the standard of care for patients with mantle-cell lymphoma (MCL) (Dreyling et al., ESMO recommendation for MCL, 2013). Previously, the German Low-Grade Lymphoma Study Group (GLSG) has shown in a randomized trial (GLSG2000) that the addition of rituximab to CHOP improves response rates in untreated advanced stage MCL patients (Lenz et al., JCO 2005). However, the trial was not powered to detect survival differences. Since 1996, patients with MCL have been included in the two consecutive randomized trials GLSG1996 (CHOP vs. MCP, Nickenig et al., Cancer 2006) and GLSG2000. Based on the mature pooled data of these trials we now aimed to compare the long-term clinical outcome of MCL patients treated with CHOP with or without rituximab. Methods: Induction treatment consisted of 4-6 cycles of MCP, CHOP, or R-CHOP. Patients younger than 66 years were subsequently randomized to either myeloablative consolidation and autologous stem cell transplantation, or interferon-alpha maintenance in the first European MCL Trial (Dreyling et al., Blood 2005), whereas older patients were designated to interferon-alpha maintenance. In 1998, randomization between CHOP and MCP (GLSG1996) was stopped due to superior response rates and more effective stem cell mobilization after CHOP, and all subsequently recruited patients were assigned to CHOP. Similarly, in 2002, randomization between CHOP and R-CHOP (GLSG2000) was stopped because of superior response rates after R-CHOP, and all subsequently recruited patients were assigned to R-CHOP. For the current evaluation, we included MCL patients prospectively assigned to either CHOP (GLSG1996 or GLSG2000) or R-CHOP (GLSG2000). We performed an intention-to-treat analysis comparing failure-free (failure: stable disease, progression, or death from any cause) and overall survival (OS) of patients prospectively assigned to R-CHOP versus CHOP, adjusting for potential imbalances in clinical risk profile based on the MIPI score (Hoster et al., JCO 2014). Results: From 1996 to 2004, 386 MCL patients have been prospectively assigned to R-CHOP (185) or CHOP (201). Clinical characteristics were comparable with median age 62 vs. 61 years for R-CHOP vs. CHOP groups, and 40% vs. 42% low risk, 38% vs. 36% intermediate risk, and 22% vs. 21% high risk MIPI. The R-CHOP group showed higher overall response (91% vs. 80%) and complete remission rates (25% vs. 15%). Median failure-free survival was 2.1 compared to 1.4 years (Figure 1, left panel) with adjusted hazard ratio 0.62 (95% CI 0.50-0.78, p Conclusions: After longer follow-up, pooled data of prospective GLSG trials showed prolonged survival by the addition of rituximab to CHOP induction in previously untreated MCL patients. Our results confirm the recommendation for immunochemotherapy as standard treatment for MCL. Compared to previous observations, clinical outcome for MCL patients has improved; however, further improvement by the introduction of more potent chemotherapy (e.g. high-dose cytarabine) or new targeted approaches is urgently warranted. Figure 1: Failure-free (left) and overall survival (right) of patients prospectively assigned to R-CHOP or CHOP in GLSG1996 or GLSG2000 trials Figure 1:. Failure-free (left) and overall survival (right) of patients prospectively assigned to R-CHOP or CHOP in GLSG1996 or GLSG2000 trials Figure 2 Figure 2. Disclosures Hoster: Roche: Travel Support Other. Off Label Use: Rituximab in mantle-cell lymphoma. Unterhalt:Roche: Travel Support Other. Hallek:Roche: Consultancy, Research Funding. Klapper:Roche: Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Although little progress has been made in the treatment of follicular lymphomas (FL) within the last few decades, several new therapeutic modalities have recently demonstrated promising activity. These include myeloablative therapy followed by autologous stem cell transplantation in younger patients in first remission revealing a significant prolongation of remission duration in three prospective randomized trials, whereas the impact on overall survival still needs to be determined. Adding the anti-CD20 antibody rituximab to conventional chemotherapy resulted in a significant increase in remission rate, remission duration and in two of four currently available prospective randomized studies even in a longer overall survival. A prolongation of remission duration was also seen when rituximab was administered as maintenance after cytoreductive therapy or by prolonged application as a single agent. Radioimmunotherapy (RIT) with radioisotopes coupled to monoclonal antibodies revealed encouraging data in several phase II studies. Prospective randomized studies are warranted, however, to define the impact of RIT on FL therapy. New therapeutic perspectives also emerge from increasing insights into the biology of the disease that unravel molecular targets for novel agents, some of which have entered clinical evaluation already.

In follicular lymphoma (FL) and mantle cell lymphoma (MCL) the monoclonal antibody rituximab may improve the prognosis when combined with chemotherapy. This was investigated in a prospective randomized study in patients with relapsed disease. A total of 147 patients were randomized to receive 4 courses of chemotherapy with 25 mg/m2 fludarabine on days 1 to 3, 200 mg/m2 cyclophosphamide on days 1 to 3, and 8 mg/m2 mitoxantrone on day 1 (FCM), alone or combined with rituximab (375 mg/m2; R-FCM). Of 128 evaluable patients, 62 were randomized for FCM and 66 for R-FCM. RFCM revealed an overall response rate of 79% (33% complete remission [CR], 45% partial remission [PR]) as compared with 58% for FCM alone (13% CR, 45% PR; P .01), with similar results in a subgroup analysis of FL (94% vs 70%) and MCL (58% vs 46%). In the total group, the R-FCMarmwassignificantlysuperiorconcerning progression-free survival (PFS; P .0381) and overall survival (OS; P .0030). In FL PFS was significantly longer in the R-FCM arm (P .0139) whereas in MCL a significantly longer OS was observed (P .0042). There were no differences in clinically relevant side effects in both study arms. Hence, the addition of rituximab to FCM chemotherapy significantly improves the outcome of relapsed or refractory FLand MCL. (Blood. 2004;104:3064-3071)

