ALBERT

Description: The addition of Rituximab (R) to front-line combination chemotherapy has substantially improved the long term perspectives of patients with advanced stage follicular lymphoma (FL) resulting in median progression free survival (PFS) times of more than 36 months. In this situation the potential role of myeloablative herapy with subsequent autologous stem cell transplantation (ASCT) in 1st remission needs to be critically reassessed. For this purpose two consecutive studies of the GLSG were analyzed both randomizing in 1st remission for Interferon alpha (IFN) maintenance therapy versus ASCT. In the GLSG trial ‘96 initial therapy comprised a randomized comparison of CHOP versus Mitoxantrone, Chlorambucil and Prednisone (MCP) (total patient number 312) while in GLSG study ‘00 CHOP was randomly compared to R-CHOP (total patient number 268). Hence, both studies had an identical treatment arm of CHOP followed by either IFN maintenance or ASCT. In both studies, the identical treatments revealed superimposable results with a 5 years PFS of 27% after CHOP and IFN maintenance and 66% after CHOP followed by ASCT. Taking these data as internal control R-CHOP followed by IFN maintenance achieved a 5 year PFS of 67% which is hence comparable to CHOP followed by ASCT. R-CHOP followed by ASCT, however, revealed a 5 year PFS of 79% with only one relapse after 24 months. Figure Figure Although the difference between R-CHOP followed by IFN maintenance or ASCT is currently not yet significant it strongly suggests a beneficial effect of ASCT in the era of R-CHOP front-line therapy particularly for intermediate of high risk patients with advanced stage FL.

Description: Abstract 3360 Poster Board III-248 Purpose Richter's syndrome (RS) occurs in 2-8% of patients with chronic lymphocytic leukaemia (CLL). Clinical outcome has been generally poor after multiagent chemotherapy with median survival of less than 1 year. The aim of this retrospective study was to evaluate whether an autologous (AutoSCT) or an allogeneic stem cell transplantation (alloSCT) offers survival benefit. There are scant data addressing this issue. Patients and Methods As patients with RS are not identified separately in the current EBMT database a request was sent to all EBMT centres known to have performed SCT in patients with CLL, high-grade lymphoma or Hodgkin's lymphoma asking for RS transplants. Inclusion criteria included a diagnosis of RS prior to SCT, age 〉 18 years, and SCT performed 1997-2007. Centers who reported RS transplants received a questionnaire to collect detailed information on disease and transplant characteristics and outcome results. Data were analyzed by descriptive statistics and survival comparisons using log rank testing and Cox modelling. Fifty nine transplants for RS were reported by 25 centres, which is the largest cohort described. Thirty nine patients (25 (64%) male) underwent AutoSCT (of whom 8 underwent a subsequent alloSCT). The median age was 56 years (range, 30-68 years) and 44% (n=17) of transplants were performed after 2003, with a TBI-containing regimen used in 5 patients. A minority (36% of cases with data known) of patients had received ≥3 lines of prior therapy. The majority of transplants (n=32; 84%) were performed within a year of diagnosis of RS, and 91% of patients (with data known) were in CR/PR at time of transplant. With a median follow-up of 27 months, 15/39 (39%) patients were alive and 13 patients were disease-free, 21 (39%) had relapsed (19 died from relapse) and 5 (13%) died of treatment-related complications after ASCT. OS was 54% and 25% at 3 and 5 yrs respectively. Relapse incidence of 49%, NRM of 14% and PFS of 37% was observed at 3 yrs. Twenty patients (12 (60%) male) underwent alloSCT from a matched sibling donor (n=10), VUD (n=8) or an alternative donor (n=2) with PBSC used in 90% of cases. The median age was 57 years (range, 42-70 years) and 70% (n=14) of transplants were performed after 2003. A majority (80%) of patients underwent alloSCT within 1 year of diagnosis of RS and had received ≥3 lines of prior therapy (71% of known cases). Conditioning was reduced-intensity (RIC) in 14 cases and myeloablative in 6 patients, with TBI used for 4 patients and T-cell depletion strategies in 13. At time of alloSCT 14 patients were in CR/PR and 5 had progressive disease (missing data in 1 case). With a median follow-up of 15 months (range, 3-94 months) 11/20 (55%) patients were alive after alloSCT, of whom 7 were in CR/PR. Overall survival (OS) was 51% and 41% at three years and 5 years respectively. Conditioning (myeloablative vs RI-conditioning; P = 0.14) and source of donor (HLA-id sib vs VUD; P = 0.97) did not statistically influence outcome. OS was not statistically affected by the variables: prior lines of therapy 〈 3 or ≥3 lines (P = 0.72), CMV serostatus recipient/donor (P = 0.23), use of T-cell depletion (P = 0.88) or disease status at time of transplant. The 3 yr OS for patients transplanted in CR/PR was 51% compared to 27% for those transplanted with progressive disease (P = 0.18). Outcome was superior for patients 〈 60 yrs at alloSCT (p=0.04). Relapse incidence of 38%, NRM of 23% and PFS of 39% was observed at 3 yrs. Acute GVHD grade II to IV occurred in 30% of patients and there were no cases of extensive chronic GVHD within reported cases. Conclusion This is the largest study that has assessed the outcome after transplantation of patients with RS. In summary patients with RS who are chemosensitive to induction therapies may benefit from consolidation with transplantation strategies. Disclosures: No relevant conflicts of interest to declare.

