ALBERT

Description: 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.

Description: 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

Description: 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.

Description: 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.

Description: 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.

Description: 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

Description: 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.

Description: 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.

Description: 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

Description: 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