Conventional chemotherapy has failed to substantially prolong survival for patients with advanced follicular lymphoma. To improve outcomes, the German Low-Grade Lymphoma Study Group (GLSG) initiated a randomized trial to compare the effect of potentially curative myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) with interferon-alpha (IFN-alpha) maintenance therapy in first remission. Three hundred seven patients (younger than 60 years) with follicular lymphoma were recruited into the trial from 130 institutions. After 2 cycles of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) or mitoxantrone-chlorambucil-prednisone (MCP) induction chemotherapy, patients were randomly assigned to either the ASCT or the IFN-alpha group. The respective therapy was started when patients achieved complete or partial remission after induction chemotherapy. Two hundred forty patients with follicular lymphoma are evaluable for the comparison of ASCT and IFN-alpha. In patients who underwent ASCT, the 5-year progression-free survival (PFS) rate was 64.7%, and in the IFN-alpha arm it was 33.3% (P < .0001). As expected, acute toxicity was higher in the ASCT group, but early mortality was below 2.5% in both study arms. In this randomized, multicenter trial, high-dose radiochemotherapy followed by ASCT significantly improved PFS compared with IFN-alpha in patients with follicular lymphoma when applied as consolidation in first remission. Longer follow-up is necessary to determine the effect of ASCT on overall survival.

Pegfilgrastim is composed of the protein filgrastim to which a 20-kDa polyethylene glycol (PEG) is covalently bound at the N-terminal residue resulting in decreased renal clearance and increased plasma half-life compared with filgrastim. This open-label, randomized, phase 2 study compared two doses of single administration pegfilgrastim (60 and 100 microg/kg) with daily doses of filgrastim (5 microg/kg/day) or no cytokine treatment after standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy for non-Hodgkin's lymphoma in 50 elderly patients. The primary endpoint was the duration of grade 4 (severe) neutropenia (absolute neutrophil count0.5 x 10(9)/l) in cycle 1. Duration of grade 4 neutropenia in cycle 1 was 2.2 (SD 1.2), 1.5 (SD 1.1), 0.8 (1.2) and 5.0 (2.0) days for patients who received pegfilgrastim 60 microg/kg, pegfilgrastim 100 microg/kg, filgrastim 5 microg/kg and no cytokine, respectively. The baseline characteristics of the pegfilgrastim and filgrastim groups were imbalanced with increased bone-marrow involvement and prior therapy in the former. When the treatment groups were balanced for these risk factors, duration of grade 4 neutropenia was comparable with 2.0 and 3.0 vs. 0.6 and 0.5 days for pegfilgrastim 100 microg/kg and filgrastim patients with and without these risk factors, respectively. The incidence of febrile neutropenia (defined as ANC0.5 x 10(9)/l and temperature38.2degrees C) was low (10% of patients). Pegfilgrastim was well tolerated with a safety profile similar to daily filgrastim. Once per chemotherapy cycle administration of pegfilgrastim was comparable to filgrastim in this clinical setting.

Summary Background Docetaxel (Taxotere®) has demonstrated high antitumour activity in first- and second-line treatment of metastatic breast cancer. This study analysed the efficacy and toxicity of docetaxel given weekly. Patients and methods Thirty-five patients with metastatic breast cancer received docetaxel, 35 mg/m2 weekly for six weeks, followed by two weeks without treatment. Additional cycles (three weeks’ treatment, two weeks’ rest) were given until disease progression. All patients had received prior chemotherapy: 32 and 5 patients had received prior anthracycline-containing and taxane-containing regimens, respectively. Docetaxel was administered for a total of 359 doses (median 9, range 6–22). Results There was one complete response (3%), 11 partial responses (31%), 17 patients with stable disease (49%) and six with disease progression (17%). Overall response rate was 34% (95% confidential interval (95% CI): 18%–51%). Median survival was 307 days; median progression-free survival was 2.6 months (range 1.5 to ≥ 5.5 months). Three patients showed grade 3 neutropenia. 14 showed grade 3 alopecia, and various grade 1–2 non-haematological toxicities were observed. Treatment was delayed in two patients due to haematotoxicity, and stopped in one patient due to painful nail toxicity. Conclusion Weekly administration of docetaxel at a dose of 35 mg/m2 is effective and of low toxicity in patients with metastatic breast cancer.

Primary effusion lymphoma (PEL) is a very rare type of lymphoma that is usually confined to the body cavities such as the pleural space, pericardium and peritoneum. PEL is associated with human herpes virus-8 (HHV-8) infection and commonly observed in HIV-infected patients. We present a case of PEL confirmed by pathology without effusion in a 38-year-old man at initial HIV diagnosis. A 38-year-old man presented with a right axillary swelling, restricted arm movement and chest pain for 3 weeks. He reported weight loss of 4 kg and night sweat without fever and/or chills. On physical examination, we found enlarged neck and axillary lymph nodes with a diameter of 3 cm, movable and hard presentation without tenderness. Elevation of the right shoulder was restricted to 20° with intact circulation and sensitivity. Lab reports showed …