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: Background High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the established standard-of-care for patients with newly diagnosed multiple myeloma (NDMM) who are young and/or fit. The number of older patients receiving HDT-ASCT is increasing, although they often receive lower-intensity treatment. Novel agent-based consolidation therapy can be used to improve responses following ASCT and prolong progression-free survival (PFS). The proteasome inhibitor bortezomib, given as post-ASCT consolidation therapy, resulted in an improved PFS compared with observation alone (median 33.6 vs 27.8 months, adjusted hazard ratio [HR] 0.70, p=0.0058) in a combined analysis of two phase 3 trials (MMY3012 [DSMM XIb; NCT00416273] and MMY3013 [DSMM X; NCT00416208]; JCO 2015;33:8511). These studies enrolled 222 patients aged ≤60 years and 158 aged 〉60 years. In this post-hoc analysis we investigated the effect of age and related treatment factors on PFS in more detail. Methods In both trials, 371 patients were randomized 1:1 following ASCT to receive four 35-day cycles of bortezomib consolidation (n=186; bortezomib 1.6 mg/m2 IV administered on days 1, 8, 15, and 22) or observation (n=185; no treatment). The primary endpoint was PFS from the start of induction chemotherapy. Response and progression were assessed at the start of each bortezomib cycle and at the end-of-treatment/observation visit (week 25), as well as during the follow-up period of 30-60 months. Patient characteristics and treatments were compared between trials; PFS following randomization was assessed separately for each study. Univariate, bivariate, and multivariate Cox regressions were conducted to evaluate the impact of treatment group, age (≤60 vs 〉60 years), single vs tandem ASCT, melphalan conditioning dose (MEL 60 group), including the HDT regimen received (MEL100 7% vs 10%; MEL140 3% vs 59%; MEL200 88% vs 31%). The rate of double transplantation was similar for the younger and older cohorts (55% vs 59%), likely due to the older patients receiving age-adjusted high-dose melphalan with a lower toxicity, allowing a similar rate of double transplantation as younger patients receiving MEL200. Among the 357 patients included in these analyses, median PFS from start of induction was 33.6 vs 27.8 months with bortezomib consolidation vs observation (log-rank p=0.0243). Median PFS for bortezomib vs observation was 33.6 vs 29.0 months (HR 0.86; p=0.3599) in the younger cohort and 33.4 vs 26.4 months (HR 0.60; p=0.0073) in the older cohort. PFS for older patients who received bortezomib consolidation was very similar to PFS in younger patients (p=0.861); survival curves were superimposable despite the older patients having received less intensive pretreatment. Univariate analysis demonstrated that treatment group (bortezomib vs observation) had an effect on PFS (HR 0.75; exploratory p-value 60 vs ≤60 years; HR 1.30), melphalan dose (200 vs

