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Observation is the current standard of care for patients with early-stage asymptomatic chronic lymphocytic leukemia (CLL), as chemotherapy-based interventions have failed to prolong survival. We hypothesized that early intervention with ibrutinib would be well tolerated and lead to superior disease control in a subgroup of early-stage patients with CLL. The phase 3, double-blind, placebo-controlled CLL12 trial randomly assigned asymptomatic, treatment-naïve Binet stage A CLL patients at increased risk of progression in a 1:1 ratio to receive ibrutinib (n = 182) or placebo (n = 181) at a dose of 420 mg daily. At a median follow-up of 31 months, the study met its primary endpoint by significantly improving event-free survival in the ibrutinib group (median, not reached vs 47.8 months; hazard ratio = 0.25; 95% confidence interval = 0.14-0.43, P < .0001). Compared with placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events (AEs). The most common serious AEs were atrial fibrillation, pneumonia, and rash in the ibrutinib group, and basal cell carcinoma, pneumonia, and myocardial infarction in the placebo group. Ibrutinib-associated risk for bleeding (33.5%) was decreased by prohibiting the use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug–drug interactions. Ibrutinib confirms efficacy in CLL patients at an early stage with an increased risk of progression. However, the results do not justify changing the current standard of “watch and wait.” This trial was registered at www.clinicaltrials.gov as #NCT02863718.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

7501 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or mantle cell lymphoma and was first published in The Lancet in 2013. The final analysis demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group compared to the CHOP-R group, with a median PFS of 69.5 vs. 31.2 months, respectively. In the current analysis, we present updated results for overall survival (OS), time-to-next-treatment (TTNT), and secondary malignancies (sNPL) with a median follow-up of 113 months for patients with indolent lymphomas (excluding MCL). Methods: 447 pts with indolent lymphomas were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: Patient characteristics were well balanced between arms; median age was 64 years. The difference in OS between the two treatment arms was not statistically significant, with 60 deaths in the B-R group vs 68 deaths with CHOP-R (HR 0.82, 95% CI 0.58 – 1.15, p = 0.249). The estimated 10-year survival rates were 71% for B-R and 66% for CHOP-R. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.52, 95% CI 0.38 – 0.69, p < 0.001). Median TTNT was not yet reached in the B-R group (95% CI 124.9 – n.y.r) vs. 56 months in the CHOP-R group (95% CI 39.1 – 82.0). Patients treated initially with B-R needed fewer second-line treatments due to disease progression compared to CHOP-R treated pts: 73 pts (34%) in the B-R group received salvage treatment compared with 106 pts (52%) in the CHOP-R group. For B-R pts, CHOP-R was used as second-line therapy 26 times (36%), whereas B-R was used for pts initially treated with CHOP-R 49 times (46%). 36 pts with sNPL were observed in the B-R group compared with 39 in the CHOP-R group, with 7 hematological malignancies in both groups to date. Conclusions: In pts with previously untreated indolent lymphomas, B-R demonstrates a PFS and TTNT benefit over CHOP-R. Clinical trial information: NCT00991211.

Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p0.0001), and stomatitis (16 [6%] vs 47 [19%]; p0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.Roche Pharma AG, Ribosepharm/Mundipharma GmbH.