Background The anti-CD20 antibody rituximab has dramatically changed the treatment paradigms for advanced stage follicular lymphoma (FL) and has improved overall survival. The question whether myeloablative treatment followed by autologous stem cell transplantation (ASCT) in first remission may add further benefit in the era of initial rituximab-chemotherapy induction remains currently unsolved. Methods We report on the long-term outcome of 940 patients, randomized for treatment with ASCT versus IFN-alpha maintenance in first remission after initial therapy with MCP, CHOP or R-CHOP in two consecutive randomized trials for patients with advanced stage FL of the GLSG . Results A total of 472 patients, (38 with initial MCP therapy, 199 with initial CHOP therapy and 224 with initial R-CHOP therapy, 13 not documented), were randomized to receive ASCT. The remaining 468 patients were randomized for IFN-maintenance (39 with MCP, 201 with CHOP and 219 with R-CHOP, 7 not documented). The patient characteristics, the initial therapy and the quality of remission were well balanced between ASCT and IFN-maintenance. After a median follow up of 8.3 years 454 pts randomized for IFN-maintenance and 445 pts randomized for ASCT were evaluable for treatment failure. The estimated failure free survival at 10 years was 32% (95% CI 0.26-0.37) for IFN-alpha maintenance and 51% (95% CI 0.45-0.57) for ASCT. For patients assigned to CHOP or MCP (no rituximab during induction) the estimated failure free survival after 10 years was 18% for IFN-maintenance and 45% for ASCT (hazard ratio 0.49, 95% CI 0.39-0.61). Among the 423 evaluable patients assigned to R-CHOP the estimated failure free survival at 10 years was 53% for IFN-maintenance and 58% for ASCT (hazard ratio 0.77, 95% CI 0.56-1.07). Conclusions After a median follow up of more than 6 years in 423 patients assigned to R-CHOP, only a small improvement in time to treatment failure could be observed for ASCT compared to IFN-alpha maintenance. This is in strong contrast to patients treated with chemotherapy only (figure 1). The promising results for ASCT observed in the pre-rituximab era cannot be confirmed after initial immuno-chemotherapy. Since the use of ASCT is hampered by relevant toxic side effects, the actual data suggest that ASCT for patients with follicular lymphomas in first line therapy is of questionable benefit. Disclosures: Hiddemann: Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Dreyling:Roche: Honoraria, Research Funding. Hoster:Roche: Honoraria, Travel Support Other. Unterhalt:Roche: Travel Support Other.

Background Great efforts have been made in the last years to improve the therapeutical options of patients with mantle cell lymphoma (MCL), a distinct lymphoma subtype characterized by dismal long term prognosis. Although radioimmunotherapy (RIT) has been shown to be effective in follicular lymphoma, only one single-center experience of 31 evaluable patients has been published so far in relapsed MCL [Wang et al., JCO 2009]. The European MCL Network conducted a phase II, prospective, multicenter trial evaluating a single dose of yttrium-90-ibritumomab tiuxetan (90Y-IT) as reinduction or consolidation in patients with relapsed or refractory MCL. Patients and Methods Relapsed or refractory MCL patients after or not eligible for autologous stem cell transplantation (ASCT) with Results Between June 2004 and September 2008, 48 eligible patients were enrolled (16 group A, 32 group B) and 45 are evaluable for response. Median age was 68 years, 75% were males. Seventy-three % presented with high or intermediate risk MCL international prognostic index (MIPI), 42% with elevated lactate dehydrogenase, and 29% had bulky disease. Median number of previous therapies was 2 (range 1-5) in group A and 4 (range 1-6) in group B; 98% of patients received prior rituximab, 29% prior radiotherapy, 13% prior ASCT, 0% prior new agents and 15% had chemorefractory disease. The major toxicities consisted of myelosuppression, with thrombocytopenia in 21 patients (53%), neutropenia in 13 (33%) and anemia in 9 (23%; all grade 3/4, respectively), and one lethal bleeding. Non-hematologic grade 3/4 toxicities were gastrointestinal (n=3), infectious (n=1), and neurological (n=1), with a single patient (2%) developing a secondary myelodysplasia. Overall response rate (ORR) was 40% (20% CR) in group A and 72% (38% CR) in group B, with 5 patients converting from PR to CR. After a median follow-up of 38 months (range: 24-53 months), median PFS was 3.7 months in group A and 8.9 months in group B, translating in a median OS of 13.8 months and 31.2 months, respectively (Figure 1). In the 25 90Y-IT responders, PFS and OS were 23 months and 33.7 months, respectively, and patients responding to immunochemotherapy (group B) also showed a more favorable time to progression (16.9 months). No difference in survival rates was noticed according to MIPI, bulky disease, number and type of previous therapies, chemorefractoriness, and median time from initial diagnosis. Conclusions To the best of our knowledge, this is the largest trial assessing 90Y-IT therapy in relapsed/refractory MCL patients. Response rates in heavily pre-treated patients were comparable to those of other targeted approaches, though 90Y-IT showed a more favorable toxicity profile. Our experience suggests, that RIT applied as consolidation therapy might be the preferred approach, seeming to improve the quality and duration of response. Finally, responses appear to be independent from established risk factors and previous therapies. Further evaluation of the role of 90Y-IT in first-line therapy of MCL patients is ongoing. Disclosures: Off Label Use: Zevalin for treatment of relapsed mantle cell lymphoma. Scholz:Bayer: Speakers Bureau; Spectrum: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Keller:Sepropharm: Consultancy. Dreyling:Jannsen: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, support of ITS, support of ITS Other; Celgene: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, support of ITS Other; Pfizer: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, support of ITS , support of ITS Other; Roche: Speakers Bureau, support of ITS , support of ITS Other; Mundipharma: support of ITS Other.

