Kurzfassung: 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.

Kurzfassung: 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 & lt; 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 & lt;0.0001), response duration (RD, 5-years RD 66% vs. 35%, p & lt;0.0001), and OS (5-years OS R-CHOP 90% vs. CHOP 84%, p = 0.0493). To analyse the impact of R-chemotherapy in different risk groups we performed subgroup analyses for patients with low (LR), intermediate (IR) or high risk (HR) according to the FLIPI: R-CHOP prolonged significantly TTF in all risk groups compared to CHOP alone (5-years TTF: 84% vs. 46% for LR (p=0.0021); 73% vs. 37% for IR (p & lt;0.0001); 49% vs. 23% for HR (p & lt;0.0001). The superiority of R-CHOP vs. CHOP could be documented in the patient group not treated with ASCT: the RD was significantly prolonged by the immunochemotherapy (5-years probability 62% vs. 26%, respectively; p & lt;0.0001). This could not be seen in the group of younger patients consolidated with ASCT (5-years probability 78% vs. 66%, p=0.43). However, the number of events was too low to draw any final conclusion. 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.

Kurzfassung: 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 〈 0.0001 and female pts. HR 0.53, 0.37 - 0.76, p = 0.0005). These data demonstrate that Rituximab functions as an equalizer with regard to sex as a prognostic factor and underlines that well established prognostic factors may lose their predictive power with the emergence of novel effective treatment approaches. 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: .

Kurzfassung: 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.

Kurzfassung: 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 〈 0.0001). From 347 patients evaluable for subsequent treatment in remission 79 younger patients (35 after CHOP and 44 after R-CHOP) received PBCT. 52 younger patients after CHOP and 69 after R-CHOP received IFN maintenance. 122 older cases received IFN (59 after CHOP and 63 after R-CHOP). For IFN treated pts. a significantly longer progression free survival (PFS) was observed after initial therapy with R-CHOP (estimated 2 yrs - PFS: 63% vs. 84%, p = 0.0004) while no differences were encountered at the time of this analysis after PBCT (estimated 2 yrs - PFS for the whole group: 86%). Hence, in FL initial therapy with R-CHOP appears to have a long lasting beneficial effect on PFS which may be in the range that has previously only been achieved by chemotherapy followed by PBCT. Similar to FL a significantly higher RR (94% vs. 75%, p = 0.005) and a longer TTF (median 14 months vs. 21 months, p = 0.0131) was observed in 122 pts. with MCL undergoing the same randomized comparison. In contrast to FL, however, no differences were revealed for the PFS after R-CHOP versus CHOP and subsequent therapy with IFN or PBCT. These data show a differential effect of adding R to CHOP for initial therapy in FL and MCL. In FL the addition of R to CHOP has a long lasting beneficial effect with a substantial impact on subsequent treatment in remission while in MCL the benefit of R seems restricted to the remission induction period only.