Introduction Observation (watch and wait) is the standard of care for patients with asymptomatic early stage CLL. Prognostic scores can be used to predict the outcome for high-risk subgroups that have rapid disease progression and poor survival. So far early treatment intervention failed to improve survival. However with development of novel targeted drugs treatment of high-risk CLL has improved. Thus, the risk-stratified management of early stage CLL needs to be re-evaluated. The CLL12-trial is the first prospective, placebo-controlled, double-blind, phase 3 trial investigating whether ibrutinib improves event-free survival (EFS) and therefore time to therapy in early stage CLL with risk of disease progression defined by a comprehensive prognostic score (Langerbeins et al, Future Oncol, 2015). Methods In this ongoing trial subjects with confirmed asymptomatic Binet stage A CLL are risk stratified according to the CLL-score (Pflug et al, Blood, 2014). Whereas low-risk patients are being observed (watch & wait), intermediate to very high-risk patients are randomized 1:1 to receive either treatment with ibrutinib at a daily dose of 420mg or placebo. A cycle is defined as 28 calendar days. Primary endpoint is EFS defined as the time between randomization until progressive disease, subsequent CLL-treatment or death. The trial is registered at www.clinicialtrialsregister.eu(EudraCT 2013-003211-22). Results At submission of the abstract, a total of 327 patients have been screened. Main reasons for screening failure (N=65) were violation of in-/exclusion criteria (N=32), withdrawal of consent (N=24) and incomplete screening (N=9). Patients were stratified using the prognostic score as follows: low (score 0-2, N=82), intermediate (score 3-5, N=125), high (score 6-10, N=39) and very high risk (score 11-14, N=6). Low-risk patients were allocated to the observational arm. The remaining 170 patients were randomized 1:1 to the experimental arm. Thus far, a total of 587 cycles have been administered with a median treatment duration of 4 cycles per patient. 46 patients have stopped the treatment prematurely. Reasons for early discontinuation were refusal of further treatment (N=26), toxicity (N=10), disease progression (N=6), concomitant use of oral anticoagulants (N=3) and lung cancer (N=1). 26 serious adverse events (SAE) including two suspected unexpected serious adverse reactions (SUSAR) have been reported for both treatment arms (placebo vs. ibrutinib): cardiac disorders (N=6), infections (N=9), nervous system disorders (N=2), vascular disorders (N=2), musculoskeletal disorders (N=2), acute renal failure (N=1), vertigo (N=1), sigmadiverticulitis (N=1), sacrumfracture (N=1), and small cell lung cancer (N=1). 15 of the reported SAE's were deemed related to the study medication. The first SUSAR was a non-ST elevation myocardial infarction in an 82-year old male patient with high comorbidity score (CIRS=6) including known coronary heart disease, hypertension, diabetes mellitus and obesity. The second SUSAR was cerebral seizure secondary to subdural bleeding reported in a 78-year old male patient with high CIRS (N=12) and concomitant use of rivaroxaban. To minimize bleeding risk the study was amended to exclude patients using novel, oral anticoagulants. Subjects receiving direct Xa-inhibitors either changed the anticoagulant or stopped the experimental treatment. Conclusion Clinical observation has been the standard of care for early stage CLL ever since. This is the first safety report of a recruiting placebo-controlled phase III trial investigating if targeted treatment with ibrutinib delays time to first therapy in early stage CLL patients. SAE's are consistent with those previously reported for ibrutinib. Concomitant use of oral anticoagulants is prohibited due to an increased risk of bleeding. This may be seen differently in trials where patients already fulfill treatment criteria. Updated safety data will be presented at the meeting. Data from randomized first-line trials in advanced CLL suggests administering the most efficacious treatment upfront to achieve longterm-remissions and prolongation of survival. Efficacy data of the CLL12 trial will be available in 2016 and will hopefully answer this question for early stage patients and guide future management of this subgroup. Disclosures Langerbeins: Mundipharma: Honoraria, Other: travel grants, Research Funding; Hoffmann-LaRoche: Honoraria, Other: travel grants, Research Funding; Janssen: Honoraria, Other: travel grants, Research Funding. Off Label Use: Ibrutinib in early stage Binet A CLL. Rhein:Janssen: Other: travel grants. Cramer:Astellas: Other: Travel grant; Gilead: Other: Travel grant, Research Funding; Janssen: Other: Travel grant, Research Funding, Speakers Bureau; Hoffman LaRoche: Other: Travel grant, Research Funding, Speakers Bureau; Glaxo Smith Klein/Novartis: Research Funding; Mundipharma: Other: Travel grant. Fink:Roche: Honoraria, Other: travel grant. Pflug:Celgene: Other: Travel grant. von Tresckow:Celgene: Other: travel grants; Janssen-Cilag: Honoraria, Research Funding; Hoffman-LaRoche: Other: travel grants, Research Funding. Stilgenbauer:AbbVie: Consultancy, Other: travel grants, Research Funding; Amgen: Consultancy, Other: travel grants, Research Funding; Boehringer-Ingelheim: Consultancy, Other: travel grants, Research Funding; Celgene: Consultancy, Other: travel grants, Research Funding; Hoffman-LaRoche: Consultancy, Honoraria, Other: travel grants, Research Funding; Genentech: Consultancy, Other: travel grants, Research Funding; Genzyme: Consultancy, Other: travel grants, Research Funding; Gilead: Consultancy, Other: travel grants, Research