4072 Background: The rationale of the NeoFLOT-trial was the intensification of neoadjuvant chemotherapy (NACT) by prolongation of preoperative treatment. This strategy is based on the notion that while perioperative treatment is notably beneficial in locally advanced gastroesophageal cancer (GEC), postoperative chemotherapy can only be applied in a fraction of patients (pts). Methods: Pts with T3, T4 and/or N+ adenocarcinoma (GEC) were eligible for this multicenter phase II trial. NACT consisted of 6 cycles of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, fluorouracil 2600 mg/m2 and docetaxel 50 mg/m2 (FLOT) applied q 2 wks. Staging was performed after 3 cycles to select pts with progressive disease (PD) for immediate surgery. Primary endpoint was the R0-resection rate. Secondary endpoints included the pathological complete response rate (pCR), histologic tumor regression grade (Becker 2003), safety, and progression-free survival (PFS). Results: From 10/2009 to 06/2011, 59 pts were enrolled of whom 58 pts were assessable for safety. Median age was 61 years (range: 32-79), 58.6% (34/58) had tumors of the gastroesophageal junction. 50 pts underwent surgery and were assessable for the primary endpoint. R0-resection rate was 86.0% (43/50). pCR was achieved in 20.0% (10/50) of pts. During NACT, 6.9% (4/58) of pts developed progressive disease. Dose reduction was performed in 43.1% (25/58) of pts resulting in a median dose intensity of 89.2%. Grade 3/4 neutropenia was observed in 29.3% (17/58) of pts, febrile neutropenia grade 3/4 in 1.7% (1/58). Common grade 3/4 non-hematologic adverse events were diarrhea (13.8% (8/58)) and mucositis (6.9% (4/58)). Treatment related mortality was 3.4% (2/58) with 2 cases of sepsis. After a median follow-up of 9.1 months, median PFS and OS have not been reached. Conclusions: These data indicate that NACT with 6 cycles FLOT is well-tolerated and highly effective in resectable GEC.

Abstract 439 Introduction. The prognosis of elderly patients with mantle cell lymphoma (MCL) is poor. Despite R-CHOP, only low rates of complete remissions (CR) are obtained and almost all patients relapse. Median overall survival (OS) used to be far below 5 years. Within the European MCL Network we performed a randomized intergroup trial to investigate both whether a fludarabine-containing induction regimen could improve the CR-rate, and whether maintenance with rituximab could prolong remission duration. Methods. Patients with stage II-IV MCL >60 yrs not eligible for high-dose therapy were randomized between either 8 × R-CHOP-21 (day 1: rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, max 2 mg and day 1–5 prednisone 100 mg) or 6 × R-FC-28 (rituximab 375 mg/m2 day 1, fludarabine 30 mg/m2 + cyclophosphamide 250 mg/m2, both iv day 1–3). Responding (CR, CRu, PR) patients underwent a second randomization between maintenance with rituximab one dose every 2 months or interferon-alfa (IFN; regular IFN weekly 3×3 MIU or pegylated IFN 1×1 μg/kg), both given until progression. First randomisation for induction therapy - R-CHOP vs R-FC: Between Jan 2004 and Oct 2010, 560 patients were entered; 457 were evaluable for response to induction. Median age was 70 yrs, 70% male, 83% stage IV, 41% intermediate and 50% high-risk MIPI. Whereas CR rates after R-FC and R-CHOP were similar (38 vs 34% CR, 52 vs 50% CR/CRu, respectively), the overall response rate was lower after R-FC (78% vs 87%; p=0.0508). Progressive disease was more frequent during R-FC (15% vs 5%). Of note, median OS was significantly inferior after R-FC (40 vs 64 months; p=0.0072). More patients died after initial progression (14% vs 4%) or in first remission (11% vs 3%) in the R-FC arm compared to R-CHOP. Hematologic grade 3–4 toxicities were more frequent during R-FC, especially thrombocytopenia (40% vs 17%). Non-hematologic grade 3–4 toxicity was rare (below 7% each), except neutropenic fever (12% R-FC; 18% R-CHOP) and infections (16% R-FC; 14% R-CHOP). Second randomisation for maintenance therapy - Interferon-alpha vs Rituximab: From the responding patients, 310 underwent the second randomization. Sixty-one percent of patients had a CR/CRu upon induction therapy. Fifty-eight percent had received R-CHOP induction. Rituximab maintenance almost doubled the remission duration compared with IFN (at 4-yrs 57% vs 26% in remission; HR 0.54, 0.35–0.87; p=0.0109). Overall survival did not differ between both maintenance arms (p=0.17). However, the subcohort of R-CHOP-treated patients showed a significant advantage after rituximab maintenance (4-yr OS 87% vs 57% after IFN; p=0.0061). Hematologic grade 3–4 toxicity was higher in the IFN arm (leukocytopenia 33% vs 16%; thrombocytopenia 15% vs 6%); non-hematologic grade 3–4 toxicity was rare, except for infections (8% IFN; 7% rituximab). R-FC followed by rituximab resulted in the highest infection rate (CTC grades 1–4: 50%), whereas all other combinations (R-CHOP followed by rituximab or IFN, and R-FC followed by IFN) ranged between 25–35%. Patients in CR/CRu or PR after induction who did not receive any maintenance for various reasons, mainly based upon patient's decisions or ongoing cytopenia after induction (n = 104), had a poor outcome (median remission duration 18 months). Conclusions. Induction therapy with R-FC is discouraged for elderly patients with MCL, whereas R-CHOP induction followed by rituximab maintenance should be considered the new standard for elderly MCL patients, to which new regimens need to be compared. Disclosures: Off Label Use: rituximab maintenance for mantle cell lymphoma. Geisler:Roche: Consultancy, Research Funding; Celgene: Consultancy; GSK: Consultancy. Tilly:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hiddemann:Roche Pharma: Honoraria, Research Funding. Dreyling:Roche: Research Funding, Scientific advisory board, Speakers Bureau.