Description: Background: The addition of rituximab to chemotherapy (R-CHOP) has been shown to improve response rates in mantle cell lymphoma (MCL), but prolongation of response duration or overall survival was not observed (Lenz et al., JCO 2005). In a similar randomized comparison of 90 patients, again the addition of rituximab to MCP showed a tendency towards higher CR rates, but no improvement of overall response rate, progression free, or overall survival (Herold et al., ICML-10, 2008). Methods: We present an update of a previously published trial randomly comparing efficacy and safety of R-CHOP to CHOP induction in previously untreated patients with advanced stage MCL. Results: Of the 123 evaluable patients, 63 patients were randomized to R-CHOP. Median age was 62 years, and risk profiles of the two treatment arms were comparable. Overall response rates were 92% vs. 75% for R-CHOP vs. CHOP (p = 0.0139) and complete remission rates 33% vs. 8% (p = 0.0008). After a median follow-up of 65 months, median time to treatment failure was prolonged from 14 months for CHOP to 28 months for R-CHOP (p = 0.0003). Similarly, median response duration was prolonged from 18 (CHOP) to 29 months (R-CHOP, p = 0.0052). So far, no significant improvement of overall survival has been observed with median not reached vs. 59 months and 5-years OS rates of 59% and 46% (p = 0.27) after R-CHOP and CHOP, respectively. Toxicity was not significantly higher for R-CHOP treated patients. Conclusions: After longer follow-up, superior remission rates, time to treatment failure, and response duration of combined immuno-chemotherapy were confirmed. However, in contrast to other lymphoma entities, improvement of overall survival has not yet been proven in MCL patients. Therefore new therapeutic options are urgently warranted to further improve the long term outcome in this otherwise dismal disease.

Description: Whilst safety and efficacy of adding rituximab to standard therapy has been reported, less information is available on the combination of rituximab (R) with HDT and autologous SCT. The German Study Group for High-Grade NHL (DSHNHL) developed a repetitive HDT program consisting of 4 courses dose escalated CHOP + Etoposide +/− R. Patients aged 18 to 60 years and elevated LDH at diagnosis were included. Mega-CHOEP consisted of four cycles of chemotherapy. Cycles 2 to 4 were followed by autologous SCT. At dose level 3 (DL3) cumulative doses of drugs were as follows: C 19.5 g/m2, H 280 mg/m2, O 8 mg, E 5.04 g/m2, P 2000 mg. When feasibility and safety of MegaCHOEP at DL3 had been demonstrated, rituximab was added (DL3R). Six cycles of rituximab (375 mg/m2) were given: one dose of rituximab prior to each cycle of chemotherapy and two additional doses 3 and 6 weeks after the last cycle of chemotherapy, respectively. From September 1999 to may 2001 35 pts with validated diagnosis of aggressive B-NHL received MegaCHOEP DL3, from June 2001 to February 2003, 72 pts received DL3R. There was a higher percentage of B-cell NHL patients with ECOG performance status 〉 1 at DL3 (42.9 %) than at DL3R (19.7 %, p = 0.012) and as consequence more patients with age-adjusted IPI high risk at DL3 (34.3 %) than at DL3R (12.7 %, p = 0.029). We observed significant differences in the incidence of WHO grade III/IV infections (DL3 9 of 123 cycles (7.3%), DL3R 48 of 236 cycles (20.3%); p=0.001) and in the percentage of patients receiving the complete program of chemotherapy (DL3:91 %, DL3R 71%; p=0.017). There were no relevant differences in other types of non-hematologic toxicity or hematopoietic recovery between treatment groups. Median observation times of patients at DL3 and DL3R were 2.6 years and 4.5 years, respectively. In univariate analysis, there was a trend to better overall survival with rituximab (75%) than without rituximab (57%) at three years (p=0.168) and a significantly better freedom from treatment failure in patients receiving DL3R as compared to DL3 with 70 % vs 50 % at 3 years (p = 0.040). In a Cox regression model adjusted for IPI, there was a trend to a higher relative risk of treatment failure of MegaCHOEP without rituximab (RR 1.8); this, however, was not statistically significant (p = 0.087). Rituximab may have beneficial influence on lymphoma control in this setting; its use, however, is accompanied by higher incidence of serious infections which subsequently compromise the dose intensity of this aggressive treatment program. The DSHNHL is currently performing a randomized study comparing MegaCHOEP+R with CHOEP−14+R.