Funding; GlaxoSmithKline: Consultancy, Other: travel grants, Research Funding; Janssen: Consultancy, Other: travel grants, Research Funding; Mundipharma: Consultancy, Other: travel grants, Research Funding. Eckart:Gilead: Honoraria; Roche: Other: travel grant. Balser:Iomedico: Other: travel grant; Janssen: Consultancy; Roche: Other: travel grant. Wendtner:Celege: Consultancy, Other: Travel grants, Research Funding; Mundipharma: Consultancy, Other: travel grants, Research Funding; Janssen-Cilag: Consultancy, Other: travel grants, Research Funding; Glaxo-SmithKline: Consultancy, Other: travel grants, Research Funding; Gilead: Consultancy, Other: travel grants, Research Funding; Genentech: Consultancy, Other: travel grants, Research Funding; Hoffmann-LaRoche: Consultancy, Other: travel grants, Research Funding; AbbVie: Consultancy, Other: travel grants, Research Funding; Pharmacyclics: Consultancy, Other: travel grants, Research Funding. Fischer:Roche: Other: Travel Grants. Eichhorst:AbbVie: Consultancy, Other: travel support, Research Funding; Celgene: Consultancy, Other: travel grant, Research Funding; Hoffman-LaRoche: Consultancy, Other: travel grant, Research Funding; Gilead: Consultancy, Other: travel grant, Research Funding; Janssen: Consultancy, Other: travel grant, Research Funding; Mundipharma: Consultancy, Other: travel grant, Research Funding. Hallek:Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Board; Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Board, Research Funding.

STEAP3/TSAP6 encodes a ferrireductase that is involved in the acquisition of iron by developing erythroblasts and steap3/tsap6 null-mice display severe microcytic anemia. We report a family in which 3 siblings born to healthy parents display transfusion-dependent hypochromic anemia. A nonsense STEAP3/TSAP6 was identified in the siblings at the heterozygous state. This mutation was inherited from their father while no mutation was found in their mother. A large variability of expression was found between normal alleles in a control population, confirming a previous report that STEAP3/TSAPS6 is an expressed quantitative trait locus (e-QTL). Determination of the relative allele expression showed that the “normal” allele was expressed at a significantly higher level in the father than in the affected siblings relative to the shared mutated allele. The blood level of STEAP3/TSAP6 mRNA was severely reduced in the siblings, while both parents were in the lower range of normal controls. The STEAP3/TSAP6 protein was also reduced in lymphocytic cell lines from the patients. Collectively, our data support the hypothesis that STEAP3/TSAP6 deficiency leads to severe anemia in the affected siblings and results from the combination of a mutated allele inherited from their father and a weakly expressed allele inherited from their mother.

Introduction: Fludarabine plus rituximab (F-R) is an established treatment option for patients (pts) with relapsed/refractory follicular lymphoma (FL), other indolent lymphoma, or mantle cell lymphoma (MCL). To further improve the treatment in this setting we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of bendamustine plus rituximab (B-R) versus F-R for pts with relapsed FL, other indolent lymphomas or MCL. Patients and Methods: 230 pts in need of treatment were randomized to rituximab 375 mg/m² (day 1) plus either bendamustine 90 mg/m² (days 1+2) or fludarabine 25 mg/m² (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however, in case of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), overall response rate (ORR), and complete response rate (CR). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: A total of 219 pts were evaluable for the analysis (114 B-R; 105 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration, and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R; 25.3% F-R). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular, 45.9% and 47.5%, respectively; Waldenström’s Macroglobulinemia, 11.9% and 11.1%; MCL, 20.2% and 21.2%; other indolent lymphomas, 23% and 20.2%. A median of 6 cycles were given in both treatment arms, with 75.2% and 53.4% of B-R and F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2014), the median observation time was 96 months. The ORR was significantly higher with B-R than with F-R (83.5% vs. 52.5%, respectively; p< 0.0001). The CR rate with B-R was also significantly higher than that with F-R (38.5% vs. 16.2%; p=0.0004). Median PFS was significantly prolonged with B-R compared with F-R (34 vs. 12 months; hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.38–0.72; p There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy, or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs. 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs. 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4% and 22.2%, respectively). 17 pts (14.9%) developed a secondary neoplasia after B-R compared with 16 pts (15.2%) after F-R. Of these, 5 pts in the B-R group, and 3 pts in the F-R group developed a secondary hematological neoplasia (2 AML [1 AML M4], 1 CML, 1 DLBCL, and 1 HD after B-R; and 2 AML M4, and 1 MDS after F-R). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.38, 95% CI 0.32-0.71; p=0.0003) and PFS (HR 0.35, 95% CI 0.31-0.62; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R) compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: B-R was more effective than F-R in this setting of relapsed FL, other indolent lymphomas and MCL due to higher overall and complete response rates, a longer PFS, and an improved OS. These data confirm the high anti-lymphoma activity of B-R. Disclosures Off Label Use: Indication and dosage of bendamustine.

Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in patients (pts) with indolent lymphomas or MCL and was presented at ASH 2009, ASCO 2012, and published in The Lancet in 2013. The final published analysis at a median follow-up of 45 months demonstrated a significantly prolonged progression-free survival (PFS) in the B-R group, compared to the CHOP-R group (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.44–0.74; p Methods: 549 pts with indolent lymphomas or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. The primary endpoint was PFS; secondary endpoints included OS, TTNT, and sNPL. Results: 514 randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. Fewer pts treated initially with B-R needed second-line treatments due to disease progression compared to CHOP-R treated pts: 93 pts (36%) in the B-R group received salvage treatment compared with 140 pts (55%) in the CHOP-R group. Of those in the CHOP-R group, 69 pts (49%) received B-R as salvage. TTNT was significantly prolonged with B-R compared with CHOP-R (HR 0.53, 95% CI 0.40-0.68; p The difference in complete response (CR) rates (independent of treatment arms) between male (n=272, median age 63 years) and female (n=242, median age 64 years) pts was statistically significant: 28.6% for male pts versus 42.1% for female pts (p=0.0016). Female pts had a longer median TTNT compared to male pts (not yet reached vs. 52.2 months, respectively; HR 0.70, 95% CI 0.54-0.90; p=0.006). The achievement of a CR was associated with significantly prolonged OS, with an estimated 10-year survival rate of 72.6% for pts with a CR and 63.6% for pts with a partial response (p=0.006). The difference in OS between the treatment arms was not statistically significant, with 65 and 76 deaths in the B-R and CHOP-R arms, respectively. The estimated 10-year survival rates were 67.4% for B-R and 60.1% for CHOP-R (p=0.262). In pts with indolent lymphomas (total group without MCL), there was a trend toward longer survival for the B-R group compared with the CHOP-R group, with 43 deaths out of 215 pts (20.0%) in B-R and 58 deaths out of 205 pts (28.3%) in CHOP-R. The estimated 10-year survival rates for pts with indolent lymphomas were 71.9% for B-R and 61.5% for CHOP-R (HR 0.70, 95% CI 0.48-1.04; p=0.076). No difference in OS was found in the subgroup of pts with MCL (n=95) (HR 1.28, 95% CI 0.69-2.39; p=0.429). Twenty sNPL were observed in the B-R group compared with 23 in the CHOP-R group, with 1 hematological malignancy in each group (1 MDS in B-R, 1 AML in CHOP-R) to date. Updated sNPL results will be presented at the ASH meeting. Conclusions: In pts with previously untreated indolent lymphomas, and in elderly pts with MCL, B-R demonstrates a PFS and TTNT benefit over CHOP-R. OS for the entire group of patients was not significantly different while treatment with B-R resulted in a trend toward survival benefit in the group of pts with indolent lymphomas. Disclosures Off Label Use: Indication and dosage of bendamustine.