Abstract 110 Background: Mantle Cell Lymphoma (MCL) has been characterized by poor long term prognosis with a median survival of only 3 to 4 years. However, outcome has improved during the last decades. In its first randomized trial, the MCL net demonstrated that myeloablative consolidation followed by ASCT resulted in a significant prolongation of PFS in advanced stage MCL (Dreyling et al Blood 2005). Recent phase II studies suggested that the addition of rituximab to CHOP like chemotherapy and/or high dose ARA-C may significantly improve remission rates and PFS. A French phase II trial using sequential R-CHOP/R-DHAP followed by ASCT showed an overall response rate of 95% with a CR rate of 61% translating into a median EFS of 83 months and a 75% survival rate at 5 years (Delarue et al ASH 2008). Methods: To evaluate the potential superiority of a high dose ARA-C containing regimen, the MCL net initiated a randomized trial comparing 6 courses of CHOP plus Rituximab followed by myeloablative radiochemotherapy (12 Gray TBI, 2×60mg/kg Cyclophosphamide) and ASCT (control arm A) versus alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen (10 Gray TBI, 4×1,5 g/m2 Ara-C, 140mg/m2 melphalan) and ASCT (experimental arm B). Patient eligibility criteria included previously untreated MCL stage II-IV up to the age of 65 years. Histological diagnosis was confirmed by a central pathology review board. The primary end point time to treatment failure (TTF) was monitored continuously by a sequential procedure based on a one sided triangular test. Stable disease after induction, progression or death from any causes, were considered as treatment failure. Sample size was calculated to detect a hazard ratio of 52% for arm B with a power of 95%. Randomization was stopped as soon as a significant difference was observed between the two arms. Results: From July 2004 to May 2010, 497 patients were randomized in 4 countries (Germany, France, Poland, Belgium). The 391 patients evaluable for the primary analysis (19 no MCL, 87 not yet documented) displayed similar characteristics in both treatment arms: median age 55 vs 56 years, male 78% vs 79%, stage IV 85% vs 79%, B symptoms 43% vs 33%, ECOG >2 5% vs 5%, elevated LDH 37% vs 38%, and MIPI low/int/high risk 61%/25%/14% vs 62%/23%/15%, respectively. After induction overall response was similarly high in both arms (A: 90% vs B: 94%; p=0.19) and CR rate and combined CR/CRu rate were significantly higher in arm B (26% vs 39%; p=0.012 and 41% vs 60%; p=0.0003). The number of patients transplanted was similar in both arms (72% vs 73%) and after transplantation overall response and CR rates were comparable in both arms (97% vs 97% and 63% vs 65%, respectively). After a median follow up of 27 months, patients in arm B experienced a significantly longer TTF (49 months vs NR; p=0.0384, hazard ratio 0.68) mainly due to a lower number of relapses after CR/CRu/PR (20% vs 10%), whereas the rate of ASCT-related deaths in remission was similar in both arms (3% vs 4%). Although CR rate after ASCT was comparable in both arms, remission duration (RD) after ASCT was superior in Arm B (48m vs NR; p=0.047). Interestingly, for patients in CR after ASCT, RD after ASCT was also presumably superior in arm B (51 months vs NR; p=0.077). At the time of analysis overall survival was similar in both arms with medians not reached and 79% vs. 80% survival rates at 3 years (p=0.74). Safety after induction was comparable in both arms except for an increased grade 3/4 hematological toxicity (Hb 8% vs 28%, WBC 48% vs 75%, platelets 9% vs 74%, respectively), an excess of renal toxicity (creatinine grade 1/2: 8% vs 38%, grade 3/4: none vs 2%), and more frequent grade 1/2 nausea and vomiting in arm B. Toxicities of both conditioning regimen were similar, except for higher grade 3/4 mucositis (43% vs. 61%) in Arm B, and higher grade 1/2 liver toxicity and constipation in Arm A. Conclusions: High dose ARA-C in addition to R-CHOP+ASCT increases significantly complete response rates and TTF without clinically relevant increase of toxicity. Therefore, induction regimen containing high dose ARA-C followed by ASCT should become the new standard of care of MCL patients up to 65 years. Disclosures: Walewski: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Feugier:roche: Consultancy, Honoraria. Bosly:Roche: Membership on an entity's Board of Directors or advisory committees. Gisselbrecht:Roche: Research Funding.