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: 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) are the standard treatment for young patients with DLBCL. The MInT trial established a subgroup with favourable prognosis as defined as aaIPI=0 and no bulky disease [Pfreundschuh et al., Lancet Oncol 2006; 7: 379-391] with a 3-year EFS of 89%, PFS of 95% and OS of 98%. We hypothesized that 4 cycles of CHOP plus 6 applications of rituximab are non-inferior to the standard treatment of 6x R-CHOP in this population. Patients and Methods: 18 to 60 year-old patients, aaIPI =0 without bulky (≥7.5 cm) disease were randomized to receive 6x R-CHOP or 4x R-CHOP+2xR at 21-day cycles. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma. The primary endpoint was progression free survival (PFS) with events defined as progressive disease, relapse or death. Assuming a 93% 3-years PFS for the 6x R-CHOP arm, it was planned to tolerate an impairment of 5.5% by reducing the number of courses to 4x R-CHOP+2xR to prove non-inferiority with a power of 80% and an alpha-error of 5% (one-sided). Results: Between 12/2005 and 10/2016, 592 patients were randomized in the international multi-center FLYER trial and 588 patients were evaluable for this final analysis. 295 patients were assigned to receive 6x R-CHOP and 293 were assigned to receive 4x R-CHOP+2xR. There were no relevant differences in demographics (median age: 48 years, 99% aaIPI=0, 1% aaIPI=1, 0.3% bulky disease), protocol adherence and toxicity between the two arms. PFS, EFS and OS after 4x R-CHOP+2xR were as good as after 6x R-CHOP. After 66 months median observation, the 3-year PFS rate of the patients receiving 4x R-CHOP+2xR was 96% vs. 94% of patients receiving 6x R-CHOP (p=0.760). The lower limit of the 95% CI of the difference between treatment arms was 0% and excludes -5.5% demonstrating the non-inferiority. The 3-year EFS was identical (89%) in both treatment arms. The 3-years OS was 99% in patients receiving 4x R-CHOP+2xR and 98% in patients receiving 6x R-CHOP. In a multivariable analysis adjusting for strata (stage and E-involvement), the hazard ratio of 4x R-CHOP+2xR compared to 6x R-CHOP was 1.0 (95% CI: 0.7-1.6; p=0.896) for EFS, 0.9 (95% CI: 0.5-1.6; p=0.797) for PFS, and 0.8 (95% CI: 0.4-1.9; p=0.671) for OS. With respect to relapse rate there was also no significant difference between the two treatment arms. 4% (95% CI 2-7%) of the patients in the 4x R-CHOP+2xR arm relapsed vs. 5% (95% CI 3-8%) of the patients in the 6x R-CHOP arm. 33% of relapses occurred in the first two years after study inclusion but continue to be seen with longer follow-up in both arms. Conclusion: In young patients with favourable prognosis DLBCL outcome after 4x R-CHOP+ 2xR is non-inferior compared to the previous standard 6x R-CHOP. Thus, chemotherapy can be spared without compromising prognosis in this population. Supported by Deutsche Krebshilfe Figure. Figure. Disclosures Poeschel: Roche: Other: Travel grants; Amgen: Other: Travel grants. Held:BMS: Consultancy, Other: Travel grants, Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel grants, Research Funding; MSD: Consultancy; Spectrum: Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Keller:Celgene: Research Funding; BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; MSD: Consultancy. Schmidt:Gilead: Honoraria, Other: Travel Grants; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: 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; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, 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. Murawski:Takeda: Consultancy; Janssen: Other: Travel grants.

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.