Abstract 2724 Background: The NHL 1 study, a prospective, multicenter, randomized, phase 3 study which compared B-R and CHOP-R as first-line treatment in indolent lymphomas and mantle cell lymphoma (MCL), demonstrated a significant benefit in progression-free survival (PFS) as well as improved tolerability for B-R compared with CHOP-R. Here we present an analysis of the impact of response quality on outcome. Methods: 514 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a maximum of 6 cycles. Results: The overall response rate in the 514 pts (261 B-R; 253 CHOP-R) was 92.7% and 91.3% in the B-R and CHOP-R arms, respectively (as presented at the last ASCO meeting, J Clin Oncol 30, 2012 (suppl; abstr 3). A complete response (CR) was observed in 39.8% in the B-R arm and in 30% in the CHOP-R arm (p=0.021). The achievement of CR was associated with a significantly prolonged PFS and overall survival (OS) (Table 1). Analysis by treatment arm revealed a trend for superior PFS and a significantly improved OS for patients achieving CR following treatment with B-R. In the CHOP-R arm, patients in CR had a significantly superior PFS compared to those in PR with a trend to superior OS. Regardless of the quality of response, PFS was superior with B-R versus CHOP-R: For patients in CR, the median PFS was not reached with B-R, whereas for CHOP-R it was 53.7 months (p=0.0204). In patients achieving PR, treatment with B-R resulted in a median PFS of 57.2 months, and this was 30.9 months with CHOP-R (p=0.0002). We noted a statistically significant difference in CR rates between male (n=272, median age 63 years) and female (n=242, median age 64 years) patients. The CR rate was 28.6% in male patients and 42.1% in female patients (p=0.0016). Female patients had a longer median PFS (51.4 months) compared to male patients (38.6 months), however, this difference was not statistically significant (p=0.0866). Conclusions: Patients in CR following first-line treatment in our study had a significantly longer PFS and OS compared to those achieving a PR. Therefore, our results strongly suggest an association between quality of response and outcome. Disclosures: No relevant conflicts of interest to declare.

3 Background: This multicenter, randomized, phase III study compared B-R and CHOP-R as first-line treatment in indolent lymphoma and MCL and was presented at ASH 2009 including a comprehensive safety analysis. Here we present an updated analysis with a cut-off date for 31 Oct 2011. Methods: 549 patients (pts) with indolent or MCL were randomized to receive B-R or CHOP-R for a max of 6 cycles. The primary endpoint was PFS. Results: 514 pts randomized pts were evaluable (261 B-R; 253 CHOP-R). Patient characteristics were well balanced between arms; median age was 64 years. At a median follow-up of 45 months, PFS was significantly prolonged with B-R compared with CHOP-R (HR 0.58, 95% CI 0.44–0.74; P 60 years (n=315). In pts with...

Abstract 856 Introduction: Promising results have been observed in two phase II studies evaluating the combination of bendamustine plus rituximab (B-R) in patients (pts) with relapsed/refractory follicular, other indolent or mantle cell lymphomas (MCL) (Rummel et al. JCO 2005; Robinson et al. JCO 2008). Fludarabine plus rituximab (F-R) is an established treatment option in this setting. Therefore, we initiated in 2003 a multicenter, randomized phase III study to compare the efficacy and safety of B-R versus F-R for pts with relapsed follicular (FL), indolent or MCL. Patients and methods: 219 pts with relapsed FL, indolent or MCL in need of treatment were randomized to rituximab 375 mg/m2 (day 1) plus either bendamustine 90 mg/m2 (days 1+2) or fludarabine 25 mg/m2 (days 1–3) q 28 days for a maximum of 6 cycles. Prophylactic use of antibiotics or granulocyte-colony stimulating factor (G-CSF) was not generally recommended; however in cases of severe granulocytopenia, G-CSF use was permitted. The primary endpoint was progression-free survival (PFS). The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 q 3 months for up to 2 years) in both arms, following regulatory approvals in this setting. Results: 11 pts were not evaluable due to protocol violations, and were not followed further. A total of 208 pts were evaluable for the final analysis (109 B-R; 99 F-R). There were no significant differences between arms for patient characteristics, including age, stage, LDH, International Prognostic Index (IPI), follicular IPI (FLIPI), bone marrow infiltration and extranodal involvement. Most pts had stage IV (71.6% B-R; 60.6% F-R) or stage III disease (21.1% B-R and 25.3% F-R, respectively). Median patient age was 68 yrs (range 38–87). Patients had received a median of 1 prior therapy (range 1–7). Histological subtypes were distributed equally between the B-R and F-R arms: follicular 45.9 % and 47.5%, respectively; immunocytoma 11.9% and 11.1%; MCL 20.2% and 21.2%; other indolent lymphomas 23% and 20.2%. A median number of 6 cycles were given in both treatment arms, with 75.2% of