Abstract 880 On behalf of the German Low-Grade Lymphoma Study Group (GLSG) and the European MCL Network Background: In younger patients with mantle cell lymphoma (MCL), autologous stem cell transplantation (ASCT) significantly prolonged response duration with a trend towards improved overall survival in a randomized trial of the European MCL Network (Dreyling et al., ASH 2008). A recently updated clinical trial of the German Low-Grade Lymphoma Study Group (GLSG) also reported a significantly prolonged response duration by the addition of Rituximab to first-line CHOP (Hoster et al., ASH 2008). By pooled analysis of these trials we investigated whether Rituximab and ASCT independently prolong response duration. Methods: The analysis included all advanced stage MCL patients of the trials “CHOP vs. MCP” (Nickenig et al., Cancer 2006), “CHOP vs. R-CHOP” (Lenz et al., JCO 2005) and European MCL trial 1 (Dreyling et al., Blood 2005) with complete or partial remission to either CHOP or R-CHOP first-line induction and randomization between ASCT and Interferon-α maintenance. Response duration was defined as time from the end of successful induction chemotherapy to relapse or death from any cause, overall survival from the end of successful induction chemotherapy to death from any cause. Stratified Kaplan-Meier curves for response duration and overall survival were calculated for the four treatment groups (CHOP without ASCT, CHOP with ASCT, R-CHOP without ASCT and R-CHOP with ASCT). By multiple Cox regression we tested whether the impact of Rituximab (R) and ASCT was independent and additive. Results: One-hundred and eighty patients with MCL were evaluable, 80 treated with R-CHOP, 78 with ASCT (CHOP without ASCT: 56, CHOP with ASCT: 46, R-CHOP without ASCT: 44 and R-CHOP with ASCT: 34). Median age was 55 years (range 34-65), the MIPI classified 71% as low risk, 22% as intermediate risk, and 6% as high risk, and baseline characteristics were comparable between treatment groups. With a median follow-up of 63 months, median response duration was 16 months after CHOP without ASCT, 26 months after R-CHOP without ASCT, 39 months after CHOP with ASCT, and 41 months after R-CHOP with ASCT. In multiple Cox regression including R and ASCT, the hazard ratios of R (0.60, 95% CI 0.42-0.86, p = 0.0056) and ASCT (0.50, 95% CI 0.35-0.70, p = 0.0001) were independently significant. There was no interaction between R and ASCT (p=0.43). Median overall survival was 54 months after CHOP without ASCT, 66 months after R-CHOP without ASCT, 90 months after CHOP with ASCT, and not reached after R-CHOP with ASCT. The hazard ratios for OS were 0.70 (95% CI 0.44-1.12, p = 0.14) for R and 0.63 (95% CI 0.41-0.97, p = 0.0379) for ASCT. Conclusions: Our results indicate an additive effect of ASCT and Rituximab in combination with CHOP on response duration in advanced stage MCL patients and support strategies of several study groups to combine Rituximab-containing induction therapies with ASCT in younger MCL patients. However, even after combined treatment approaches, delayed relapses have been observed, supporting the use of maintenance therapy and the introduction of molecular targeted therapeutical strategies. Disclosures: Hoster: Roche: Travel Support. Off Label Use: Rituximab in Mantle Cell Lymphoma. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees. Dührsen:Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Gisselbrecht:Roche: Research Funding, Speakers Bureau. Unterhalt:Roche: Travel Support. Dreyling:Roche: Honoraria, Research Funding.

We have previously reported that compared to CHOP alone the addition of Rituximab (R) to CHOP significantly increases the response rate (RR), the time to treatment failure (TTF) and also the overall survival (OS) in patients with newly diagnosed advanced follicular lymphoma. However, in the previous report, the median observation time was short with 18 months and no data were reported on the outcome of different risk groups according to the FLIPI (Hiddemann et al., Blood 2005). We now report on the treatment outcome of 552 patients with advanced stage follicular lymphoma randomized between R-CHOP versus CHOP alone after a median follow up of 58 months. Responding patients < 60 yrs. of age underwent a second randomization in first remission for Interferon alpha maintenance (IFN) versus myeloablative radio-chemotherapy with subsequent stem cell transplantation (ASCT), whereas all older pts received IFN maintenance. R-CHOP induced a significantly higher RR (97% vs. 91%, p=0.005). Furthermore immunochemotherapy resulted in significantly longer TTF (median not reached vs. 35 months, 5-years TTF 65% vs. 32%, p These data with a mature follow-up demonstrate that first–line R-CHOP significantly improves response rate and TTF in patients with FL compared to the respective chemotherapy alone. However, they also demonstrate that R-chemotherapy might be not sufficient for a long-lasting improvement. This indicates the necessity to perform clinical trials that test whether adding consolidation and/or maintenance after initial cytoreduction further improves treatment outcome.

Background: Combined immuno-chemotherapy incorporating Rituximab with various chemotherapy regimens has resulted in increased response rates and prolonged progression-free and even overall survival in numerous trials. However, a constant relapse pattern has been observed even after such an optimized first line treatment. Methods: In a subgroup analysis of the GLSG trial for relapsed indolent lymphoma (R-FCM followed by Rituximab maintenance), response and long term results of patients with previous Rituximab containing treatment were compared with the Rituximab naive control group. Induction comprised of 4 courses of chemotherapy with Fludarabine, Cyclophosphamide and Mitoxantrone (FCM) plus Rituximab. Patients responding with a complete (CR) or partial remission (PR) were randomized for observation only versus Rituximab maintenance (4 applications at month 3 and 9). Results: 18 of 268 patients (arm A) with relapsed lymphoma had already previously received a R-containing regimen, the remainder 250 patients (arm B) were Rituximab naive. Overall response (arm A: 83 % vs. group B: 77%) and CR rate (arm A: 39% vs. arm B: 23%) were comparable in both subsets of study patients. Accordingly, progression-free survival after R-FCM was comparable in both subgroups of patients (median PFS in arm A: 15 months, arm B: 27 months) and overall survival as well. Especially, no disadvantage in the Rituximab pretreated patient group was detectable. 9 of the Rituximab pretreated patients responding to R-FCM induction therapy were randomized to maintenance treatment. After a median observation time of 20 months, 3 patients had relapsed and 6 patients remained in remission (3 of them for >20 months) resulting in a similar PFS after rituximab maintenance as in patients who were Rituximab naive. Conclusion: This subgroup analysis strongly suggests that a Rituximab containing salvage therapy induction as well as maintenance is a highly effective treatment option even in patients who received Rituximab in first line therapy.

