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In this multinational, phase III study, the safety and efficacy of NEPA, a convenient, fixed-dose antiemetic combination of netupitant, a highly selective NK 1 receptor antagonist (RA), and palonosetron, a distinct 5-HT 3 RA, were evaluated over multiple cycles of highly and moderately emetogenic chemotherapy. NEPA was shown to be safe, well tolerated and highly effective over 1961 chemotherapy cycles.

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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<0.001). Median PFS was 69.5 versus 31.2 months, respectively. The PFS benefit with B-R was maintained in all histological subtypes except marginal zone lymphoma. The PFS benefit with B-R was independent of age; HR 0.52 (P=0.002) in pts ≤60 years (n=199), and HR 0.62 (P=0.002) in pts >60 years (n=315). In pts with normal LDH (62%), PFS was significantly prolonged with B-R compared with CHOP-R (P<0.001), while in the elevated LDH group (38%) PFS was numerically, but not significantly increased with B-R compared with CHOP-R (P=0.118). In patients with follicular lymphoma, FLIPI subgroups defined by 0–2 factors (favorable) and 3–5 factors (unfavorable) had a longer PFS with B-R than with CHOP-R (P=0.043 and P=0.068 for the favorable and unfavorable FLIPI subgroups, respectively). Seventy four salvage treatments had been initiated in the B-R group; compared with 116 in the CHOP-R group, of those in the CHOP-R group 52 pts received B-R as salvage regimen. Overall survival did not differ between the treatment arms, with 43 and 45 deaths in the B-R and CHOP-R arms, respectively. Twenty secondary malignancies 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). Conclusions: In patients with previously untreated indolent lymphoma, and elderly patients with MCL, B-R demonstrates a PFS benefit and improved tolerability compared with CHOP-R.

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.

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<0.0001) and for leukocytopenia grade 3+4 (BR 12,1% vs CHOP-R 38,2%; p<0.0001). G-CSF was more often used in CHOP-R treated pts (20,0% of all cycles) than it was used in the B-R group (4,0%) (p<0.0001). The B-R regimen was better tolerated by the pts as evidenced by a lower rate of alopecia (15% (only grade 1) in B-R vs 62% CHOP-R), a lower number of infectious complications (95 in BR vs 121 in CHOP-R, p=0.0403), a lower incidence of peripheral neuropathy (B-R n=18; CHOP-R n=73; p<0.0001), and fewer episodes of stomatitis (B-R n=16; CHOP-R n=47; p<0.0001). Only drug-associated erythematous skin reaction (urticaria, rash) was more often seen with B-R (n=42) than with CHOP-R (n=23) (p=0.0122). 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: .

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&lt;0.0001). Compared to placebo, ibrutinib did not increase overall toxicity, yielding similar incidence and severity of adverse events. The most common serious adverse events 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 use of oral anticoagulants through an amendment of the study protocol and by avoiding CYP3A4 drug-drug interactions. Taken together, ibrutinib confirms efficacy in CLL patients at early stage with increased risk of progression. However, the results do not justify to change the current standard of 'watch and wait'. The trial is registered at clinicaltrials.gov as NCT02863718.