B-R pts and 53.4% of F-R pts receiving 6 cycles, respectively. At the time of this analysis (June 2010), the median observation time was 33 months. Median PFS was significantly prolonged with B-R compared with F-R (30 vs 11 months; hazard ratio [HR] 0.51, 95 % confidence interval [CI] 0.34–0.67; p There were no significant differences in the rates of alopecia, stomatitis, erythema, allergic reactions, peripheral neuropathy or infectious episodes between groups. Hematologic toxicities were also similar between arms: 8.9% grade 3/4 neutropenia with B-R vs 9.1% with F-R; 11.8% grade 3/4 leukocytopenia with B-R vs 12.4% with F-R. The overall incidence of serious adverse events was similar for the B-R and F-R groups (17.4 and 22.2%, respectively). An unplanned subanalysis showed that rituximab maintenance therapy significantly prolonged overall survival (HR 0.21, 95% CI 0.22–0.67; p=0.0008) and PFS (HR 0.27, 95% CI 0.27–0.59; p< 0.0001) in the small group of 40 pts who received this treatment (23 B-R, 17 F-R), compared with those who did not. Although the numbers are too small in this non-randomized comparison to draw some validated conclusions, these results appear to confirm the favorable role of rituximab maintenance. Conclusions: These data confirm the efficacy of B-R in pts with relapsed FL, indolent or MCL, and, in this setting, demonstrate a superior PFS benefit for this regimen in comparison with F-R. Disclosures: No relevant conflicts of interest to declare.

Abstract 3090 Introduction: Long term survival among patients (pts) with low grade/indolent Non-Hodgkin lymphoma (iNHL) is increasingly common, and as a consequence, a consideration of potential therapy-related sequelae, such as secondary neoplasia (sNPL), is of particular importance. Bendamustine plus rituximab (B-R) is an effective treatment option with a favorable toxicity profile in pts with iNHL. However, no data have been reported concerning later, therapy-associated complications with B-R. The aim of this study was to determine the incidence of therapy-related myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and solid tumors after B-R, in comparison with other anti-lymphoma chemotherapy regimens, in pts with follicular (FL), other indolent or mantle cell lymphoma (MCL). Patients and methods: Data for this analysis were obtained from 2 randomized studies, including a total of 697 pts: 1) StiL-study NHL-1, comparing B-R (bendamustine 90 mg/m2, d1+2, rituximab 375 mg/m2, d1; q 28 days) with CHOP-R (q 21 days) as first-line therapy in 513 pts (260 B-R, 253 CHOP-R) (median age 64 yrs, range 31–83); 2) StiL-study NHL-2, comparing B-R with F-R (fludarabine 25mg/m2, d1–3, rituximab 375mg/m2, d1; q 28 days) in 184 pts (median age 68 yrs, range 38–87) with relapsed disease (96 B-R, 88 F-R). Patients in this NHL-2 study had received a median of 1 prior therapy (range 1–7). Result: At the time of this analysis (May 2010), the median observation time was 35 months for NHL-1 pts and 33 months for NHL-2 pts. Most pts in both studies received 6 cycles of therapy. In the NHL-1 study, 16 pts (6.2%) developed sNPL after B-R as first-line treatment, compared with 19 (7.5%) after CHOP-R. Most (87.5%) sNPL were solid tumours: 4 gastrointestinal, 4 urothelium, 2 prostate, 2 squamous epithelium, 1 bronchial, and 1 adrenal after B-R; 6 gastrointestinal, 5 prostate, 3 bronchial, 2 breast, 1 melanoma, 1 urothelium, and 1 endocrinal pancreas after CHOP-R. The rate of secondary hematological NPL did not differ between arms; 1 MDS and 1 T-cell-lymphoma after B-R, 1 AML and 1 Hodgkin lymphoma after CHOP-R. The median time from initiation of study therapy to diagnosis of sNPL was 18.5 months for B-R, and 14 months for CHOP-R. 5 pts in the B-R group, and 2 in the CHOP-R group received additional chemotherapy after completing study therapy, and before diagnosis of sNPL. In the NHL-2 study, 6 pts (6.3%) developed sNPL after B-R as relapse therapy, compared with 9 (10.3%) after F-R (p=0.42). Of these, 3 pts in the B-R group, and 2 pts in the F-R group developed a secondary hematological NPL (2 MDS, 1 Hodgkin lymphoma after B-R; 2 AML/MDS after F-R). Solid tumors were observed in 3 pts following B-R (2 urothelium, 1 squamous epithelium), and in 8 pts following F-R (3 squamous epithelium, 2 bronchial, 1 gastrointestinal, 1 urothelium, 1 anal). The median time from initiation of study therapy to diagnosis of sNPL was 33 months for the B-R group and 24.5 months for the F-R group. Conclusion: This ongoing evaluation shows comparable rates of secondary MDS/AML and other sNPL between B-R and CHOP-R or F-R. This observation, combined with data from other studies showing improved efficacy with B-R compared with CHOP-R or F-R, confirm the value of B-R as a treatment option in patients with follicular, indolent or MCL. Longer follow-up of the patient cohorts reported here will provide important additional information on the rate of sNPL with B-R compared with other anti-lymphoma regimens. Disclosures: No relevant conflicts of interest to declare.