7502 Background: Rituximab (R) prolongs the progression-free survival (PFS) in patients with follicular lymphoma (FL) when given either simultaneously with or as maintenance after chemotherapy only. Methods: In the current study the impact of R maintenance after remission induction with an R-containing combined immuno-chemotherapy (R-FCM) was evaluated. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized 4 courses of chemotherapy with Fludarabine (25 mg/m2/d days 1–3), Cyclophosphamide (200 mg/m2/d days 1–3) and Mitoxantrone (8 mg/m2/d day 1) (FCM) ± Rituximab (375 mg/m2/d day 0). Patients entering a complete (CR) or partial remission (PR) underwent a second randomization for R maintenance (4 weekly doses (375 mg/m2/d) at three and nine months after end of induction) or observation only. Randomization was stratified for histology, prior therapies (up to 2 lines vs. >2), induction (±R), and response (CR vs. PR). After improved outcome of the R-FCM arm had been observed in the initial 147 randomized patients, all subsequent patients received a combined immuno-chemotherapy induction. Results: 176 of 195 randomized cases are evaluable, 138 of whom had received an R-containing induction. In these patients (as well as the total group) the median PFS after end of induction has not been reached in the R-maintenance arm in contrast to 17 months in patients with no further treatment (p = 0.001). This improvement was seen both in FL (n = 81; p = 0,035) and MCL (n = 47; p = 0,049). More importantly, overall survival rate was also improved after R maintenance with borderline significance (3 y rate 82% vs. 55%; p = 0,056). No major sided effects of R maintenance have been observed and the rate of serious infections was similar in both study arms (p = 0.72). Conclusions: The final analysis of this study confirms that R maintenance after combined immuno-chemotherapy (R-FCM) is highly effective and improves the progression-free survival—with a strong trend towards improved overall survival—of patients with relapsed FL and MCL. [Table: see text]

Preceding studies have shown that Rituximab prolongs the time to treatment failure (TTF) and response duration (RD) in follicular lymphoma (FL) when given either together with chemotherapy or as maintenance after a no R containing therapy. In the current study the impact of R maintenance on RD was evaluated after remission induction by an R-chemo combination. Patients with advanced stage relapsed or refractory FL and mantle cell lymphoma (MCL) were eligible. The study design comprized a first randomization between 4 courses of chemotherapy with Fludarabine (25mg/m2/d days 1–3), Cyclophosphamide (200mg/m2/d days 1–3) and Mitoxantrone (8mg/m2/d day 1) (FCM) versus FCM plus Rituximab (375mg/m2/d on day 0) (R-FCM). Patients entering a complete (CR) or partial remission (PR) underwent a second randomzation for observation only versus R maintenance with 4 weekly doses of R (375mg/m2/d) to be given at three and nine month after end of therapy. Both randomizations were stratified for histology and preceding therapy. The first randomization was stopped after 147 patients demonstrating a significant improvement for the R-FCM therapy in initial response, progression free survival and even overall survival (OS). So all subsequent patients received R-FCM. 174 cases are currently evaluable for the second randomization, 136 of whom had received R-FCM for remission induction. In these patients the median RD has not been reached in the R-maintenance arm whereas it is 17 months in patients with no further treatment after R-FCM (p=0.0024). This improvement was seen both in FL and MCL. This study demonstrates that R maintenance after R-FCM salvage therapy is highly effective and improves the outcome of patients with relapsed FL and MCL.

6528 Background: Rituximab monotherapy has shown a high activity in relapsed follicular lymphomas. Recently, phase III studies indicated that its addition to chemotherapy may further improve the progression-free survival substantially. Methods: In 1998 the GLSG embarked on a multicenter national trial in patients with relapsed or refractory follicular and mantle cell lymphoma. As most patients had received CHOP for first line treatment, a fludarabine-containing regimen (FCM) was chosen for salvage therapy followed by an optional Rituximab maintenance. A total of 4 courses were given. After the statistical analysis confirmed the significantly improved response rate of the combined study arm (R-FCM), 111 subsequent patients were designated to immuno-chemotherapy. Results: 122 of 244 currently evaluable patients (50%) had follicular, 95 patients (39%) mantle cell and 24 patients (10%) other indolent lymphomas. In 67 randomized patients with follicular lymphoma, complete (39% vs. 23%, p=0.013) as well as over...

6527 Background: Rituximab (R) was shown to prolong the time to treatment failure (TTF) and response duration (RD) in follicular lymphoma (FL) when given either together with chemotherapy or as mai...

In advanced stage follicular lymphoma conventional chemotherapy is non-curative and no major improvement in overall survival has been achieved by different regimens. Similarly, MCL, a lymphoma subtype with an especially poor clinical outcome, cannot be cured by conventional chemotherapy. In 1996, the German Low Grade Lymphoma Study Group (GLSG) started a randomized trial to evaluate the efficacy of two different anthracycline/anthrachinon containing regimens comparing CHOP (cyclophosphamide 750 mg/m2 day 1, vincristine 1.4 mg/m2 day 2, adriamycine 50 mg/m2 day 1, prednisone 100 mg/m2 days 1–5) and MCP (mitoxantrone 8 mg/m2 days 1–2, chlorambucil 3x3 mg/m2 days 1–5; prednisone 25 mg/m2 days 1–5). 415 previously untreated patients with advanced stage indolent lymphoma were prospectively randomized to receive either 6–8 cycles of CHOP or MCP and are evaluable for induction therapy. 277 patients (67%) had a follicular lymphoma, 86 (21%) had a mantle cell lymphoma and 52 (13%) patients had another indolent histology. Responders up to 60 years were subsequently assigned to either myeloablative radiochemotherapy and autologous stem cell transplantation or to interferon-a maintenance (IFNa ), all other patients received IFNa. As stem cell mobilization was hampered in the MCP arm (only 44% sucessful mobilisations after MCP, 93% after CHOP; p=0.0003), from July 1998 all younger patients were asssigned to the CHOP arm. 86% complete and partial remissions (18% CR) were observed in the CHOP arm, whereas after MCP an overall response rate of 77% was obtained (14% CR, p=0.0094). In subgroup analysis similar improvement of remission rates were detected in follicular lymphoma (91% vs 82%, p=0.026) and mantle cell lymphomas (87% vs 73%, p=0.080). No differences, were observed, however, between both regimens for progression-free survival in both lymphoma subtypes. Overall survival was comparable for FL in both study arms (74% vs 69% at five years, p=0.29). In MCL, overall survival was slightly higher in the CHOP arm (5y OS: 57% vs. 31%; p=0.0578), but this difference was mostly due to unbalanced patient characteristics (IPI). In conclusion, CHOP appears superior to MCP in achieving a higher initial response rate but has no long term impact on response duration or overall survival.