Abstract 405 Introduction: Promising results have been observed in two phase-II studies evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas (Rummel et al., JCO 2005; Robinson et al., JCO 2008). In order to further investigate the role of the combination B-R we initiated a multicenter randomized phase-III study in October 2003 to compare efficacy and safety of B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for patients with follicular (FL), indolent and mantle cell lymphomas (MCL). Patients and Methods: 549 patients (pts) in need of treatment for their disease were randomized to receive Rituximab 375 mg/m2 (day 1) plus either Bendamustine 90 mg/m2 (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was progression-free survival (PFS). Patients characteristics, including age, stage, LDH, IPI, FLIPI, bone marrow infiltration and extranodal involvement did not statistically significant differ between both arms. The median patient age was 64 years (range 31-83) (64 yrs for B-R and 63 yrs for CHOP-R). Most patients were in stage IV (76,9% in BR and 77,5 in CHOP-R) and stage III (19,2% in B-R and 18,6% in CHOP-R). Histologies were distributed equally between B-R and CHOP-R: follicular 55% and 56%, mantle cell 18% and 19%, and other indolent lymphomas 27% and 24%, respectively. Prophylactic use of antibiotics or growth factors were not generally recommended in this protocol. Results: Of the 549 pts 36 pts were not evaluable: 10 did not receive any study medication, 9 due to withdrawal of consent, 13 due to incorrect diagnosis (4 × DLBCL, 3 × CLL, 2 × MM, 1 × HD, 3 × solid tumors), and 4 for other reasons. 513 randomized pts are evaluable for the final analysis (B-R: n=260; CHOP-R: n=253). Out of these 9 pts were not evaluable for response evaluation: 4 pts (3 × CHOP-R, 1 × B-R) due to early death in neutropenic sepsis, 3 pts due to a subsequent change of therapy after severe toxicity in 1st cycle of CHOP-R, 1 B-R pt due to progress of disease, and 1 B-R due to early death. All patients were counted for evaluation of PFS, overall survival (OS), event-free survival (EFS; an event was defined by a response less than a partial response, disease progression, relapse, or death from any cause), and for time to next treatment (TTNT). A median number of 6 cycles was given in both treatment arms each. 82% of B-R pts and 86% of CHOP-R pts received 6 cycles. At the time of analysis in August 2009, the median observation time was 32 months. Overall response rate for pts treated with B-R was similar to the CHOP-R group (93,8% vs 93,5%, respectively). The CR rate was significantly higher with 40,1% for B-R compared to 30,8% for CHOP-R (p=0.0323). The median PFS, EFS and TTNT were significantly longer after B-R compared to after CHOP-R: PFS 54,8 months for B-R versus (vs) 34,8 months for CHOP-R (p=0.0002), Hazard Ratio (HR) 0.5765 (95% confidence interval (CI) 0.4292 to 0.7683); EFS 54 months for B-R vs 31 months for CHOP-R (p=0.0002, HR 0.6014 (95% CI 0.4515 to 0.7845); and TTNT median not yet reached in the B-R group vs 40,7 months in the CHOP-R group (p=0.0002; HR 0.5416, 95% CI 0.3897 to 0.7491). OS did not differ between both groups at this point of time. Thus far, 67 deaths have been observed (B-R: 34; CHOP-R: 33). CHOP-R treatment was more frequently associated with serious adverse events (SAE) (n=49 in B-R vs n=74 in CHOP-R). Significant differences in hematologic toxicities were observed for neutropenia grade 3+4 (BR 10,7% vs CHOP-R 46,5%; p Conclusions: In this final analysis the combination of Bendamustine plus Rituximab improves PFS and CR rates while showing a better tolerability profile. These promising results suggest that B-R does have the potential to become a new standard first-line treatment option for patients with FL, MCL, and indolent lymphomas. Disclosures: Rummel: Roche Pharma AG: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Amgen: Honoraria. Maschmeyer:OrthoBiotech: .

Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003, we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). The trial was calculated to power the study to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. The study is closed according to the planned recruitment schedule. Results: 546 patients have been randomized. For this second interim analysis, 437 patients are evaluable for response (B-R: n=221; CHOP-R: n=212). Median patient age is 64 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 41% for B-R compared to 33% for CHOP-R. The median follow-up time for both groups is 28 months. Thus far, 50 deaths have been observed (B-R: 25; CHOP-R: 25). Progressive or relapsed disease has been documented during the follow-up period: 58 in pts treated with B-R and 75 in the CHOP-R group. The median EFS for B-R is not yet reached, the median EFS for CHOP-R is 39 months with no statistical significant difference for the EFS between both groups. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (0% with B-R vs. 89% CHOP-R) and a lower number of infectious complications (number of patients with infections of any grade were 56 (25%) in the B-R group vs. 78 (37%) in CHOP-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 36% CHOP-R treated pts compared with 19% in pts treated with B-R, while in the CHOP-R group more frequently G-CSF was used. Conclusions: In this second interim analysis, the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. Further updated results will be presented at this time.

Background: Promising results have been observed in our previous phase-II study evaluating the combination of Bendamustine plus Rituximab (B-R) in patients with relapsed/refractory indolent or mantle cell lymphomas. An overall response rate (ORR) of 90%, including a 60% rate of complete remissions (CR) was documented. Objective: In October 2003 we initiated a multicenter randomized phase-III study to compare efficacy and safety of the combination B-R versus CHOP plus Rituximab (CHOP-R) as first-line therapy for follicular, indolent and mantle cell lymphomas. Methods: Patients (pts) were randomized to receive Rituximab 375 mg/qm (day 1) plus either Bendamustine 90 mg/qm (days 1+2) every 28 days or the standard CHOP regimen every 21 days for a maximum of 6 cycles. The primary endpoint was event-free survival (EFS). A sample size of 474 pts were calculated to power the study sufficiently to demonstrate a non-inferior EFS associated with B-R treatment, as defined by a difference in EFS between the two regimes of less than 10% after 3 years. An event was defined by a response less than a partial response, disease progression, relapse, or death from any cause. Results: So far 439 patients have been randomized. 273 patients are evaluable for response for this first interim analysis (B-R: n=139; CHOP-R: n=134). Median patient age is 63 years. Histologies are equally distributed between arms: follicular 52%, mantle cell 20%, and other indolent lymphomas 28% in both treatment groups, each. The ORR for pts treated with B-R was similar to that associated with CHOP-R (94% vs 93%, respectively). CR was also similar at 51% for B-R compared to 40% for CHOP-R. The median observation time for both groups is 17 months. Thus far, 15 deaths have been observed (B-R: 7; CHOP-R: 8). Progressive or relapsed disease has been documented during the follow-up period: 27 in pts treated with B-R and 32 in the CHOP-R group. The B-R regimen appears to have a better toxicity profile, as evidenced by a lower rate of total alopecia (40% CHOP-R vs. 0% with B-R) and a lower number of infectious complications (41 in CHOP-R pts vs. 19 in the B-R group). Correlating, the CHOP-R regimen was more hematotoxic: WHO grade 3/4 leukocytopenia was reported in 41% CHOP-R treated pts compared with 12% in pts treated with B-R. Conclusions: In this first interim analysis the combination of Bendamustine plus Rituximab appears to be non-inferior to the standard CHOP-R while showing a better tolerability profile. The study will be closed in December 2007 according to the planned patient recruitement schedule. Updated results will be presented at this time.