The addition of Rituximab (R) to combination chemotherapy has been shown to increase the remission rate (RR) and to prolong the time to treatment failure (TTF) both in follicular lymphoma (FL) and mantle cell lymphoma (MCL). The impact of the R-chemo combination on subsequent therapy in remission, however, remains unclear. The GLSG embarked on two parallel studies in FL and MCL comprizing a prospective randomized comparison of R-CHOP versus CHOP alone followed by a second randomization in remission for Interferon alpha maintenance (IFN) versus myeloablative radio-chemotherapy with subsequent stem cell transplantation (PBCT) in patients < 60 yrs. of age while all older pts. received IFN maintenance. In 428 pts. with FL R-CHOP revealed a significantly higher RR (96% vs. 90%, p = 0.011) and a longer TTF (median not reached vs. 2.6 yrs, p

The membrane enzyme 5′-nucleotidase (5′-N) has been characterized as an ectoenzyme in many different tissues of different species. The ecto-property means that a major portion of this molecule including the active center and the carbohydrate side chains is located in the extracellular space. Thus, the enzyme represents an interesting surface marker. This is especially true in lymphoid cells, where we observe charcteristic differences in expression of this marker in various subpopulations, in cell lines and in different forms of leukemias and lymphomas. The latter observation can even be used diagnostically in selected cases 1,2. Therefore, a method of detection of the molecule independent of the overall measurement of enzyme activity, for example by monoclonal antibodies (MABs) seemed desirable. In addition specific immunological reagents should be useful tools for further biochemical studies. In the foliowing a number of monoclonal antibodies against the human enzyme shall be described.

Abstract 3706 Poster Board III-642 Sex has been recognized as an important prognostic factor for the treatment outcome of patients with lymphoma. Thus, several retrospective analyses have shown that male sex is associated with an inferior outcome in advanced stage follicular lymphoma. This was confirmed in a retrospective analyses of 1795 patients with follicular lymphoma using Cox regression analysis, in which male sex was independently associated with inferior survival (Solal-Celigny et al., Blood 2004). We now analyzed the prognostic impact of sex on treatment outcome of 1172 patients with follicular lymphoma treated first line with CHOP or R-CHOP in prospectively randomized clinical trials of the German Low-Grade Lymphoma Study Group (GLSG). From these, 616 pts were treated with CHOP, 556 pts with R-CHOP. FLIPI was equally distributed between the two treatment arms (low risk 14% vs. 14%, intermediate risk 42% vs. 41% and high risk 44% vs. 45 %, respectively). 48% of the patients were male (50% in the CHOP and 46% in the R-CHOP arm). For all patients there was a significantly inferior time to treatment failure (TTF) for male patients with a median of 43 months compared to 61 months for female patients (p=0.0035). In the patient group treated with CHOP alone the median TTF was 30 months for male vs. 40 months for female patients (p=0.0041). The observation that male sex was associated with inferior treatment outcome was seen both in the elderly (above 60 yrs of age) as well as the younger patient group (below 60 yrs of age). However, after treatment with R-CHOP sex did not affect treatment outcome anymore with virtually the same results in male vs. female patients (for the total group and for patients < 60yrs TTF median not reached in both arms, p = n.s.; for pts > 60 yrs TTF 81 vs. 84 months, respectively, p=n.s.). In multivariate analysis, also adjusting for FLIPI risk factors, male sex showed up as an independent prognostic factor for patients treated with CHOP alone (HR 1.82; 1.32 – 2.5; p=0.0002), but not for patients treated with R-CHOP (HR 1.06; 0.68 - 1.66, p = 0.79; p=0.0476 for the interaction term of sex with Rituximab). Based on this, male patients had the highest benefit when rituximab was added to CHOP (R-CHOP vs. CHOP: male pts HR 0.31,0.21 - 0.46, p Disclosures: Buske: Roche: Honoraria. Hoster:Roche: travel support. Dreyling:Roche: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Research Funding. Unterhalt:Roche: .

After immunization of mice with partially purified human placental 5′-nucleotidase hybrid cells were produced following the standard protocol. Culture supernatants were screened for the ability to inhibit enzyme activity. From 18 different hybrids showing significant inhibition 5 were established as clones. Properties of the MABs were studied in ascites fluid and in purified Ig-preparations. Inhibition of the MABs is directed against the enzyme in membrane bound and solubilized form and there is no tissue specificity. Similar inhibitory titers were observed with the MABs coated on plastic. The MABs belong to the IgG 1 and IgG 2b subclasses. Some of them show a marked temperature dependence in their inhibitory potency. They are not directed against the sugar moiety of the 5′-N molecule. In fluorescence studies with PBL a smaller subpopulation, compared to polyclonal antisera, shows a positive reaction with the MABs. The titers for optimal fluorescence are much lower than for inhibition. Results of flow-cytometric studies relating cell size to positive reaction with the MABs will be reported.